Canonical and Noncanonical Androgen Metabolism and Activity

Statins and prostate cancer—hype or hope? The epidemiological perspective

“…As such, it has been hypothesised that statins may synergise with ADT by blocking accumulation of intratumoral cholesterol thereby reducing the substrate for de novo androgen synthesis within the prostate [57]. Given that more advanced tumours upregulate enzymes necessary for de novo androgen synthesis [58][59][60], it may be that statins have a stronger effect in later-stage tumours, enriched in the context of salvage ADT. Indeed, inverse associations reported by the various observational studies completed to date (Table 1) appear slightly stronger among patients receiving salvage ADT, typically administrated later during the disease course compared to primary ADT.…”

Statins and adrenal androgen levels in prostate cancer: A new twist

“…However, a potential impact of statins on de novo intratumoural steroid synthesis is unlikely in primary prostate tumours or in a substantial subset of castration resistant PCa (CRPC) tumours, in which the key enzymes required for de novo androgen synthesis (e.g. CYP11A and CYP17A) are not simultaneously expressed [3]. In contrast, primary and metastatic CRPC tumours largely express the more limited number of downstream enzymes (e.g.…”

“…AKR1C3, SRD5A1 or 2) required for conversion of circulating adrenal androgens to active metabolites. In these tumours, any impact of statin therapy on intratumoural androgens is more likely to occur via a decrease in the circulating pool of testicular and/or adrenal androgens available for uptake and conversion [3,4]. In this regard, it is notable that statins might even more directly decrease androgen levels via inhibition of testicular 17-ketosteroid-oxidreductase activity, a primary enzymatic function of AKR1C3 [5].…”

“…This casts significant doubt as to whether a 4% or 0.66 nmol/L change in serum T associated with statin use could have a meaningful impact on prostate androgen exposure such as that invoked in a primary prevention setting [9]. Likewise, in castrate patients, an impact of statins on testicular androgens is unlikely to be meaningful in context of the 95% suppression of serum T and 75% suppression of prostate tissue T already achieved by ADT [3]. These observations suggest a statin mediated effect on serum T levels, whether sufficient to impact other endpoints such as erectile function not-withstanding, is unlikely to have a meaningful impact on prostate tumour androgens in either the eugonadal or castrate setting.…”

“…While requiring confirmation, these data suggest for the first time that statins may indeed modify the intratumour androgen pool, but not by limiting T and DHT. 11 hydroxy AED (11OHAED) is an abundant product of the adrenal gland that undergoes peripheral conversion to 11KAED, 11-Keto T (11KT) and 11-OH T (11OHT) [3]. While 11OHAED and 11KAED are not active at the androgen receptor (AR), recent studies demonstrate that their immediate metabolites 11OHT and 11KT (generated by the activity of AKR1C3) activate wild type AR with potency that is 50% and 100% of T, respectively.…”