JU INSIGHT: Extensive Alteration of Androgen Precursor Levels After Castration in Prostate Cancer Patients and Their Association With Active Androgen Level
By: Mélanie Rouleau, PhD; Bertrand Neveu, PhD; Patrick Caron, BSc; Fannie Morin, MD, FRCSC; Paul Toren, MD, PhD, FRCSC; Louis Lacombe, MD, FRCSC; Véronique Turcotte, MSc; Éric Lévesque, MD, PhD, FRCSC; Chantal Guillemette, PhD; Frédéric Pouliot, MD, PhD, FRCSC | Posted on: 01 Dec 2022
Rouleau M, Neveu B, Caron P, et al. Extensive alteration of androgen precursor levels after castration in prostate cancer patients and their association with active androgen level. J Urol. 2022;208(6):1214-1225.
Study Need and Importance
Androgen receptor is the main driver of prostate cancer cell proliferation and is primarily activated by gonadal testosterone and dihydrotestosterone (DHT) metabolized from testosterone. At low androgen levels as seen after castration, intratumoral conversion of adrenal androgen precursors and alternative biosynthesis pathways contribute significantly to androgen receptor activity. While the inhibition of androgen precursors synthesis by steroidogenesis inhibitors (like abiraterone acetate) is known to decrease prostate cancer proliferation, the impact of androgen deprivation therapy (ADT) on androgen precursor levels has not been studied in depth.
What We Found
In this study, we report the analysis of 15 circulating steroids before and after castration and their association with DHT and testosterone levels. We found that pharmacological castration can significantly modulate the levels of 13 steroids out of the 15 studied. Besides the expected decrease in testosterone and DHT levels, the levels of androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androsterone, androstenediol, estrone, estrone-sulfate, estradiol, and androsterone/3α-diol-3/3α-diol-17-glucuronide were significantly decreased in castrated compared to eugonadal patients. Also, we show that testosterone levels were strongly associated with multiple steroids under eugonadal conditions, whereas they were weakly affected by precursor steroids in castrated patients. By contrast, DHT levels under ADT were associated with testosterone and the backdoor pathway metabolite androsterone. In castration-resistant patients, levels of androstenedione were significantly associated with testosterone level, while testosterone was the only steroid associated with DHT levels.
Our study is limited by the limited number of patients included and the absence of correlation between steroid levels and clinical outcomes.
Interpretations for Patient Care
In conclusion, we show ADT significantly reduces the levels of 13 circulating steroids including androgen precursors produced by adrenals. These results provide further rationale to intensify treatments with androgen receptor axis signaling pathway inhibitors in patients with prostate cancer undergoing ADT.