Extensive alteration of androgen precursor levels after castration in prostate cancer patients and their association with active androgen level: Importance for treatment intensification
Frédéric Pouliot1, Mélanie Rouleau1, Bertrand Neveu1, Patrick Caron2, Fannie Morin1, Paul Toren1, Louis Lacombe1, Véronique Turcotte2, Éric Lévesque3, Chantal Guillemette2.
1Department of Surgery, Cancer Research Center, Centre Hospitalier Universitaire (CHU) de Québec-Université Laval, Quebec, QC, Canada; 2Pharmacy Faculty, Université Laval and CHU de Québec-Université Laval, Quebec, QC, Canada; 3Medicine Faculty, Université Laval and CHU de Québec-Université Laval, Quebec, QC, Canada
Introduction: Dihydrotesterone (DHT) and testosterone are thought to be major contributors of prostate cancer progression and resistance. We studied the modulation of 15 circulating steroids induced by castration and their association with DHT and testosterone levels.
Methods: A total of 116 serum samples were collected from 99 prostate cancer patients and categorized either as eugonadal, castration-sensitive (CSPC), castration-resistant (CRPC), or CRPC under abiraterone acetate. Serum levels of 15 steroids were measured using mass spectrometry and compared between groups using ANOVA. Intrapatient association of steroid levels and the androgens testosterone and DHT were assessed using Pearson correlation and linear regression.
Results: Testosterone, DHT, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androsterone, androstenediol, estrone, estrone-sulfate, estradiol, and androsterone/3α-diol-3/3α-diol-17-glucuronide levels were significantly decreased in CSPC (castrated) compared to eugonadal patients. Testosterone levels were strongly associated with multiple steroids under eugonadal conditions, whereas they were sparsely affected by precursor steroids in castrated patients. By contrast, DHT levels under androgen deprivation therapy (ADT) were associated with testosterone and the backdoor pathway metabolite androsterone. In CRPC patients, levels of androstenedione were significantly associated with testosterone level, while testosterone was the only steroid that predicted DHT levels.
Conclusions: ADT significantly reduces the levels of 13 circulating steroids. Upon ADT initiation, the backdoor pathway metabolite androsterone strongly predicted DHT levels. Under CRPC conditions, androstenedione was significantly associated with testosterone levels, suggesting the presence of tumor-related circulating androgens in these patients. These results provide further rationale to intensify treatments with androgen receptor axis signaling pathway inhibitors in patients with prostate cancer.
