Abiraterone acetate treatment lowers 11-oxygenated androgens

Wright, Connor; O’Day, Patrick; Alyamani, Mohammed; Sharifi, Nima; Auchus, Richard J.

doi:10.1530/eje-19-0905

Cited by 51 publications

(35 citation statements)

References 34 publications

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“…Glucocorticoid treatment significantly decreased circulating T and 11-oxygenated androgens through suppression of the HPA-axis. Potent suppression of 11-oxygenated androgens has previously been observed in patients treated with abiraterone acetate and prednisone (27).…”

Section: Discussionmentioning

confidence: 78%

“…Glucocorticoid treatment significantly decreased circulating T ( P < 0.01) and 11-oxygenated androgens ( P < 0.05 and P < 0.01, respectively) through suppression of the HPA axis. Potent suppression of 11-oxygenated androgens has previously been observed in patients treated with abiraterone acetate and prednisone ( 27 ). Abiraterone acetate suppresses the production of adrenal androgens through direct inhibition of CYP17A1, rather than negative feedback.…”

Section: Discussionmentioning

confidence: 88%

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11-Ketotestosterone: the resilience of a potent androgen in prostate cancer patients after castration

Snaterse¹,

Dessel²,

Riet³

et al. 2021

JCI Insight

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BACKGROUND Continued androgen receptor (AR) signaling constitutes a key target for treatment in metastatic castration-resistant prostate cancer (CRPC). Studies have identified 11-ketotestosterone (11KT) as a potent AR agonist, but it is unknown if 11KT is present at physiologically relevant concentrations in patients with CRPC to drive AR activation. The goal of this study was to investigate the circulating steroid metabolome including all active androgens in patients with CRPC. METHODS Patients with metastatic CRPC ( n = 29) starting a new line of systemic therapy were included. Sequential plasma samples were obtained for measurement of circulating steroid concentrations by multisteroid profiling employing liquid chromatography–tandem mass spectrometry. Metastatic tumor biopsy samples were obtained at baseline and subjected to RNA sequencing. RESULTS 11KT was the most abundant circulating active androgen in 97% of patients with CRPC (median 0.39 nmol/L, range: 0.03–2.39 nmol/L), constituting 60% (IQR 43%–79%) of the total active androgen (TA) pool. Treatment with glucocorticoids reduced 11KT by 84% (49%–89%) and testosterone by 68% (38%–79%). Circulating TA concentrations at baseline were associated with a distinct intratumor gene expression signature comprising AR-regulated genes. CONCLUSION The potent AR agonist 11KT is the predominant circulating active androgen in patients with CRPC and, therefore, one of the potential drivers of AR activation in CRPC. Assessment of androgen status should be extended to include 11KT, as current clinical approaches likely underestimate androgen abundance in patients with CRPC. TRIAL REGISTRATION Netherlands Trial Register: NL5625 (NTR5732). FUNDING Daniel den Hoed Foundation and Wellcome Trust (Investigator Award WT209492/Z/17/Z).

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 88%

11-Ketotestosterone: the resilience of a potent androgen in prostate cancer patients after castration

Snaterse¹,

Dessel²,

Riet³

et al. 2021

JCI Insight

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“…Sera for 11OHA4, 11OHT, 11KA4, and 11KT were analyzed by LC-MS/MS as previously described by Wright et al [28] (University of Michigan, Ann Arbor, MI, USA). The lower limit of quantification (LLOQ), defined as the minimum concentration achieving an extrapolated signal-to-noise ratio of 3, ranged from 3 ng/dL (0.1 nmol/L) (11OHT, 11KA4, and 11KT) to 10 ng/dL (0.3 nmol/L) (11OHA4).…”

