What type of tissue is ovary

Hematoxylin-eosin staining showed the central clot being invaded with fibroblasts not shown. In parallel sections stained immunocytochemically C , the fibroblast-shaped cells stain for keratin.

D, Higher magnification of the area outlined by the square in panel C. The arrows in A, B, and D indicate darkly staining, keratin-positive cells. The short arrows in panel c indicate the boundaries between the luteal cells and the scar forming in the central region of the corpus luteum. Ovarian cancer is the fourth or fifth most common cause of death from all cancers among women in the Western world and the leading cause of death from gynecological malignancies.

The epithelial ovarian carcinomas, i. Although screening tests are available for patient follow-up and for the detection of advanced cases 79 , there are no reliable means for early detection except for genetic screening in a small proportion of individuals 80 , and to date no test has been shown to reduce mortality.

The etiology of the epithelial ovarian carcinomas is poorly understood. Over the years, environmental agents that have been implicated but not proven to play a role include diet, talc, industrial pollutants, smoking, asbestos, and infectious agents 7. Epidemiological studies point to possible racial and geographic, social, and hormonal causative factors 7 , 81 — There is convincing evidence that nulliparity and, probably, hyperovulation treatment for infertility increase the risk of ovarian cancer, while oral contraceptives and pregnancies are protective.

These observations support the hypothesis, first proposed by Fathalla in and subsequently supported by epidemiological and experimental data 84, 85; reviewed in Ref. Recently, it has been suggested that inflammation may be a contributing factor in ovarian cancer development, because tubal ligation and hysterectomies act as protective factors, perhaps by preventing passage of environmental initiators of inflammation The risk increases from 1.

There is also a strong association with familial breast cancer, and a lesser association with familial cancers of the colon and endometrium. Three hereditary ovarian cancer syndromes with autosomal dominance reviewed in Ref.

Hereditary site-specific ovarian cancer, where a family history of ovarian cancer only is associated with an overall 3. No specific gene responsible for this syndrome has been identified. In this syndrome, the increase in risk has not been defined.

Germline mutations in two genes involved in this syndrome, BRCA1 and BRCA2, appear to be responsible for a high proportion of cancers in women with familial cancer histories. BRCA1, in particular, plays a major role in ovarian cancer susceptibility Intensive screening for BRCA1 mutations is ongoing but the large size of the gene and the great variety of different mutations that have been found complicate screening and risk predictions The observation that BRCA1 and BRCA2 germline mutations cause increases in cancer incidence predominantly in the breast, ovary, and prostate, although they are present in all tissues, points to interrelationships with hormonal influences.

Interactions between BRCA1 and estrogen as well as PRL have indeed been reported in cancer cells 92 — 94 , but there seems to be no information available on similar interactions in normal OSE. Importantly, not all of the carriers of these predisposing mutations develop ovarian cancer, which suggests a role for interactions with other, as yet unidentified, genetic and epigenetic influences. There have been several contradictory reports on the occurrence of histological changes in the OSE of overtly normal ovaries that were removed by prophylactic oophorectomy from healthy women with histories of familial ovarian cancer.

A nonblind study 95 demonstrated increased papillomatosis and pseudostratification of the OSE, as well as an increase in inclusion cysts and invaginations in ovaries from women with familial ovarian cancer. In another blind study, only nuclear changes were observed in the OSE of such women 96 , while in two other reports no significant differences were observed 97 , Thus, it is still not clear whether , in situ , overtly normal OSE from women with family histories of ovarian cancer is distinct at the phenotypic level.

Histopathologically and immunocytochemically, ovarian carcinomas are among the most complex of all human malignancies 99 , One of the most unusual aspects of ovarian carcinogenesis is the change in differentiation that accompanies neoplastic progression. As discussed above, OSE is a simple, rather primitive epithelium with some stromal features, but as it progresses to malignancy it loses its stromal characteristics and acquires the characteristics of the Mullerian duct-derived epithelia, i.

This aberrant differentiation occurs in such a high proportion of ovarian carcinomas that it serves as the basis for the classification of a high proportion of these cancers as serous fallopian tube-like , endometrioid endometrium-like , and mucinous endocervical-like adenocarcinomas Fig.

Among the less common forms are clear cell carcinomas that express features resembling mesonephros. It has also been proposed that at least some endometrioid carcinomas may arise in endometriotic lesions derived from endometrial implants , and that some mucinous ovarian adenocarcinomas may actually be metastases of gastrointestinal malignancies because the mucus in these lesions is of the gastrointestinal rather than the endocervical variety Mullerian differentiation of ovarian tumors.

