Progesterone Receptors In Meningiomas Research Articles

The Expression of Progesterone Receptors in Meningiomas of Different Grades

Background: Meningiomas are slow growing intracranial and intraspinal neoplasms with a tendency to recur locally. WHO grades them as I (benign), II (atypical) and III (anaplastic) in order of their increasing aggressiveness, based on histological parameters and brain parenchymal invasion. Progesterone receptors (PR) are more prevalent amongst the lower grade meningiomas. The objective of this study was to determine the immunohistochemical expression of progesterone receptors in meningiomas of different grades.Material and Methods: A total of 100 cases were selected over a period of 2.5 years. Three to five microns’ thick sections stained with Hematoxylin and Eosin were examined microscopically by a team of two Histopathologists and graded into grades I, II and III, according to 2016 WHO classification criteria. Another section of the original tumor was stained with progesterone receptor antibody using the conventional immunoperoxidase method. Stained slides were than examined by the same team of Histopathologists and declared positive (if nuclear staining was observed in more than 10% of tumor cells) or negative. Statistical analysis was done using SPSS version 21.Results: Out of a total of 100 cases of meningioma, there were 79 cases of benign/typical WHO grade I, 15 cases of atypical/ WHO grade II and 6 cases of anaplastic/ WHO grade III tumor. PR status was positive in 89.8 % (71/79) of grade I meningiomas and 46.6 % (7/15) of grade II/Atypical meningiomas. The 06 cases of Anaplastic/WHO grade III tumors were negative for PR. There was a higher prevalence of Progesterone receptors in female patients (89.8%; 53/59) as compared to male meningioma patients (60.9%; 25/41).Conclusion: We observed a decreased expression of progesterone receptor in higher grades of meningioma in this study. It is an effort to explore conservative treatment options for inoperable lesions, as anti-progesterone therapy may hold a promise as a new treatment option in the near future.

Nonneuroendocrine Neoplasms of the Pituitary Region.

Although most sellar lesions are related to pituitary adenomas, the region gives rise to a variety of neoplasms that can be associated with substantial morbidity and/or mortality. Information from reviews and guidelines of relevant societies dealing with such neoplasms, as well as articles that have provided new developments that made important contributions to their pathogenesis and treatment up to 2018, were obtained: public indexes such as PubMed/MEDLINE were used with the relevant search items. Sellar neoplasms have a worse outcome than pituitary adenomas that is related not only to their natural history but also to side effects of therapies and evolving endocrine and/or hypothalamic deficiencies. Recent imaging advances have established the radiological fingerprint of some of these neoplasms, and several chromosomal aberrations have also been identified. Although established approaches along with new surgical and radiotherapeutic approaches remain the main treatment modalities, recent evidence has provided insight into their molecular pathogenesis involving, other than chemotherapy, treatments with targeted agents as in gliomas and craniopharyngiomas bearing BRAF mutations. Development of predictive markers of recurrences may also identify high-risk patients, including proliferative markers and expression of the progesterone receptor in meningiomas, and lead to less aggressive surgery. Owing to the rarity and complexity of these neoplasms, patients should be managed in dedicated centers. The diagnosis and management of sellar neoplasms necessitate a multidisciplinary approach. Following evolving recent advances in their diagnosis and therapy, such a multidisciplinary approach needs to be extended to establish evidence-based diagnostic and management plans.

Inverse correlation of cell proliferation and expression of progesterone receptors in tumor spheroids and monolayer cultures of human meningiomas.

