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Endocrinology Feb 2021A healthy nutritional state is required for all aspects of reproduction and is signaled by the adipokine leptin. Leptin acts in a relatively narrow concentration range:... (Review)
Review
A healthy nutritional state is required for all aspects of reproduction and is signaled by the adipokine leptin. Leptin acts in a relatively narrow concentration range: too much or too little will compromise fertility. The leptin signal timing is important to prepubertal development in both sexes. In the brain, leptin acts on ventral premammillary neurons which signal kisspeptin (Kiss1) neurons to stimulate gonadotropin releasing hormone (GnRH) neurons. Suppression of Kiss1 neurons occurs when agouti-related peptide neurons are activated by reduced leptin, because leptin normally suppresses these orexigenic neurons. In the pituitary, leptin stimulates production of GnRH receptors (GnRHRs) and follicle-stimulating hormone at midcycle, by activating pathways that derepress actions of the messenger ribonucleic acid translational regulatory protein Musashi. In females, rising estrogen stimulates a rise in serum leptin, which peaks at midcycle, synchronizing with nocturnal luteinizing hormone pulses. The normal range of serum leptin levels (10-20 ng/mL) along with gonadotropins and growth factors promote ovarian granulosa and theca cell functions and oocyte maturation. In males, the prepubertal rise in leptin promotes testicular development. However, a decline in leptin levels in prepubertal boys reflects inhibition of leptin secretion by rising androgens. In adult males, leptin levels are 10% to 50% of those in females, and high leptin inhibits testicular function. The obesity epidemic has elucidated leptin resistance pathways, with too much leptin in either sex leading to infertility. Under conditions of balanced nutrition, however, the secretion of leptin is timed and regulated within a narrow level range that optimizes its trophic effects.
Topics: Adipocytes; Animals; Female; Humans; Hypothalamo-Hypophyseal System; Leptin; Male; Ovary; Reproduction; Signal Transduction; Testis
PubMed: 33165520
DOI: 10.1210/endocr/bqaa204 -
Endocrine Reviews Apr 2019The midcycle surge of LH sets in motion interconnected networks of signaling cascades to bring about rupture of the follicle and release of the oocyte during ovulation.... (Review)
Review
The midcycle surge of LH sets in motion interconnected networks of signaling cascades to bring about rupture of the follicle and release of the oocyte during ovulation. Many mediators of these LH-induced signaling cascades are associated with inflammation, leading to the postulate that ovulation is similar to an inflammatory response. First responders to the LH surge are granulosa and theca cells, which produce steroids, prostaglandins, chemokines, and cytokines, which are also mediators of inflammatory processes. These mediators, in turn, activate both nonimmune ovarian cells as well as resident immune cells within the ovary; additional immune cells are also attracted to the ovary. Collectively, these cells regulate proteolytic pathways to reorganize the follicular stroma, disrupt the granulosa cell basal lamina, and facilitate invasion of vascular endothelial cells. LH-induced mediators initiate cumulus expansion and cumulus oocyte complex detachment, whereas the follicular apex undergoes extensive extracellular matrix remodeling and a loss of the surface epithelium. The remainder of the follicle undergoes rapid angiogenesis and functional differentiation of granulosa and theca cells. Ultimately, these functional and structural changes culminate in follicular rupture and oocyte release. Throughout the ovulatory process, the importance of inflammatory responses is highlighted by the commonalities and similarities between many of these events associated with ovulation and inflammation. However, ovulation includes processes that are distinct from inflammation, such as regulation of steroid action, oocyte maturation, and the eventual release of the oocyte. This review focuses on the commonalities between inflammatory responses and the process of ovulation.
Topics: Female; Humans; Inflammation; Luteinizing Hormone; Ovulation
PubMed: 30496379
DOI: 10.1210/er.2018-00075 -
Reproduction (Cambridge, England) Sep 2020Historically, research in ovarian biology has focused on folliculogenesis, but recently the ovarian stroma has become an exciting new frontier for research, holding... (Review)
Review
Historically, research in ovarian biology has focused on folliculogenesis, but recently the ovarian stroma has become an exciting new frontier for research, holding critical keys to understanding complex ovarian dynamics. Ovarian follicles, which are the functional units of the ovary, comprise the ovarian parenchyma, while the ovarian stroma thus refers to the inverse or the components of the ovary that are not ovarian follicles. The ovarian stroma includes more general components such as immune cells, blood vessels, nerves, and lymphatic vessels, as well as ovary-specific components including ovarian surface epithelium, tunica albuginea, intraovarian rete ovarii, hilar cells, stem cells, and a majority of incompletely characterized stromal cells including the fibroblast-like, spindle-shaped, and interstitial cells. The stroma also includes ovarian extracellular matrix components. This review combines foundational and emerging scholarship regarding the structures and roles of the different components of the ovarian stroma in normal physiology. This is followed by a discussion of key areas for further research regarding the ovarian stroma, including elucidating theca cell origins, understanding stromal cell hormone production and responsiveness, investigating pathological conditions such as polycystic ovary syndrome (PCOS), developing artificial ovary technology, and using technological advances to further delineate the multiple stromal cell types.
