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Steroid Metabolism in Human Health and Disease 2.0

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: closed (31 May 2023) | Viewed by 18613

Special Issue Editor


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Guest Editor
Pediatric Endocrinology, Diabetology and Metabolism, University Children’s Hospital Bern And Department of Biomedical Research, University of Bern, Freiburgstrasse 15, 3010 Bern, Switzerland
Interests: steroid metabolism; steroidogenesis; pregnenolone; cytochrome P450; P450 oxidoreductase; CYP17A1; CYP19A1; androgens; estrogens
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Steroid hormones are necessary for life, from salt balance by mineralocorticoids, sugar balance by glucocorticoids, to the growth, reproductive, and sexual functions of sex steroids.

Steroid hormones are synthesized from cholesterol, starting from conversion, to pregnenolone, which is then converted to many different metabolites in a series of metabolic reactions.

Defects in the steroid metabolism cause a wide range of disorders, including the most common endocrine disorder in women, polycystic ovary syndrome. Therefore, control of steroid hormones production and signalling is an attractive target for the treatment of many metabolic disorders, including hormonal dependent cancers (targeting CYP17A1 and the androgen receptor in prostate cancer, and aromatase in breast cancer).

This Special Issue will focus on the molecular biology and biochemistry of steroid hormones in health and disease, and potential topics of interest may include, but are not limited, to the following:

  1. Molecular, cellular, and structural biology of steroid hormone production, regulation, and signalling in humans.
  2. Genetics and pathology of metabolic disorders caused by the changes in steroid metabolism, including the study of human mutations causing disordered steroidogenesis.
  3. Novel genes and mechanisms regulating steroid biosynthesis.
  4. Targeting of steroid hormone production, regulation, and signalling in metabolic disorders, including hormone-dependent cancers, by drugs and protein therapeutics.

Through this Special Issue, we aim to provide the latest work on the topic of steroid metabolism in human health and disease by experts in the field to a broad range of readership.

Dr. Amit V. Pandey
Guest Editor

Manuscript Submission Information

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Keywords

  • Steroid biosynthesis
  • Steroidogenesis
  • Androgen
  • Estrogen
  • Hormone-dependent cancers
  • Metabolic disorders
  • Steroid metabolizing enzymes

Published Papers (7 papers)

