Metabolomic effects of androgen deprivation therapy treatment for prostate cancer

Abstract

Androgen deprivation therapy (ADT) is the main treatment strategy for men with metastatic prostate cancer (PC). However, ADT is associated with various metabolic disturbances, including impaired glucose tolerance, insulin resistance and weight gain, increasing risk of diabetes and cardiovascular death. Much remains unknown about the metabolic pathways and disturbances altered by ADT and the mechanisms. We assessed the metabolomic effects of ADT in the serum of 20 men receiving ADT. Sera collected before (baseline), 3 and 6 months after initiation of ADT was used for the metabolomics and lipidomics analyses. The ADT‐associated metabolic changes were identified by univariable and multivariable statistical analysis, ANOVA, and Pearson correlation. We found multiple key changes. First, ADT treatments reduced the steroid synthesis as reflected by the lower androgen sulfate and other steroid hormones. Greater androgen reduction was correlated with higher serum glucose levels, supporting the diabetogenic role of ADT. Second, ADT consistently decreased the 3‐hydroxybutyric acid and ketogenesis. Third, many acyl‐carnitines were reduced, indicating the effects on the fatty acid metabolism. Fourth, ADT was associated with a corresponding reduction in 3‐formyl indole (a.k.a. indole‐3‐carboxaldehyde), a microbiota‐derived metabolite from the dietary tryptophan. Indole‐3‐carboxaldehyde is an agonist for the aryl hydrocarbon receptor and regulates the mucosal reactivity and inflammation. Together, these ADT‐associated metabolomic analyses identified reduction in steroid synthesis and ketogenesis as prominent features, suggesting therapeutic potential of restricted ketogenic diets, though this requires formal testing. ADT may also impact the microbial production of indoles related to the immune pathways. Future research is needed to determine the functional impact and underlying mechanisms to prevent ADT‐linked comorbidities and diabetes risk.

The effects of low-carbohydrate diets on the metabolic response to androgen-deprivation therapy in prostate cancer

“…In addition, we noted a cluster of metabolites which were repressed in the control arm but elevated in the LCD arm (Fig 2A, red bar expanded into Fig 2C). These metabolites, affected by ADT in opposite direction in the control vs. LCD arm, included 3-hydroxyburtyric acid, hydroxybutyryl-carnitine, 2-hydroxyburtyric acid and many acyl-carnitines previously noted to be repressed by ADT in the control arm (21). These results indicate that LCD reversed the ADT-reduced ketones and acyl-carnitines levels (Fig 2C) and linking these two classes of metabolites found to be reduced by ADT(21).…”

“…As previously described (10) (21), IRB approval was obtained at Duke, Durham Veterans Affairs Medical Center [VAMC], and Greater Los Angeles VAMC. PC men initiating ADT were approached and if they agreed to participate, they signed a written consent that allowed future analyses.…”

“…Fasting blood samples collected at BL, M3, and M6 were used for metabolomics analysis utilizing GC/MS-TOF (Gas chromatography–Mass Spectrometry Time of Flight analyzer), QqQ LC (Liquid Chromatography)-HILIC (Hydrophilic interaction chromatography)-MS/MS, and TripleTOF LC-RP-MS as described previously (21,23).…”

“…Other analyses aimed to identify therapeutic targets to treat PC (16-18) or elucidate the metabolic response to the PC treatments. While ADT is the standard treatment for metastatic PC with significant metabolic side effects, however, to date, only three studies have analyzed the metabolome on serum from PC patients receiving ADT (19-21). Briefly, Saylor et al reported 56 significantly altered metabolites after receiving 3 months of ADT, including androgen steroids, bile acid metabolites and lipid β-and Ω-oxidation (20).…”

“…The second study identified seven ADT-associated metabolites, which reverted to control levels after ADT was stopped (19). Recently, we reported the serum metabolomic and lipidomic profiling of PC patients in the control arm of the CAPS1 trial after 3 and 6 months of ADT treatment (21). As expected, ADT lowered androsterone sulfate and the degree of reduction was significantly correlated with increased serum glucose, supporting a diabetogenic role of ADT.…”