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Genes Jun 2021From fetal life until senescence, the ovary is an extremely active tissue undergoing continuous structural and functional changes. These ever-changing events are best... (Review)
Review
From fetal life until senescence, the ovary is an extremely active tissue undergoing continuous structural and functional changes. These ever-changing events are best summarized by a quotation attributed to Plato when describing motion in space and time-'nothing ever is but is always becoming…'. With respect to the ovary, these changes include, at the beginning, the processes of follicular formation and thereafter those of follicular growth and atresia, steroidogenesis, oocyte maturation, and decisions relating to the number of mature oocytes that are ovulated for fertilization and the role of the corpus luteum. The aims of this review are to offer some examples of these complex and hitherto unknown processes. The ones herein have been elucidated from studies undertaken in vitro or from normal in vivo events, natural genetic mutations or after experimental inactivation of gene function. Specifically, this review offers insights concerning the initiation of follicular growth, pathologies relating to poly-ovular follicles, the consequences of premature loss of germ cells or oocytes loss, the roles of (anti-Müllerian hormone) and (bone morphogenetic protein) genes in regulating follicular growth and ovulation rate together with species differences in maintaining luteal function during pregnancy. Collectively, the evidence suggests that the oocyte is a key organizer of normal ovarian function. It has been shown to influence the phenotype of the adjacent somatic cells, the growth and maturation of the follicle, and to determine the ovulation rate. When germ cells or oocytes are lost prematurely, the ovary becomes disorganized and a wide range of pathologies may arise.
Topics: Animals; Biological Evolution; Female; Humans; Oogenesis; Ovary; Ovulation
PubMed: 34207147
DOI: 10.3390/genes12060928 -
Biomolecules Dec 2022The ovary is a female reproductive organ that plays a key role in fertility and the maintenance of endocrine homeostasis, which is of great importance to women's health.... (Review)
Review
The ovary is a female reproductive organ that plays a key role in fertility and the maintenance of endocrine homeostasis, which is of great importance to women's health. It is characterized by a high heterogeneity, with different cellular subpopulations primarily containing oocytes, granulosa cells, stromal cells, endothelial cells, vascular smooth muscle cells, and diverse immune cell types. Each has unique and important functions. From the fetal period to old age, the ovary experiences continuous structural and functional changes, with the gene expression of each cell type undergoing dramatic changes. In addition, ovarian development strongly relies on the communication between germ and somatic cells. Compared to traditional bulk RNA sequencing techniques, the single-cell RNA sequencing (scRNA-seq) approach has substantial advantages in analyzing individual cells within an ever-changing and complicated tissue, classifying them into cell types, characterizing single cells, delineating the cellular developmental trajectory, and studying cell-to-cell interactions. In this review, we present single-cell transcriptome mapping of the ovary, summarize the characteristics of the important constituent cells of the ovary and the critical cellular developmental processes, and describe key signaling pathways for cell-to-cell communication in the ovary, as revealed by scRNA-seq. This review will undoubtedly improve our understanding of the characteristics of ovarian cells and development, thus enabling the identification of novel therapeutic targets for ovarian-related diseases.
Topics: Female; Animals; Endothelial Cells; Oocytes; Ovary; Granulosa Cells; Sequence Analysis, RNA
PubMed: 36671432
DOI: 10.3390/biom13010047 -
Human Reproduction Update Sep 2020Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are found widespread in drinking water, foods, food packaging materials and other consumer products. Several PFAS...
BACKGROUND
Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are found widespread in drinking water, foods, food packaging materials and other consumer products. Several PFAS have been identified as endocrine-disrupting chemicals based on their ability to interfere with normal reproductive function and hormonal signalling. Experimental models and epidemiologic studies suggest that PFAS exposures target the ovary and represent major risks for women's health.
OBJECTIVE AND RATIONALE
This review summarises human population and toxicological studies on the association between PFAS exposure and ovarian function.