A, Ovarian cortex with metaplastic OSE covering part of the ovarian surface arrow. To the left and in the upper part of the figure, a tumor with numerous papillae and gland-like structures has formed.

On the basis of its resemblance to the complex epithelium of the oviduct, this tumor is classified as a serous ovarian adenocarcinoma. B, Higher magnification of the tumor in panel A, illustrating the formation of papillae, cilia, and densely packed nuclei characteristic of serous type OSE-derived neoplasms. C, Mucinous differentiation of an ovarian tumor of borderline malignancy, resembling endocervix and also celomic epithelium in its differentiation.

Hematoxylin and eosin. Histologically, the tumors form polarized epithelia, papillae, cysts, and glandular structures. Thus, unlike carcinomas in most other organs in which epithelial cells become less differentiated in the course of neoplastic progression than the epithelium from which they arise, the differentiation of ovarian carcinomas is more complex than that of OSE Fig.

Only in the late stages do these specialized epithelial features diminish although they can persist even when the tumors are metastatic or in the ascites form Tissue culture studies have shown that with neoplastic progression OSE cells not only develop complex epithelial phenotypes, but also become firmly committed to these phenotypes and unresponsive to signals causing mesenchymal conversion of normal OSE.

Such unresponsiveness to environmental cues reflects the autonomy from normal control mechanisms that characterizes malignant tumors in general. E-cadherin expression by normal, metaplastic, and neoplastic OSE. Frozen sections, stained immunocytochemically for E-cadherin A, Ovarian surface. Normal, flat-to-cuboidal OSE on the right is E-cadherin negative.

On the left , the cells are columnar and Ecadherin positive. C, Higher magnification of the epithelium lining the cyst in panel B. The cells are columnar, ciliated with interspersed secretory cells, resembling oviductal epithelium.

D, Epithelial ovarian carcinoma with E-cadherin outlining intercellular junctions. The high frequency of Mullerian differentiation-associated changes in early stages of ovarian cancer suggests that they might confer a selective advantage on the transforming OSE.

The basis for such putative selective advantage s is currently being investigated. Thus, Mullerian differentiation might enhance epithelio-mesenchymal exchanges of blood-borne and paracrine factors that support malignant transformation and growth. Histopathologically detectable early malignant changes occur more frequently in OSE-lined clefts and inclusion cysts Fig.

The evidence for inclusion cysts as the preferred sites of ovarian carcinogenesis was reviewed by Scully 51 , 52 : 1 Most early carcinomas appear to be confined within the ovary without involvement of its surface; 2 tubal metaplasia is 10 times more common in epithelial inclusion cysts than on the ovarian surface; 3 inclusion cysts are significantly more numerous and the OSE lining them is 2—3 times more often metaplastic in women with contralateral epithelial ovarian tumors than in women without such cancers ; 4 several ovarian carcinoma tumor markers e.

The localization of early malignant changes in crypts and cysts has given rise to speculations that neoplastic progression may be promoted by the particular microenvironment to which preneoplastic OSE is exposed within these confined spaces. Genetic changes. The genetic basis of the epithelial ovarian carcinomas is too complex to be reviewed in detail here, but numerous excellent reviews exist on this subject. In brief, amplification, altered expression, and mutations in a number of oncogenes and tumor suppressor genes play a role in the development of ovarian epithelial neoplasms.

Oncogenes that are frequently overexpressed or amplified in ovarian carcinomas include cMYC, particularly in serous adenocarcinomas ; KRAS, especially in mucinous carcinomas that may exhibit enteric mucinous differentiation ; and ERBB2, EGF-R, and cFMS the receptor for colony-stimulating factor 1 , all of which are associated with a poor prognosis — Recently, phosphatidyl inositol 3 kinase PI3K and its downstream effector AKT2 were also shown to be amplified in a significant proportion of ovarian carcinomas , As mentioned in Section IV.

The epidemiology, histopathology, and clinical course of OSE-derived ovarian carcinomas differ profoundly from those of the mesotheliomas, which arise in extraovarian mesothelium, e. This difference reflects, among other factors, the different developmental histories of these two components of the pelvic peritoneum, which may include inductive signals emanating from the ovary and acting on the developing OSE 2 , 6 , The detailed procedures used for isolating and culturing normal human OSE were summarized previously and have recently been described in detail Briefly, in our laboratory, specimens for culture are obtained from overtly normal ovaries at surgery for nonmalignant gynecological diseases.

