Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review

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Graphical abstract

Highlights

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The serum metabolome does not reflect steroids activated in an intracrine manner.
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The urinary steroid metabolome reflects steroid biosynthesis and metabolism.
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Defined pathways link the circulating and urinary steroid metabolomes.
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Modern mass spectrometry techniques allow for comprehensive steroid profiling.

Abstract

Advances in technology have allowed for the sensitive, specific, and simultaneous quantitative profiling of steroid precursors, bioactive steroids and inactive metabolites, facilitating comprehensive characterization of the serum and urine steroid metabolomes. The quantification of steroid panels is therefore gaining favor over quantification of single marker metabolites in the clinical and research laboratories. However, although the biochemical pathways for the biosynthesis and metabolism of steroid hormones are now well defined, a gulf still exists between this knowledge and its application to the measured steroid profiles. In this review, we present an overview of steroid hormone biosynthesis and metabolism by the liver and peripheral tissues, specifically highlighting the pathways linking and differentiating the serum and urine steroid metabolomes. A brief overview of the methodology used in steroid profiling is also provided.

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Most cited references 314

Record: found
Abstract: found
Article: not found

K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension.

Murim Choi, Ute Scholl, Peng Yue … (2011)

Endocrine tumors such as aldosterone-producing adrenal adenomas (APAs), a cause of severe hypertension, feature constitutive hormone production and unrestrained cell proliferation; the mechanisms linking these events are unknown. We identify two recurrent somatic mutations in and near the selectivity filter of the potassium (K(+)) channel KCNJ5 that are present in 8 of 22 human APAs studied. Both produce increased sodium (Na(+)) conductance and cell depolarization, which in adrenal glomerulosa cells produces calcium (Ca(2+)) entry, the signal for aldosterone production and cell proliferation. Similarly, we identify an inherited KCNJ5 mutation that produces increased Na(+) conductance in a Mendelian form of severe aldosteronism and massive bilateral adrenal hyperplasia. These findings explain pathogenesis in a subset of patients with severe hypertension and implicate loss of K(+) channel selectivity in constitutive cell proliferation and hormone production.

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Record: found
Abstract: found
Article: found

Is Open Access

Worldwide Distribution of Cytochrome P450 Alleles: A Meta‐analysis of Population‐scale Sequencing Projects

Y Zhou, M Ingelman-Sundberg, VM Lauschke (2017)

Genetic polymorphisms in cytochrome P450 (CYP) genes can result in altered metabolic activity toward a plethora of clinically important medications. Thus, single nucleotide variants and copy number variations in CYP genes are major determinants of drug pharmacokinetics and toxicity and constitute pharmacogenetic biomarkers for drug dosing, efficacy, and safety. Strikingly, the distribution of CYP alleles differs considerably between populations with important implications for personalized drug therapy and healthcare programs. To provide a global distribution map of CYP alleles with clinical importance, we integrated whole‐genome and exome sequencing data from 56,945 unrelated individuals of five major human populations. By combining this dataset with population‐specific linkage information, we derive the frequencies of 176 CYP haplotypes, providing an extensive resource for major genetic determinants of drug metabolism. Furthermore, we aggregated this dataset into spectra of predicted functional variability in the respective populations and discuss the implications for population‐adjusted pharmacological treatment strategies.

0 comments Cited 222 times – based on 0 reviews      Review now

Record: found
Abstract: found
Article: not found

Sources of estrogen and their importance.

E.R Simpson (2003)

In premenopausal women, the ovaries are the principle source of estradiol, which functions as a circulating hormone to act on distal target tissues. However, in postmenopausal women when the ovaries cease to produce estrogen, and in men, this is no longer the case, because estradiol is no longer solely an endocrine factor. Instead, it is produced in a number of extragonadal sites and acts locally at these sites as a paracrine or even intracrine factor. These sites include the mesenchymal cells of adipose tissue including that of the breast, osteoblasts and chondrocytes of bone, the vascular endothelium and aortic smooth muscle cells, and numerous sites in the brain. Thus, circulating levels of estrogens in postmenopausal women and in men are not the drivers of estrogen action, they are reactive rather than proactive. This is because in these cases circulating estrogen originates in the extragonadal sites where it acts locally, and if it escapes local metabolism then it enters the circulation. Therefore, circulating levels reflect rather than direct estrogen action in postmenopausal women and in men. Tissue-specific regulation of CYP19 expression is achieved through the use of distinct promoters, each of which is regulated by different hormonal factors and second messenger signaling pathways. Thus, in the ovary, CYP19 expression is regulated by FSH which acts through cyclic AMP via the proximal promoter II, whereas in placenta the distal promoter I.1 regulates CYP19 expression in response to retinoids. In adipose tissue and bone by contrast, another distal promoter--promoter I.4--drives CYP19 expression under the control of glucocorticoids, class 1 cytokines and TNFalpha. The importance of this unique aspect of the tissue-specific regulation of aromatase expression lies in the fact that the low circulating levels of estrogens which are observed in postmenopausal women have little bearing on the concentrations of estrogen in, for example, a breast tumor, which can reach levels at least one order of magnitude greater than those present in the circulation, due to local synthesis within the breast. Thus, the estrogen which is responsible for breast cancer development, for the maintenance of bone mineralization and for the maintenance of cognitive function is not circulating estrogen but rather that which is produced locally at these specific sites within the breast, bone and brain. In breast adipose of breast cancer patients, aromatase activity and CYP19 expression are elevated. This occurs in response to tumor-derived factors such as prostaglandin E2 produced by breast tumor fibroblasts and epithelium as well as infiltrating macrophages. This increased CYP19 expression is associated with a switch in promoter usage from the normal adipose-specific promoter I.4 to the cyclic AMP responsive promoter, promoter II. Since these two promoters are regulated by different cohorts of transcription factors and coactivators, it follows that the differential regulation of CYP19 expression via alternative promoters in disease-free and cancerous breast adipose tissue may permit the development of selective aromatase modulators (SAMs) that target the aberrant overexpression of aromatase in cancerous breast, whilst sparing estrogen synthesis in other sites such as normal adipose tissue, bone and brain.

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Author and article information

Contributors

Karl-Heinz Storbeck

Journal

Journal ID (nlm-ta): J Steroid Biochem Mol Biol

Journal ID (iso-abbrev): J. Steroid Biochem. Mol. Biol

Title: The Journal of Steroid Biochemistry and Molecular Biology

Publisher: Pergamon

ISSN (Print): 0960-0760

ISSN (Electronic): 1879-1220

Publication date PMC-release: 1 November 2019

Publication date (Print): November 2019

Volume: 194

Electronic Location Identifier: 105439

Affiliations

[a ]Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UK

[b ]Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa

[c ]Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK

[d ]Department of Paediatric Endocrinology and Diabetes, Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Birmingham, UK

[e ]NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust & University of Birmingham, Birmingham, UK

[f ]UCSF Benioff Children’s Hospital Oakland Research Institute, Oakland, CA, USA

Author notes

[* ]Corresponding author at: Department of Biochemistry, Stellenbosch University, Private Bag X1, Matieland, 7602, South Africa. storbeck@ 123456sun.ac.za

[1]

Joint senior authors.

Article

Publisher ID: S0960-0760(19)30279-1 Publisher ID: 105439

DOI: 10.1016/j.jsbmb.2019.105439

PMC ID: 6857441

PubMed ID: 31362062

SO-VID: 8a94bd3d-dd19-4d25-ba38-70b08948ecbf

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

History

Date received : 15 May 2019

Date revision received : 24 July 2019

Date accepted : 25 July 2019

Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: A comprehensive review

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