SEARCH METHODS
A comprehensive review was performed by searching PubMed. Search terms included an extensive list of PFAS and health terms ranging from general keywords (e.g. ovarian, reproductive, follicle, oocyte) to specific keywords (including menarche, menstrual cycle, menopause, primary ovarian insufficiency/premature ovarian failure, steroid hormones), based on the authors' knowledge of the topic and key terms.
OUTCOMES
Clinical evidence demonstrates the presence of PFAS in follicular fluid and their ability to pass through the blood-follicle barrier. Although some studies found no evidence associating PFAS exposure with disruption in ovarian function, numerous epidemiologic studies, mostly with cross-sectional study designs, have identified associations of higher PFAS exposure with later menarche, irregular menstrual cycles, longer cycle length, earlier age of menopause and reduced levels of oestrogens and androgens. Adverse effects of PFAS on ovarian folliculogenesis and steroidogenesis have been confirmed in experimental models. Based on laboratory research findings, PFAS could diminish ovarian reserve and reduce endogenous hormone synthesis through activating peroxisome proliferator-activated receptors, disrupting gap junction intercellular communication between oocyte and granulosa cells, inducing thyroid hormone deficiency, antagonising ovarian enzyme activities involved in ovarian steroidogenesis or inhibiting kisspeptin signalling in the hypothalamus.
WIDER IMPLICATIONS
The published literature supports associations between PFAS exposure and adverse reproductive outcomes; however, the evidence remains insufficient to infer a causal relationship between PFAS exposure and ovarian disorders. Thus, more research is warranted. PFAS are of significant concern because these chemicals are ubiquitous and persistent in the environment and in humans. Moreover, susceptible groups, such as foetuses and pregnant women, may be exposed to harmful combinations of chemicals that include PFAS. However, the role environmental exposures play in reproductive disorders has received little attention by the medical community. To better understand the potential risk of PFAS on human ovarian function, additional experimental studies using PFAS doses equivalent to the exposure levels found in the general human population and mixtures of compounds are required. Prospective investigations in human populations are also warranted to ensure the temporality of PFAS exposure and health endpoints and to minimise the possibility of reverse causality.
Topics: Cross-Sectional Studies; Endocrine Disruptors; Environmental Exposure; Female; Fluorocarbons; Humans; Ovarian Follicle; Ovarian Reserve; Ovary; Pregnancy; Prospective Studies; Reproduction
PubMed: 32476019
DOI: 10.1093/humupd/dmaa018 -
Fertility and Sterility Dec 2020Ovarian reserve is defined as the number of oocytes remaining in the ovary, or oocyte quantity (oocyte number). Markers of ovarian reserve include hormone levels and... (Review)
Review
Ovarian reserve is defined as the number of oocytes remaining in the ovary, or oocyte quantity (oocyte number). Markers of ovarian reserve include hormone levels and sonographically measured features of the ovaries. These markers can be useful as predictors of oocyte yield following controlled ovarian stimulation and oocyte retrieval. However, they are poor predictors of reproductive potential independently from age. This document replaces the document of the same name last published in 2012 (Fertil Steril 2012;98:1407-15).
Topics: Advisory Committees; Female; Humans; Infertility, Female; Oocyte Retrieval; Ovarian Reserve; Ovary; Reproduction
PubMed: 33280722
DOI: 10.1016/j.fertnstert.2020.09.134 -
Journal of Assisted Reproduction and... Jan 2022Platelet-rich plasma (PRP) therapy has been used as an adjunct to fertility treatments in women with very low ovarian reserve and premature ovarian insufficiency. Recent... (Review)
Review
PURPOSE
Platelet-rich plasma (PRP) therapy has been used as an adjunct to fertility treatments in women with very low ovarian reserve and premature ovarian insufficiency. Recent literature in both humans and animals suggest that intraovarian PRP administration in the setting of poor ovarian reserve may help ovarian function and increase the chances of pregnancy.
METHODS
A comprehensive literature search through PubMed, MEDLINE databases, and recent abstracts published at relevant society meetings was performed and resulted in 25 articles and 2 abstracts published that studied effect of PRP on the ovaries for the purpose of reproduction.
