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Type: Thesis
Title: Sex Hormone-Binding Globulin: Regulation and Role as a Marker of Chronic Disease Risk
Author: Gyawali, Prabin
Issue Date: 2019
School/Discipline: Adelaide Medical School
Abstract: Sex hormone-binding globulin (SHBG) is dimeric glycoprotein synthesised in hepatocytes and secreted into the circulation. SHBG binds sex-steroids and protects them from rapid degradation. SHBG is involved in the regulation of de novo lipogenesis in the liver. The synthesis and secretion of SHBG from the liver are regulated by hormonal, metabolic, nutritional, and genetic factors. There is increasing interest in SHBG because it is a determinant of total testosterone (TT) concentration, and maybe a marker of cardiometabolic disease risk. There are little data available from population-based studies on the determinants of serum SHBG. Furthermore, there is evidence for and against SHBG as a marker of risk for incident type 2 diabetes (T2D) and cardiovascular disease (CVD). SHBG is also expressed in, but not secreted from the prostate. However, as in the liver, it modulates and may also be associated with lipid metabolism. Prostate cancer (PCa) is both androgen-dependent and dependent on fatty acids as an energy supply. I, therefore, hypothesised that 1) SHBG of hepatic origin may be a marked of dysregulated lipid metabolism and associated with cardiometabolic disease risk, and 2) the expression of SHBG in the prostate will be a marker of aggressive PCa and androgen ablation. The studies that comprise this thesis aimed: 1. To determine, in a longitudinal cohort of community-dwelling men, 1.1. the cross-sectional and longitudinal determinants of circulating SHBG levels; 1.2. the associations of serum SHBG & sex steroids with incident T2D; 1.3. the associations of serum SHBG & sex steroids with incident CVD and CVD-related mortality. 2. To test the hypothesis that SHBG expression in the prostate increased in PCa by determining the nature of the SHBG transcripts expressed and mRNA expression, together with SHBG protein, in normal, benign, and malignant prostate. These studies have shown that: 1. We found that, 1.1. Serum SHBG levels have a positive relationship with aging, thyroxine, and TT, and an inverse relationship with abdominal total fat mass, triglycerides, and oestradiol. My work has suggested that variation in serum SHBG reflects de novo lipogenesis within the liver that occurs in the context of insulin resistance. 1.2. Low TT, not SHBG and other sex steroids, is independently associated with an increased risk of T2D development over a 5-year follow-up period. 1.3. High SHBG and low TT, are independently associated with an increased risk of incident CVD, but not with increased risk of CVD related mortality. 2. SHBG mRNA and protein are increased in PCa at all stages compared with normal and with benign prostatic hyperplasia (BPH). Multiple SHBG transcripts of variable length were identified in the prostate. The dominant transcript varied between PCa cases and in response to androgen receptor antagonists. Taken together, these data suggest that SHBG levels reflect the metabolic state in particular glucose, lipid and sex steroids metabolism and SHBG is a marker for incident CVD but not T2D. SHBG expression and transcript size may be markers for the aggressive behaviour of PCa and resistance to androgen ablation, deserves further attention in PCa studies.
Advisor: Wittert, Gary A.
Heilbronn, Leonie K.
Martin, Sean A.
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2019
Keywords: Sex hormone-binding globulin
men's health
type 2 diabetes
cardiovascular disease
prostate cancer
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