Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood

Davio, Angela; Woolcock, Helen; Nanba, Aya T; Rege, Juilee; O’Day, Patrick; Ren, Jianwei; Zhao, Lili; Ebina, Hirotaka; Auchus, Richard J.; Rainey, William E.; Turcu, Adina F.

doi:10.1210/clinem/dgaa343

Cited by 57 publications

(47 citation statements)

References 25 publications

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“…We found that the 11-oxygenated androgen precursors 11OHA4 and 11KA4 persist after castration and correlate with 11KT. The concentrations detected in our patients without exogenous glucocorticoid treatment are comparable to previously reported concentration of 11OHA4 and 11KA4 in elderly men (17). In line with previous reports, we found that 11OHA4 is the most abundant 11-oxygenated androgen in the circulation, with a median concentration of 2.7 nmol/L (0.48 -5.1 nmol/L) in all CRPC patients, and 4.96 nmol/L (3.05 -6.13 nmol/) in patients who did not receive exogenous glucocorticoid treatment.…”

Section: Discussionsupporting

confidence: 91%

“…The adrenal-derived steroid 11-ketotestosterone (11KT) is of particular interest, as it is one of a few endogenous steroids capable of activating the AR at sub-nanomolar concentrations, similar to T and DHT (13)(14)(15). In healthy adult men, circulating T concentrations exceed those of 11KT (16,17). During ADT, gonadal steroidogenesis is inhibited and T concentrations typically fall below 0.5 nmol/L (18), which is lower than 11KT concentrations in healthy men (16).…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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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“…Subsequent studies have shown that 11KT circulates at similar or higher levels than T in healthy women and represents the predominant circulating androgen in androgen-excess conditions such as polycystic ovary syndrome and congenital adrenal hyperplasia ( 7-10 ). Moreover, unlike classic androgens, circulating levels of 11-oxygenated androgens appear not to decline after menopause ( 8 , 11 ).…”

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confidence: 99%

11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool

et al. 2020

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Androgens are the obligatory precursors of estrogens. In humans, classic androgen biosynthesis yields testosterone, thought to represent the predominant circulating active androgen both in men and women. However, recent work has shown that 11-ketotestosterone, derived from the newly described 11-oxygenated androgen biosynthesis pathway, makes a substantial contribution to the active androgen pool in women. Considering that classic androgens are the obligatory substrates for estrogen biosynthesis catalyzed by cytochrome P450 aromatase, we hypothesized that 11-oxygenated androgens are aromatizable. Here we use steroid analysis by tandem mass spectrometry to demonstrate that human aromatase generates 11-oxygenated estrogens from 11-oxygenated androgens in 3 different cell-based aromatase expression systems and in human ex vivo placenta explant cultures. We also show that 11-oxygenated estrogens are generated as a byproduct of the aromatization of classic androgens. We show that 11β-hydroxy-17β-estradiol binds and activates estrogen receptors α and β and that 11β-hydroxy-17β-estradiol and the classic androgen pathway-derived active estrogen, 17β-estradiol, are equipotent in stimulating breast cancer cell line proliferation and expression of estrogen-responsive genes. 11-oxygenated estrogens were, however, not detectable in serum from individuals with high aromatase levels (pregnant women) and elevated 11-oxygenated androgen levels (patients with congenital adrenal hyperplasia or adrenocortical carcinoma). Our data show that while 11-oxygenated androgens are aromatizable in vitro and ex vivo, the resulting 11-oxygenated estrogens are not detectable in circulation, suggesting that 11-oxygenated androgens function primarily as androgens in vivo.

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“…However, when assessing the effect of age on androgen activation in peripheral tissues, age-related changes in the supply of androgen precursors from circulation need to be considered, in addition to age-dependent changes in the expression of androgen-activating and -inactivating enzymes in the peripheral target tissues of androgen action. While circulating levels of classic androgens significantly decline with age, levels of 11-oxygenated androgens remain constant across adulthood (29,30). Hence, the peripheral activation of 11-oxygenated androgens is favored over the activation of classic androgens not only by the substrate preference of the key androgen activating enzyme AKR1C3, but also by constant high substrate availability across the life span.…”

Section: Discussionmentioning

confidence: 99%

Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens

Schiffer

Bossey

Akerman

et al. 2020

Preprint

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ContextAndrogens are important modulators of immune cell function impacting proliferation, differentiation and cytokine production. The local generation of active androgens from circulating androgen precursors is an important mediator of androgen action in peripheral androgen target cells of tissue.ObjectiveTo characterize the activation of classic and 11-oxygenated androgens in human peripheral blood mononuclear cells (PBMCs).MethodsPBMCs and natural killer cells were isolated from healthy male donors and incubated ex vivo with precursors and end products of the classic and 11-oxygenated androgen pathways. Steroid concentrations were quantified by liquid chromatography-tandem mass spectrometry. The expression of genes encoding steroid metabolizing enzymes was assessed by quantitative PCR.ResultsThe enzyme AKR1C3 is the major reductive 17β-hydroxysteroid dehydrogenase in PBMCs and has higher activity for the generation of the active 11-oxygenated androgen 11-ketotestosterone than for the generation of the classic androgen testosterone from their respective precursors. Natural killer cells are the major site of AKR1C3 expression and activity within the PBMC compartment. Steroid 5α-reductase type 1 catalyzes the 5α-reduction of classic but not 11-oxygenated androgens in PBMCs. Lag time prior to the separation of cellular components from whole blood sample increases 11KT serum concentrations in a time-dependent fashion, with significant increases detected from two hours after blood collection.Conclusions11-oxygenated androgens are the preferred substrates for androgen activation by AKR1C3 in PBMCs, primarily conveyed by natural killer cell AKR1C3 activity, yielding 11KT the major active androgen in PBMCs. Androgen metabolism by PBMCs can affect the levels of 11-oxygenated androgens measured in serum samples, if samples are not separated in a timely fashion.

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Sex Differences in 11-Oxygenated Androgen Patterns Across Adulthood

Cited by 57 publications

References 25 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

11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool

Peripheral blood mononuclear cells preferentially activate 11-oxygenated androgens

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