Fragments of OSE are gently scraped from the ovarian surface with a rubber scraper or with the blunt side of a scalpel or other suitable instrument and immediately placed into sterile culture medium; it is imperative that the tissue remain sterile and does not dry, which happens very rapidly.

OSE is also very loosely attached to the underlying ovarian cortex and is easily lost by excessive handling. If the surgery involves the removal of the ovaries, the OSE is obtained either by the surgeon while the ovaries are still in situ , or by a member of the research team after removal from the patient.

OSE can also be obtained by the surgeon laparoscopically at the time of minor gynecological procedures that are carried out by this approach. The cultures are left undisturbed for at least 4 days, grown to confluence, and then routinely passaged and split when confluent, with 0.

The cultures usually proliferate for three to four passages splits and then senesce. They are defined as senescent if they are composed of large flat cells that do not reach confluence over 1 month.

OSE cells in low-passage culture can undergo epithelio-mesenchymal conversion, which tends to extend their life span by a few passages Fig. This phenomenon varies in frequency and the underlying mechanisms have not been defined.

Reduced-serum, and serum-free media were designed for human OSE and used to study mitogenic effects of growth factors and hormones , For a long time there was no explanation for this phenomenon.

However, it was reported recently that OSE proliferation is regulated by extracellular calcium by means of calcium-sensing receptors and that human OSE proliferated only at calcium concentrations above 0.

Waymouth medium has a calcium concentration of 0. Morphology of OSE in culture. A, Primary epithelial culture with a compact, cobblestone-like growth pattern. B, Passage 2 with flat epithelial OSE cells.

Note a small group of granulosa cells in the lower right corner. C, Passage 5 with OSE cells that have undergone epithelio-mesenchymal conversion and have assumed fibroblast-like shapes. Such cells are initially keratin positive but tend to lose keratin with time and passages in culture 16 , Cultured OSE is highly responsive to environmental influences.

Over several passages under standard culture conditions, freshly explanted OSE cells respond to the culture environment by modulating from an epithelial to a more mesenchymal phenotype Table 1. Immediately upon explantation into primary culture they retain mesenchymal markers that are present in vivo , such as vimentin, and acquire additional mesenchymal characteristics, such as collagen type III secretion.

They rapidly lose some epithelial differentiation markers, including villin and desmoplakin, but retain others, e. With passages in culture, the cells may assume a more definitive fibroblast-like phenotype as indicated by a change to anterior-posterior polarity, reduced intercellular cohesion, gel contraction, increased secretion of collagen types I and III, and loss of the epithelial marker keratin 27 , 78 , Such epithelio-mesenchymal conversion is more consistent and prominent in three-dimensional than in two-dimensional culture 29 , It is enhanced by epithelial growth factor 16 , collagen substrata 29 , and ascorbate our unpublished data.

It varies widely in frequency between laboratories and within laboratories with time. The reasons for this variation and the precise mechanisms underlying the mesenchymal conversion of OSE have not been defined, but they most likely depend on as yet undefined serum factors.

Similar epithelio-mesenchymal conversions occur in the culture of other mesodermally derived epithelia reviewed in Refs. Generally, cells respond to explantation into culture as they would to wounding and undergo changes in phenotype and in gene expression that are similar to those that occur in regenerative responses.

In analogy, the response of OSE cells to explantation into culture likely mimics their normal response to ovulatory rupture. Thus, the phenotype observed in culture should perhaps be compared with that of regenerating OSE rather than to the phenotype of stationary OSE covering a nonovulating ovary. Comparison of epithelial and mesenchymal markers on OSE in situ and in culture.

Thus, OSE cells not only modulate to fibroblast-like forms morphologically, but have the capacity to autonomously produce complex connective tissue-type ECMs.

Whether this autonomy contributes to the spread of OSE-derived tumors by providing tumor-derived stroma remains to be determined. Human OSE cells also secrete chymotrypsin-like and elastase-like peptidases, metalloproteases, and plasminogen activator inhibitor. Protease activity varies with the type of ECM on which the cells are maintained 27 , OSE cells from normal human ovaries do not appear to secrete plasminogen activator.

