**5.1. Estrogen receptors**

GBM exhibits different endocrine characteristics. GBM expresses high levels of estrogen receptor alpha (mRNA ER*α*) and low levels of estrogen receptor beta (ERß); expression of mRNA ER*α* is positively correlated to the survival of GBM patients and could be used as a prognostic factor [26]. In contrast, the low expression of ERß in GBM has been related to a worse prognosis for survival and could be used as a biomarker for prognosis too [27,28]. Furthermore, activation of the signaling pathways induced by ER*β* suppresses glioma growth in a model in vivo [29].

The coactivator family of estrogen receptors (SRC) is composed of three members, SRC‐1, SRC‐ 2, and SRC‐3 [30,31]. SRC‐1 increases the transcriptional activity of ER [32,33]; it also partici‐ pates in the tumor progression and survival of several lines of human cancer [34,35]. SRC‐2 is localized in different regions of the brain and mediates a variety of steroids‐dependent functions [36,37]. SRC‐3 is overexpressed in different types of cancer (breast, ovary, prostate, stomach, endometrium, esophagus, and pancreas) [38,39,40,41]. In astrocytoma cell lines, SRC1 and SRC‐3 have been detected [42]. 17‐*/i>* estradiol induces the growth of several cell lines of human astrocytoma through the ER*α*, and its interaction with SRC‐1 and SRC3 suggests that ER*α* has an important role in the growth of astrocytoma [43].

#### **5.2. Progesterone receptors in GBM**

Progesterone receptors (PRs) are expressed in 100% of high‐grade astrocytomas. The predominant isoform expression of PR in GBM is PRB. In astrocytomas, the molecular mechanisms involved in the differential expression of PR isoforms are unknown. It is important to know what PR isoform is expressed in the brain tumor, because progesterone can exert different cell functions depending on the expression pattern of PR isoforms [44,45]. In several cell contexts, human PRB functions as a transcriptional activator of progesterone‐ responsive genes, whereas PRA acts a repressor of transcriptional steroid hormone receptors inclusive PRB [46]; PR expression assessed by immunohistochemistry directly correlates with the histological grades of astrocytomas; these results suggest that PR‐positive tumors possess a high proliferative potential [47]. However, no conclusive data exists about the PR as a marker of prognosis.

Progesterone significantly decreases GBM tumor growth and promotes the survival time in approximately 60% of mice. Synergistic effects of progesterone and Temozolomide (TMZ) have been observed in the glioblastoma cell lines U87MG and U118MG. A significant decrease in PCNA (a marker of cell proliferation) expression in both U87MG and U118 cell lines was observed by the effect of progesterone alone (80 μM) or by the combination of 80 μM progesterone and 100 μM TMZ, when compared to control, and this has a significantly statistic outcome than that with TMZ alone. Cell survival was reduced in 58%, with the combined treatment of progesterone and TMZ (P 80 μM + TMZ 100 μM after) when compared to that with MTZ alone. Further, progesterone inhibited O‐6‐methylguanine‐ DNA‐methyltransferase (MGMT) expression as well as the EGFR/PI3K/AkT/mTOR signaling pathway, which is highly active in GBM. Progesterone + TMZ also inhibited the cell migration, suggesting that the combination therapy could contain the spread of tumor in vivo [48].

#### **5.3. Androgen receptor in GBM**

The androgen receptor (AR) is present in astrocytomas of low and high grades, with a higher expression in AA compared to astrocytomas grade I, II, and GBM. AR expression no affect the survival time of GBM patients [49,50] described a higher expression of AR in GBM tumors in women and men compared to periphery normal brain tissue.

#### **5.4. Aromatase**

genetic alterations at the population level were similar to those reported in Europe. This study noted a positive association between *EGFR* amplification and *p16 INK4a* deletion.

GBM is the most aggressive form of malignant glioma. Several syndromes are associated with the increased incidence of GBM, such as Lynch syndrome, Li–Fraumeni syndrome, melano‐ ma–neural system tumor syndrome, Ollier disease, and Maffucci syndrome [16]. A small proportion (5–10%) of patients has a family history of glioma. Genes too exist that are involved in gliomagenesis and participate in glioma growth, such as telomerase reverse transcriptase (TERT) [17], *EGFR* [18,19], coiled‐coil domain containing protein 26 (*CCDC26*) [20],Cyclin‐ dependent Kinase inhibitor 2B [17], *TP53* [21,22,23], and the regulator of telomere elongation

GBM exhibits different endocrine characteristics. GBM expresses high levels of estrogen receptor alpha (mRNA ER*α*) and low levels of estrogen receptor beta (ERß); expression of mRNA ER*α* is positively correlated to the survival of GBM patients and could be used as a prognostic factor [26]. In contrast, the low expression of ERß in GBM has been related to a worse prognosis for survival and could be used as a biomarker for prognosis too [27,28]. Furthermore, activation of the signaling pathways induced by ER*β* suppresses glioma growth

The coactivator family of estrogen receptors (SRC) is composed of three members, SRC‐1, SRC‐ 2, and SRC‐3 [30,31]. SRC‐1 increases the transcriptional activity of ER [32,33]; it also partici‐ pates in the tumor progression and survival of several lines of human cancer [34,35]. SRC‐2 is localized in different regions of the brain and mediates a variety of steroids‐dependent functions [36,37]. SRC‐3 is overexpressed in different types of cancer (breast, ovary, prostate, stomach, endometrium, esophagus, and pancreas) [38,39,40,41]. In astrocytoma cell lines, SRC1 and SRC‐3 have been detected [42]. 17‐*/i>* estradiol induces the growth of several cell lines of human astrocytoma through the ER*α*, and its interaction with SRC‐1 and SRC3 suggests

Progesterone receptors (PRs) are expressed in 100% of high‐grade astrocytomas. The predominant isoform expression of PR in GBM is PRB. In astrocytomas, the molecular mechanisms involved in the differential expression of PR isoforms are unknown. It is important to know what PR isoform is expressed in the brain tumor, because progesterone can exert different cell functions depending on the expression pattern of PR isoforms [44,45].

that ER*α* has an important role in the growth of astrocytoma [43].

**4. Glioblastoma multiforme risk factors**

**5. Endocrine characteristics of GBM**

helicase 1 (*RTEL1*) [24,25].

70 Neurooncology - Newer Developments

**5.1. Estrogen receptors**

in a model in vivo [29].

**5.2. Progesterone receptors in GBM**

Aromatase is an enzyme encoded by *CYP19* gene localized in chromosome 15q 21.2. It converts androgens in estrogens; this enzyme is expressed mainly in ovary, testis, placenta, brain, lung, stomach, and adipose tissue [51]. Aromatase is composed of 503 amino acids and is the major source for estrogen production in postmenopausal women. The aromatase works in three steps; first, the C19 methyl group of androgenic substrate is oxidized to formic acid in concomitant aromatization of ring A to the characteristic phenolic ring A of estrogen [52].

Aromatase expression in GBM tumor is negatively correlated to the survival of GBM patients and has been proposed as a possible prognosis biomarker for astrocytomas [29].

17–ß estradiol levels in GBM tumor are highest, compared to low‐grade astrocytomas (I, II) or astrocytoma anaplastic (grade III). The concentration of 17–ß estradiol in GBM seems to be directly involved in the tumor growth.
