A Counterregulatory Mechanism Impacting Androgen Suppression Therapy
Abstract
Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) analogues is a mainstay of prostate cancer treatment. This project explores a novel counterregulatory response that may limit the efficacy of ADT. A key player in this process isHSD17B3, an enzyme required for the conversion of androstenedione to testosterone in testicular Leydig cells (LCs). Normally gonadotropin stimulation of LCs is accompanied by upregulation of genes in the testosterone synthetic pathway. The effect of GnRHanalogues on LC function was modeled by conditional deletion of Gata4, a transcription factor known to positively regulate multiple genes involved in steroidogenesis. Gata4 deletion led to decreased expression of several genes in the testosterone biosynthetic pathway (Cyp11a1,Hsd3b1, and Cyp17a1). Unexpectedly, the final gene in the pathway, Hsd17b3, was up regulated in the deleted cells. This paradoxical increase in Hsd17b3 expression was recapitulated when normal LCs were incubated with conditioned medium from GATA4-deficient LCs, implying that a hormone mediates the process. Preliminary results suggest that a loss of LC-derived estrogen in the conditioned media accounts for the effect. If this counterregulatory mechanism also operates in human LCs, it could contribute to inadequate androgen suppression in patients who undergo ADT with GnRH analogues.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2016
- Accession Number
- AD1008359
Entities
People
- David M Wilson
Organizations
- Washington University in St. Louis