Doctoral Degrees (Physiological Sciences)

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Browsing Doctoral Degrees (Physiological Sciences) by Subject "Androgens"

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    The role of DHEA in the aetiology of modern chronic disease
    (Stellenbosch : Stellenbosch University, 2020-04) Powrie, Yigael Samuel Louis; Smith, Carine; Swart, Amanda C.; Stellenbosch University. Faculty of Science. Dept. of Physiological Sciences.
    ENGLISH ABSTRACT: Dehydroepiandrosterone (DHEA) is an androgenic steroid predominantly viewed as the main precursor to androgen and estrogen hormones in the human body. DHEA exists as a sulphated ester known as DHEAS, which is also the most predominant steroid hormone in human circulation. A decline in circulating DHEA concentrations is associated with age, inflammatory disease, as well as neurodegenerative pathologies. It has numerous demonstrated neuroprotective, anti-inflammatory and anti-glucocorticoid effects. The human adrenal glands and gonads are the main sites for DHEA biosynthesis in the periphery, but historical evidence has suggested that central steroid biosynthesis, termed neurosteroidogenesis, is responsible for the presence of DHEA in the brain. The process of neurosteroidogenesis has to date proven to be an elusive process, as only a handful of relatively dated studies have provided evidence for its existence. Furthermore, clear differences are apparent in systemic rodent steroidogenesis and human steroidogenesis, the latter of which most the evidence of neurosteroidogenesis is formulated upon. In order to exploit the numerous reported beneficial effects of DHEA in the brain, it is pertinent that we understand how it is synthesised, how it may exert its effects centrally and whether species differences will affect the function thereof. Utilising the sensitivity and specificity of Ultra-Performance Convergence Chromatography (UPC2)-tandem mass spectrometry we comprehensively assessed the ability of primary human astrocytes (pHAs) and primary rat brain ex vivo mixed cell cultures (pRBMCs) to synthesise DHEA from a known substrate, pregnenolone, in the presence or absence of steroidogenic modulators. Additionally, we also sought to elucidate the ability of the cells to metabolise DHEA, in either the presence or absence of steroidogenic modulators. Both pHAs and pRBMCs were unable to synthesise DHEA from pregnenolone as the substrate in the absence or presence of steroidogenic modulators. pHAs and pRBMCs were able to convert pregnenolone in progesterone, demonstrating 3β-HSD activity. Additionally, although both cell populations were unable to demonstrate DHEA biosynthesis, they were able to convert exogenous DHEA into androstenedione and androstenediol, demonstrating not only 3β-HSD, but17β-HSD activity as well. This is the first study demonstrating androstendiol biosynthesis by human glial cells. The inability of pHAs and pRBMCs to synthesise DHEA from pregnenolone as a substrate contradicts available literature. The metabolism of exogenous DHEA into downstream metabolites suggests that the numerous beneficial effects of DHEA are not due to the steroids itself, but rather its metabolites. This current characterisation of DHEA metabolism both questions our current understanding of DHEA biosynthesis in the brain and holds promise for new therapeutic development in modern chronic disease and specifically neurodegeneration.