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Physiological Reviews Oct 2023Mammalian eggs (oocytes) are formed during fetal life and establish associations with somatic cells to form primordial follicles that create a store of germ cells (the... (Review)
Review
Mammalian eggs (oocytes) are formed during fetal life and establish associations with somatic cells to form primordial follicles that create a store of germ cells (the primordial pool). The size of this pool is influenced by key events during the formation of germ cells and by factors that influence the subsequent activation of follicle growth. These regulatory pathways must ensure that the reserve of oocytes within primordial follicles in humans lasts for up to 50 years, yet only approximately 0.1% will ever be ovulated with the rest undergoing degeneration. This review outlines the mechanisms and regulatory pathways that govern the processes of oocyte and follicle formation and later growth, within the ovarian stroma, through to ovulation with particular reference to human oocytes/follicles. In addition, the effects of aging on female reproductive capacity through changes in oocyte number and quality are emphasized, with both the cellular mechanisms and clinical implications discussed. Finally, the details of current developments in culture systems that support all stages of follicle growth to generate mature oocytes in vitro and emerging prospects for making new oocytes from stem cells are outlined.
Topics: Animals; Humans; Female; Oocytes; Ovarian Follicle; Ovary; Oogenesis; Mammals; Aging
PubMed: 37171807
DOI: 10.1152/physrev.00032.2022 -
Human Reproduction Update Jul 2023Regulated cell death is a fundamental component of numerous physiological processes; spanning from organogenesis in utero, to normal cell turnover during adulthood, as... (Review)
Review
BACKGROUND
Regulated cell death is a fundamental component of numerous physiological processes; spanning from organogenesis in utero, to normal cell turnover during adulthood, as well as the elimination of infected or damaged cells throughout life. Quality control through regulation of cell death pathways is particularly important in the germline, which is responsible for the generation of offspring. Women are born with their entire supply of germ cells, housed in functional units known as follicles. Follicles contain an oocyte, as well as specialized somatic granulosa cells essential for oocyte survival. Follicle loss-via regulated cell death-occurs throughout follicle development and life, and can be accelerated following exposure to various environmental and lifestyle factors. It is thought that the elimination of damaged follicles is necessary to ensure that only the best quality oocytes are available for reproduction.
OBJECTIVE AND RATIONALE
Understanding the precise factors involved in triggering and executing follicle death is crucial to uncovering how follicle endowment is initially determined, as well as how follicle number is maintained throughout puberty, reproductive life, and ovarian ageing in women. Apoptosis is established as essential for ovarian homeostasis at all stages of development and life. However, involvement of other cell death pathways in the ovary is less established. This review aims to summarize the most recent literature on cell death regulators in the ovary, with a particular focus on non-apoptotic pathways and their functions throughout the discrete stages of ovarian development and reproductive life.
SEARCH METHODS
Comprehensive literature searches were carried out using PubMed and Google Scholar for human, animal, and cellular studies published until August 2022 using the following search terms: oogenesis, follicle formation, follicle atresia, oocyte loss, oocyte apoptosis, regulated cell death in the ovary, non-apoptotic cell death in the ovary, premature ovarian insufficiency, primordial follicles, oocyte quality control, granulosa cell death, autophagy in the ovary, autophagy in oocytes, necroptosis in the ovary, necroptosis in oocytes, pyroptosis in the ovary, pyroptosis in oocytes, parthanatos in the ovary, and parthanatos in oocytes.
OUTCOMES
Numerous regulated cell death pathways operate in mammalian cells, including apoptosis, autophagic cell death, necroptosis, and pyroptosis. However, our understanding of the distinct cell death mediators in each ovarian cell type and follicle class across the different stages of life remains the source of ongoing investigation. Here, we highlight recent evidence for the contribution of non-apoptotic pathways to ovarian development and function. In particular, we discuss the involvement of autophagy during follicle formation and the role of autophagic cell death, necroptosis, pyroptosis, and parthanatos during follicle atresia, particularly in response to physiological stressors (e.g. oxidative stress).