Plasminogen activator detected in culture medium conditioned by OSE from an ovary with inflammatory disease may be derived from contaminating inflammatory cells 29 , OSE also expresses integrins that bind to laminin, collagens, fibronectin, and vitronectin and vary in type and amount with the substratum 29 , These properties are likely important in the roles of OSE in ovulation and postovulatory repair and may also influence the phenotypes of OSE-derived malignancies.

Intercellular adhesion. Similar to its in vivo phenotype 31 , 32 , intercellular contact of cultured OSE is maintained by N-cadherin, which is expressed constitutively while Ecadherin is expressed only conditionally, when OSE cell shapes approach those of metaplastic epithelium In contrast to the human, cultured rat OSE expresses E-cadherin consistently N-cadherin-mediated adhesion appears to have an antiapoptotic effect in OSE of the rat , but whether it has a similar function in the human is not known.

In general, expression of N-cadherin alone or of N- and E-cadherin together characterize adhesive mechanisms of mesodermally derived tissues reviewed in Ref. Pathological changes in OSE, including neoplastic conversion and endometriosis, often involve three-dimensional formations such as OSE-lined clefts and cysts. In collagen gel cultures, human OSE cells converted to a mesenchymal form, dispersed in the gel in a manner resembling connective tissue fibroblasts, and then remained stationary and eventually died This system may represent an experimental model for OSE-derived endometriosis , When cultured on the rat OSE-derived matrix plus collagen gel, the OSE cells again converted to a mesenchymal form and dispersed and then contracted the relatively loose matrix into smaller, denser structures Such contractile function is generally considered as characteristic of fibroblasts in the process of wound healing.

On Matrigel, OSE cells aggregated into solid cell clumps. Depending on the lot of Matrigel, the cells showed a varying propensity to lyse the matrix and eventually form monolayers on the underlying plastic This variation may have depended on growth factor contaminants known to occur in Matrigel.

In their ability to lyse this matrix, these presumably normal cells resembled cancer cells, which are commonly assumed to be the only cells capable of invading Matrigel. In Spongostan, cells were grown for several weeks until they filled the sponges. In contrast to ovarian cancer cells, which form epithelial linings along the sponge spicules, human OSE cells under these conditions again underwent mesenchymal conversion: they assumed morphological and functional characteristics of stromal cells as they dispersed in intercellular spaces, took on fibroblast-like shapes, and secreted ECM Thus, in all three-dimensional systems except for Matrigel, OSE cells converted to mesenchymal phenotypes.

One of the problems in human OSE research is the small number and short life span of cells obtained at surgery. Expression of these genes does not truly immortalize human OSE cell lines in that their population-doubling capacity is greatly extended but not infinite; however, the lines provide sufficiently large cell numbers for molecular studies. One advantage of these lines is that they tend to retain some, although not all, of the tissue-specific properties of the cells from which they are derived.

For example, many of these lines retain keratin, and most, if not all of them, continue to express N-cadherin and lack E-cadherin in common with normal, and in contrast to neoplastic OSE.

Although such lines are nontumorigenic in SCID mice 18 , their growth controls are profoundly disturbed, which confer on them properties of neoplastic cells such as genetic instability, increased saturation density reduced serum requirements, and variable degrees of anchorage independence.

These adenocarcinomas resembled Mullerian duct-derived epithelia in that they formed papillae and cysts and expressed CA and E- cadherin. While the exact relationships between the introduction of T-antigen and E-cadherin to tumorigenicity need to be examined in additional lines, this is the first experimental transformation of normal human OSE to ovarian adenocarcinoma cells and the first direct confirmation that OSE is capable of such a transformation.

The results support the hypothesis that E-cadherin may act as an inducer of the Mullerian epithelial differentiation that accompanies neoplastic conversion of OSE Important issues that are frequently overlooked in the interpretation of data derived from studies of OSE are the structural and physiological differences among OSE from different species.

For extrapolations of results to human OSE, one of the best tissue culture models appears to be bovine OSE because of the relative similarity between the reproductive systems of these two species One example of differences between species, discussed in Section III.

A , is the constitutive expression of E-cadherin by OSE of rodents and pigs but not humans. Other differences include the dependence of human but not rat OSE on high calcium levels in culture media for growth and the propensity of rat OSE but not human OSE to undergo spontaneous transformation to immortal cell lines in culture In this species, the responses to hormonal stimulation are associated with morphological changes that differ significantly from those of the human 2 , 59 , The differences between OSE from different sources are likely related to variations in the reproductive biology of different species and might provide clues for the striking interspecies variation in their propensity to develop epithelial ovarian cancers.

