Accession Number : AD1014057


Title :   A Counterregulatory Mechanism Impacting Androgen Suppression Therapy


Descriptive Note : Technical Report,01 Mar 2015,31 May 2016


Corporate Author : Washington University Saint Louis United States


Personal Author(s) : Wilson,David


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1014057.pdf


Report Date : 01 Aug 2016


Pagination or Media Count : 77


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 tecbiosynthetic pathway (Cyp11a1,Hsd3b1, and Cyp17a1). Unexpectedly, the final gene in the pathway, Hsd17b3, was upregulated in the deleted cells. This paradoxicalincrease 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 mediaaccounts for the effect. If this counterregulatory mechanism also operates in human LCs, it could contribute to inadequate androgensuppression in patients who undergo ADT with GnRH analogues.


Descriptors :   prostate cancer , androgens , estrogens , therapy , cells (biology) , hormones , enzymes , testosterone , gene expression , gonadotropins , transcription (genetics)


Distribution Statement : APPROVED FOR PUBLIC RELEASE