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

Abstract

Background: Prostate cancer (PC) is the second most lethal cancer for men. For metastatic PC, standard first-line treatment is androgen deprivation therapy (ADT).While effective, ADT has many metabolic side effects. Previously, we found in serum metabolome analysis that ADT reduced androsterone sulfate, 3-hydroxybutyric acid, acyl-carnitines but increased serum glucose. Since ADT reduced ketogenesis, we speculate that low-carbohydrate diets (LCD) may reverse many ADT-induced metabolic abnormalities in animals and humans.Methods: In a multicenter trial of patients with PC initiating ADT randomized to no diet change (control) or LCD, we previously showed that LCD intervention led to significant weight loss, reduced fat mass, improved insulin resistance, and lipid profiles. To determine whether and how LCD affects ADT-induced metabolic changes, we analyzed serum metabolites after 3-, and 6-months of ADT on LCD versus control.Results: We found androsterone sulfate was most consistently reduced by ADT and was slightly further reduced in the LCD arm. Contrastingly, LCD intervention increased 3-hydroxybutyric acid and various acyl-carnitines, counteracting their reduction during ADT. LCD also reversed the ADT-reduced lactic acid, alanine, and S-adenosyl methionine (SAM), elevating glycolysis metabolites and alanine. While the degree of androsterone reduction by ADT was strongly correlated with glucose and indole-3-carboxaldehyde, LCD disrupted such correlations.Conclusions: Together, LCD intervention significantly reversed many ADT-induced metabolic changes while slightly enhancing androgen reduction. Future research is needed to confirm these findings and determine whether LCD can mitigate ADT-linked comorbidities and possibly delaying disease progression by further lowering androgens.

Personalized Medicine for Prostate Cancer: Is Targeting Metabolism a Reality?

“…Recent studies examining metabolomic profiles of men receiving ADT reported a reduction in acyl-carnitines and ketone bodies, indicating ADT-induced systemic changes in fatty acid metabolism (135,136). Meanwhile, low-carbohydrate diets reversed this alteration in fatty acid metabolism while slightly increasing androgen suppression (137). This emphasizes the importance of diet in maximizing ADT therapeutic activity while minimizing its effects on altering metabolism.…”

Insulin-Lowering Diets in Metastatic Cancer

“…At 3 months, those in the LCD/walking group had lost more weight, had reduced fat mass, lower percent body fat, improved insulin resistance, lower hemoglobin A1c, higher high-density lipoprotein (HDL), and lower triglycerides compared to those in the control group [51]. The diet and exercise intervention also enhanced reduction of androsterone sulfate by androgen deprivation therapy [50]. However, there were no significant differences in prostate-specific antigen (PSA) levels, suggesting no significant difference in disease burden between the arms; while the authors did not specify the proportion of men in each arm with metastatic disease, baseline PSA levels were elevated in the range of 18-21 ng/mL and were similar between treatment arms.…”

“…Two of the eight mice in the 15% carbohydrate group died of non-cancer causes which may suggest that severe carbohydrate restriction could be deleterious [49]. While this safety signal has not been borne out in studies of KD or LCD in men with early stage prostate cancer, these dietary strategies have not been tested for safety specifically in the metastatic prostate cancer setting [50,51]. IF strategies have also been tested.…”

Metabolic Response to Androgen Deprivation Therapy of Prostate Cancer

“…Our findings are consistent with the hypothesis that more prominent reduced glycolysis under LCD is associated with slower PC progression. We previously showed that androgen sulfate, the main driver of PC growth, was most consistently reduced by ADT [ 31 , 61 ]. In this analysis, alterations in androgen sulfate did not show a correlation with PSADT.…”