Indifferent Gonad Research Articles

Anatomical and Histological Characteristics of Gonad of Tropical Eel <i>Anguilla bicolor</i> McClelland, 1844 in Different Length Body Size

The sex status of Anguilla bicolor McClelland is difficult to be distinguished between males and females. Thus, we evaluated 309 fishes from The Serayu River, with length and weight range around 9 - 81 cm and 0.59 - 1260 g respectively to access the anatomical and histological characteristics of their gonads for each sex. Parameters assessed were body sizes, eye diameter, fin length, and gonad weight. The results showed that body length, weight, eye index, and gonadosomatic index of the male were significantly smaller (p<0.01) than those of the females. Fins index was not significantly different (p>0.05) between males and females. The histological structure of gonad showed that the eel gonads can be classified as either indifferent gonads, testis, or ovary based on the length of body size. Collecting all the data together it can be concluded that A. bicolor is a gonochoric.

Gonadal Differentiation of Nilem Fish (Osteochilus vittatus) Utilizing Temperature Treatment

Background: Gonad differentiation in some teleostei is a critical phase of gonad development. Gonad differentiation in some fish such as the tilapia group is influenced by environmental factors, namely temperature. The aim of this study was to determine the differentiation process of Nilem fish gonads (Osteochilus vittatus) under the influence of temperature. Methods: One day after fertilization (days postfertilization/dpf) fish were exposed to different medium temperature ranges, namely: 28-29 oC, 30-31 oC, 32-33 oC, and room temperature as a control for 35 days. The percentage of fish survival was calculated on the 35th day by calculating the number of surviving fish divided by the total number of fish in 1 tank times 100%. Thirty fish in each treatment were measured for body length at day 10 dpf and day 35 dpf to determine fish growth. Six fish 35 dpf from each treatment were fixed in 70% alcohol for making histological preparations using the paraffin method, Haematoxylin-Eosin staining. Fish survival data growth data in the form of fish length were analyzed using Anova. Gonadal differentiation data were analyzed descriptively. Results: There was no significant difference in the growth of fish in all treatment and control groups. The average survival rate of fish in all treatment and control groups was 100%. Observation of the gonads showed that the gonads were not differentiated in all treatment and control groups. Conclusion: The room temperature range up to 33 oC supports the growth of Nilem fish with gonad development in the indifferent gonad stage.

Gender Dysphoria: A Review Investigating the Relationship Between Genetic Influences and Brain Development.

Gender dysphoria (GD) is a facet of modern human biology which is believed to be derived from the sexual differentiation of the brain. GD “involves a conflict between a person’s physical or assigned gender and the gender with which he/she/they identify”, as defined in the DSM-5. Individuals report feeling uncomfortable and faced with prejudice from those around them, affecting their mental health. Elucidating the relationship between genetic influences on gonadal and brain development could give an insight into understanding this clinical condition. To explore this issue, a review of the literature database was carried out. Evidence suggests that abnormal biological processes, including mutations in certain genes, can lead to abnormal gonadal development, causing some fetuses to present with indifferent gonads and to be reassigned at birth to the default female sex. This disparity in genetic influences relates to an increased likelihood of a diagnosis of GD. An investigation into complete androgen insensitivity syndrome, involving androgen receptor (AR) gene mutation, suggests that such individuals also experience GD. It is known that the brains of males and females are different. Evidence further suggests that brain anatomy and neuronal signaling pathways are more closely aligned with a person’s perceived gender identity. Individuals who present with discordant gonadal and brain developments experience psychological challenges that may contribute to a state of unease or generalized dissatisfaction with their biological sex. These point to a possible biological and genetic underpinning of GD as stemming from a discordance between gonadal and brain development. However, not enough evidence has associated these differences with GD. Further research is required to elucidate the true mechanisms and possible inheritance pattern of GD for a better education and greater understanding by clinicians and the general public on perceptions regarding GD.

Bone morphogenetic protein and retinoic acid synergistically specify female germ-cell fate in mice.