Topics: Female; Humans; Ovarian Follicle; Ovary; Polycystic Ovary Syndrome; Stromal Cells; Theca Cells
PubMed: 32716007
DOI: 10.1530/REP-19-0501 -
International Journal of Molecular... Sep 2021Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in... (Review)
Review
Myo-inositol (myo-Ins) and D-chiro-inositol (D-chiro-Ins) are natural compounds involved in many biological pathways. Since the discovery of their involvement in endocrine signal transduction, myo-Ins and D-chiro-Ins supplementation has contributed to clinical approaches in ameliorating many gynecological and endocrinological diseases. Currently both myo-Ins and D-chiro-Ins are well-tolerated, effective alternative candidates to the classical insulin sensitizers, and are useful treatments in preventing and treating metabolic and reproductive disorders such as polycystic ovary syndrome (PCOS), gestational diabetes mellitus (GDM), and male fertility disturbances, like sperm abnormalities. Moreover, besides metabolic activity, myo-Ins and D-chiro-Ins deeply influence steroidogenesis, regulating the pools of androgens and estrogens, likely in opposite ways. Given the complexity of inositol-related mechanisms of action, many of their beneficial effects are still under scrutiny. Therefore, continuing research aims to discover new emerging roles and mechanisms that can allow clinicians to tailor inositol therapy and to use it in other medical areas, hitherto unexplored. The present paper outlines the established evidence on inositols and updates on recent research, namely concerning D-chiro-Ins involvement into steroidogenesis. In particular, D-chiro-Ins mediates insulin-induced testosterone biosynthesis from ovarian thecal cells and directly affects synthesis of estrogens by modulating the expression of the aromatase enzyme. Ovaries, as well as other organs and tissues, are characterized by a specific ratio of myo-Ins to D-chiro-Ins, which ensures their healthy state and proper functionality. Altered inositol ratios may account for pathological conditions, causing an imbalance in sex hormones. Such situations usually occur in association with medical conditions, such as PCOS, or as a consequence of some pharmacological treatments. Based on the physiological role of inositols and the pathological implications of altered myo-Ins to D-chiro-Ins ratios, inositol therapy may be designed with two different aims: (1) restoring the inositol physiological ratio; (2) altering the ratio in a controlled way to achieve specific effects.
Topics: Diabetes, Gestational; Female; Humans; Inositol; Molecular Structure; Polycystic Ovary Syndrome; Pregnancy; Signal Transduction; Testosterone; Theca Cells
PubMed: 34638926
DOI: 10.3390/ijms221910575 -
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 -
Frontiers in Bioscience (Landmark... Mar 2019Primordial germ cell migration and homing within the gonadal ridge during early embryo development requires oocyte-secreted polypeptide, growth factors, growth and... (Review)
Review
Primordial germ cell migration and homing within the gonadal ridge during early embryo development requires oocyte-secreted polypeptide, growth factors, growth and differentiation factors (GDFs), bone morphogenetic proteins, stem cell factor (SCF), and basic fibroblast growth factor (bFGF). During embryogenesis, the germ cells migrate into developing gonads and undergo intra-ovarian development which involves the contact of primordial germ cells with other cells. Further follicular development and differentiation is tightly regulated by hormones and by intraovarian regulators. Maturation of cumulus-oocyte complexes and ovulation are directly controlled by FSH and LH and requires activation of mitogen-activated protein kinase in granulosa cells. The selection of dominant follicles is driven by a series of proliferation and apoptotic events. Together, the available data suggests that follicular development is regulated both by systemic and local factors.
Topics: Animals; Apoptosis; Cell Differentiation; Down-Regulation; Endocrine System; Estrogens; Female; Granulosa Cells; Hormones; Humans; Intercellular Signaling Peptides and Proteins; Macaca mulatta; Male; Mice; Oocytes; Ovarian Follicle; Ovary; Rats; Receptors, Notch; Signal Transduction; Spermatogenesis; Testosterone; Theca Cells
PubMed: 30844725
DOI: 10.2741/4763 -
Frontiers in Bioscience (Scholar... Jan 2011Folliculogenesis is a complex process involving dramatic morphological and functional changes in granulosa and theca cells. This process is sequential and dictated... (Review)
Review
Folliculogenesis is a complex process involving dramatic morphological and functional changes in granulosa and theca cells. This process is sequential and dictated specifically by tightly regulated response to endocrine hormones and intra-ovarian regulators. In mammalian ovaries, only a few number of presented follicles in a fetal ovary can reach ovulatory status during follicular development; more than 99% of the follicles in the ovary undergo a degenerative process known as "atresia" induced by apotosis. It is characterized by distinct biochemical and morphological changes such as DNA fragmentation, plasma membrane blebbing and cell volume shrinkage. Apoptosis in ovary is regulated by a number of endocrine, locally produced intracellular mediators in a stage-specific and time-dependent manner. New knowledge of hormones and cell factors which regulate granulosa cell or oocyte apoptosis and their possible signaling pathways underlying intracellular events has made important contributions in advancing our understanding mechanism of follicular atresia.