Therefore, in order to avoid reporting confusing and irreproducible results, it is mandatory to specify species in discussions of OSE. One of the pressing problems in ovarian cancer management is the lack of markers for the detection of preneoplastic or early neoplastic changes in the OSE. Our laboratory and others have investigated this problem by studying the properties of overtly normal OSE from women with histories of familial ovarian cancer and, in particular, women with proven predisposing mutations.

As stated in Section IV. B , the evidence for phenotypic changes in OSE in situ of women with these predisposing mutations is controversial. However, it appears that such OSE expresses an altered phenotype in culture that might reveal early changes and, perhaps, be a source of predictive markers for ovarian carcinogenesis 78 , , As discussed earlier in this review, normal OSE cells have a tendency to undergo epithelio-mesenchymal conversion in culture.

In contrast, ovarian carcinoma cells are nonresponsive to the environmental signals that induce this conversion and remain epithelial in culture indefinitely. CA is an ovarian tumor marker used to monitor the clinical progress of ovarian cancer patients, but it is also an epithelial differentiation marker that is expressed by normal oviductal and endometrial epithelium.

This hypothesis was supported by subsequent observations that showed an increased tendency of FH-OSE cells to retain an epithelial cellular morphology and growth patterns in two- and three-dimensional culture and to express the epithelial markers keratin and E-cadherin more frequently and over longer periods in culture than NFH-OSE.

At the same time, the capacities for sponge contraction and collagen type III secretion, which are mesenchymal markers, were reduced compared with NFH-OSE cultures 36 , As Met is characteristically expressed by epithelial cells, the presence of this receptor represents yet another epithelial differentiation marker that persists longer in FH-OSE. In view of the capacity of HGF to induce glandular morphogenesis , Met expression may enhance the susceptibility of the FH-OSE cells to the aberrant Mullerian differentiation that accompanies ovarian carcinogenesis , In lanes 1—7, each lane represents a different case.

The passages p. Similar to other cell types , the appearance of both HGF and Met expression in FH-OSE may reflect increased autonomy of differentiation and growth controls that represent an early step in their pre neoplastic progression. Effects of HGF stimulation on protein kinase phosphorylation assessed by phosphorylation-induced reductions of kinase mobilities on Western blots.

The bottom band represents unphosphorylated forms of the kinases, whereas the upper bands represent different phosphorylated forms. Together, these data suggest that some of the factors that enhance the expression of epithelial characteristics, including Met levels, in the malignant progression of ovarian surface epithelial tumors — may preexist in FH-OSE, and that FH-OSE may have acquired some of the autocrine regulatory mechanisms that characterize malignant cells.

Such increased autonomy would indicate an early step or predisposition to neoplastic progression by FH-OSE and would provide a basis for the propensity of such OSE to undergo neoplastic progression. An additional difference from NFH-OSE was observed in SV large T antigen-immortalized FH-OSE cultures, which were found to exhibit increased telomeric instability and a reduced growth potential indicative of greater proximity to replicative senescence These observations are particularly relevant to the unexplained earlier age of onset that characterizes ovarian cancer in women with hereditary ovarian cancer syndromes A possible reason why differences between FH-OSE and NFH-OSE were detected mainly in culture may relate to the particular nature of these changes: most of them involve differences in the stability, rather than type, of phenotypic characteristics in culture.

Since the response of cells to explantation into culture is thought to mimic their response to injury, the nature of the changes suggests the interesting possibility that FH-OSE may respond abnormally to regenerative stimuli.

This possibility is particularly intriguing in view of the apparent role of ovulation as a predisposing factor in ovarian carcinogenesis 8 , Normal OSE cells secrete, and have receptors for, agents with growth- and differentiation-regulatory capabilities.

Compared with the wealth of information available on the endocrinology of the follicular components of the ovary and on ovarian cancer, research about the roles of such agents in OSE physiology has been limited and, as a result, information on this topic is fragmentary. GnRH and gonadotropins. It has been shown that gonadotropins stimulate cell proliferation of normal OSE of several species in vivo and in vitro 59 , The presence of these receptors lends support to the hypothesis that the high FSH levels in peri- and postmenopausal women may play a promoting role in ovarian carcinogenesis, since this is the age of the peak incidence of epithelial ovarian carcinomas No direct effects of these steroids on OSE proliferation have been demonstrated , but there is increasing evidence for indirect actions.