The mechanism for sex determination in mammalian germ cells remains unclear. Here, we reconstitute the female sex determination in mouse germ cells invitro under a defined condition without the use of gonadal somatic cells. We show that retinoic acid (RA) and its key effector, STRA8, are not sufficient to induce the female germ-cell fate. In contrast, bone morphogenetic protein (BMP) and RA synergistically induce primordial germ cells (PGCs)/PGC-like cells (PGCLCs) derived from embryonic stem cells (ESCs) into fetal primary oocytes. The induction is characterized by entry into the meiotic prophase, occurs synchronously and recapitulates cytological and transcriptome progression invivo faithfully. Importantly, the female germ-cell induction necessitates a proper cellular competence-most typically, DNA demethylation of relevant genes-which is observed in appropriately propagated PGCs/PGCLCs, but not in PGCs/PGCLCs immediately after induction. This provides an explanation for the differential function of BMP signaling between PGC specification and female germ-cell induction. Our findings represent a framework for a comprehensive delineation of the sex-determination pathway in mammalian germ cells, including humans.

Fibroblast growth factor signaling is required for early somatic gonad development in zebrafish.

The vertebrate ovary and testis develop from a sexually indifferent gonad. During early development of the organism, primordial germ cells (the gamete lineage) and somatic gonad cells coalesce and begin to undergo growth and morphogenesis to form this bipotential gonad. Although this aspect of development is requisite for a fertile adult, little is known about the genetic regulation of early gonadogenesis in any vertebrate. Here, we provide evidence that fibroblast growth factor (Fgf) signaling is required for the early growth phase of a vertebrate bipotential gonad. Based on mutational analysis in zebrafish, we show that the Fgf ligand 24 (Fgf24) is required for proliferation, differentiation, and morphogenesis of the early somatic gonad, and as a result, most fgf24 mutants are sterile as adults. Additionally, we describe the ultrastructural elements of the early zebrafish gonad and show that distinct somatic cell populations can be identified soon after the gonad forms. Specifically, we show that fgf24 is expressed in an epithelial population of early somatic gonad cells that surrounds an inner population of mesenchymal somatic gonad cells that are in direct contact with the germ cells, and that fgf24 is required for stratification of the somatic tissue. Furthermore, based on gene expression analysis, we find that differentiation of the inner mesenchymal somatic gonad cells into functional cell types in the larval and early juvenile-stage gonad is dependent on Fgf24 signaling. Finally, we argue that the role of Fgf24 in zebrafish is functionally analogous to the role of tetrapod FGF9 in early gonad development.

The Morphogenesis of the Sexually Indifferent Gonads in the Rabbit

The present study aimed to point out the prenatal developmental stages of the indifferent gonads in rabbit. About 50 embryos and fetuses aged 11 to 18 days postcoitum were used in this study. The embryos of 9 days-old up to 13 days-old fetuses were fixed firstly within the uterus by using modified Davidson's fixative and then were transferred with the caudal halves of the fetuses aged from 14 to 18 days postconception into 10% Neutral buffered formalin for 24 to 48 hours. The specimens were prepared using routine histological work. The morphogenesis of the sexually indifferent gonad of the rabbit was studied by high-resolution light microscopy. The results showed that the gonadal ridges were detected at the 12th day postconception as a cellular thickening covered by coelomic epithelium on either sides of the dorsal mesentery and attached to the developing pronephros. As the development progressed the gonadal ridge increased in size and cellular constituents and became housing blood vessels and germ cells. The current work concluded that the gonads of the rabbit remained indifferent and neither testis nor ovary was observed until the 17th day postconception.

PRENATAL DEVELOPMENT OF THE RETE TESTIS AND MEDIASTINUM TESTIS IN DROMEDARY CAMEL (CAMELUS DROMEDARIES)

The present investigation was carried out to demonstrate the sequential stages of the prenatal development of the rete testis and mediastinum testis by histological methods. Ninety eight male camel embryos with varying CVRL ranging from (2.2 cm -105 cm) were used in the current study. The indifferent gonads appeared in embryos of 2.2 cm CVRL in the form of two small bilateral cellular masses medial to the mesonephrii. The parenchyma of the indifferent gonads didn’t show any pattern of cord like arrangement. ). In embryos of 4 cm CVRL embryos the primordia of the tunica albuginea was detected in the form of thin layer of mesenchymal cells surrounding the developing gonad. In embryos of 6.5 cm CVRL the primordia of the presumptive mediastinum testis was evident nearby the mesorchium in the form of delicate fibrous and vascular structure. In embryos of 23-25 cm CVRL the central portion of the testis was clearly devoid of the testicular cords, but equipped with the vasal tubules of the rete testis and the mediastinum which was extended in the form of an axial cord within the centrum of the testis. In embryos of 30-32 cm CVRL the straight radicals of rete testis revealed anastomosis with the neighboring testicular cords. In embryos of 69 cm CVRL the mediastinum testis revealed more fibrous component of interlacing and corrugated collagenic fibers that coursed in the form of strand like bundles in-between the branches of the rete testis. Moreover, the mediastinum was colonized by cellular aggregations of mitotically active interstitial endocrine cells. The connection between the tubules of the rete testis and the efferent ductules was observed in embryos of 88 cm CVRL near the head pole of the testis. The tubules of the rete testis were found to be lined with single cell layer of cuboidal epithelium throughout the whole period studied ,