RESULTS
This review article presents all the data published to date pertaining to intraovarian PRP injection and pregnancy, both naturally and after in vitro fertilization. It also presents the most recent data on the use of ovarian PRP in in vitro and animal model studies highlighting the possible mechanisms by which PRP could impact ovarian function.
CONCLUSIONS
Even though recent commentaries questioned the use of PRP as an "add-on" therapy in fertility treatment because it has not been thoroughly studied, the recent basic science studies presented here could increase awareness for considering more serious research into the efficacy of PRP as an adjunct for women with poor ovarian reserve, premature ovarian insufficiency, and even early menopause who are trying to conceive using their own oocytes. Given its low-risk profile, the hypothetical benefit of PRP treatment needs to be studied with larger randomized controlled trials.
Topics: Adult; Drug Administration Routes; Female; Humans; Ovary; Ovulation Induction; Platelet-Rich Plasma
PubMed: 35175511
DOI: 10.1007/s10815-021-02385-w -
Nature Communications Jul 2019The ovary is perhaps the most dynamic organ in the human body, only rivaled by the uterus. The molecular mechanisms that regulate follicular growth and regression,...
The ovary is perhaps the most dynamic organ in the human body, only rivaled by the uterus. The molecular mechanisms that regulate follicular growth and regression, ensuring ovarian tissue homeostasis, remain elusive. We have performed single-cell RNA-sequencing using human adult ovaries to provide a map of the molecular signature of growing and regressing follicular populations. We have identified different types of granulosa and theca cells and detected local production of components of the complement system by (atretic) theca cells and stromal cells. We also have detected a mixture of adaptive and innate immune cells, as well as several types of endothelial and smooth muscle cells to aid the remodeling process. Our results highlight the relevance of mapping whole adult organs at the single-cell level and reflect ongoing efforts to map the human body. The association between complement system and follicular remodeling may provide key insights in reproductive biology and (in)fertility.
Topics: Adult; Base Sequence; Endothelial Cells; Female; Granulosa Cells; Humans; Myocytes, Smooth Muscle; Ovarian Follicle; Ovulation; Sequence Analysis, RNA; Theca Cells; Uterus
PubMed: 31320652
DOI: 10.1038/s41467-019-11036-9 -
Journal of Assisted Reproduction and... Apr 2022Ovarian age is classically considered the main cause of female reproductive infertility. In women, the process proceeds as an ongoing decline in the primordial follicle... (Review)
Review
Ovarian age is classically considered the main cause of female reproductive infertility. In women, the process proceeds as an ongoing decline in the primordial follicle stockpile and it is associated with reduced fertility in the mid-thirties, irregular menstruation from the mid-forties, cessation of fertility, and, eventually, menopause in the early fifties. Reproductive aging is historically associated with changes in oocyte quantity and quality. However, besides the oocyte, other cellular as well as environmental factors have been the focus of more recent investigations suggesting that ovarian decay is a complex and multifaceted process. Among these factors, we will consider mitochondria and oxidative stress as related to nutrition, changes in extracellular matrix molecules, and the associated ovarian stromal compartment where immune cells of both the native and adaptive systems seem to play an important role. Understanding such processes is crucial to design treatment strategies to slow down ovarian aging and consequently prolong reproductive lifespan and, more to this, alleviaingt side effects of menopause on the musculoskeletal, cardiovascular, and nervous systems.
Topics: Aging; Female; Granulosa Cells; Humans; Infertility, Female; Oocytes; Ovarian Follicle; Ovary
PubMed: 35352316
DOI: 10.1007/s10815-022-02478-0 -
Aging Cell Nov 2020Fibrosis is a hallmark of aging tissues which often leads to altered architecture and function. The ovary is the first organ to show overt signs of aging, including...