Although there is no evidence for a direct mitogenic effect of ovarian steroids on OSE, it has been known for a long time that corticosteroids enhance OSE proliferation in culture and that combinations of EGF and hydrocortisone are among the most potent mitogens for cultured OSE 16 see below.

Steroidogenic factor 1, a transcription factor that regulates the differentiation of granulosa cells and inhibits their proliferation, is also growth inhibitory in rat OSE cells EGF family. Among growth factors, those of the EGF family were among the first reported to stimulate human and rabbit OSE proliferation either with or without costimulation by corticosteroids 16 , 56 , , EGF not only stimulates proliferation of human OSE cells but also profoundly affects their differentiation: within a few days of EGF treatment, the cells convert from an epithelial to the spindle-shaped morphology and lose epithelial differentiation markers such as keratin EGF is not present in large amounts in the plasma but is released from platelets during the clotting process.

In the ovary, EGF should therefore be present in increased amounts due to the hemorrhage that occurs during follicular rupture The resulting localized stimulation of the OSE likely contributes to its rapid postovulatory proliferation and perhaps also to epithelio-mesenchymal conversion of OSE cells trapped within the ruptured follicle.

EGF has numerous functions in the ovary, which include inhibition of FSH induction of LH receptors , inhibition of estrogen production and of theca differentiation , and stimulation of progestin biosynthesis It was also demonstrated immunohistochemically in human theca cells, suggesting that it plays a role in the reproductive functions of the ovary Amphiregulin, another EGF homolog, is also a potent mitogen for OSE cells and appears to control OSE and ovarian cancer cell proliferation in a complex manner , These receptors interact in multiple ways that modify their influence on a variety of cells reviewed in Ref.

Other growth factors. The latter function involves alterations in intracellular calcium levels and can be mimicked by N-cadherin-mediated intercellular adhesion , Welt et al. At the protein level, OSE produced inhibin only. In view of the close developmental relationship between the Mullerian ducts and OSE, it might be expected that AMH should affect OSE cells; however, no information on this topic seems to be available.

A growth factor with pleiotropic effects, which has attracted increasing attention in recent years, is HGF and its receptor, Met. HGF is produced primarily by mesenchymal and stromal cells and acts on epithelial cells by a paracrine mechanism through its receptor tyrosine kinase encoded by the c -met protooncogene , During mouse development, HGF is produced by the mesenchyme at the urogenital region in the vicinity of Met-expressing epithelia, suggesting that the development and morphogenesis of urogenital organs, including ovary, depend on a paracrine regulation of HGF-Met In the adult ovary, including human, the expression of Met persists in the OSE, granulosa cells, and Mullerian epithelia — , , This suggests that expression of the Met receptor might be a feature characteristic of celomic epithelial derivatives at the urogenital ridge through local differentiation.

There are two possible explanations for this discrepancy. First, there may be species differences among human, bovine, rat, and mouse OSE. For example, HGF decreases N-cadherin-mediated cell contacts, increases intracellular calcium concentration, and ultimately induces apoptosis in vitro if these cells are cultured on plastic In vivo , these modulations may regulate the contributions of OSE to follicular rupture before ovulation and to postovulatory repair.

HGF levels are transcriptionally regulated by a variety of steroid hormones, cytokines, and growth factors, including estrogen and gonadotropins. Estrogen increases the expression of HGF in the ovary, but not in other organs such as kidney and liver, suggesting that this may be a crucial part of the mechanism through which estrogen mediates cell growth and differentiation in the ovary The level of HGF is lowest at ovulation and is highest in the late follicular phase and during the luteal phase, suggesting that apoptosis and mitotic activity of OSE before and after ovulation might be regulated via HGF Together, these findings illustrate the role of HGF in normal OSE physiology and show that both cell-ECM interaction and hormonal regulation during the menstrual cycle determine the outcomes.

These agents have regulatory effects on follicular growth and differentiation, ovulation, and the distribution of intraovarian cells of the immune system 55 , and IL-1 enhances OSE proliferation Little is known about the regulation of cytokine expression in OSE, but it may be relevant that ovarian steroid hormones regulate GM-CSF production by uterine epithelial cells, which are developmentally related to OSE Ovarian carcinomas also secrete and have receptors for agents with growth-regulatory capabilities.

