Reproductive epidemiology of glial tumors may reveal novel treatments: high-dose progestins or progesterone antagonists as endocrino-immune modifiers against glioma

Abstract

Female gender, contraceptives, and menopausal hormone replacement treatments containing progesterone analogues associate with higher risk of meningiomas yet with lower risk of gliomas. Progesterone receptor (PR) expression and mifepristone treatment was highly discussed for meningiomas. However, much less is known in regard to progesterone actions in gliomas despite PR expression strongly correlates with their grade. Meningiomas and gliomas may grow faster during gestation; but paradoxically, parousity reduces lifetime risk of gliomas which can be explained with dichotomous cell growth-stimulating and inhibitory actions of progesterone at low versus high levels. Progesterone levels gradually increase in gestation up to 200-fold and the incidence of highly angiogenic brain tumors decreases in the last trimester. Indeed, progesterone stimulates glial tumor cell growth at low doses (10 nM) while induces cell kill at higher doses. During gestation, some immune pathways are activated to protect the mother and the fetus against microbial pathogens. In parallel, high-dose medroxyprogesterone acetate (MPA) used in treatment of endometrial carcinoma decreases tumoral expression of PR-B and increases infiltration of cytotoxic T lymphocytes and natural killer cells. MPA also synergies with IL-2 in clinical treatment of renal cancer. In both glioma and meningioma, the dominant cytosolic PR is PR-B which increases cell growth, while PR-A limits cell growth. This seems also paradoxical at the first glance due to opposite behavior of these tumors in diverse endocrine conditions. High-dose progestins may inhibit brain tumor growth by downregulating PR-B, yet the dosage thresholds may differ between glial and meningeal tumors due to higher total PR expression in meningiomas. Supporting this proposal, certain progestins were reported to stimulate meningioma growth in anecdotal reports, but same agents at much higher doses reduced meningioma cell proliferation in pilot clinical studies. PR antagonist mifepristone reduced meningioma growth in some clinical studies, but lacked efficacy in others. In fact, mifepristone also has partial PR agonist efficacy and acts in synergy with MPA to block EC growth. Hence, a similar mechanism of receptor downregulation may also account for mifepristone. Both MPA and mifepristone also harbor myeloprotective features against chemotherapy. Ulipristal is another contraceptive PR antagonist and exerts promising anticancer activity on drug-resistant ovarian cancer and BRCA1-mutant breast cancer cells, which can be tested in animal glioblastoma models. We propose that progestins strongly deserve to be investigated in experimental models of glioblastoma alone and in combination with immunostimulating agents.

Inference of Subpathway Activity Profiles Reveals Metabolism Abnormal Subpathway Regions in Glioblastoma Multiforme

“…No related studies have shown that it is related to the occurrence and development of GBM. However, previous research has established that downstream cholesterol and sterol hormones regulated by 00100_6 will affect the progression of GBM ( 35 , 55 – 58 ). In addition, vitamin D metabolism is directly regulated by calcidiol 1-monooxygenase ( CYP27B1 ) and vitamin D 1,25-hydroxylase ( CYP105A1 ) downstream of the metabolic subpathway 00100_6, and studies have shown that the level of 25-hydroxyvitamin D (25(OH)D) in the serum of intermediates of vitamin D metabolism is opposite to that of patients with GBM-specific subtypes ( 59 ).…”

Progesterone at high doses reduces the growth of U87 and A172 glioblastoma cells: Proteomic changes regarding metabolism and immunity

“…2 Even though pregnancy may accelerate GBM growth, parity lowers the lifelong risk of GBM, which may associate with the fact that high dose and prolonged exposure to P4 may eliminate cells leading to GBM growth. 2 Based on fine structural features, P4 is proposed to induce an oligodendroglial differentiation shift in GBM cells. 7 Despite the P4 receptor is a steroid receptor that has the highest correlation with glial tumor grade 2,15 ; there exist surprisingly few studies which assessed the effects of P4 on the biological behavior of GBMs.…”

“…Despite some controversies, many available studies demonstrate that female gender, parity, and hormone replacement treatment reduce the risk of GBMs, while the reverse is true for meningiomas. 1,2 In pregnancy, the levels of progesterone (P4) gradually increase up to 200-fold to around 160 µM. Even though pregnancy may accelerate the growth of gliomas, the most angiogenic brain tumors are encountered lesser during the last trimester when the natural 17-OH-progesterone levels reach peak levels.…”

Antiproliferative effect of mifepristone (RU486) on human neuroblastoma cells (SK-N-SH): in vitro and in vivo studies

“…Tumor fragments were implanted at day 1 and tumor growth was monitored for each experimental group at the time indicated by measuring the average tumor diameter (two perpendicular axes of the tumor were measured by a Vernier caliper). The volume of the tumor is reported in mm 3 according to the formula 4/3pr 3 .…”

“…The presence of hormone receptors in neoplastic cells, which can interfere with cell growth, opens new perspectives in the control of tumors (2). Thus, hormones such as progesterone and cortisol have been reported to influence cell growth in various types of tumors (3,4). For instance, it has been reported that high doses of natural progesterone inhibit the growth of human neuroblastoma cells (SK-N-AS) both in vitro and in vivo by suppression of cell proliferation and induction of apoptosis (4).…”