11β-Hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione

Swart, Amanda C.; Schloms, Lindie; Storbeck, Karl-Heinz; Bloem, Liezl M.; Toit, Therina du; Quanson, Jonathan L.; Rainey, William E.; Swart, Pieter

doi:10.1016/j.jsbmb.2013.04.010

Cited by 85 publications

(41 citation statements)

References 44 publications

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“…However, recent data suggest that additional, less well-characterized steroids of adrenal origin, including 11beta-hydroxyandrostenedione (11OH-AED) and 11-deoxcorticosterone (DOC) may also be converted to downstream metabolites that mediate AR activation8-11. Herein we briefly discuss the currently recognized role and metabolic pathways underlying the generation and activity of residual tumor androgens in CRPC.…”

Section: Introductionmentioning

confidence: 93%

Section: Novel Derivatives Of Adrenal Steroids Capable Of Activating mentioning

confidence: 99%

“…These include DOC, the immediate precursor to corticosterone in the mineralocorticoid pathway, and 11OH-AED, derived from the hydroxylase activity of adrenal CYP11B1 on AED (Figure 1) 8-11. In particular, recent data demonstrate that the 5α reduced metabolites of DOC and 11OH-AED can mediate wild type AR activation 8-11. Given the well-recognized presence of SRD5A activity in CRPC tissue, these observations suggest that in the low androgen environment of CRPC, alternative sources of 5α-reduced ligands may supplement AR activation normally mediated by the canonical 5α-reduced agonist 5α-DHT.…”

Section: Novel Derivatives Of Adrenal Steroids Capable Of Activating mentioning

confidence: 99%

“…In addition to producing the C-19 steroids DHEA-S, DHEA and AED, the adrenal gland secretes 11OH-AED, derived from the CYP11B1 mediated hydroxylation of AED (Figure 1) 9, 11. The low androgenic potential of this metabolite (with 35-fold less androgen activity than 5α-DHT) 55 had historically rendered it of little biologic interest, and its production from AED was primarily viewed as a mechanism to inactivate AED and regulate adrenal androgen output 56.…”

Section: Novel Derivatives Of Adrenal Steroids Capable Of Activating mentioning

confidence: 99%

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Beyond T and DHT - Novel Steroid Derivatives Capable of Wild Type Androgen Receptor Activation

Mostaghel¹

2014

Int. J. Biol. Sci.

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While androgen deprivation therapy (ADT) remains the primary treatment for metastatic prostate cancer (PCa), castration does not eliminate androgens from the prostate tumor microenvironment, and residual intratumoral androgens are implicated in nearly every mechanism by which androgen receptor (AR)-mediated signaling promotes castration-resistant disease. The uptake and intratumoral (intracrine) conversion of circulating adrenal androgens such as dehydroepiandrosterone sulfate (DHEA-S) to steroids capable of activating the wild type AR is a recognized driver of castration resistant prostate cancer (CRPC). However, less well-characterized adrenal steroids, including 11-deoxcorticosterone (DOC) and 11beta-hydroxyandrostenedione (11OH-AED) may also play a previously unrecognized role in promoting AR activation. In particular, recent data demonstrate that the 5α-reduced metabolites of DOC and 11OH-AED are activators of the wild type AR. Given the well-recognized presence of SRD5A activity in CRPC tissue, these observations suggest that in the low androgen environment of CRPC, alternative sources of 5α-reduced ligands may supplement AR activation normally mediated by the canonical 5α-reduced agonist, 5α-DHT. Herein we review the emerging data that suggests a role for these alternative steroids of adrenal origin in activating the AR, and discuss the enzymatic pathways and novel downstream metabolites mediating these effects. We conclude by discussing the potential implications of these findings for CRPC progression, particularly in context of new agents such as abiraterone and enzalutamide which target the AR-axis for prostate cancer therapy.

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Section: Introductionmentioning

confidence: 93%

Section: Novel Derivatives Of Adrenal Steroids Capable Of Activating mentioning

confidence: 99%

Section: Novel Derivatives Of Adrenal Steroids Capable Of Activating mentioning

confidence: 99%

Section: Novel Derivatives Of Adrenal Steroids Capable Of Activating mentioning

confidence: 99%

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Beyond T and DHT - Novel Steroid Derivatives Capable of Wild Type Androgen Receptor Activation

Mostaghel¹

2014

Int. J. Biol. Sci.

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“…This metabolite was previously thought to be a “waste product” of adrenal androgen production [34-36]. However, 11β-hydroxylation of androstenedione, catalyzed by CYP11B1, forms 11β-hydroxyandrostenedione, a precursor to an alternative pathway to active 11-oxygenated androgens [37, 38] (Fig. 1).…”

Section: Overview Of Adrenal Steroidogenesismentioning

confidence: 99%

Monogenic Disorders of Adrenal Steroidogenesis

2018

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Disorders of adrenal steroidogenesis comprise autosomal recessive conditions affecting steroidogenic enzymes of the adrenal cortex. Those are located within the 3 major branches of the steroidogenic machinery involved in the production of mineralocorticoids, glucocorticoids, and androgens. This mini review describes the principles of adrenal steroidogenesis, including the newly appreciated 11-oxygenated androgen pathway. This is followed by a description of pathophysiology, biochemistry, and clinical implications of steroidogenic disorders, including mutations affecting cholesterol import and steroid synthesis, the latter comprising both mutations affecting steroidogenic enzymes and co-factors required for efficient catalysis. A good understanding of adrenal steroidogenic pathways and their regulation is crucial as the basis for sound management of these disorders, which in the majority present in early childhood.

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Canonical and Noncanonical Androgen Metabolism and Activity

Storbeck

Mostaghel

2019

Advances in Experimental Medicine and Biology

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11β-Hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5α-reductase yielding 11β-hydroxy-5α-androstanedione

Cited by 85 publications

References 44 publications

Beyond T and DHT - Novel Steroid Derivatives Capable of Wild Type Androgen Receptor Activation

Beyond T and DHT - Novel Steroid Derivatives Capable of Wild Type Androgen Receptor Activation

Monogenic Disorders of Adrenal Steroidogenesis

Canonical and Noncanonical Androgen Metabolism and Activity

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