Circulating adrenal 11-oxygenated androgens are associated with clinical outcome in endometrial cancer

Abstract

ContextRecent evidence support that androgens play an important role in the etiology of endometrial cancer (EC). Adrenal-derived 11-oxygenated androgens are highly potent agonists of the androgen receptor (AR), comparable to testosterone (T) and dihydrotestosterone (DHT) that have not been studied in the context of EC.MethodologyWe studied a cohort of 272 newly diagnosed postmenopausal EC cases undergoing surgical treatment. Circulating concentrations of seven 11-oxygenated androgens including precursors, potent androgens and their metabolites were established in serum samples collected before and 1 month after surgery using a validated liquid chromatography tandem mass spectrometry method (LC-MS/MS). Free (unconjugated) and total (free + sulfate and glucuronide conjugates following enzymatic hydrolysis) were analyzed in relation to clinicopathological features, recurrence and disease-free survival (DFS).ResultsLevels of 11-oxygenated androgens were weakly correlated to those of canonical androgens such as testosterone (T) and dihydrotestosterone (DHT), with no evidence of their association with clinicopathological features. Levels of 11-oxygenated androgens declined after surgery but remained higher in overweight and obese compared to normal weight cases. Higher levels of preoperative free 11-ketoandrosterone (11KAST) were associated with an increased risk of recurrence (Hazard ratio (HR) of 2.99 (95%CI=1.09-8.18); P=0.03). Postoperative free 11β-hydroxyandrosterone (11OHAST) levels were adversely associated with recurrence and DFS (HR = 3.23 (1.11-9.40); P=0.03 and 3.27 (1.34-8.00); P=0.009, respectively).Conclusion11-oxygenated androgen metabolites emerge as potential prognostic markers of EC.

C11-hydroxy and C11-oxo C19 and C21 Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors

“…Data also show that 11OHAST is a poor 11βHSD2 substrate with more than 80% of it not converted to 11KAST. Although investigations into inactive downstream C11-oxy C 19 steroids are limited, 11OHAST in serum has been reported to be consistently higher than 11KAST, corroborating our in vitro findings [ 35 , 58 , 59 , 60 ]. In both men (21–72 yrs) and women (premenopausal), circulating 11OHAST was significantly higher than 11KAST (~100-fold) [ 60 ].…”

“…In addition, 11K3αdiol was identified as a PRB agonist at 100 nM and 1 µM. Although circulating concentrations have yet to be established, a cohort of precursor steroids have, however, been detected [ 35 , 77 ]. 11K5⍺diol is a direct product resulting in the biosynthesis of 11KDHT or 11KAST by various AKR1C/17βHSD isozymes [ 77 ].…”

“…Many disease states have recently been associated with increased levels of C11-oxy Many disease states have recently been associated with increased levels of C11oxy C 19 steroid metabolites such as prostate cancer (PCa), benign prostatic hyperplasia (BPH), polycystic ovary syndrome (PCOS), breast cancer (BC) and endometrial cancer (EC) [23,24,31,[35][36][37]. In addition, the expression of both AR and PR isoforms have been identified in tissues (prostate, ovary, breast and endometrium) associated with these pathophysiological conditions [38][39][40][41][42].…”