Fibrosis is a hallmark of aging tissues which often leads to altered architecture and function. The ovary is the first organ to show overt signs of aging, including increased fibrosis in the ovarian stroma. How this fibrosis affects ovarian biomechanics and the underlying mechanisms are unknown. Using instrumental indentation, we demonstrated a quantitative increase in ovarian stiffness, as evidenced by an increase in Young's modulus, when comparing ovaries from reproductively young (6-12 weeks) and old (14-17 months) mice. This ovarian stiffness was dependent on collagen because ex vivo enzyme-mediated collagen depletion in ovaries from reproductively old mice restored their collagen content and biomechanical properties to those of young controls. In addition to collagen, we also investigated the role of hyaluronan (HA) in regulating ovarian stiffness. HA is an extracellular matrix glycosaminoglycan that maintains tissue homeostasis, and its loss can change the biomechanical properties of tissues. The total HA content in the ovarian stroma decreased with age, and this was associated with increased hyaluronidase (Hyal1) and decreased hyaluronan synthase (Has3) expression. These gene expression differences were not accompanied by changes in ovarian HA molecular mass distribution. Furthermore, ovaries from mice deficient in HAS3 were stiffer compared to age-matched WT mice. Our results demonstrate that the ovary becomes stiffer with age and that both collagen and HA matrices are contributing mechanisms regulating ovarian biomechanics. Importantly, the age-associated increase in collagen and decrease in HA are conserved in the human ovary and may impact follicle development and oocyte quality.
Topics: Adult; Aging; Animals; Collagen; Extracellular Matrix; Female; Humans; Hyaluronan Synthases; Mice; Ovary
PubMed: 33079460
DOI: 10.1111/acel.13259 -
Science Advances Jun 2022The female ovary contains a finite number of oocytes, and their release at ovulation becomes sporadic and disordered with aging and with obesity, leading to loss of...
The female ovary contains a finite number of oocytes, and their release at ovulation becomes sporadic and disordered with aging and with obesity, leading to loss of fertility. Understanding the molecular defects underpinning this pathology is essential as age of childbearing and obesity rates increase globally. We identify that fibrosis within the ovarian stromal compartment is an underlying mechanism responsible for impaired oocyte release, which is initiated by mitochondrial dysfunction leading to diminished bioenergetics, oxidative damage, inflammation, and collagen deposition. Furthermore, antifibrosis drugs (pirfenidone and BGP-15) eliminate fibrotic collagen and restore ovulation in reproductively old and obese mice, in association with dampened M2 macrophage polarization and up-regulated MMP13 protease. This is the first evidence that ovarian fibrosis is reversible and indicates that drugs targeting mitochondrial metabolism may be a viable therapeutic strategy for women with metabolic disorders or advancing age to maintain ovarian function and extend fertility.
Topics: Animals; Collagen; Female; Fibrosis; Humans; Longevity; Mice; Obesity; Oocytes; Ovary
PubMed: 35714185
DOI: 10.1126/sciadv.abn4564 -
Journal of Ovarian Research Apr 2023Ovarian aging is a natural and physiological aging process characterized by loss of quantity and quality of oocyte or follicular pool. As it is generally accepted that... (Review)
Review
Ovarian aging is a natural and physiological aging process characterized by loss of quantity and quality of oocyte or follicular pool. As it is generally accepted that women are born with a finite follicle pool that will go through constant decline without renewing, which, together with decreased oocyte quality, makes a severe situation for women who is of advanced age but desperate for a healthy baby. The aim of our review was to investigate mechanisms leading to ovarian aging by discussing both extra- and intra- ovarian factors and to identify genetic characteristics of ovarian aging. The mechanisms were identified as both extra-ovarian alternation of hypothalamic-pituitary-ovarian axis and intra-ovarian alternation of ovary itself, including telomere, mitochondria, oxidative stress, DNA damage, protein homeostasis, aneuploidy, apoptosis and autophagy. Moreover, here we reviewed related Genome-wide association studies (GWAS studies) from 2009 to 2021 and next generation sequencing (NGS) studies of primary ovarian insufficiency (POI) in order to describe genetic characteristics of ovarian aging. It is reasonable to wish more reliable anti-aging interventions for ovarian aging as the exploration of mechanisms and genetics being progressing.
Topics: Female; Animals; Ovary; Genome-Wide Association Study; Ovarian Follicle; Oocytes
PubMed: 37024976
DOI: 10.1186/s13048-023-01151-z