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Research

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19 pages, 6710 KiB  
Article
Neuroplastin Expression in Male Mice Is Essential for Fertility, Mating, and Adult Testosterone Levels
by Juanjuan Chen, Xiao Lin, Soumee Bhattacharya, Caroline Wiesehöfer, Gunther Wennemuth, Karin Müller and Dirk Montag
Int. J. Mol. Sci. 2024, 25(1), 177; https://doi.org/10.3390/ijms25010177 - 22 Dec 2023
Cited by 1 | Viewed by 956
Abstract
Male reproduction depends on hormonally driven behaviors and numerous genes for testis development and spermatogenesis. Neuroplastin-deficient (Nptn−/−) male mice cannot sire offspring. By immunohistochemistry, we characterized neuroplastin expression in the testis. Breeding, mating behavior, hormonal regulation, testicular development, and spermatogenesis [...] Read more.
Male reproduction depends on hormonally driven behaviors and numerous genes for testis development and spermatogenesis. Neuroplastin-deficient (Nptn−/−) male mice cannot sire offspring. By immunohistochemistry, we characterized neuroplastin expression in the testis. Breeding, mating behavior, hormonal regulation, testicular development, and spermatogenesis were analyzed in cell-type specific neuroplastin mutant mice. Leydig, Sertoli, peritubular myoid, and germ cells express Np, but spermatogenesis and sperm number are not affected in Nptn−/− males. Neuroplastin lack from CNS neurons or restricted to spermatogonia or Sertoli cells permitted reproduction. Normal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) blood levels in Nptn−/− males support undisturbed hormonal regulation in the brain. However, Nptn−/− males lack mounting behavior accompanied by low testosterone blood levels. Testosterone rise from juvenile to adult blood levels is absent in Nptn−/− males. LH-receptor stimulation raising intracellular Ca2+ in Leydig cells triggers testosterone production. Reduced Plasma Membrane Ca2+ ATPase 1 (PMCA1) in Nptn−/− Leydig cells suggests that Nptn−/− Leydig cells produce sufficient testosterone for testis and sperm development, but a lack of PMCA-Np complexes prevents the increase from reaching adult blood levels. Behavioral immaturity with low testosterone blood levels underlies infertility of Nptn−/− males, revealing that Np is essential for reproduction. Full article
(This article belongs to the Special Issue Steroid Metabolism in Human Health and Disease 2.0)
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14 pages, 2232 KiB  
Article
DHEA and Its Metabolites Reduce the Cytokines Involved in the Inflammatory Response and Fibrosis in Primary Biliary Cholangitis
by Małgorzata Blatkiewicz, Katarzyna Sielatycka, Katarzyna Piotrowska and Ewa Kilańczyk
Int. J. Mol. Sci. 2023, 24(6), 5301; https://doi.org/10.3390/ijms24065301 - 10 Mar 2023
Cited by 2 | Viewed by 1561
Abstract
Dehydroepiandrosterone (DHEA) is an abundant steroid and precursor of sex hormones. During aging, the reduction in DHEA synthesis causes a significant depletion of estrogens and androgens in different organs, such as the ovaries, brain, and liver. Primary Biliary Cholangitis (PBC) is a cholestatic [...] Read more.
Dehydroepiandrosterone (DHEA) is an abundant steroid and precursor of sex hormones. During aging, the reduction in DHEA synthesis causes a significant depletion of estrogens and androgens in different organs, such as the ovaries, brain, and liver. Primary Biliary Cholangitis (PBC) is a cholestatic liver disease that begins with immune-mediated bile duct damage, and is followed by liver fibrosis, and finally, cirrhosis. PBC primarily affects postmenopausal women, with an average age of diagnosis of 65 years, but younger women are also affected. Here, we analyzed the levels of DHEA, estradiol (E2), and estriol (E3) in the PBC sera of females at an age of diagnosis under 40 (n = 37) and above 65 (n = 29). Our results indicate that in PBC patients at an age of diagnosis under 40, E2 was significantly lower compared to that in healthy women. In contrast, the levels of DHEA and E3 were in a normal range. Furthermore, ELISA assays revealed that in PBC patients at an age of diagnosis above 65, the levels of DHEA, E2, and E3 significantly declined in comparison to those in younger patients. In addition, flow cytometry analysis showed that the level of IL-8 significantly decreased while the level of TNF-α increased in older PBC patients compared to younger ones. Moreover, we showed for the first time that the sulfonated form of DHEA, DHEA-S, reduces the levels of both pro-inflammatory interleukins, IL-8 and TNF-α, in PBC-like cholangiocytes (H69-miR506), while it diminishes the level of the pro-fibrotic interleukin, IL-13, in hepatocytes (Hep-G2). Finally, we demonstrated that the expression of the pro-fibrotic agent TGF-β significantly increased in both the early (F0–F3) and cirrhotic (F4) stages of PBC, and this elevation was accompanied by higher α-SMA expression. Full article
(This article belongs to the Special Issue Steroid Metabolism in Human Health and Disease 2.0)
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14 pages, 2361 KiB  
Article
Loss of Protein Stability and Function Caused by P228L Variation in NADPH-Cytochrome P450 Reductase Linked to Lower Testosterone Levels
by Maria Natalia Rojas Velazquez, Mathias Noebauer and Amit V. Pandey
Int. J. Mol. Sci. 2022, 23(17), 10141; https://doi.org/10.3390/ijms231710141 - 4 Sep 2022
Cited by 2 | Viewed by 2078
Abstract
Cytochrome P450 oxidoreductase (POR) is the redox partner of steroid and drug-metabolising cytochromes P450 located in the endoplasmic reticulum. Mutations in POR cause a broad range of metabolic disorders. The POR variant rs17853284 (P228L), identified by genome sequencing, has been linked to lower [...] Read more.
