Case Reports in Neurological MedicineMeningiomas are slow-growing benign brain tumors. The etiology of meningioma is safe anabolic steroids uk unknown, and exposure to high-dose ionizing radiation and coexistence with certain rare genetic conditions explain only a small fraction of the incidence of the ohrmonal. The evidence that implicates gender-specific hormones in the pathogenesis of meningioma emanates from data showing increased growth of meningiomas during pregnancy and change in size during menses. Observational data have identified the menopause and oophorectomy as conferring protection against the risk of developing meningiomas, while adiposity is positively associated with the disease. These tumors are also positively associated with breast cancer, although they express a different gonadal steroid receptor repertoire. These observations suggest that progesterone influences tumor growth. A hormonal therapy for meningioma antagonist such as mifepristone therefore hormonal therapy for meningioma inhibit tumor growth.
Meningioma and hormonal influences. - PubMed - NCBI
Recurrent meningiomas constitute an uncommon but significant problem after standard therapy failure. Speculation that meningiomas may be subject to endocrine influence was supported by both immunohistochemical analyses and epidemiological data. Therefore, alternative strategies such as endocrine therapy have been suggested. Although evidence of consistent findings for the role of specific hormonal exposures is mounting, there are numerous discrepancies about the mitogenic effect of hormonal manipulation on meningioma cells.
A better understanding of the molecular mechanisms involved in meningioma pathogenesis may not only lead to the identification of novel diagnostic and prognostic markers but may also facilitate the development of new pathogenesis-based targeted strategies. Meningiomas are common tumours of the central nervous system, which originate from the meningeal coverings of the spinal cord and the brain.
Although the cell of origin has yet to be proven, meningiomas are probably derived from arachnoidal cap cells Riemenschneider et al. Surgery is considered as the standard first-line treatment in meningiomas. Its primary goal is the complete removal of the meningioma. However, the decision to operate is guided by the clinical history of the patient, symptoms, accessibility of the tumour and estimation of the clinical benefit achievable by surgery Bindal et al.
However, some meningiomas recur or are resected subtotally because of anatomical problems such as their location at the skull base and are deferred to postoperative or salvage radiotherapy. The indications for radiotherapy are atypical or anaplastic meningiomas, recurrences or inaccessible meningiomas. Postoperative radiation therapy after the first resection of benign meningiomas is still controversial.
However, it is currently used in cases of incomplete resection or in cases of tumour progression. This unresolved issue should be examined prospectively in a randomized study that compares a policy of watchful waiting versus adjuvant conformal irradiation EORTC trial.
In a minority of patients, regrowth of tumour tissue after irradiation is a major clinical problem. An English-language literature search was conducted to identify all published studies assessing hormonal influences on meningiomas, in order to highlight potential prognostic and therapeutic values of endocrine therapy.
Data for this review were identified by searches of Medline and Cancerlit. References identified from within retrieved articles were also used. There was no limitation on year of publication and no abstract forms were included. The aetiology of primary brain tumours remains a controversial issue and the only somewhat well-established risk factors for meningioma are ionizing radiation Sadetzki et al.
A significant increased risk of meningioma has also been advocated in some hereditary syndromes where the mismatch repair gene or the deletion of neurofibromatosis type 2 gene NF2 have been associated with the occurrence of cerebral benign tumours Louis et al.
Mutations in the NF2 gene probably account for the formation of more than half of all meningiomas Simon et al. Although a role of head injury for the induction of meningiomas has been suspected, this question cannot be answered definitely. It was suggested that the local alteration of the blood brain barrier might be involved by a consequent massive influx of cytokines into the extravasal space. Moreover, it was also advocated that several genes would be upregulated after traumatic brain injury, including genes controlling transcription regulation, signal transduction and intercellular adhesion Michael et al.
In adults' meningiomas, epidemiological data have identified a ratio of 2: Although a possible hormonal association between breast cancer and meningiomas has not been clarified, the simultaneous occurrence of meningiomas and breast cancer is an unusual but well-known event and several cases have been reported with or without brain metastasis Brandis et al.
