Volume 8, Issue 1

Over the past 60 years, androgen deprivation therapy has been the mainstay of treatment of metastatic prostate cancer. However, research findings suggest that androgen deprivation therapy inflicts serious adverse effects on overall health and reduces the quality of life. Among the adverse effects known to date are insulin resistance, diabetes, metabolic syndrome fatigue, erectile dysfunction, and cardiovascular disease. In this clinical perspective, we discuss the relationship between induced androgen deficiency and a host of pathologies in the course of treatment with androgen deprivation therapy for prostate cancer patients.

Among the major physiological functions of steroid hormones is regulation of carbohydrate, fat, and protein metabolism. Mitochondria, through oxidative phosphorylation, play a critical role in modulating a host of complex cellular metabolic pathways to produce chemical energy to meet the metabolic demand for cellular function. Thus, androgens may regulate cellular metabolism and energy production by increased mitochondrial numbers, activation of respiratory chain components, and increased transcription of mitochondrial-encoded respiratory chain genes that code for enzymes responsible for oxidative phosphorylation. Androgen deficiency is associated with increased insulin resistance, type 2 diabetes (T2DM), metabolic syndrome, obesity, and increased overall mortality. One common link among all these pathologies is mitochondrial dysfunction. Contemporary evidence exists suggesting that testosterone deficiency (TD) contributes to mitochondrial dysfunction, including structural alterations and reduced expression and activities of metabolic enzymes. Here, we postulate that TD contributes to symptoms of fatigue, insulin resistance, T2DM, cardiovascular risk, and metabolic syndrome through a common mechanism involving impairment of mitochondrial function.

Steroid sulfonation in the human brain has not been well characterized. The major sulfotransferase (SULT) isoforms that conjugate steroids in humans are SULT1E1, SULT2A1, and SULT2B1b. SULT2B1b catalyzes the sulfonation of 3β-hydroxysteroids, including neurosteroids dehydroepiandrosterone and pregnenolone, as well as cholesterol and several hydroxycholesterols. SULT2B1b mRNA and protein expression were detected in adult and fetal human brain sections, whereas neither mRNA, nor protein expression were identified for SULT1E1 or SULT2A1. Using immunohistochemical analysis, SULT2B1b expression was detected in neurons and oligodendrocytes in adult brain and in epithelial tissues in 28-week-old fetal brain. Sulfonation of cholesterol, oxysterols, and neurosteroids in the brain is apparently catalyzed by SULT2B1b since expression of neither SULT2A1 nor SULT1E1 was detected in human brain sections. SULT2B1b mRNA and protein were also detected in human U373-MG glioblastoma cells. Both mRNA and protein expression of liver X receptor (LXR)-β, but not LXR-α, were detected in U373-MG cells, and LXR-β activation resulted in a decrease in SULT2B1b protein expression. Since hydroxycholesterols are important physiological LXR activators, this suggests a role for regulation of sterol metabolism by LXR and SULT2B1b. Therefore, elucidating key enzymes in the metabolism of cholesterol and neuro­steroids could help define the properties of steroid conjugation in the human brain.