WIDER IMPLICATIONS
Improved knowledge of the roles of each regulated cell death pathway in the ovary is vital for understanding ovarian development, as well as maintenance of ovarian function throughout the lifespan. This information is pertinent not only to our understanding of endocrine health, reproductive health, and fertility in women but also to enable identification of novel fertility preservation targets.
Topics: Adult; Animals; Female; Humans; Apoptosis; Granulosa Cells; Mammals; Oocytes; Ovarian Follicle; Ovary; Regulated Cell Death; Homeostasis
PubMed: 36857094
DOI: 10.1093/humupd/dmad005 -
Molecular Biology Reports Aug 2023According to the World Health Organization, infertility is a public health problem that affects around 48 million couples and 186 million individuals worldwide.... (Review)
Review
INTRODUCTION
According to the World Health Organization, infertility is a public health problem that affects around 48 million couples and 186 million individuals worldwide. Endocrine disruptors are one of the causes that raise more concern, given that it is a problem that has evolved with the progress of society. Many chemicals are used by food industry, entering food chain, and directly affecting human health. Endocrine disruptors have the capacity of interfering with the normal hormonal action, metabolism, and biosynthesis, which can lead to a variation of the normal hormonal homeostasis. Some of these endocrine disruptors are highly associated with diseases that are positively correlated with female infertility, such as polycystic ovary syndrome, endometriosis, irregular menstrual cycle and also disturbances on processes as steroidogenesis and development of the ovarian follicles.
RESULTS
The present literature review covers various aspects of the possible relationship between endocrine disruptors and female infertility. Bisphenol A and its metabolites, phthalates, dioxins, organochlorine, and organophosphate compounds are groups of chemicals considered to have the capacity to disrupt endocrine activity and herein addressed. The results reported in in vivo studies and in clinical trials addressing endocrine disruptors and female infertility were discussed as well as their possible mechanism of action.
CONCLUSIONS
Large, double-blind, placebo-controlled randomized clinical trials are needed to better understand the mechanisms of action of endocrine disruptors in female infertility, as well as the doses and frequency of exposure responsible for it.
Topics: Humans; Female; Infertility, Female; Environmental Pollutants; Endocrine Disruptors; Endometriosis; Ovarian Follicle; Randomized Controlled Trials as Topic
PubMed: 37402067
DOI: 10.1007/s11033-023-08583-2 -
Science (New York, N.Y.) Nov 2023Sex determination in mammals depends on the differentiation of the supporting lineage of the gonads into Sertoli or pregranulosa cells that govern testis and ovary...
Sex determination in mammals depends on the differentiation of the supporting lineage of the gonads into Sertoli or pregranulosa cells that govern testis and ovary development, respectively. Although the Y-linked testis-determining gene has been identified, the ovarian-determining factor remains unknown. In this study, we identified -KTS, a major, alternatively spliced isoform of the Wilms tumor suppressor WT1, as a key determinant of female sex determination. Loss of - variants blocked gonadal differentiation in mice, whereas increased expression, as found in Frasier syndrome, induced precocious differentiation of ovaries independently of their genetic sex. In XY embryos, this antagonized expression, resulting in male-to-female sex reversal. Our results identify -KTS as an ovarian-determining factor and demonstrate that its time of activation is critical in gonadal sex differentiation.
Topics: Animals; Female; Male; Mice; Ovary; Sex Determination Processes; Sex-Determining Region Y Protein; Testis; WT1 Proteins; Protein Isoforms
PubMed: 37917714
DOI: 10.1126/science.add8831 -
Gut Microbes 2024Ovarian aging occurs prior to the aging of other organ systems and acts as the pacemaker of the aging process of multiple organs. As life expectancy has increased,... (Review)
Review
Ovarian aging occurs prior to the aging of other organ systems and acts as the pacemaker of the aging process of multiple organs. As life expectancy has increased, preventing ovarian aging has become an essential goal for promoting extended reproductive function and improving bone and genitourinary conditions related to ovarian aging in women. An improved understanding of ovarian aging may ultimately provide tools for the prediction and mitigation of this process. Recent studies have suggested a connection between ovarian aging and the gut microbiota, and alterations in the composition and functional profile of the gut microbiota have profound consequences on ovarian function. The interaction between the gut microbiota and the ovaries is bidirectional. In this review, we examine current knowledge on ovary-gut microbiota crosstalk and further discuss the potential role of gut microbiota in anti-aging interventions. Microbiota-based manipulation is an appealing approach that may offer new therapeutic strategies to delay or reverse ovarian aging.