Breast cancer and meningioma present some similar features that might account for their association: Furthermore, menopause and oophorectomy have been identified as conferring protection against the risk of developing meningiomas, while excess of adiposity is positively associated with the disease Kannan et al.
Some authors described growth of meningiomas after oestrogen—progestin therapy Gazzeri et al. Exposures for cases and controls matched on age within 5 years were obtained by interview. Risk of meningioma appeared modestly elevated in past OC users and in current users. However, the confidence intervals were wide and no significant association between meningioma risk and duration of OC use was found.
Discrepant results were recently obtained by Blitshteyn et al. A logistic regression analysis, adjusted for age, demonstrated a significantly positive association between a diagnosis of meningioma and HRT use. Similarly, Wigertz et al. Further evaluation of exogenous hormone use in women with meningioma is needed with particular attention to stratification by hormonal receptor status, duration of and age at use as well as tumour receptor subtype Claus et al. Several studies have shown that hyperinsulinaemia could promote carcinogenesis in breast cancer.
This mechanism might possibly involve activity of insulin growth factor I Stoll , Hudelist et al. As gene expression of different insulin-like growth factors has also been reported in meningioma, it is therefore of interest to delineate a possibility of hyperinsulinaemia as a triggering factor in both meningioma and breast cancer.
Other authors hypothesized that because obesity affects male steroid hormone synthesis, male patients with meningiomas might exhibit a high obesity rate, suggesting a hormonal influence on meningiomas in men as well as women Aghi et al. Moreover, the human progesterone receptor PGR gene shares the same location as the mammary oncogene FGF3 in chromosomal 11q13 Law et al.
Although this proximity may explain the role of progesterone in breast cancer, the role of oncogene FGF3 in the genesis of meningiomas is not yet known. Besides, both meningiomas and breast cancers overexpress the MYC oncogene. Genes on the long arm of chromosome 22 and near the NF2 gene were most frequently noted to have expression variation, with significant up-regulation in PGR-positive versus PGR-negative lesions, suggesting a higher rate of 22q loss in PGR-negative lesions.
It remains difficult to interpret the results from epidemiological trials that are most often biased and retrospectively analysed. Epidemiological reports frequently include all women regardless of menopausal status. Moreover, effects of exogenous hormones are not the main hypothesis examined. Another weakness of those studies is the lack of detailed information on when in time the patients had taken hormones and what types of compounds they had used.
Epidemiological background, including female predominance in meningiomas incidence, suggested that growth of meningiomas is hormone dependent. However, it is obvious that further studies remain necessary. It has been demonstrated that most of meningiomas express hormone receptors on their cell membranes, although to a variable extent Marosi et al. Besides, intensity of immunoreaction was stronger in grade I than in grade II tumours Omulecka et al.
In the past two decades, the relationship between sexual hormone receptors and meningiomas has been the subject of several studies Markwalder et al. In opposite, loss of this expression would be accompanied by a more aggressive tumoral behaviour. A lack of receptors or the presence of ER correlates with an accumulation of qualitative and quantitative karyotype abnormalities, a higher proportional involvement of chromosomes 14 and 22 in de novo tumours and an increasing potential for aggressive clinical behaviour, progression and recurrence of meningiomas Pravdenkowa et al.
These results seem to be consistent with those from a long-term prospective analysis of 62 meningiomas in 53 patients. Besides, Ki is an important predictive tool of meningioma natural history Bruna et al.
However, recent results from a retrospective analysis of 55 patients with benign meningiomas could not demonstrate a correlation between PGR expression and patterns of recurrence after seemingly complete removal Mairui et al. Authors assessed the expression of PGR and the proliferation marker mindbomb homolog 1 MIB-1 in the primary tumours of 30 cases of benign, completely resected, recurrent meningiomas, when compared with 63 cases of meningiomas without recurrence for 14 or more years Strik et al.
They concluded to significantly higher risk for recurrence odds ratio 3. These findings support previous studies and demonstrate an association between low expression of PGR and higher risk of recurrence. In a recent retrospective study of 31 patients with meningioma undergoing neurosurgical resection, PGR and ER were measured via immunohistochemistry and then compared with gene expression profiling results.