Vascular endothelial growth factor A: just one of multiple mechanisms for sex-specific vascular development within the testis?

Testis development from an indifferent gonad is a critical step in embryogenesis. A hallmark of testis differentiation is sex-specific vascularization that occurs as endothelial cells migrate from the adjacent mesonephros into the testis to surround Sertoli-germ cell aggregates and induce seminiferous cord formation. Many in vitro experiments have demonstrated that vascular endothelial growth factor A (VEGFA) is a critical regulator of this process. Both inhibitors to VEGFA signal transduction and excess VEGFA isoforms in testis organ cultures impaired vascular development and seminiferous cord formation. However, in vivo models using mice which selectively eliminated all VEGFA isoforms: in Sertoli and germ cells (pDmrt1-Cre;Vegfa(-/-)); Sertoli and Leydig cells (Amhr2-Cre;Vegfa(-/-)) or Sertoli cells (Amh-Cre;Vegfa(-/-) and Sry-Cre;Vegfa(-/-)) displayed testes with observably normal cords and vasculature at postnatal day 0 and onwards. Embryonic testis development may be delayed in these mice; however, the postnatal data indicate that VEGFA isoforms secreted from Sertoli, Leydig or germ cells are not required for testis morphogenesis within the mouse. A Vegfa signal transduction array was employed on postnatal testes from Sry-Cre;Vegfa(-/-) versus controls. Ptgs1 (Cox1) was the only upregulated gene (fivefold). COX1 stimulates angiogenesis and upregulates, VEGFA, Prostaglandin E2 (PGE2) and PGD2. Thus, other gene pathways may compensate for VEGFA loss, similar to multiple independent mechanisms to maintain SOX9 expression. Multiple independent mechanism that induce vascular development in the testis may contribute to and safeguard the sex-specific vasculature development responsible for inducing seminiferous cord formation, thus ensuring appropriate testis morphogenesis in the male.

Differentiation of bipotential gonads in buffalo foetus: A histomorphological study

The present study was conducted on buffalo fetuses during early prenatal life to determine the developmental stages from the gonadal ridge to form bipotential gonads. The present study was conducted on the gonads of buffalo fetuses from 2.5 to 4.2 cm CVRL to determine the development of bipotential gonads from the gonadal ridge. The gonadal ridge appeared as a globular or rectangular thickening on the ventromedial surface of mesonephros at 2.5–3.0 cm CVRL (40–42 days). It was lined by simple cuboidal type of epithelium and contained mesenchymal cells, immature RBC’s, differentiating fibroblasts and primordial germ cells. The formation of indifferent gonad started at 3.5 cm CVRL as paired rounded structures, which were attached to the mesonephros by a thin stalk and were present completely separated from the mesonephros at 4.0 cm CVRL. At 3.5 cm CVRL, these gonads were lined by simple cuboidal type of germinal epithelium with some interspersed PGC’s. The PGC’s and epithelium proliferated and penetrated into the underlying mesenchymal tissue to form primitive sex cords. In the centre of indifferent gonads the blastema was observed at 4 cm CVRL. The blastema had variable shape and prominent nucleus.

Differentiation and morphogenesis of the ovary and expression of gonadal development-related genes in the protogynous hermaphroditic ricefield eel Monopterus albus.