Cytochrome P450 oxidoreductase (POR) is the redox partner of steroid and drug-metabolising cytochromes P450 located in the endoplasmic reticulum. Mutations in POR cause a broad range of metabolic disorders. The POR variant rs17853284 (P228L), identified by genome sequencing, has been linked to lower testosterone levels and reduced P450 activities. We expressed the POR wild type and the P228L variant in bacteria, purified the proteins, and performed protein stability and catalytic functional studies. Variant P228L affected the stability of the protein as evidenced by lower unfolding temperatures and higher sensitivity to urea denaturation. A significant decline in the rate of electron transfer to cytochrome c and thiazolyl blue tetrazolium (MTT) was observed with POR P228L, while activities of CYP3A4 were reduced by 25% and activities of CYP3A5 and CYP2C9 were reduced by more than 40% compared with WT POR. The 17,20 lyase activity of CYP17A1, responsible for the production of the main androgen precursor dehydroepiandrosterone, was reduced to 27% of WT in the presence of the P228L variant of POR. Based on in silico and in vitro studies, we predict that the change of proline to leucine may change the rigidity of the protein, causing conformational changes in POR, leading to altered electron transfer to redox partners. A single amino acid change can affect protein stability and cause a severe reduction in POR activity. Molecular characterisation of individual POR mutations is crucial for a better understanding of the impact on different redox partners of POR. Full article
(This article belongs to the Special Issue Steroid Metabolism in Human Health and Disease 2.0)
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21 pages, 8830 KiB  
Article
Immunofluorescent Evidence for Nuclear Localization of Aromatase in Astrocytes in the Rat Central Nervous System
by Diána Kata, Ilona Gróf, Zsófia Hoyk, Eszter Ducza, Mária A. Deli, István Zupkó and Imre Földesi
Int. J. Mol. Sci. 2022, 23(16), 8946; https://doi.org/10.3390/ijms23168946 - 11 Aug 2022
Cited by 3 | Viewed by 2486
Abstract
Estrogens regulate a variety of neuroendocrine, reproductive and also non-reproductive brain functions. Estradiol biosynthesis in the central nervous system (CNS) is catalyzed by the enzyme aromatase, which is expressed in several brain regions by neurons, astrocytes and microglia. In this study, we performed [...] Read more.
Estrogens regulate a variety of neuroendocrine, reproductive and also non-reproductive brain functions. Estradiol biosynthesis in the central nervous system (CNS) is catalyzed by the enzyme aromatase, which is expressed in several brain regions by neurons, astrocytes and microglia. In this study, we performed a complex fluorescent immunocytochemical analysis which revealed that aromatase is colocalized with the nuclear stain in glial fibrillary acidic protein (GFAP) positive astrocytes in cell cultures. Confocal immunofluorescent Z-stack scanning analysis confirmed the colocalization of aromatase with the nuclear DAPI signal. Nuclear aromatase was also detectable in the S100β positive astrocyte subpopulation. When the nuclear aromatase signal was present, estrogen receptor alpha was also abundant in the nucleus. Immunostaining of frozen brain tissue sections showed that the nuclear colocalization of the enzyme in GFAP-positive astrocytes is also detectable in the adult rat brain. CD11b/c labelled microglial cells express aromatase, but the immunopositive signal was distributed only in the cytoplasm both in the ramified and amoeboid microglial forms. Immunostaining of rat ovarian tissue sections and human granulosa cells revealed that aromatase was present only in the cytoplasm. This novel observation suggests a new unique mechanism in astrocytes that may regulate certain CNS functions via estradiol production. Full article
(This article belongs to the Special Issue Steroid Metabolism in Human Health and Disease 2.0)
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19 pages, 3785 KiB  
Article
Characterization of Mutations Causing CYP21A2 Deficiency in Brazilian and Portuguese Populations
by Mayara J. Prado, Shripriya Singh, Rodrigo Ligabue-Braun, Bruna V. Meneghetti, Thaiane Rispoli, Cristiane Kopacek, Karina Monteiro, Arnaldo Zaha, Maria L. R. Rossetti and Amit V. Pandey
Int. J. Mol. Sci. 2022, 23(1), 296; https://doi.org/10.3390/ijms23010296 - 28 Dec 2021
Cited by 2 | Viewed by 2395
Abstract
Deficiency of 21-hydroxylase enzyme (CYP21A2) represents 90% of cases in congenital adrenal hyperplasia (CAH), an autosomal recessive disease caused by defects in cortisol biosynthesis. Computational prediction and functional studies are often the only way to classify variants to understand the links to disease-causing [...] Read more.
Deficiency of 21-hydroxylase enzyme (CYP21A2) represents 90% of cases in congenital adrenal hyperplasia (CAH), an autosomal recessive disease caused by defects in cortisol biosynthesis. Computational prediction and functional studies are often the only way to classify variants to understand the links to disease-causing effects. Here we investigated the pathogenicity of uncharacterized variants in the CYP21A2 gene reported in Brazilian and Portuguese populations. Physicochemical alterations, residue conservation, and effect on protein structure were accessed by computational analysis. The enzymatic performance was obtained by functional assay with the wild-type and mutant CYP21A2 proteins expressed in HEK293 cells. Computational analysis showed that p.W202R, p.E352V, and p.R484L have severely impaired the protein structure, while p.P35L, p.L199P, and p.P433L have moderate effects. The p.W202R, p.E352V, p.P433L, and p.R484L variants showed residual 21OH activity consistent with the simple virilizing phenotype. The p.P35L and p.L199P variants showed partial 21OH efficiency associated with the non-classical phenotype. Additionally, p.W202R, p.E352V, and p.R484L also modified the protein expression level. We have determined how the selected CYP21A2 gene mutations affect the 21OH activity through structural and activity alteration contributing to the future diagnosis and management of CYP21A2 deficiency. Full article
(This article belongs to the Special Issue Steroid Metabolism in Human Health and Disease 2.0)
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Review