Topics: Female; Humans; Gastrointestinal Microbiome; Ovary; Aging; Microbiota
PubMed: 38170622
DOI: 10.1080/19490976.2023.2295394 -
GeroScience Aug 2023Ovarian reserve is a term used to estimate the total number of immature follicles present in the ovaries. Between birth and menopause, there is a progressive decrease in... (Review)
Review
Ovarian reserve is a term used to estimate the total number of immature follicles present in the ovaries. Between birth and menopause, there is a progressive decrease in the number of ovarian follicles. Ovarian aging is a continuous physiological phenomenon, with menopause being the clinical mark of the end of ovarian function. Genetics, measured as family history for age at the onset of menopause, is the main determinant. However, physical activity, diet, and lifestyle are important factors that can influence the age of menopause. The low estrogen levels after natural or premature menopause increased the risk for several diseases, resulting in increased mortality risk. Besides that, the decreasing ovarian reserve is associated to reduced fertility. In women with infertility undergoing in vitro fertilization, reduced markers of ovarian reserve, including antral follicular count and anti-Mullerian hormone, are the main indicators of reduced chances of becoming pregnant. Therefore, it becomes clear that the ovarian reserve has a central role in women's life, affecting fertility early in life and overall health later in life. Based on this, the ideal strategy for delaying ovarian aging should have the following characteristics: (1) be initiated in the presence of good ovarian reserve; (2) maintained for a long period; (3) have an action on the dynamics of primordial follicles, controlling the rate of activation and atresia; and (4) safe use in pre-conception, pregnancy, and lactation. In this review, we therefore discuss some of these strategies and its feasibility for preventing a decline in the ovarian reserve.
Topics: Pregnancy; Humans; Female; Ovary; Longevity; Reproduction; Aging; Fertility
PubMed: 36913129
DOI: 10.1007/s11357-023-00768-8 -
Nature Aging Jan 2024Ovarian aging leads to diminished fertility, dysregulated endocrine signaling and increased chronic disease burden. These effects begin to emerge long before follicular...
Ovarian aging leads to diminished fertility, dysregulated endocrine signaling and increased chronic disease burden. These effects begin to emerge long before follicular exhaustion. Female humans experience a sharp decline in fertility around 35 years of age, which corresponds to declines in oocyte quality. Despite a growing body of work, the field lacks a comprehensive cellular map of the transcriptomic changes in the aging mouse ovary to identify early drivers of ovarian decline. To fill this gap we performed single-cell RNA sequencing on ovarian tissue from young (3-month-old) and reproductively aged (9-month-old) mice. Our analysis revealed a doubling of immune cells in the aged ovary, with lymphocyte proportions increasing the most, which was confirmed by flow cytometry. We also found an age-related downregulation of collagenase pathways in stromal fibroblasts, which corresponds to rises in ovarian fibrosis. Follicular cells displayed stress-response, immunogenic and fibrotic signaling pathway inductions with aging. This report provides critical insights into mechanisms responsible for ovarian aging phenotypes. The data can be explored interactively via a Shiny-based web application.
Topics: Humans; Female; Mice; Animals; Ovary; Aging; Oocytes; Fertility; Signal Transduction
PubMed: 38200272
DOI: 10.1038/s43587-023-00552-5 -
Nature Aging Jan 2024The ovary ages earlier than most other tissues, yet the underlying mechanisms remain elusive. Here a comprehensive analysis of transcriptomic landscapes in different...
