ORF29-05 - LRH-1-Dependent Intestinal Steroidogenesis Links Inherited HSD3B1 to Bile Acid Dysregulation during Androgen Deprivation Therapy

Androgen deprivation therapy (ADT) is a cornerstone of advanced prostate cancer treatment but induces systemic metabolic toxicities that limit long-term outcomes. The molecular mechanisms connecting androgen suppression to extra-tumoral metabolic dysfunction remain poorly defined. Here, we identify a previously unrecognized intestinal steroid-bile acid regulatory axis that provides a mechanistic link between inherited steroidogenic capacity and bile acid remodeling during ADT.
Untargeted and targeted serum metabolomic profiling of prostate cancer patients receiving ADT combined with androgen receptor pathway inhibitors revealed an ADT-initiated reduction in circulating bile acids across two independent clinical cohorts. These changes were genotype dependent and most pronounced in carriers of the adrenal-permissive HSD3B1 (1245C) allele, the most common inherited genetic determinant of prostate cancer mortality.
Mechanistic studies revealed the terminal ileum as a unique site of extra-gonadal HSD3B1 expression. Single-cell transcriptomics, immunohistochemistry, and functional assays demonstrated exclusive co-expression and activity of 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1) and the apical sodium-dependent bile acid transporter SLC10A2 (ASBT) in human ileal enterocytes. Ileal 3βHSD1 was enzymatically active and functionally sufficient to regulate ASBT-dependent bile acid uptake through local conversion of dehydroepiandrosterone to downstream androgens, defining the intestine as a previously unappreciated steroidogenic organ. We further demonstrated that Liver Receptor Homolog-1 (LRH-1; NR5A2) is necessary for coordinated regulation of intestinal HSD3B1 and SLC10A2. Pharmacologic or genetic inhibition of LRH-1 suppressed both steroidogenic and bile acid transport programs independent of androgen receptor signaling. Under androgen-deprivation conditions, LRH-1-mediated regulation of bile acid transport persisted despite glucocorticoid receptor loss. This was accompanied by compensatory HSD11B2 upregulation, enhancing local glucocorticoid inactivation.
Together, these findings establish an LRH-1-HSD3B1-SLC10A2 axis linking inherited steroidogenic capacity to intestinal bile acid handling during ADT. This provides a mechanistic basis for bile acid alterations associated with ADT-related metabolic toxicity and nominates LRH-1-dependent intestinal steroid metabolism as a therapeutic target to mitigate systemic side effects while preserving oncologic efficacy.