Section: Methodsmentioning

confidence: 99%

The Unique Role of 11-Oxygenated C19 Steroids in Both Premature Adrenarche and Premature Pubarche

et al. 2020

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Introduction: Recent studies have shown 11-oxygenated androgens (11oAs) are the dominant androgens in premature adrenarche (PA). Our objective was to compare 11oAs and conventional androgens in a well-defined cohort of children with PA or premature pubarche (PP) and correlate these androgens with metabolic markers. Methods: A prospective cross-sectional study was conducted at a university hospital. Fasting early morning serum steroids (including 11oAs) and metabolic biomarkers were compared and their correlations determined in children ages 3–8 years (F) or 3–9 years (M) with PA or PP (5 M and 15 F) and healthy controls (3 M and 8 F). Results: There were no differences between PA, PP, and controls or between PA and PP subgroups for sex, BMI z-score, or criteria for childhood metabolic syndrome. Dehydroepiandrosterone sulfate (DHEAS) was elevated only in the PA subgroup, as defined. 11oAs were elevated versus controls in PA and PP although no differences in 11oAs were noted between PA and PP. Within the case cohort, there was high correlation of T and A4 with 11-ketotestosterone and 11β-hydroxyandrostenedione. While lipids did not differ, median insulin and HOMA-IR were higher but not statistically different in PA and PP. Conclusions: PA and PP differ only by DHEAS and not by 11oAs or insulin sensitivity, consistent with 11oAs – rather than DHEAS – mediating the phenotypic changes of pubarche. Case correlations suggest association of 11oAs with T and A4. These data are the first to report the early morning steroid profiles including 11oAs in a well-defined group of PA, PP, and healthy children.

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“…From the samples, 11 steroids, including 11oxC19 steroids (11OHA4, 11KA4, 11OHT, 11KT) were extracted and quantified as described elsewhere ( 18 ), with minor modifications in sample processing to minimize potential decomposition of cortisol and cortisone into 11OHA4 and 11KA4, respectively ( 19 ). Target steroid analytes were chromatographically separated using a Kinetex 2.1 × 150 mm 2.6-μm particle size resolving column in a 20-minute cycle.…”

Section: Methodsmentioning

confidence: 99%

Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors

Schröder

Turcu

O’Day

et al. 2021

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Testicular adrenal rest tumors (TART) are a common complication in males with classic 21-hydroxylase deficiency (21OHD). TART are likely to contribute to the androgen excess in 21OHD patients, but a direct quantification of steroidogenesis from these tumors has not been yet done. Objective Define the production of 11-oxygenated 19-carbon (11oxC19) steroids by TART. Participants and methods Steroids were measured in left (n=7) and right (n=4) spermatic vein- and simultaneously taken peripheral blood (n=7) samples from seven men with 21OHD and TART using liquid chromatography-tandem mass spectrometry. For comparison, we also measured the peripheral steroid concentrations in five adrenalectomized patients and twelve age- and BMI-matched controls. Additionally, steroids were quantified in TART cell- and adrenal cell-conditioned medium, with and without adrenocorticotropic hormone (ACTH) stimulation. Results Compared to peripheral blood of 21OHD patients with TART, the spermatic vein samples displayed the highest gradient for 11β-hydroxytestosterone (11OHT; 96-fold) of the 11oxC19 steroids, followed by 11-ketotestosterone (47-fold) and 11β-hydroxyandrostenedione (11OHA4; 29-fold), suggesting production of these steroids in TART. TART cells produced higher levels of testosterone, and lower levels of A4 and 11OHA4 after ACTH stimulation compared to adrenal cells, indicating ACTH-induced production of testosterone in TART. Conclusion In patients with 21OHD, TART produce 11oxC19 steroids, but in different proportions than the adrenals. The very high ratio of 11OHT in spermatic- versus peripheral vein blood suggests the 11-hydroxylation of testosterone by TART, and the in vitro results indicate that this metabolism is ACTH-sensitive.

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Abiraterone acetate treatment lowers 11-oxygenated androgens

Cited by 51 publications

References 34 publications

11-Ketotestosterone: the resilience of a potent androgen in prostate cancer patients after castration

11-Ketotestosterone: the resilience of a potent androgen in prostate cancer patients after castration

The Unique Role of 11-Oxygenated C19 Steroids in Both Premature Adrenarche and Premature Pubarche

Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors

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