Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation
Open accessAbstract
CONTEXT: A broad analysis of adrenal gland-derived 19-carbon (C19) steroids has not been reported. This is the first study that uses liquid chromatography-tandem mass spectrometry to quantify 9 C19 steroids (androgens and their precursors), estrone, and estradiol in the adrenal vein (AV) of women, before and after ACTH stimulation. OBJECTIVE: The objective of this study was to define the adrenal androgen metabolome in women before and after ACTH infusion. DESIGN: This was a retrospective study. PATIENTS: Seven women, aged 50.4 ± 5.4 years, with suspected diagnosis of an adrenal aldosterone-producing adenoma were included in the study. METHODS: AV and iliac serum samples were collected before and after administration of ACTH (15 minutes). AV samples were analyzed using for concentrations of 9 unconjugated C19 steroids, estrone, and estradiol. Dehydroepiandrosterone sulfate (DHEA-S) was quantified by radioimmunoassay. RESULTS: AV levels of DHEA-S were the highest among the steroids measured. The most abundant unconjugated C19 steroids in AV were 11β-hydroxyandrostenedione (11OHA), dehydroepiandrosterone (DHEA), and androstenedione (A4). ACTH significantly increased the adrenal output of 9 of the 12 steroids that were measured. ACTH increased the mean AV concentration of DHEA-S by 5-fold, DHEA by 21-fold, A4 by 7-fold, and 11OHA by 5-fold. 11β-Hydroxytestosterone and testosterone were found to be potent androgen receptor agonists when tested with an androgen-responsive cell reporter model. CONCLUSION: The current study indicates that the adrenal gland secretes primarily 3 weak androgens, namely DHEA, 11OHA, and A4. Active androgens, including testosterone and 11β-hydroxytestosterone, are also produced but to a lesser degree.
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DHEAS is the most abundant steroid in circulation.
“This results in significant DHEAS output and accounts for DHEAS being the most abundant steroid in circulation (Table 2) [39,41].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [39]
Some DHEA is converted to androstenediol by AKR1C3, which exhibits minor expression in zona reticularis.
“Some of the resulting DHEA is converted to androstenediol by AKR1C3, which exhibits minor expression in the zona reticularis [39].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [39]
Low levels of 11KA4 and 11KT have been reported in adrenal vein samples and are suggested to result from some HSD11B2 activity in adrenal.
“Low levels of 11-ketoandrostenedione (11KA4) and 11-ketotestosterone (11KT) have also been reported in adrenal vein samples and are suggested to result from some HSD11B2 activity in the adrenal [39].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [39]
11OHA4 is by far predominant product due to significantly higher levels of A4 produced in zona reticularis.
“However, 11OHA4 is by far the predominant product due to the significantly higher levels of A4 produced in the zona reticularis [39].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [39]
Differences in concentration of 11KA4 measured in adrenal vein and inferior vena cava suggest that 11KA4 is predominantly produced from conversion of 11OHA4 in peripheral tissue expressing HSD11B2 such as kidney.
“However, differences in the concentration of 11KA4 measured in the adrenal vein and inferior vena cava suggest that 11KA4 is predominantly produced from conversion of 11OHA4 in peripheral tissue expressing HSD11B2 such as the kidney [39,69].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [39]
DHEAS is primarily thought to serve as an inactive waste product of adrenal steroidogenesis, produced to prevent an excessive androgen load.
“However, it is primarily thought to serve as an inactive waste product of adrenal steroidogenesis, produced to prevent an excessive androgen load [39,40,279].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [39]
11KA4 is the next most abundant 11-oxygenated androgen precursor in circulation.
“11KA4 is the next most abundant 11-oxygenated androgen precursor in circulation (Table 2) [39,41,68,69,289].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [39]
Although multiple studies have measured circulating concentrations of 11-oxygenated androgens in healthy control groups, there are significant variations in the levels reported and no reference ranges have been established to date.
“However, although multiple studies have measured the circulating concentrations of 11-oxygenated androgens in healthy control groups, there are significant variations in the levels reported and as such, no reference ranges have been established to date [39,41,68,69,289].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [39]
In the adrenal, DHEA can be converted to A4 by HSD3B2 and A4 can be transformed to T by AKR1C3.