Topics: Apoptosis; Corpus Luteum; Female; Follicular Atresia; Humans; Ovarian Follicle; Ovary; Signal Transduction
PubMed: 21196405
DOI: 10.2741/s180 -
Molecular and Cellular Endocrinology Jul 2013Alterations of ovarian follicle morphology and function have been well documented in women with PCOS. These include increased numbers of growing preantral follicles,... (Review)
Review
Alterations of ovarian follicle morphology and function have been well documented in women with PCOS. These include increased numbers of growing preantral follicles, failure of follicle growth beyond the mid-antral stage, evidence of granulosa call degeneration, and theca cell hyperplasia. Functional abnormalities include paradoxical granulosa cell hyperresponsiveness to FSH which is clinically linked to ovarian hyperstimulation during ovulation induction. In addition, there is likely a primary theca cell defect that accounts for the majority of excess androgen production in this disorder. The precise mechanisms responsible for altered follicle function are not completely clear. However, several factors appear to influence normal advancement of follicle development as well as impair ovarian steroidogenesis. These include intra- as well as extraovarian influences that distort normal ovarian growth and disrupt steroid production by follicle cells.
Topics: Androgens; Animals; Anti-Mullerian Hormone; Estrogens; Female; Follicle Stimulating Hormone; Granulosa Cells; Humans; Insulin; Luteinizing Hormone; Ovarian Follicle; Ovulation; Polycystic Ovary Syndrome
PubMed: 22874072
DOI: 10.1016/j.mce.2012.07.011 -
Endocrine Reviews Feb 2018The major goal of this review is to summarize recent exciting findings that have been published within the past 10 years that, to our knowledge, have not been presented... (Review)
Review
The major goal of this review is to summarize recent exciting findings that have been published within the past 10 years that, to our knowledge, have not been presented in detail in previous reviews and that may impact altered follicular development in polycystic ovarian syndrome (PCOS) and premature ovarian failure in women. Specifically, we will cover the following: (1) mouse models that have led to discovery of the derivation of two precursor populations of theca cells in the embryonic gonad; (2) the key roles of the oocyte-derived factor growth differentiation factor 9 on the hedgehog (HH) signaling pathway and theca cell functions; and (3) the impact of the HH pathway on both the specification of theca endocrine cells and theca fibroblast and smooth muscle cells in developing follicles. We will also discuss the following: (1) other signaling pathways that impact the differentiation of theca cells, not only luteinizing hormone but also insulinlike 3, bone morphogenic proteins, the circadian clock genes, androgens, and estrogens; and (2) theca-associated vascular, immune, and fibroblast cells, as well as the cytokines and matrix factors that play key roles in follicle growth. Lastly, we will integrate what is known about theca cells from mouse models, human-derived theca cell lines from patients who have PCOS and patients who do not have PCOS, and microarray analyses of human and bovine theca to understand what pathways and factors contribute to follicle growth as well as to the abnormal function of theca.
Topics: Animals; Cell Differentiation; Corpus Luteum; Female; Fertility; Gonads; Growth Differentiation Factor 9; Hedgehog Proteins; Humans; Ovarian Diseases; Theca Cells
PubMed: 29028960
DOI: 10.1210/er.2017-00164 -
International Journal of Molecular... May 2021In this paper, newly discovered mechanisms of atresia and cell death processes in bovine ovarian follicles are investigated. For this purpose the mRNA expression of...
In this paper, newly discovered mechanisms of atresia and cell death processes in bovine ovarian follicles are investigated. For this purpose the mRNA expression of receptor interacting protein kinases 1 and 3 ( and ) of the granulosa and theca cells derived from healthy and atretic follicles are studied. The follicles were assigned as either healthy or atretic based on the estradiol to progesterone ratio. A statistically significant difference was recorded for the mRNA expression of a and between granulosa cells from healthy and atretic follicles. To further investigate this result a systems biology approach was used. The genes playing roles in necroptosis, apoptosis and atresia were chosen and a network was created based on human genes annotated by the IMEx database in Cytoscape to identify hubs and bottle-necks. Moreover, correlation networks were built in the Cluepedia plug-in. The networks were created separately for terms describing apoptosis and programmed cell death. We demonstrate that necroptosis (RIPK-dependent cell death pathway) is an alternative mechanism responsible for death of bovine granulosa and theca cells. We conclude that both apoptosis and necroptosis occur in the granulosa cells of dominant follicles undergoing luteinisation and in the theca cells from newly selected follicles.
Topics: Animals; Apoptosis; Cattle; Cell Death; Female; Gene Ontology; Gene Regulatory Networks; Granulosa Cells; Models, Biological; Ovarian Follicle; Protein Interaction Maps; RNA, Messenger; Receptor-Interacting Protein Serine-Threonine Kinases; Systems Biology; Theca Cells
PubMed: 34063056
DOI: 10.3390/ijms22094888