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Molecular Insights in Steroid Biosynthesis and Metabolism
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Molecular Insights in Steroid Biosynthesis and Metabolism

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: 20 July 2025 | Viewed by 11185

Special Issue Editor

Dr. Amanda C. Swart

E-Mail Website
Guest Editor
Department of Biochemistry, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa
Interests: steroid biosynthesis and metabolism; biochemistry; molecular endocrinology; physiology; natural plant products

Special Issue Information

Dear Colleagues,

Steroid hormones are biosynthesized from cholesterol by the adrenal, gonads, placenta, and skin. In addition, steroid hormones are produced in the metabolism of precursor steroids in non-endocrine tissue such as the intestine, brain, kidneys, and adipose tissue, which express the appropriate steroidogenic enzymes. Since steroids play a pivotal role in normal physiology, steroid hormone dysfunction will be central to pathophysiology. Steroid hormone dysfunction has been associated with a host of clinical conditions linked to disorders due to deficient steroidogenic enzymes, the onset of Alzheimer’s, cancer, and kidney disease.

Steroid hormones have a central role within the endocrine system, controlling major physiological processes that include reproduction, sexual differentiation, growth, and development. Steroid hormones regulate cellular metabolism and energy balance while also maintaining nutrients, electrolyte, and water equilibrium in the blood. Steroids are also of important in the development and sexual differentiation of the brain. Besides having neuroprotective effects, these hormones influence cognition, stress, and memory performance. Steroid hormones also support the mobilization of the body’s defenses against stressors concerning inflammation and immunity. In regulating the innate immune response, steroids additionally influence the intestinal microbiota, with the microbiota in turn increasing inflammation by modulating steroid levels. Steroid hormones impact cardiovascular disease as do endogenous cardiac steroids, with endogenous ouabain influencing not only systemic blood pressure and heart functions but also kidney and brain functions.

The practice of hormone supplementation contributes either to the maintenance or to the disruption of the natural steroid hormone equilibrium. The supplementation of sex steroids includes hormone replacement therapies such as those replacing lost estrogen in menopause and testosterone supplementation in aging men. Within this context, anabolic steroids have far-reaching effects on the endocrine system, but their use or abuse continues regardless of these steroid derivatives contributing to disordered physiological processes and neurophysiological changes. 

The aim of this SI is to cover a wide range of topics and areas of interest. These include (but are not restricted to) the abovementioned aspects of steroidogenesis. Both original research and reviews will be considered.

Dr. Amanda C. Swart
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • steroid biosynthesis
  • steroid metabolism
  • aldo-keto reductase (AKR)
  • cytochrome P450
  • steroid reductase (SRD5A)
  • 17β-hydroxysteroid dehydrogenases (17βHSD)
  • 11β-hydroxysteroid dehydrogenase (11βHSD)
  • reproduction and sexual differentiation
  • endogenous cardiac steroids
  • anabolic steroids
  • prostate cancer
  • gut microbiome
  • immune system
  • inflammation
  • cardiovascular disease (CVD)
  • kidney function
  • hormone replacement therapy (HRT)

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Published Papers (6 papers)

