Testicular vs adrenal sources of hydroxy-androgens in prostate cancer

Abstract

Neoadjuvant androgen deprivation therapy (NADT) is one strategy for the treatment of early-stage prostate cancer; however, the long-term outcomes of NADT with radical prostatectomy including biochemical failure-free survival are not promising. One proposed mechanism is incomplete androgen ablation. In this study, we aimed to evaluate the efficiency of serum hydroxy-androgen suppression in patients with localized high-risk prostate cancer under NADT (leuprolide acetate plus abiraterone acetate and prednisone) and interrogate the primary sources of circulating hydroxy-androgens using our recently described stable isotope dilution liquid chromatography mass spectrometric method. For the first time, three androgen diols including 5-androstene-3β,17β-diol (5-adiol), 5α-androstane-3α,17β-diol (3α-adiol), 5α-androstane-3β,17β-diol (3β-adiol), the glucuronide or sulfate conjugate of 5-adiol and 3α-adiol were measured and observed to be dramatically reduced after NADT. By comparing patients that took leuprolide acetate alone vs leuprolide acetate plus abiraterone acetate and prednisone, we were able to distinguish the primary sources of these androgens and their conjugates as being of either testicular or adrenal in origin. We find that testosterone, 5α-dihydrotestosterone (DHT), 3α-adiol and 3β-adiol were predominately of testicular origin. By contrast, dehydroepiandrosterone (DHEA), epi-androsterone (epi-AST) and their conjugates, 5-adiol sulfate and glucuronide were predominately of adrenal origin. Our findings also show that NADT failed to completely suppress DHEA-sulfate levels and that two unappreciated sources of intratumoral androgens that were not suppressed by leuprolide acetate alone were 5-adiol-sulfate and epi-AST-sulfate of adrenal origin.

A Comprehensive Analysis of Steroid Hormones and Progression of Localized High-Risk Prostate Cancer

“…3). This observation is of biologic significance, as A5diol, a major metabolite of DHEA in prostate homogenates (31,32) has been shown to have dual actions in cancer cells binding both the androgen and estrogen receptors (33,34). We also observed a trend for an association between A5diol levels and the development of metastatic disease.…”

“…Indeed, large studies are required in men with localized prostate cancer, especially in those at high risk of recurrence, where circulating levels of these hormones might (i) improve prognostication/stratification, (ii) help refine the circulating hormonal milieu associated with adverse clinical outcomes, and (iii) advance hormonal strategies of patients with progressive disease. On the basis of the natural history of prostate cancer progression following biochemical recurrence (41), and knowing that intracellular levels of A5diol and DHEA-S remain at significant levels in patients on androgen-deprivation therapy (32,35,36), the ongoing follow-up of the PROCURE cohort will ultimately allow, in an approximately 5-10-year timeframe horizon, to assess the impact of these hormones on the development of metastasis, castration-resistant disease, and prostate cancer mortality.…”

Racial differences in androgen metabolism and receptor signaling in prostate cancer

“…These data suggest that DHT levels in the serum can be a surrogate indicator of AND levels in the serum of AA men with PrCa. AND can be converted to epiandrosterone that is further sulfated to act as a reserve for DHT production 50 . The median levels of epiandrosterone in the serum were similar between the two racial groups (Table 1).…”

Sex steroids in the tumor microenvironment and prostate cancer progression

“…These results differed from localized prostatectomy tissue, suggesting resistant prostate tumors develop capacities to metabolize steroids, which differs from treatment-naive tumors. Finally, a recent analysis of prostate tissue from men who received neoadjuvant leuprolide acetate ± abiraterone acetate identified that DHEA, epi-androsterone and their metabolites were predominantly of adrenal origin, whereas testosterone, DHT, 3α-adiol and 3β-adiol levels were of testicular origin (Zang et al 2017). This intratumoral androgen synthesis results in persistently higher androgen levels in the prostate: while serum androgens drop by ~95% following ADT, intraprostatic androgens decline by only 70% (Mostaghel et al 2007).…”