The potential roles of peptide hormones, sex steroids, and growth factors in ovarian cancer are discussed below. GnRH acts as a key hormone in the regulation of the pituitary gonadal axis , This concept is based on the detection of binding sites for GnRH, as well as the expression of GnRH and its receptor gene transcripts in these tumors.

GnRH and its analogs have been shown to be efficient in treatment of the sex steroid-responsive tumors of ovary, breast, and endometrium in vivo and in vitro — , , In vivo , long acting GnRH agonists are thought to act by desensitizing or down-regulating the GnRH receptors in the pituitary, resulting in a subsequent decline in gonadotropins that serve as tumor growth factors.

The suppression of endogenous LH and FSH secretion by GnRH-agonist treatment results in growth inhibition of heterotransplanted ovarian cancers in animal models In vitro, GnRH and its analogs have been shown to inhibit the growth of a number of GnRH receptor-bearing ovarian cancer cell lines. For instance, Emons et al. During the first five months of development, a finite number of primordial follicles form in the fetal ovary.

These follicles consist of oocytes surrounded by a single layer of squamous follicular cells. These primordial follicles remain in the process of the first meiotic division.

At puberty, they begin to develop further and become primary follicles. The primary follicle has a central oocyte and is surrounded by a single layer of cuboidal cells.

The zona pellucida is a thin band that separates these two layers. The late primary follicle stage is achieved when the follicular cells proliferate into a stratified epithelium known as the zona granulosa. The zona pellucida can be seen even more clearly in this image. The characteristic feature that distinguishes secondary from primary follicles is the appearance of a follicular antrum within the granulosa layer. This gap contains fluid known as liquor folliculi.

Also visible in this image are the oocyte and the zona pellucida. The follicle is surrounded by the theca interna, whose cells produce hormones. The Graafian follicle is the follicular stage after the first meiotic division but before ovulation. It therefore contains a 2N haploid oocyte.

It is characterized by a large follicular antrum that makes up most of the follicle. The secondary oocyte, having undergone the first meiotic division, is located eccentrically. It is surrounded by the zona pellucida and a layer of several cells known as the corona radiata. When released from the Graafian follicle and into the oviduct, the ovum will contain three layers: oocyte, zona pellucida and corona radiata.

The corpus luteum is the endocrine remains of the collapsed follicle. The center contains the remains of the blood clot that formed after ovulation.

Surrounding the clot are glanulosa lutein cells and on the outside theca lutein cells. The granulosa lutein cells have an appearance characteristic of steroid-producing cells, with pale cytoplasm indicating the presence of lipid droplets. Theca lutein cells are smaller and more deeply stained. If fertilization and implantation ensue, the corpus luteum will be maintained by hCG and remain active as the corpus luteum of pregnancy. The genital tract makes up the rest of the female reproductive system: fallopian tubes take the ova to the uterus.

The uterus is a muscular organ, and its mucosal lining undergoes hormone dependent changes. The vagina is a muscular tube that leads to the outside. The ovaries are small almond shaped structures, covered by a thick connective tissue capsule - the tunica albuginea. This is covered by a simple squamous mesothelium called the germinal epithelium.

Characterize the histological features of the oviduct, uterus, cervix, and vagina, with particular attention to the mucosal linings of these tissues. Describe the cellular organization of the placenta, including the juxtaposition of the maternal and fetal circulations. Recognize some key pathology related to the female reproductive system. Pre-Lab Reading Overview of the Female Reproductive System The female reproductive system is composed of two gonads known as ovaries, two oviducts, the uterus, the vagina and external genitalia, and two mammary glands.

Its development, maturation, and functioning is dependent upon a complex interplay of hormones from the hypothalamus, pituitary gland, adrenal glands, ovaries, and placenta. The system has six primary functions:. The ovary is the female gonad and is composed of two regions with indistinct boundaries:. The ovarian epithelium is a single layer of squamous or low columnar cells that forms the external covering of the ovary. It does not correspond to the germinal epithelium of the male seminiferous tubules, which is the site of sperm production and development.

There are several developmental stages that precede the maturation and release of the ovum. All of these occur within the cortex of the ovary:. Upon ovulation, the Graafian follicle bursts and the ovum , composed of the oocyte, zona pellucida, and corona radiata is expelled into the peritoneal cavity near the oviduct. The second meiotic division and formation of the second polar body does not occur until fertilization. Several primordial follicles enter each ovarian cycle, but typically only one ovum is released.

The remaining follicles degenerate and are called atretic follicles.