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Research

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21 pages, 1531 KiB  
Article
NR5A1/SF-1 Collaborates with Inhibin α and the Androgen Receptor
by Rawda Naamneh Elzenaty, Chrysanthi Kouri, Idoia Martinez de Lapiscina, Kay-Sara Sauter, Francisca Moreno, Núria Camats-Tarruella and Christa E. Flück
Int. J. Mol. Sci. 2024, 25(18), 10109; https://doi.org/10.3390/ijms251810109 - 20 Sep 2024
Viewed by 1194
Abstract
Steroidogenic factor 1 (SF-1) is a nuclear receptor that regulates steroidogenesis and reproductive development. NR5A1/SF-1 variants are associated with a broad spectrum of phenotypes across individuals with disorders of sex development (DSDs). Oligogenic inheritance has been suggested as an explanation. SF-1 interacts [...] Read more.
Steroidogenic factor 1 (SF-1) is a nuclear receptor that regulates steroidogenesis and reproductive development. NR5A1/SF-1 variants are associated with a broad spectrum of phenotypes across individuals with disorders of sex development (DSDs). Oligogenic inheritance has been suggested as an explanation. SF-1 interacts with numerous partners. Here, we investigated a constellation of gene variants identified in a 46,XY severely undervirilized individual carrying an ACMG-categorized ‘pathogenic’ NR5A1/SF-1 variant in comparison to the healthy carrier father. Candidate genes were revealed by whole exome sequencing, and pathogenicity was predicted by different in silico tools. We found variants in NR1H2 and INHA associated with steroidogenesis, sex development, and reproduction. The identified variants were tested in cell models. Novel SF-1 and NR1H2 binding sites in the AR and INHA gene promoters were found. Transactivation studies showed that wild-type NR5A1/SF-1 regulates INHA and AR gene expression, while the NR5A1/SF-1 variant had decreased transcriptional activity. NR1H2 was found to regulate AR gene transcription; however, the NR1H2 variant showed normal activity. This study expands the NR5A1/SF-1 network of interacting partners, while not solving the exact interplay of different variants that might be involved in revealing the observed DSD phenotype. It also illustrates that understanding complex genetics in DSDs is challenging. Full article
(This article belongs to the Special Issue Molecular Insights in Steroid Biosynthesis and Metabolism)
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18 pages, 1029 KiB  
Article
The Role of 11-Oxygenated Androgens and Endocrine Disruptors in Androgen Excess Disorders in Women
by Jana Vitku, Anezka Varausova, Tereza Skodova, Lucie Kolatorova, Michala Vosatkova, Josef Vcelak, Jana Vrbikova, Marketa Simkova and Michaela Svojtkova
Int. J. Mol. Sci. 2024, 25(17), 9691; https://doi.org/10.3390/ijms25179691 - 7 Sep 2024
Viewed by 1630
Abstract
Polycystic ovary syndrome (PCOS) and idiopathic hirsutism (IH) are androgen excess disorders requiring the determination of classic androgen levels for diagnosis. 11-oxygenated androgens have high androgenic potential, yet their clinical value in those disorders is not clear. Additionally, the role of endocrine disruptors [...] Read more.
Polycystic ovary syndrome (PCOS) and idiopathic hirsutism (IH) are androgen excess disorders requiring the determination of classic androgen levels for diagnosis. 11-oxygenated androgens have high androgenic potential, yet their clinical value in those disorders is not clear. Additionally, the role of endocrine disruptors (EDs), particularly in IH, remains understudied. We analyzed 25 steroids and 18 EDs in plasma samples from women with IH, PCOS, and controls using LC-MS/MS. Cytokine levels and metabolic parameters were assessed. Comparisons included non-obese women with PCOS (n = 10), women with IH (n = 12) and controls (n = 20), and non-obese versus obese women with PCOS (n = 9). Higher levels of 11-oxygenated androgens were observed in women with PCOS compared to those with IH, but not controls. Conversely, 11-oxygenated androgen levels were lower in women with IH compared to controls. Cytokine levels did not differ between women with IH and controls. Bisphenol A (BPA) levels were higher in obese women with PCOS compared to non-obese women with PCOS. Bisphenol S occurrence was higher in women with PCOS (90%) compared to controls (65%) and IH (50%). Significant correlations were found between androgens (11-ketotestosterone, androstenedione, testosterone) and insulin and HOMA-IR, as well as between immunomodulatory 7-oxygenated metabolites of DHEA and nine interleukins. Our data confirms that PCOS is a multiendocrine gland disorder. Higher BPA levels in obese women might exacerbate metabolic abnormalities. IH was not confirmed as an inflammatory state, and no differences in BPA levels suggest BPA does not play a role in IH pathogenesis. Full article
(This article belongs to the Special Issue Molecular Insights in Steroid Biosynthesis and Metabolism)
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20 pages, 1098 KiB  
Article
C11-hydroxy and C11-oxo C19 and C21 Steroids: Pre-Receptor Regulation and Interaction with Androgen and Progesterone Steroid Receptors
by Rachelle Gent, Desmaré Van Rooyen, Stephen L. Atkin and Amanda C. Swart
Int. J. Mol. Sci. 2024, 25(1), 101; https://doi.org/10.3390/ijms25010101 - 20 Dec 2023
Cited by 3 | Viewed by 1717
Abstract
C11-oxy C19 and C11-oxy C21 steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation of C11-oxy steroids by 11β-hydroxysteroid dehydrogenase (11βHSD) interconversion and potential agonist and antagonist activity associated with [...] Read more.
C11-oxy C19 and C11-oxy C21 steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation of C11-oxy steroids by 11β-hydroxysteroid dehydrogenase (11βHSD) interconversion and potential agonist and antagonist activity associated with the androgen (AR) and progesterone receptors (PRA and PRB). Steroid conversions were investigated in transiently transfected HEK293 cells expressing 11βHSD1 and 11βHSD2, while CV1 cells were utilised for agonist and antagonist assays. The conversion of C11-hydroxy steroids to C11-oxo steroids by 11βHSD2 occurred more readily than the reverse reaction catalysed by 11βHSD1, while the interconversion of C11-oxy C19 steroids was more efficient than C11-oxy C21 steroids. Furthermore, 11-ketodihydrotestosterone (11KDHT), 11-ketotestosterone (11KT) and 11β-hydroxydihydrotestosterone (11OHDHT) were AR agonists, while only progestogens, 11β-hydroxyprogesterone (11βOHP4), 11β-hydroxydihydroprogesterone (11βOHDHP4), 11α-hydroxyprogesterone (11αOHP4), 11α-hydroxydihydroprogesterone (11αOHDHP4), 11-ketoprogesterone (11KP4), 5α-pregnan-17α-diol-3,11,20-trione (11KPdione) and 21-deoxycortisone (21dE) exhibited antagonist activity. C11-hydroxy C21 steroids, 11βOHP4, 11βOHDHP4 and 11αOHP4 exhibited PRA and PRB agonistic activity, while only C11-oxo steroids, 11KP4 and 11-ketoandrostanediol (11K3αdiol) demonstrated PRB agonism. While no steroids antagonised the PRA, 11OHA4, 11β-hydroxytestosterone (11OHT), 11KT and 11KDHT exhibited PRB antagonism. The regulatory role of 11βHSD isozymes impacting receptor activation is clear—C11-oxo androgens exhibit AR agonist activity; only C11-hydroxy progestogens exhibit PRA and PRB agonist activity. Regulation by the downstream metabolites of active C11-oxy steroids at the receptor level is apparent—C11-hydroxy and C11-oxo metabolites antagonize the AR and PRB, progestogens the former, androgens the latter. The findings highlight the intricate interplay between receptors and active as well as “inactive” C11-oxy steroids, suggesting novel regulatory tiers. Full article
(This article belongs to the Special Issue Molecular Insights in Steroid Biosynthesis and Metabolism)
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Graphical abstract