The ovarian differentiation, morphogenesis and expression of some putative gonadal development-related genes were analysed in the ricefield eel Monopterus albus, a protogynous hermaphroditic teleost with a single elongate ovary. At c. 1 day post-hatching (dph), the gonadal ridge was colonized with primordial germ cells (PGCs) at the periphery and transformed into the gonadal primordium, which appeared to contain two germinal epithelia. At c. 7 dph, four ovarian cavities appeared in the gonadal tissue with two in each germinal epithelial compartment, and the indifferent gonad might have begun to differentiate into the ovary. The oocytes at the leptotene stage in meiosis I appeared at c. 14 dph, and oocytes at the diplotene stage at c. 30 dph. As development proceeded, the connective tissue separating the two germinal epithelia disappeared, and two of the four ovarian cavities collapsed into one. At 60 dph, the gonad had already taken the shape as observed in the adults. One outer and two inner ovarian cavities could be easily recognized, with slightly basophilic primary growth oocytes usually residing close to the outer ovarian cavity. The expression of cyp19a1a and erb in the early gonad was detected at 6 dph. The abundant expression of foxl2 coincided with the up-regulation of cyp19a1a at 8 dph onwards. The expression of dmrt1 isoforms was not detectable until 8 dph for dmrt1a and dmrt1b and until 33 dph for dmrt1d. The earlier appearance of cyp19a1a compared to dmrt1 transcripts in the indifferent gonad may contribute to the initial differentiation of the gonad towards the ovary in M. albus.

Spatiotemporal expression patterns of doublesex and mab-3 related transcription factor 1 in the chicken developing gonads and Müllerian ducts

Sex of birds is genetically determined by the inheritance of sex chromosomes (ZZ for male and ZW for female), and the Z-linked gene named doublesex and mab-3 related transcription factor 1 (DMRT1) is a candidate sex-determining gene in avian species. However, the mechanisms underlying sex determination in birds are not yet understood, and the expression patterns of the DMRT1 protein in urogenital tissues have not been identified. In the current study, we used immunohistochemistry to investigate the detailed expression patterns of the DMRT1 protein in the urogenital systems (including Müllerian ducts) in male and female chicken embryos throughout embryonic development. Gonadal somatic cells in the male indifferent gonads showed stronger expressions of DMRT1 compared with those in the female indifferent gonads well before the presumptive period of the sex determination, and Sertoli cells forming testicular cords expressed DMRT1 in the testes after sex determination. Germ cells expressed DMRT1 equally in males and females after sex determination. The expression was continuous in males, but in females it gradually disappeared from the germ cells in the central part of the cortex of the left ovary toward both edges. The DMRT1 was also detected in the tubal ridge, which is a precursor of the Müllerian duct, and at the mesenchyme and outermost coelomic epithelium of the Müllerian duct in both sexes. Strong expression was observed in the males, but it was restricted to coelomic epithelium after the regression of the duct started. Thus, we observed the detailed spatiotemporal expression patterns of DMRT1 in the developing chicken urogenital systems throughout embryonic development, suggesting its various roles in the development of urogenital tissues in the chicken embryo.

The masculinization programming window.

Sexual differentiation is a tightly regulated series of events which transform the indifferent gonads and genitalia into sex-specific structures. This is driven by hormones produced by the fetal testes, primarily testosterone (T). However, masculinization of each structure does not occur synchronously and, until recently, it was presumed that androgens also control this masculinization over a broad period of fetal life, coincident with the period of fetal T production. However, a common fetal masculinization programming window (MPW) has been identified in male and female rodent models in which androgens must act to masculinize all components of the reproductive tract and allow their later complete development. Impaired androgen action only within this MPW can induce cryptorchidism and hypospadias. This MPW is likely to occur between 8-14 weeks' gestation in humans. Studies in transgenic mice have begun to investigate some of the underlying mechanisms involved. Anogenital distance is predictive of the incidence of disorders, such as azoospermia, hypospadias and cryptorchidism, and could provide a noninvasive, lifelong indicator of androgen action within this MPW, useful in clinical assessment of patients with disorders of sexual development. In addition, several diagnostic characteristics of the external genitalia are also useful in investigating this MPW.