The progesterone receptor (PgR) can be detected in 60 to 70% of meningiomas using immunohistochemistry] in situ. Whereas in monolayer tissue cultures the PgR is only rarely expressed, we were able recently to demonstrate the preservation of the PgR in fragment spheroid cultures of meningiomas. The aim of the present study was to evaluate the stability of PgR expression in meningioma spheroids in vitro and the correlation of PgR expression and cell proliferation in spheroids and whether meningioma cells reaggregated to spheroids from monolayer cultures to reexpress the PgR again. Tumor fragment spheroids (Weeks 1-6) and cell monolayers (Passages 1 and 3) of 15 PgR-positive meningiomas were investigated by immunohistochemistry for the expression of PgRs and their proliferative activity, as demonstrated by positivity for the proliferation-related antigen Ki-67. To study PgR reexpression in reaggregated spheroids, Northern blots were performed. In addition, a reverse transcriptase-polymerase chain reaction technique was established and evaluated in combination with immunohistochemistry. Growth of meningioma spheroids was quantified in the presence of progesterone and the specific antagonist onapristone. The PgR remained stable in spheroids for 6 weeks in 9 of 13 cases that were able to be evaluated. All tumor fragment spheroids exhibited a proliferation index of 5 to 40% Ki-67-positive cells. Monolayer cell cultures, on the other hand, failed to express PgRs but revealed higher proliferation indices (40-90%) to a significant extent. The detection of PgR messenger ribonucleic acid in reaggregated spheroids by means of reverse transcriptase-polymerase chain reaction correlated to the nuclear expression of PgR in immunohistochemistry. Neither progesterone nor its antagonist onapristone altered spheroid growth in vitro. The expression of the PgR in meningiomas is preserved in spheroid cultures with low proliferation indices for at least 6 weeks, whereas monolayer cell cultures with a high proliferative activity lack PgR expression. The inverse pattern of Ki-67-positive cells in the outer regions of the spheroids and PgR-expressing tumor cells in the spheroid centers leads us to the conclusion that proliferating meningioma tumor cells do not express PgRs. This might also explain why tumor cell growth in vitro was neither affected by progesterone nor by onapristone. Monolayer cell cultures can be reaggregated to spheroids, the consequence being a reexpression of PgRs and, therefore, a down-regulation of proliferation.

Progesterone and Glucocorticoid Receptor Activation in Meningiomas

THE POSSIBILITY THAT the female sex steroid progesterone plays a role in meningioma proliferation has been suggested by a number of investigators, and it has been shown that many meningiomas have high-affinity progesterone binding sites. There has been a long-standing debate in the literature as to whether the progesterone receptors that are present in meningiomas are functional. We recently showed, by the use of immunohistochemistry, that the progesterone receptor in meningiomas is localized to the nucleus, suggesting that the receptor is in a location to be activated. In this study, eight meningioma cell cultures were transiently transfected with a construct that contains two palindromic progesterone/glucocorticoid response elements in front of the thymidine kinase promoter and the chloramphenicol acetyl sequence of the tyrosine aminotransferase gene. In all meningioma cell cultures, an increase in the transcription of the progesterone response element construct was observed in the presence of dexamethasome, suggesting that the glucocorticoid receptor in meningiomas is functional. An increase in transcription was observed with the addition of promegestone (R5020), a progesterone agonist, only in meningioma cell cultures that were expressing the progesterone receptor. These data show that both the progesterone and the glucocorticoid receptor in meningiomas are functional and support the concept that progestins and glucocorticoids may play an important role in meningioma growth.

Progesterone and Glucocorticoid Receptor Activation in Meningiomas

The possibility that the female sex steroid progesterone plays a role in meningioma proliferation has been suggested by a number of investigators, and it has been shown that many meningiomas have high-affinity progesterone binding sites. There has been a long-standing debate in the literature as to whether the progesterone receptors that are present in meningiomas are functional. We recently showed, by the use of immunohistochemistry, that the progesterone receptor in meningiomas is localized to the nucleus, suggesting that the receptor is in a location to be activated. In this study, eight meningioma cell cultures were transiently transfected with a construct that contains two palindromic progesterone/glucocorticoid response elements in front of the thymidine kinase promoter and the chloramphenicol acetyl sequence of the tyrosine aminotransferase gene. In all meningioma cell cultures, an increase in the transcription of the progesterone response element construct was observed in the presence of dexamethasone, suggesting that the glucocorticoid receptor in meningiomas is functional. An increase in transcription was observed with the addition of promegestone (R5020), a progesterone agonist, only in meningioma cell cultures that were expressing the progesterone receptor. These data show that both the progesterone and the glucocorticoid receptor in meningiomas are functional and support the concept that progestins and glucocorticoids may play an important role in meningioma growth.

