Sex Hormone Binding Globulin (SHBG) is the major serum carrier of sex hormones. However, growing evidence suggests that SHBG is internalised and plays a role in regulating intracellular hormone action. This study was to determine whether SHBG plays a role in testosterone uptake, metabolism, and action in the androgen sensitive LNCaP prostate cancer cell line. Internalisation of SHBG and testosterone, the effects of SHBG on testosterone uptake, metabolism, regulation of androgen responsive genes, and cell growth were assessed. LNCaP cells internalised SHBG by a testosterone independent process. Testosterone was rapidly taken up and effluxed as testosterone-glucuronide; however this effect was reduced by the presence of SHBG. Addition of SHBG, rather than reducing testosterone bioavailability, further increased testosterone-induced expression of prostate specific antigen and enhanced testosterone-induced reduction of androgen receptor mRNA expression. Following 38 hours of testosterone treatment cell morphology changed and growth declined; however, cotreatment with SHBG abrogated these inhibitory effects. These findings clearly demonstrate that internalised SHBG plays an important regulatory and intracellular role in modifying testosterone action and this has important implications for the role of SHBG in health and disease.

Hormonal manipulation plays a significant role in the treatment of advanced hormone naïve prostate cancer and castration-resistant prostate cancer (CRPC) with or without previous chemotherapy. Combination of gonadotropin releasing hormone (GnRH) agonists and androgen receptor (AR) antagonists (combined androgen blockade; CAB) is the first line therapy for advanced hormone naïve prostate cancer, but current strategies are developing novel GnRH antagonists to overcome disadvantages associated with GnRH agonist monotherapy and CAB in the clinical setting. Abiraterone acetate and enzalutamide are hormonal agents currently available for patients with CRPC and are both shown to improve overall survival versus placebo. Recently, in clinical trials, testosterone has been administered in cycles with existing surgical and chemical androgen deprivation therapies (ADT) (intermittent therapy) to CRPC patients of different stages (low risk, metastatic) to abate symptoms of testosterone deficiency and reduce cost of treatment from current hormonal therapies for patients with CRPC. This review will provide an overview on the therapeutic roles of hormonal manipulation in advanced hormone naïve and castration-resistant prostate cancers, as well as the development of novel hormonal therapies currently in preclinical and clinical trials.