Impact of sex in the prevalence and progression of glioblastomas: the role of gonadal steroid hormones

Abstract

Background: As in other types of cancers, sex is an essential factor in the origin and progression of glioblastomas. Research in the field of endocrinology and cancer suggests that gonadal steroid hormones play an important role in the progression and prevalence of glioblastomas. In the present review, we aim to discuss the actions and mechanism triggered by gonadal steroid hormones in glioblastomas.

Main body: Glioblastoma is the most common malignant primary brain tumor. According to the epidemiological data, glioblastomas are more frequent in men than in women in a 1.6/1 proportion both in children and adults. This evidence, and the knowledge about sex influence over the prevalence of countless diseases, suggest that male gonadal steroid hormones, such as testosterone, promote glioblastomas growth. In contrast, a protective role of female gonadal steroid hormones (estradiol and progesterone) against glioblastomas has been questioned. Several pieces of evidence demonstrate a variety of effects induced by female and male gonadal steroid hormones in glioblastomas. Several studies indicate that pregnancy, a physiological state with the highest progesterone and estradiol levels, accelerates the progression of low-grade astrocytomas to glioblastomas and increases the symptoms associated with these tumors. In vitro studies have demonstrated that progesterone has a dual role in glioblastoma cells: physiological concentrations promote cell proliferation, migration, and invasion while very high doses (out physiological range) reduce cell proliferation and increases cell death.

Conclusion: Gonadal steroid hormones can stimulate the progression of glioblastomas through the increase in proliferation, migration, and invasion. However, the effects mentioned above depend on the concentrations of these hormones and the receptor involved in hormone actions. Estradiol and progesterone can exert promoter or protective effects while the role of testosterone has been always associated to glioblastomas progression.

Keywords: Estradiol; Glioblastoma; Prevalence; Progesterone; Progression; Sex differences; Testosterone.

Fig. 1

Influence of E2, P4, and T in the prevalence and progression of glioblastoma. Women and men synthesize E2, P4, and T from cholesterol, in the reproductive system, adrenal gland, and brain. Gonadal steroid hormones can also reach the brain by crossing the blood-brain barrier. The evidence accumulated to date suggests that E2, P4, and T from both sources have an important role in glioblastoma progression. However, the significance of E2, P4, and T in the 1.6 males:females prevalence of glioblastoma has not been completely determined. Results obtained nowadays suggest that the role of these hormones in glioblastomas depends on the concentration of hormones and the availability of the isoforms or subtypes of their receptors

Fig. 2

Molecular mechanisms of E2, P4, and T action in glioblastoma cells. Once in glioblastoma cells, E2, P4, and T can activate intracellular o membrane receptors, and according to the cellular context, different effects will be triggered. Effects induced by E2 are mainly mediated by the ERα/ERβ ratio. In a context with an ERα prevalence, E2 is associated with glioblastoma progression through enhancing proliferation, EMT, migration, and invasion, while ERβ prevalence is associated with cell death. In the case of P4 and its metabolites, a dual behavior is associated with the concentration of the former. Low levels of P4 induce an increase in proliferation, migration, and invasion while high levels induce processes related to cell death. P4 exerts its action through the PR or mPRs. The effects of T and its metabolites have been always associated with events that promote the progression of glioblastomas