The presence of progesterone receptors in arachnoid granulations and in the lining of arachnoid cysts: its relevance to expression of progesterone receptors in meningiomas.

Progesterone receptors (PR) were identified with an enzyme immunoassay in cytosols from human arachnoid granulations and arachnoid cysts. Meningiomas presumably originate from subdural endothelium which is abundantly present in these structures. In the three cases studied, oestrogen receptors were absent. The presence of PR in subdural endothelium may provide further ground for the expression of PR in meningiomas.

Immunohistochemical study of estrogen receptor-related antigen, progesterone, and estrogen receptors in human intracranial meningiomas

The estrogen receptor-related antigen (ER-D5) is a serine phosphoprotein associated with the estrogen receptor that is present only in estrogen receptor- (ER) positive tissues and has no relation with progesterone receptor (PR). This study was performed to evaluate whether immunostaining of these proteins correlated with the proliferative potential of meningiomas as evaluated by clinicopathologic features. Immunohistochemical staining of ER-D5, ER, and PR were performed on paraffin embedded sections of meningiomas from 34 patients. Twenty two (64.7%) of the 34 meningiomas tested were positive for ER-D5 with exclusively cytoplasmic immunostaining. All of the cases were positive for PR but not for ER. Progesterone receptors in meningiomas were cytoplasmic and/or nuclear. The correlation of ER-D5 reactivity with histologic subtypes showed positivity rates for meningotheliomatous meningiomas of 71.4%, fibroblastic 41.7%, transitional 80%, anaplastic 100% and hemangiopericytic 100%. ER-D5 positivity rates in primary and recurrent meningiomas were 59.3% and 85.7%, respectively. Normal arachnoid tissue was positive for PR but negative for ER-D5 and ER. Patient age and sex has no significant influence on the positivity rate of meningiomas. The mean number of AgNORs in ER-D5-positive and -negative meningiomas had no statistical significance. This study suggests that ER-D5 has some role in the growth of the meningioma and that the expression of ER-D5 in human meningioma is independent of ER as it is in breast cancer. The localization of PR in the meningioma cells indicate that at least some of these cells are functionally active.

Estrogen and Progesterone Receptors in Meningiomas: Comparison of Nuclear Binding, Dextran-Coated Charcoal, and Immunoperoxidase Staining Assays

We studied the status of estrogen (ER) and progesterone (PR) receptors in meningiomas removed from 52 patients, comparing dextran-coated charcoal (DCC), nuclear binding (NB), and immunoperoxidase (IP) assays. Each of the assays was performed independently by investigators well-experienced with these assays. The NB assay is a new assay that measures functional steroid receptors--that is, the activation of the receptor and its binding to the nucleus. The assay is very sensitive and requires a relatively small amount of tissue as compared with the DCC assay. In agreement with data from other studies. PR were detected in most meningiomas by all 3 methods: in 69% of the cases by NB, in 76% by DCC, and in 89% by IP. ER were detected in only a few cases: in 33% by NB, in 2% by DCC, and in none by the IP assay. The agreement for PR sites was 62% for all 3 assays; it was 66% between the NB and DCC assays, 67% between the NB and IP assays, and 86% between the DCC and IP assays. Of 26 cases that were positive by the DCC assay, 6 (23%) were negative by NB. The overall agreement for all three ER assays was 65%. The data suggest that the majority of meningiomas contain high-affinity receptors for progesterone, that estrogen receptors are present in only a few meningiomas, and that some of these estrogen and progesterone receptors appear to be functional.

Immunocytochemical evidence of progesterone receptors in human meningiomas

The presence of progesterone receptors in meningioma tissue is demonstrated by use of highly specific monoclonal antibodies against the rabbit progesterone receptors which cross-react with human progesterone receptors in breast cancer cells, thus giving evidence of the existence of genuine progesterone receptors in human meningiomas.

Estrogen- and progesterone-receptors in meningiomas: Review article

Since 1979 much attention has been payed in the literature to the presence and importance of estrogen- and progesterone-receptors in meningiomas. The existence of these receptors seems to be proven, but the question about their biological activity is not solved conclusively. If the hypothesis of a biological activity of the estrogen- and progesterone-receptors in meningiomas is confirmed, some patients could benefit from a hormonal therapy.

