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

Prostate cancer (PC) is the second most lethal cancer for men and metastatic PC is treated by androgen deprivation therapy (ADT). While effective, ADT has many metabolic side effects. Previously, serum metabolome analysis showed that ADT reduced androsterone sulfate, 3-hydroxybutyric acid, acyl-carnitines while 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. To test this possibility, we conducted a multi-center trial of PC patients initiating ADT randomized to no diet change (control) or LCD. We previously showed LCD led to significant weight loss, reduced fat mass, improved insulin resistance and lipid profiles. To determine whether and how LCD affects ADT-induced metabolic effects, we analyzed serum metabolites after 3-, and 6-months of ADT on LCD vs. control. We found androsterone sulfate was most consistently reduced by ADT, and was slightly further reduced by LCD. Contrastingly, LCD 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, amino acids and sulfur-containing metabolites. While the degree of ADT-reduced androsterone was strongly correlated with glucose and indole-3-carboxaldehyde, LCD disrupted such correlation. However, many LCD-induced changes were seen at 3-but not 6-month, suggesting metabolic adaption. Together, LCD 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. Statement of translational relevanceProstate cancer (PC) is the most common non-skin cancer and second leading cause of cancer-related death in men. While androgen deprivation therapy (ADT) is the main treatment for metastatic PC, it has many metabolic side effects. Previous serum metabolome analysis of PC patients receiving ADT identified reduced ketogenesis. Therefore, low-carbohydrate diets (LCD), ketogenic in nature, may reverse many ADT-induced metabolic abnormalities. We conducted a 6-month multi-center trial of no diet change (control) vs. LCD in men initiating ADT. We found that LCD reversed many ADT-induced metabolic abnormalities while slightly further reducing androgen levels. Also, LCD disrupted the diabetogenic effects of ADT, but some effects seen at 3-month were lost at 6-month, suggesting metabolic adaptation to LCD. These data suggest the potential metabolic benefits of LCD with potential to enhance ADT efficacy. Larger studies testing whether LCDs mitigate metabolic side effects and slow disease progression are warranted given acceptable safety profiles, metabolic benefits, and possibly lowered androgens.