Presentation Authors: Jen-Tsan Chi*, Pao-Hwa Lin, Durham, NC, Emily Chen, Vladimir Tolstikov, Framingham, MA, Taofik Oyekunle, Durham, NC, Fei Gao, Rangaprasad Sarangarajan, Niven Narain, Michael Kiebish, Framingham, MA, Stephen Freedland, Los Angeles, CA
Introduction: Androgen deprivation therapy (ADT) is linked with metabolic disturbances such as impaired glucose tolerance, insulin resistance, weight gain, and bone loss, putting men at increased risk of diabetes and cardiovascular death. However, the metabolic pathways altered by ADT and how this occurs is unknown. In a prospective 6-month randomized trial, we showed many of these metabolic disturbances are prevented by a low carbohydrate diet (LCD) intervention with advice to walk more vs. control (asked to make no lifestyle changes). We used banked serum from this trial to assess the metabolomic changes due to ADT alone or ADT plus LCD in prostate cancer (PC) patients.
Methods: Sera collected at baseline, 3-, and 6-month was used for metabolomics and lipidomics analyses. The relevant metabolic changes associated with each treatment and ADT-affected androgen reduction were identified by one-way ANOVA, MetaboAnalyst analysis, and Pearson correlation.
Results: 42 patients were randomized (N=20 LCD, N=22 control), 40 completed baseline (N=19 LCD, N=21 control) and 34 completed 6-month visit but only 29 had blood collected (LCD:11/14; control: 18/20). First, as expected, ADT alone reduced steroid synthesis as reflected by lower androgen sulfate and other steroid hormones. The degree of androgen reduction was negatively correlated with serum glucose (r=-0.66), supporting the diabetogenic role of ADT. Second, a consistent reduction in 3-hydroxybutyric acid was observed, indicating reduced ketogenesis. Third, ADT was associated with a corresponding reduction in Indole-3-carboxaldehyde, a microbiota-derived metabolite from dietary tryptophan. Indole-3-carboxaldehyde is an agonist for the aryl hydrocarbon receptor in intestinal immune cells to stimulate the production of IL22 which regulates mucosal reactivity and inflammation. Lastly, ADT alone also reduced fatty acid metabolism, acyl-carnitines, increased SAH, SAM, uremic toxins (p-cresol, p-cresol sulfate) and o-Acetylserine. Combining ADT with a LCD reversed many of the ADT-associated metabolic changes, including reduced ketogenesis and Indole-3-carboxaldehyde, suggesting its potential to mitigate ADT-linked metabolic dysregulation.
Conclusions: Metabolomic analysis identified important mechanistic insights of metabolic dysregulation of ADT including ketogenesis and microbial production of indoles which is related to immune pathways. Future research is needed to confirm the findings and examine further the underlying mechanisms and functional impact of ADT and the reversal of a LCD on metabolic homeostasis to prevent ADT-linked comorbidities.
Source of Funding: Atkins Foundation, AUA, NIH, and Berg.