17 pages, 2883 KiB  
Article
Asymmetries of Left and Right Adrenal Glands in Neural Innervation and Glucocorticoids Production
by Rengui Saxu, Yong Yang and Harvest F. Gu
Int. J. Mol. Sci. 2023, 24(24), 17456; https://doi.org/10.3390/ijms242417456 - 14 Dec 2023
Cited by 1 | Viewed by 2013
Abstract
The adrenal gland is paired peripheral end organs of the neuroendocrine system and is responsible for producing crucial stress hormones from its two functional compartments, the adrenal cortex, and the adrenal medulla under stimuli. Left–right asymmetry in vertebrates exists from the central nervous [...] Read more.
The adrenal gland is paired peripheral end organs of the neuroendocrine system and is responsible for producing crucial stress hormones from its two functional compartments, the adrenal cortex, and the adrenal medulla under stimuli. Left–right asymmetry in vertebrates exists from the central nervous system to peripheral paired endocrine glands. The sided difference in the cerebral cortex is extensively investigated, while the knowledge of asymmetry of paired endocrine glands is still poor. The present study aims to investigate the asymmetries of bilateral adrenal glands, which play important roles in stress adaptation and energy homeostasis via steroid hormones produced from the distinct functional zones. Left and right adrenal glands from male C57BL/6J mice were initially histologically analyzed, and high-throughput RNA sequencing was then used to detect the gene transcriptional difference between left and right adrenal glands. Subsequently, the enrichment of functional pathways and ceRNA regulatory work was validated. The results demonstrated that the left adrenal gland had higher tissue mass and levels of energy expenditure, whereas the right adrenal gland appeared to be more potent in glucocorticoid secretion. Further analysis of adrenal stem/progenitor cell markers predicted that Shh signaling might play an important role in the left–right asymmetry of adrenal glands. Of the hub miRNAs, miRNA-466i-5p was identified in the left–right differential innervation of the adrenal glands. Therefore, the present study provides evidence that there are asymmetries between the left and right adrenal glands in glucocorticoid production and neural innervation, in which Shh signaling and miRNA-466i-5p play an important role. Full article
(This article belongs to the Special Issue Molecular Insights in Steroid Biosynthesis and Metabolism)
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Review