After examination of gene expression for meningioma cases by hormone receptor status, Claus et al. In opposite, the ER status was not relevant Maiuri et al.
Although the role of sexual steroid hormones in genesis of meningiomas is yet not clarified, there is growing evidence that progesterone may at least contribute to the growth of PGR-positive meningiomas Marosi et al. This suggests that PGR status may be a clinical marker for genetic subgroups of meningioma and warrant further examination.
Almost all studies frequently included meningiomas with different resection grades, histological subtypes and a substantial number of atypical meningiomas. Sexual hormone receptor status should routinely be studied for its prognostic value especially in female patients and should be taken into account in tumour grading. Besides, the initial receptor status of a tumour may change in the progression or recurrence of tumour, thus have some prognostic and therapeutic implications.
Moreover, there has been a long-standing debate in the literature as to whether the PGR that are present in meningiomas are functional. Abnormally spliced forms of ER have been reported in human meningiomas, which do not bind the ligand, but may constitutively induce PGR expression. However, it was suggested that promegestone R , a progesterone agonist, would increase transcription only in meningioma cell cultures that express the PGR, supporting the concept that progestins may play a role in meningioma growth Carroll et al.
It remains to be elucidated whether these transcripts are or will be translated to a biologically active protein. These considerations may explain why the breast cancer drugs do not affect meningioma growth in a desirable way.
No association between PGR status or proliferation LI and variables such as tumour location, first-time resection versus reoperation, and histological subtype has been reported in the literature so far.
However, significantly higher MIB-1 indices have been found in recurrent than primary meningioma Wolfsberger et al. As these patients represent the best candidates for adjuvant hormonal therapy, further assessment of these potential changes remains necessary. Epidemiological and immunohistochemical data have led to some attempts of treatment with anti-hormonal therapies for patients with PGR-positive meningioma Strik et al.
After repeated surgery and radiotherapy, the number of patients affected by recurrent, progressive and symptomatic meningiomas is small. However, these patients with poor prognosis represent a major therapeutic challenge. Few data are available on benefit of hormonotherapy in unresectable meningioma on progression.
Supported by promising results in breast cancer treatment, new chemotherapeutic approaches based on hormone manipulation were tested in patients with meningioma, making long-term anti-progestational therapy a logical treatment strategy Grunberg Postoperative radiation is currently used in cases of incomplete resection or tumour progression.
For that reason, reports that assessed the role of endocrine therapy in meningioma management included patients with progressive disease after either postoperative radiotherapy or primary radiotherapy. Mifepristone RU is an oral anti-progestational commonly used in adjuvant strategy or metastatic treatment of ER-positive breast cancer with a significant benefit in global survival. Mifepristone inhibits the transcriptional activity of PGR by complex mechanisms at concentration much lower than progestins Edwards et al.
The use of progesterone antagonists in the palliation of meningioma has been discussed repeatedly for more than 10 years Markwalder et al. These data were the first to suggest that selected meningiomas are subject to hormonal influence in vitro and encouraged further development of alternative modes of therapy for recurrent and unresectable meningiomas Olson et al.
Later, the effect of medroxyprogesterone acetate MPA on growth fractions of ex vivo meningiomas was demonstrated in using the Ki monoclonal antibody Markwalder et al.
Growth fractions in samples from five meningioma patients not treated with MPA were determined for comparison. The percentage of Kipositive cells in meningioma tissue was lower by a factor of 6, 5 and 3 respectively, after MPA therapy. In meningioma specimens from patients receiving no MPA therapy, Kipositive cells were present in 1. Authors concluded that MPA reduced the growth fractions of most meningiomas and would be suitable for adjuvant hormonotherapy.
However, further reports were more disappointing. Most patients initially had complaints such as nausea, vomiting and asthenia. In four patients, prednisone 7. Mifepristone treatment resulted in control of tumour growth in six out of ten patients with recent evidence of tumour growth.