The involvement of proliferation and apoptosis in the early human gonad development

Distributions of the Ki-67, TP53, caspase-3 and AIFM1 markers were histologically investigated in the 5th to 9th week developing gonads of 12 human conceptuses using immunohistochemical and immunofluorescence methods. Between the 5th and 8th developmental week, proliferation gradually increased in the surface gonad epithelium (26-52%) and stroma (19-42%), but then slightly decreased in the surface epithelium (35%) during the early foetal period. In medulla, low proliferation activity decreased from 15 to 12% between the 7th and 9th week. At earliest stages of gonadal development, primordial germ cells (PGC) were only rarely TP53 positive. In the 7th and 8th week, almost all PGC-s displayed TP53 positivity, while their number decreased in early fetal period. During the investigated period, caspase-3 reactivity gradually decreased in surface epithelium, while it increased in PGC and medulla of developing gonad AIFM1-positivity first appeared in surface gonad epithelium and then predominantly in PCG-s while caspase-3 characterized different cell populations within the developing gonad. AIFM1 and caspase-3 co-localized only during the migration of PCG-s. The number and distribution of Ki-67, TP53, caspase-3 and AIFM1 reacting cells changed coincidently with development end regression of the sex cords in indifferent and early fetal gonad. Our results indicate that the number of PGC might be controlled by balance of TP53 and AIFM1, leading to caspase-3 independent cell death. Other cell populations are probably eliminated by caspase-3-dependent cell death. Both pathways of cell death seem to operate during early human gonad development, while their intensity varies depending on the cell type and developmental period analysed.

Development of the germinal ridge and ovary in the African elephant (Loxodonta africana)

The follicular reserve and its ontogeny in the elephant are of interest because elephants have the longest reproductive life of all land-based mammals. They also have the longest recorded pregnancy, which allows a protracted view of the series of significant events involved in the development of the embryonic and fetal gonads. The large elephant population of Zimbabwe provided the opportunity to collect conceptuses from elephants culled for management reasons and hunted professionally. Five embryos aged 76-96 days and the ovaries of four fetuses aged 4.8-11.2 months were fixed in 4% buffered formalin and studied by conventional histological sectioning and a stereological protocol to calculate the follicle reserve of each fetus. These observations enabled the conclusion that the migration of primordial germ cells into the indifferent gonad terminates at around 76 days of gestation while entry of oogonia into meiosis along with first follicle formation starts at around 5 months. Peak numbers of follicles are present by mid-gestation towards the end of the 6-month mitotic-meiotic transition period. It appears that the cortex of the elephant fetal ovary at mid-gestation (11 months) has already reached a developmental stage exhibited by the ovaries of many other mammals at full term.

Status of SOX9 in the testesof SRY negative and positive azoospermic males

In mammals, after expression of SRY in the sexually indifferent gonad, several genes encoding transcription factors and growth factors induced spermatogenesis and androgen production in testes. However, the etiology of SRY-negative XX men and pathologic difference of seminiferous tubules between SRY positive and negative men were unclear. We investigated several genes involved in gonad differentiation in XX male patients.

A Role for Estrogen in Somatic Cell Fate of the Mammalian Gonad.

Estrogen is both necessary and sufficient to drive ovarian development in many nonmammalian vertebrates. However, the role of estrogen in the mammalian gonad is less clear. Mouse ovarian development can proceed in the absence of estrogen signaling, but granulosa cell fate cannot be maintained. Estrogen receptor expression is conserved in the indifferent gonad of all mammals and many species also express the CYP19 gene that encodes aromatase, in the early ovary. Furthermore, estrogen is sufficient to drive ovarian development of the indifferent gonad in marsupial mammals. Here we review the function of estrogen in the mammalian gonad and propose a model for its action in establishing and maintaining ovarian somatic cell fate.

Is a Sex-Determining Gene(s) Necessary for Sex-Determination in Amphibians? Steroid Hormones May Be the Key Factor

Amphibians have 2 genetic sex-determining systems, one with male (XX/XY) and one with female (ZZ/ZW) heterogamety. While the ancestral state of sex-determination is thought to be female heterogamety, male and female heterogametic types were probably once interchangeable. The Japanese frog Rana rugosa has both XX/XY and ZZ/ZW systems within a single species in certain local populations. However, steroid hormones can alter the phenotypic sex epigenetically. In R. rugosa, steroidogenic enzyme expression starts before sex-determination in the indifferent gonad, and these enzymes become active in both male and female tadpoles. Androgens are produced in the indifferent gonad of male tadpoles at high levels, whereas estrogens are synthesized in females. In this regard, the observed enhanced expression of the hormone-metabolizing genes, CYP19 in the female gonad and CYP17 in males, may be crucial for sex-determination. Moreover, with FSH known to increase estrogen synthesis in the vertebrate ovary, observed upregulation of FSH receptor (FSHR) expression in the indifferent gonad of female tadpoles is intriguing. These data suggest that steroid hormones could be crucial for sex-determination in R. rugosa, with the consequence that upregulation of CYP19 and FSHR expression is necessary for female and CYP17 for male sex-determination.