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36 pages, 17970 KiB  
Review
Updates on Mechanisms of Cytochrome P450 Catalysis of Complex Steroid Oxidations
by F. Peter Guengerich, Yasuhiro Tateishi, Kevin D. McCarty and Francis K. Yoshimoto
Int. J. Mol. Sci. 2024, 25(16), 9020; https://doi.org/10.3390/ijms25169020 - 20 Aug 2024
Cited by 2 | Viewed by 2064
Abstract
Cytochrome P450 (P450) enzymes dominate steroid metabolism. In general, the simple C-hydroxylation reactions are mechanistically straightforward and are generally agreed to involve a perferryl oxygen species (formally FeO3+). Several of the steroid transformations are more complex and involve C-C bond scission. [...] Read more.
Cytochrome P450 (P450) enzymes dominate steroid metabolism. In general, the simple C-hydroxylation reactions are mechanistically straightforward and are generally agreed to involve a perferryl oxygen species (formally FeO3+). Several of the steroid transformations are more complex and involve C-C bond scission. We initiated mechanistic studies with several of these (i.e., 11A1, 17A1, 19A1, and 51A1) and have now established that the dominant modes of catalysis for P450s 19A1 and 51A1 involve a ferric peroxide anion (i.e., Fe3+O2¯) instead of a perferryl ion complex (FeO3+), as demonstrated with 18O incorporation studies. P450 17A1 is less clear. The indicated P450 reactions all involve sequential oxidations, and we have explored the processivity of these multi-step reactions. P450 19A1 is distributive, i.e., intermediate products dissociate and reassociate, but P450s 11A1 and 51A1 are highly processive. P450 17A1 shows intermediate processivity, as expected from the release of 17-hydroxysteroids for the biosynthesis of key molecules, and P450 19A1 is very distributive. P450 11B2 catalyzes a processive multi-step oxidation process with the complexity of a chemical closure of an intermediate to a locked lactol form. Full article
(This article belongs to the Special Issue Molecular Insights in Steroid Biosynthesis and Metabolism)
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18 pages, 3252 KiB  
Review
5β-Dihydrosteroids: Formation and Properties
by Trevor M. Penning and Douglas F. Covey
Int. J. Mol. Sci. 2024, 25(16), 8857; https://doi.org/10.3390/ijms25168857 - 14 Aug 2024
Cited by 1 | Viewed by 1390
Abstract
5β-Dihydrosteroids are produced by the reduction of Δ4-3-ketosteroids catalyzed by steroid 5β-reductase (AKR1D1). By analogy with steroid 5α-reductase, genetic deficiency exists in AKR1D1 which leads to errors in newborn metabolism and in this case to bile acid deficiency. Also, like the [...] Read more.
5β-Dihydrosteroids are produced by the reduction of Δ4-3-ketosteroids catalyzed by steroid 5β-reductase (AKR1D1). By analogy with steroid 5α-reductase, genetic deficiency exists in AKR1D1 which leads to errors in newborn metabolism and in this case to bile acid deficiency. Also, like the 5α-dihydrosteroids (e.g., 5α-dihydrotestosterone), the 5β-dihydrosteroids produced by AKR1D1 are not inactive but regulate ligand access to nuclear receptors, can act as ligands for nuclear and membrane-bound receptors, and regulate ion-channel opening. For example, 5β-reduction of cortisol and cortisone yields the corresponding 5β-dihydroglucocorticoids which are inactive on the glucocorticoid receptor (GR) and provides an additional mechanism of pre-receptor regulation of ligands for the GR in liver cells. By contrast, 5β-pregnanes can act as neuroactive steroids at the GABAA and NMDA receptors and at low-voltage-activated calcium channels, act as tocolytic agents, have analgesic activity and act as ligands for PXR, while bile acids act as ligands for FXR and thereby control cholesterol homeostasis. The 5β-androstanes also have potent vasodilatory properties and work through blockade of Ca2+ channels. Thus, a preference for 5β-dihydrosteroids to work at the membrane level exists via a variety of mechanisms. This article reviews the field and identifies gaps in knowledge to be addressed in future research. Full article
(This article belongs to the Special Issue Molecular Insights in Steroid Biosynthesis and Metabolism)
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