Endocrine Abstracts

Recent years have seen many exciting developments in the field of steroidogenesis. These include improved diagnostics through mass spectrometry, novel clinical relevance attributed to steroids previously deemed irrelevant and successful implementation of new anti-cancer treatments. Prostate cancer is a prime example of the latter with the recent confirmation that castration-resistant disease is still androgen-dependent and susceptible to hormonal manipulation with next generation steroidogenic enzyme inhibitors and anti-androgens. In advanced stages of prostate cancer hormonal treatment leads to complex and incompletely understood changes in circulating steroid hormones levels. CYP17 inhibitors like abiraterone acetate lead to accumulation of mineralocorticoid precursors and progesterone metabolites. This ensues a steroid flux into the alternative pathway to 5α-dihydrotestosterone (DHT) with intermediates such as allopregnanolone and androstanediol. Our data in parental and abiraterone-resistant prostate cancer cells show a functional block at the level of CYP17 in prostate cancer cells, preventing de novo steroid synthesis and local activation of CYP17 precursors. However, accumulation of other steroid hormones intratumorally could affect nuclear receptor activation. Concurrently, interaction with supplemented glucocorticoids leads to a complex interaction between wild type, mutant and splice variants of nuclear receptors and DNA regulatory elements. Further research into pre-receptor regulation of steroid hormones combined with innovative genome-wide receptor-DNA binding analyses will pave the way towards comprehensive understanding of their effects. In turn, this could secure efficient targeting of the detrimental sequelae of steroid hormones in prostate cancer and other endocrine diseases.