Estrogen and progesterone receptors in intracranial tumors.

Cytoplasmic estrogen receptor (ER) and progesterone receptor (PR) proteins were measured by a dextran-coated charcoal absorption technique in 19 intracranial tumors (10 meningiomas, two acoustic neurinomas, two glioblastomas, one primary tumor of neuroectodermal origin, one hemangioblastoma, one metastasis of carcinoma, one chordoma, and one pituitary adenoma). Positive PR values (greater than or equal to 10 fmol/mg of protein) were found in nine meningiomas (90% of these tumors), in the chordoma, in one glioblastoma, and in the hemangioblastoma, whereas positive ER values were recorded only in the pituitary adenoma and in one glioblastoma. Evidence of PR in meningiomas might explain their predominance in women. A possible pharmacological therapy, based on these findings, is discussed.

Estrogen and progestin receptors in meningiomas: clinicopathological correlations.

Estradiol and progesterone receptors were studied in 44 patients with meningiomas and correlated to the clinicopathological features and amount of preoperative corticosteroid therapy. Thirty-four (77%) of the meningiomas contained high titers of specific high-affinity cytosol [3H]promegestone (R 5020) binding sites (mean 2,902 fmol/g tumor; range 0-9,598 fmol/g tumor) whereas only miniscule amounts of a nonspecific cytoplasmic [3H]estradiol binding component (mean 48 fmol/g tumor; range 0-201 fmol/g tumor) were detectable. No nuclear binding activity for [3H]estradiol was demonstrable. There was no convincing correlation between high PR activity and the age, sex, or menopausal status of the patients. The correlation study between the amount of preoperative corticosteroid therapy with the amount of [3H]promegestone binding revealed no dose relationship. Correlating [3H]promegestone content with the histologic type, we found 96% of meningothelial, 71% of transitional, and 40% of fibroplastic meningiomas to contain progesterone receptors. The necessity of in vitro studies is stressed to assess the biosynthesis and biological activity of the progesterone receptor in meningiomas, which is apparently not estrogen regulated, as is the case in other estrogen target tissues.

Estrogen and progesterone receptors in meningiomas in relation to clinical and pathologic features

Tumor estradiol and progesterone binding sites were studied in 34 patients with meningioma. Twenty of the meningiomas contained very low titers (mean, 45 fmol/g of tumor; range, 0-201 fmol/g of tumor) of a nonspecific cytoplasmic [ 3H]estradiol binding component, whereas 26 of the tumors contained high titers of specific high-affinity cytosol [ 3H]promegestone (R5020; progesterone) binding sites (mean, 1476 fmol/g of tumor; range, 0-8328 fmol/g of tumor). No nuclear binding activity for [ 3H]estradiol could be detected in 12 of the 34 meningiomas studied, irrespective of the progesterone binding activity. There was no correlation between high progesterone binding activity and the age or the sex of the patient, nor between tumor location and cellular mitotic index. However, progesterone binding activity was present more frequently in meningothelial (95%, 18/21 patients) than in transitional (55%, 5/9 patients) or fibroplastic (25%, 1/4 patients) tumor histologic types. These data suggest that the cellular biosynthesis of the progesterone binding component in meningiomas is not estrogen regulated as it is in other classic estrogen target tissues, such as the breast.

Estrogen- and progesterone-receptor proteins in intracranial tumors

Estrogen and progesterone receptors have been measured in 13 intracranial tumors (eight meningiomas, two acoustic neurinomas, one primary tumor of neuroectodermal origin, one giant-celled glioblastoma, and one metastasis of carcinoma). Evidence is provided of the presence of progesterone receptors in meningiomas (87.5%). We could not find clear evidence of estrogen receptors in any tumor of this series. Presence of progesterone receptors in meningiomas suggests an explanation for the greater incidence of these tumors in women and their rapid growth during pregnancy.

478 Estrogen and progesterone receptors in meningiomas in relation to clinical and pathological features

478 Estrogen and progesterone receptors in meningiomas in relation to clinical and pathological features