The ovary ages earlier than most other tissues, yet the underlying mechanisms remain elusive. Here a comprehensive analysis of transcriptomic landscapes in different organs in young and middle-aged mice revealed that the ovaries showed earlier expression of age-associated genes, identifying increased NADase CD38 expression and decreased NAD levels in the ovary of middle-aged mice. Bulk and single-cell RNA sequencing revealed that CD38 deletion mitigated ovarian aging, preserving fertility and follicle reserve in aged mice by countering age-related gene expression changes and intercellular communication alterations. Mechanistically, the earlier onset of inflammation induced higher expression levels of CD38 and decreased NAD levels in the ovary, thereby accelerating ovarian aging. Consistently, pharmacological inhibition of CD38 enhanced fertility in middle-aged mice. Our findings revealed the mechanisms underlying the earlier aging of the ovary relative to other organs, providing a potential therapeutic target for ameliorating age-related female infertility.
Topics: Animals; Female; Mice; Aging; NAD; Ovarian Follicle; Ovary; Membrane Glycoproteins; ADP-ribosyl Cyclase 1
PubMed: 38129670
DOI: 10.1038/s43587-023-00532-9 -
Aging Cell Sep 2023Recent advances highlight the pivotal role of nicotinamide adenine dinucleotide (NAD ) in ovarian aging. However, the roles of de novo NAD biosynthesis on ovarian aging...
Recent advances highlight the pivotal role of nicotinamide adenine dinucleotide (NAD ) in ovarian aging. However, the roles of de novo NAD biosynthesis on ovarian aging are still unknown. Here, we found that genetic ablation of Ido1 (indoleamine-2,3-dioxygenase 1) or Qprt (Quinolinate phosphoribosyl transferase), two critical genes in de novo NAD biosynthesis, resulted in decreased ovarian NAD levels in middle-aged mice, leading to subfertility, irregular estrous cycles, reduced ovarian reserve, and accelerated aging. Moreover, we observed impaired oocyte quality, characterized by increased reactive oxygen species and spindle anomalies, which ultimately led to reduced fertilization ability and impaired early embryonic development. A transcriptomic analysis of ovaries in both mutant and wild-type mice revealed alterations in gene expression related to mitochondrial metabolism. Our findings were further supported by the observation of impaired mitochondrial distribution and decreased mitochondrial membrane potential in the oocytes of knockout mice. Supplementation with nicotinamide riboside (NR), an NAD booster, in mutant mice increased ovarian reserve and improved oocyte quality. Our study highlights the importance of the NAD de novo pathway in middle-aged female fertility.
Topics: Female; Mice; Animals; NAD; Ovary; Mice, Knockout
PubMed: 37332134
DOI: 10.1111/acel.13904 -
Protein & Cell May 2024The ovary is indispensable for female reproduction, and its age-dependent functional decline is the primary cause of infertility. However, the molecular basis of ovarian...
The ovary is indispensable for female reproduction, and its age-dependent functional decline is the primary cause of infertility. However, the molecular basis of ovarian aging in higher vertebrates remains poorly understood. Herein, we apply spatiotemporal transcriptomics to benchmark architecture organization as well as cellular and molecular determinants in young primate ovaries and compare these to aged primate ovaries. From a global view, somatic cells within the non-follicle region undergo more pronounced transcriptional fluctuation relative to those in the follicle region, likely constituting a hostile microenvironment that facilitates ovarian aging. Further, we uncovered that inflammation, the senescent-associated secretory phenotype, senescence, and fibrosis are the likely primary contributors to ovarian aging (PCOA). Of note, we identified spatial co-localization between a PCOA-featured spot and an unappreciated MT2 (Metallothionein 2) highly expressing spot (MT2high) characterized by high levels of inflammation, potentially serving as an aging hotspot in the primate ovary. Moreover, with advanced age, a subpopulation of MT2high accumulates, likely disseminating and amplifying the senescent signal outward. Our study establishes the first primate spatiotemporal transcriptomic atlas, advancing our understanding of mechanistic determinants underpinning primate ovarian aging and unraveling potential biomarkers and therapeutic targets for aging and age-associated human ovarian disorders.
Topics: Female; Animals; Ovary; Aging; Transcriptome
PubMed: 38126810
DOI: 10.1093/procel/pwad063