“In the adrenal, DHEA can further be converted to A4 by HSD3B2 and A4 can be transformed to T by the low adrenal levels of aldo-keto-reductase family 1C3 (AKR1C3, also known as 17β-hydroxysteroid dehydrogensae type 5, HSD17B5), which has 17β-hydroxysteroid dehydrogenase (17βHSD) activity (Nakamura et al., 2009b, Rainey and Nakamura, 2008, Rege et al., 2013).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Rege et al., 2013
The adrenal glands produce significant levels of inactive C19 androgen precursors DHEA, DHEAS, A4 and 11OHA4, which in the majority are released into circulation.
“While the adrenal glands only produce low levels of the active androgen T, they produce significant levels of the inactive C19 androgen precursors dehydroepiandrosterone (DHEA, androst-5-ene-3βol-17-one) and its sulfate ester DHEAS, androstenedione (A4, androst-4-ene-3,17-dione) and 11β-hydroxyandrostenedione (11OHA4), which in the majority are released into circulation (Rege et al., 2013).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Rege et al., 2013
Adrenal vein sampling of healthy women has shown that the adrenal secretes DHEAS (low micromolar range) >> DHEA, 11OHA4, A4 (medium nanomolar ranges) > 5-diol, 11KA4, T, 11OHT, 11KT and DHT (low nanomolar ranges).
“Adrenal vein sampling of healthy women has shown that the adrenal secretes DHEAS (low micromolar range) » DHEA, 11OHA4, A4 (medium nanomolar ranges) > 5-diol, 11-ketoandrostenedione (11KA4), T, 11OHT, 11-ketotestosterone (11KT) and DHT (low nanomolar ranges) (Rege et al., 2013).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Rege et al., 2013
The expression of HSD11B2 is required for the activation of 11OHA4, which is the primary 11-oxygenated C19 androgen precursor in circulation.
“It should also be noted that the expression of HSD11B2, which encodes the oxidative HSD11B isoform, is required for the activation of 11OHA4, which is the primary 11-oxygenated C19 androgen precursor in circulation (Rege et al., 2013, Storbeck et al., 2013, Swart et al., 2013) (Table 2).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Rege et al., 2013
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- Authors
- Rege, J., Nakamura, Y., Satoh, F., Morimoto, R., Kennedy, M. R., Layman, L. C., Honma, S., Sasano, H., & Rainey, W. E.
- Affiliations
- Augusta University (US)
- Tohoku University (JP)
- Harbor BioSciences, Inc (M.R.K.), San Diego, California 92122
- Section of Reproductive Endocrinology, Infertility, and Genetics, Department of Obstetrics and Gynecology, Institute of Molecular Medicine and Genetics, Neuroscience Program (L.C.L.), Georgia Health Sciences University, Augusta, Georgia 30912
- ASKA Pharmaceutical (Japan) (JP)
- University of Michigan (US)
- Corresponding author
- Rainey, William E.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2013-03-01
- Volume
- 98
- Issue
- 3
- Pages
- 1182-1188
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC3590473
- OpenAlex
- W2120466082
- Cited by
- 227
- References
- 24
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 11 · 2023: 15 · 2022: 28 · 2021: 31 · 2020: 17 · 2019: 25 · 2018: 15 · 2017: 18 · 2016: 17 · 2015: 9 · 2014: 13 · 2013: 5
- FWCI
- 11.56
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK069950, R01DK069950)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Keywords
- adrenal vein, ACTH stimulation test, dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione, 11β-hydroxyandrostenedione, 11β-hydroxytestosterone, testosterone, estrone, estradiol, androgen receptor agonists, women
- MeSH terms
- Adrenal Cortex, Adrenocorticotropic Hormone, Androgens, Androstenedione, Androstenols, Cells, Cultured, Chromatography, Liquid, Dehydroepiandrosterone, Estradiol, Estrone, Female, Hormones, Humans, Middle Aged, Receptors, Androgen, Retrospective Studies, Testosterone, Veins, Dehydroepiandrosterone Sulfate, Tandem Mass Spectrometry, Metabolome
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