11-Ketotestosterone and 11-Ketodihydrotestosterone in Castration Resistant Prostate Cancer: Potent Androgens Which Can No Longer Be Ignored

Abstract

Dihydrotestosterone (DHT) is regarded as the most potent natural androgen and is implicated in the development and progression of castration resistant prostate cancer (CRPC). Under castrate conditions, DHT is produced from the metabolism of the adrenal androgen precursors, DHEA and androstenedione. Recent studies have shown that the adrenal steroid 11β-hydroxyandrostenedione (11OHA4) serves as the precursor to the androgens 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT). In this study we comprehensively assess the androgenic activity of 11KT and 11KDHT. This is the first study, to our knowledge, to show that 11KT and 11KDHT, like T and DHT, are potent and efficacious agonists of the human androgen receptor (AR) and induced both the expression of representative AR-regulated genes as well as cellular proliferation in the androgen dependent prostate cancer cell lines, LNCaP and VCaP. Proteomic analysis revealed that 11KDHT regulated the expression of more AR-regulated proteins than DHT in VCaP cells, while in vitro conversion assays showed that 11KT and 11KDHT are metabolized at a significantly lower rate in both LNCaP and VCaP cells when compared to T and DHT, respectively. Our findings show that 11KT and 11KDHT are bona fide androgens capable of inducing androgen-dependant gene expression and cell growth, and that these steroids have the potential to remain active longer than T and DHT due to the decreased rate at which they are metabolised. Collectively, our data demonstrates that 11KT and 11KDHT likely play a vital, but overlooked, role in the development and progression of CRPC.

A systematic review of randomized controlled trials investigating the efficacy and safety of testosterone therapy for female sexual dysfunction in postmenopausal women

“…Both 11 KT and 11KDHT are potent agonists of the human androgen receptor (AR). Studies are required to investigate whether levels of 11 KT and 11KDHT are significantly related to sexual function in women during menopause transition …”

Monogenic Disorders of Adrenal Steroidogenesis

“…Further conversion via 11-keto-androstenedione generates 11-keto-testosterone (11-keto-T) and further downstream 11-keto-dihydrotestosterone (11-keto-DHT) [34, 39]. Importantly, the in vitro androgen receptor-transactivating activity of 11-keto-T and 11-keto-DHT is similar to that of testosterone and DHT [32, 39-41]. The implications of this additional androgen class are wide-ranging: recent studies have shown that they play a key role in androgen excess states, representing the majority of circulating androgens in polycystic ovary syndrome [42].…”

Clinical significance of 11-oxygenated androgens

“…Steroids can be inactivated via 3α-hydroxysteroid dehydrogenases (3αHSD), and/or by conjugation, such as the sulfation or glucuronidation reactions carried out by sulfotrasferase and uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes, respectively. In an in vitro model provided by two androgen-dependent prostate cancer cell lines (LNCaP and VCaP), 11KT and 11KDHT were metabolized to inactive products significantly more slowly than T and DHT, respectively [39]. Furthermore, du Toit and colleagues showed that while most T was conjugated to T-glucuronide by 48 h in the LNCaP cells, 11KT and 11KDHT were only poorly glucuronidated [37].…”

“…These findings suggest that intracellular 11KT and 11KDHT remain available to activate AR longer than T and DHT. Indeed, using the same cell lines, Pretorius and colleagues showed that 11KT and 11DHT activate the expression of endogenous AR-regulated genes ( KLK3 , TMPRSS2 and FKBP5 ) and induced cellular proliferation [39]. …”