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21 pages, 1516 KiB  
Review
Vitamin D3 Metabolism and Its Role in Temporomandibular Joint Osteoarthritis and Autoimmune Thyroid Diseases
by Michał Szulc, Renata Świątkowska-Stodulska, Elżbieta Pawłowska and Marcin Derwich
Int. J. Mol. Sci. 2023, 24(4), 4080; https://doi.org/10.3390/ijms24044080 - 17 Feb 2023
Cited by 4 | Viewed by 3992
Abstract
The aim of this review was to present the metabolism of vitamin D3, as well as to discuss the role of vitamin D3 in bone metabolism, temporomandibular joint osteoarthritis (TMJ OA), and autoimmune thyroid diseases (AITD) on the basis of [...] Read more.
The aim of this review was to present the metabolism of vitamin D3, as well as to discuss the role of vitamin D3 in bone metabolism, temporomandibular joint osteoarthritis (TMJ OA), and autoimmune thyroid diseases (AITD) on the basis of the literature. Vitamin D3 plays a significant role in human health, as it affects the calcium-phosphate balance and regulates the bone metabolism. Calcitriol impresses the pleiotropic effect on human biology and metabolism. Its modulative function upon the immune system is based on the reduction of Th1 cell activity and increased immunotolerance. Vitamin D3 deficiency may lead to an imbalance in the relationship between Th1/Th17 and Th2, Th17/Th reg, and is considered by some authors as one of the possible backgrounds of autoimmune thyroid diseases (AITD), e.g., Hashimoto’s thyroiditis or Graves’ disease. Moreover, vitamin D3, through its direct and indirect influence on bones and joints, may also play an important role in the development and progression of degenerative joint diseases, including temporomandibular joint osteoarthritis. Further randomized, double blind studies are needed to unequivocally confirm the relationship between vitamin D3 and abovementioned diseases and to answer the question concerning whether vitamin D3 supplementation may be used in the prevention and/or treatment of either AITD or OA diseases. Full article
(This article belongs to the Special Issue Steroid Metabolism in Human Health and Disease 2.0)
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19 pages, 1052 KiB  
Review
Hormone-Glutamine Metabolism: A Critical Regulatory Axis in Endocrine-Related Cancers
by Fengyuan Xu, Jialu Shi, Xueyun Qin, Zimeng Zheng, Min Chen, Zhi Lin, Jiangfeng Ye and Mingqing Li
Int. J. Mol. Sci. 2022, 23(17), 10086; https://doi.org/10.3390/ijms231710086 - 3 Sep 2022
Cited by 4 | Viewed by 3048
Abstract
The endocrine-related cancers and hormones are undoubtedly highly interconnected. How hormones support or repress tumor induction and progression has been extensively profiled. Furthermore, advances in understanding the role of glutamine metabolism in mediating tumorigenesis and development, coupled with these in-depth studies on hormone [...] Read more.
The endocrine-related cancers and hormones are undoubtedly highly interconnected. How hormones support or repress tumor induction and progression has been extensively profiled. Furthermore, advances in understanding the role of glutamine metabolism in mediating tumorigenesis and development, coupled with these in-depth studies on hormone (e.g., estrogen, progesterone, androgen, prostaglandin, thyroid hormone, and insulin) regulation of glutamine metabolism, have led us to think about the relationship between these three factors, which remains to be elucidated. Accordingly, in this review, we present an updated overview of glutamine metabolism traits and its influence on endocrine oncology, as well as its upstream hormonal regulation. More importantly, this hormone/glutamine metabolism axis may help in the discovery of novel therapeutic strategies for endocrine-related cancer. Full article
(This article belongs to the Special Issue Steroid Metabolism in Human Health and Disease 2.0)
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