Steroid Hormone Biosynthesis Metabolism Is Associated With Fatigue Related to Androgen Deprivation Therapy for Prostate Cancer

Abstract

Background: Androgen deprivation therapy (ADT) is a cornerstone treatment for prostate cancer. Despite the clinical benefits, ADT is associated with multiple adverse effects including fatigue. The goal of the study was to examine metabolomic changes to better understand cancer-related fatigue specific to ADT treatment.

Methods: A total of 160 plasma samples collected from participants with (+ADT, n = 58) or without neoadjuvant ADT (-ADT, n = 102) prior to radiation therapy for treatment of non-metastatic localized prostate cancer were included in the study. Fatigue and sleep-related impairment were measured using the Patient Reported Outcomes Measurement Information System. Plasma metabolites were identified and measured using untargeted ultrahigh-performance liquid chromatography/mass spectrometry metabolomics analyses. Partial least square discriminant analysis was used to identify discriminant metabolite features, and the diagnostic performance of selected classifiers was quantified using AUROC curve analysis. Pathway enrichment analysis was performed using metabolite sets enrichment analyses.

Findings: Steroid hormone biosynthesis pathways, including androstenedione metabolism as well as androgen and estrogen metabolism, were overrepresented by metabolites that significantly discriminated samples in the +ADT from the -ADT group. Additional overrepresented metabolic pathways included amino acid metabolism, glutathione metabolism, and carnitine synthesis. Of the metabolites that were significantly different between the groups, steroid hormone biosynthesis metabolites were most significantly correlated with fatigue severity. Sleep-related impairment was strongly correlated with fatigue severity and inversely correlated with ADT-induced reduction in androsterone sulfate.

Conclusions: Patients with non-metastatic prostate cancer receiving neoadjuvant ADT prior to radiation therapy reported relatively more severe fatigue. Increased fatigue in this population may be attributable to sleep-related impairment associated with alterations in steroid hormone biosynthesis. Findings in this study provide a basis for further research of changes in sleep patterns and their role in this specific subcategory of cancer-related fatigue caused by the treatment.

Keywords: androgen deprivation therapy; androgen metabolism; cancer-related fatigue; metabolomics; prostate cancer; radiation therapy; steroid hormone biosynthesis.

FIGURE 1

Metabolic profiles of patients with non-metastatic prostate cancer with (+ADT, n = 58) or without androgen deprivation therapy (−ADT, n = 102). (A) Volcano plot of metabolites of the +ADT group compared to −ADT. The y axis represents p-value converted to negative log 10 scale, and the x axis represents log2 fold change. Significant metabolites (fold change > 1.5, FDR ≤ 0.1) were highlighted in red. (B) Pairwise PLSDA score plot of the top five components. (C) PLSDA two-dimensional plot ellipses representing 95% confidence intervals. (D) ROC curve demonstrating the specificity and sensitivity of the PLSDA model discriminating the +ADT group from the −ADT group. AUC = 0.839, 95% CI (0.725, 0.903). Excellent classification is indicated by an AUC > 0.90. (E) Metabolite set enrichment analysis (MSEA) of significant metabolites.

FIGURE 2

Androgen deprivation therapy broadly affected metabolites related to steroid hormone biosynthesis. (A) Androsterone sulfate was significantly decreased in patients with ADT. Sulfated (B–H) and glucuronidated androgen metabolites (I–L) were significantly decreased in the +ADT group. *p < 0.05 and false-discovery rate ≤ 10%.

FIGURE 3

Additional metabolic pathways that were overrepresented by metabolites significantly distinguished the +ADT from the −ADT group. (A) Box plots of individual metabolites related to amino acid metabolism. (B) Box plots of individual metabolites related to glutathione metabolism. (C) Box plots of individual metabolites related to carnitine and mitochondrial fatty acid oxidation metabolism.

FIGURE 4

Steroid hormone biosynthesis was associated with fatigue severity. (A) Box plot showing the PROMIS-fatigue T-scores of the −ADT PROMIS-Fatigue T-scores of the −ADT group (44.34 ± 7.81) and the +ADT group (47.92 ± 7.28). *Indicates statistical significance (p = 0.0064). Scores above the dotted lines are considered fatigued (24% of −ADT, 40% of +ADT). (B) Correlations of PROMIS-Fatigue T-score and metabolites that was significantly different between the two groups. X axis indicates the correlation coefficient. Colors of the bars indicate FDR-adjusted p-values. (C) Metabolite set enrichment analysis of metabolites that significantly correlated with PROMIS-Fatigue T-scores. Steroid hormone biosynthesis (KEGG ID: M00107), including androgen and estrogen metabolism (SMPDB ID: SMP0000068) as well as androstenedione metabolism (SMPDB ID: SMP0030406), were significantly overrepresented.

FIGURE 5

Reduced steroid hormone biosynthesis metabolites were associated with increased severity of cancer-related fatigue. PROMIS-Fatigue T-scores significantly correlated with major androgen metabolites including (A) androsterone sulfate (r = –0.26, p = 0.0009), (B) epiandrosterone sulfate (r = –0.25, p = 0.0016), (C) etiocholanolone glucuronide (r = –0.19, p = 0.018), and (D) dehydroepiandrosterone sulfate (DHEA-S) (r = –0.18, p = 0.023). PROMIS-Fatigue T-scores also correlated with sulfated metabolites of androgen including (E) androstenediol (3beta,17beta) monosulfate (r = –0.26, p = 0.0008), (F) 5alpha-androstan-3beta,17beta-diol disulfate (r = –0.21, p = 0.0083), (G) 5alpha-androstan-3beta,17beta-diol monosulfate (r = –0.20, p = 0.012), (H) 5alpha-androstan-3alpha,17alpha-diol monosulfate (r = –0.22, p = 0.0062), and (I) 5alpha-androstan-3beta,17alpha-diol disulfate (r = –0.17, p = 0.028).

FIGURE 6

Fatigue severity was associated with ADT-related increase in sleep impairment. (A) Box plot showing the PROMIS-SRI T scores of the −ADT PROMIS-Fatigue T-scores of the −ADT group (42.67 ± 9.24) and the +ADT group (47.2 ± 9.95). *Indicates statistical significance (p = 0.0053). Scores above the dotted lines are considered fatigued (25% of −ADT, 41% of +ADT). (B) PROMIS-SRI T-score was highly correlated with PROMIS-Fatigue T-score (r = 0.75, p = 1.28 × 10^{– 29}). (C) Androsterone sulfate levels significantly correlated with PROMIS-SRI T-scores (r = –0.19, p = 0.020).

FIGURE 7

Mechanism of fatigue related to androgen deprivation therapy. Androgen deprivation therapy, which inhibits androgen receptor signaling, results in steroid hormone metabolism dysregulation and leads to sleep impairment by affecting circadian rhythm regulation, nocturia, and hot flashes. At the same time, androgen deprivation also results in dysregulated carnitine homeostasis and glutathione metabolism, leading to mitochondrial dysfunction and oxidative stress, respectively. Mitochondrial dysfunction further increase oxidative stress and contributes to inflammation-induced sickness behavior that includes fatigue.