β-catenin/Tcf-signaling appears to establish the murine ovarian surface epithelium (OSE) and remains active in selected postnatal OSE cells

BackgroundWnts are a family of secreted signaling molecules involved in a number of developmental processes including the establishment of cell fate, polarity and proliferation. Recent studies also implicate wnts in epithelial adult stem cell maintenance, renewal and differentiation. Wnts transduce their signal through one of three signaling pathways. The best studied, the wnt/β-catenin pathway, leads to an increase in intracellular β-catenin which acts as a co-transcription factor with members of the Tcf/Lef family. A number of wnts are expressed in the ovary, specifically in the membrana granulosa and ovarian surface epithelium (OSE). We investigated the spatio-temporal pattern of β-catenin/Tcf expression in the OSE using responsive transgenic (TopGal) mice.ResultsThe generated β-galactosidase response (lacZ+) identified the cell population that overlies the medio-lateral surface of the indifferent gonad at embryonic day (E) 11.5. From E12.5 onwards, lacZ expression disappeared in cells covering the testis but remained with ovary development. LacZ+ OSE cells were present throughout embryonic and postnatal ovarian development but demonstrated an age-dependent decrease to a small proportion when animals were weaned and remained at this proportion with aging. Flow cytometric (FACS) and ovarian section analyses showed lacZ+ cells constitute approximately 20% of OSE in postnatal (day 1) mice which fell to 8% in 5 day-old animals while in prepubertal and adult mice this accounted for only 0.2% of OSE. Apoptosis was undetected in OSE of neonates and β-catenin/Tcf-signaling cells were proliferative in neonatal mice indicating that neither cell death nor proliferation failure was responsible for the proportion alteration. It appeared that lacZ+ cells give rise to lacZ- cells and this was confirmed in cell cultures. The DNA-binding dye DyeCycle Violet was used to set up the side population (SP) assay aimed at identifying subpopulations of OSE cells with chemoresistance phenotype associated with ABCG2 transporter activity. FACS analysis revealed lacZ+ cells exhibit cytoprotective mechanisms as indicated by enrichment within the SP.ConclusionsThe study raises the possibility that wnt/β-catenin-signaling cells constitute a progenitor cell population and could underlie the pronounced histopathology observed for human ovarian cancer.

A role for estrogen in somatic cell fate of the mammalian gonad

Estrogen is both necessary and sufficient to drive ovarian development in many nonmammalian vertebrates. However, the role of estrogen in the mammalian gonad is less clear. Mouse ovarian development can proceed in the absence of estrogen signaling, but granulosa cell fate cannot be maintained. Estrogen receptor expression is conserved in the indifferent gonad of all mammals and many species also express the CYP19 gene that encodes aromatase, in the early ovary. Furthermore, estrogen is sufficient to drive ovarian development of the indifferent gonad in marsupial mammals. Here we review the function of estrogen in the mammalian gonad and propose a model for its action in establishing and maintaining ovarian somatic cell fate.

Mammalian foetal ovarian development: consequences for health and disease

The development of a normal ovary during foetal life is essential for the production and ovulation of a high-quality oocyte in adult life. Early in embryogenesis, the primordial germ cells (PGCs) migrate to and colonise the genital ridges. Once the PGCs reach the bipotential gonad, the absence of the sex-determining region on the Y chromosome (SRY) gene and the presence of female-specific genes ensure that the indifferent gonad takes the female pathway and an ovary forms. PGCs enter into meiosis, transform into oogonia and ultimately give rise to oocytes that are later surrounded by granulosa cells to form primordial follicles. Various genes and signals are implicated in germ and somatic cell development, leading to successful follicle formation and normal ovarian development. This review focuses on the differentiation events, cellular processes and molecular mechanisms essential for foetal ovarian development in the mice and humans. A better understanding of these early cellular and morphological events will facilitate further study into the regulation of oocyte development, manifestation of ovarian disease and basis of female infertility.