|
1
|
Ceolin C, Scala A, Rocca MS, Scagnet B, Marton M, Simonato C, Ziliotto C, De Rui M, Camozzi V, Giannini S, Basso D, Musso G, Ferlin A, Sergi G, Garolla A. Influence of androgen receptor on bone health in transgender adults: insights from the COMET study. J Endocrinol Invest 2025; 48:1237-1248. [PMID: 39746882 DOI: 10.1007/s40618-024-02522-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 12/24/2024] [Indexed: 01/04/2025]
Abstract
PURPOSE Previous studies show that transgender and gender-diverse (TGD) individuals, especially those assigned male at birth (AMAB), often have low bone mineral density (BMD) before beginning gender-affirming hormone therapy (GAHT). The reasons for this are not fully understood, and the potential role of androgen receptor (AR) polymorphisms - known to affect bone density in the general population - has not been explored. This study aims to assess the impact of AR polymorphisms on bone health in the TGD population. METHODS This is an observational study involving 135 TGD and 107 cisgender participants. Collected data included hormonal profiles and phospho-calcium metabolism, bone geometry and density (Dual Energy X-ray Absorptiometry and peripheral Quantitative Computed Tomography). For the genetic study related to the AR, genomic DNA was extracted from peripheral blood leukocytes. RESULTS TGD individuals had lower BMD values compared to their cisgender peers. In a subgroup of 129 individuals (86 TGD and 43 cisgender), we assessed the length of the polymorphic tracts of the AR gene and observed no differences between the groups. AR polymorphisms showed significant correlations only with cortical BMD in both TGD and cisgender assigned females at birth (AFAB) individuals, and negative correlations with trabecular BMD in both cisgender men and women. CONCLUSIONS Our study suggests that AR polymorphisms do not play a significant role in the low BMD values observed in TGD individuals at baseline. Further research is necessary to better understand the impact of factors such as lifestyle on the bone health of TGD individuals.
Collapse
Affiliation(s)
- Chiara Ceolin
- Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy.
- Department of Neurobiology, Care Sciences and Society, Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
- Regional Reference Center for Gender Incongruence (CRRIG) of the Veneto Region, University Hospital of Padova, Padua, Italy.
| | - Alberto Scala
- Regional Reference Center for Gender Incongruence (CRRIG) of the Veneto Region, University Hospital of Padova, Padua, Italy
- Unit of Andrology and Reproductive Medicine, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Maria Santa Rocca
- Unit of Andrology and Reproductive Medicine, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Bianca Scagnet
- Unit of Andrology and Reproductive Medicine, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Massimiliano Marton
- Unit of Andrology and Reproductive Medicine, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Cristina Simonato
- Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Chiara Ziliotto
- Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Marina De Rui
- Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Valentina Camozzi
- Regional Reference Center for Gender Incongruence (CRRIG) of the Veneto Region, University Hospital of Padova, Padua, Italy
- Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Sandro Giannini
- Regional Reference Center for Gender Incongruence (CRRIG) of the Veneto Region, University Hospital of Padova, Padua, Italy
- Clinica Medica 1, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Daniela Basso
- Regional Reference Center for Gender Incongruence (CRRIG) of the Veneto Region, University Hospital of Padova, Padua, Italy
- Laboratory Medicine Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Giulia Musso
- Regional Reference Center for Gender Incongruence (CRRIG) of the Veneto Region, University Hospital of Padova, Padua, Italy
- Laboratory Medicine Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Alberto Ferlin
- Regional Reference Center for Gender Incongruence (CRRIG) of the Veneto Region, University Hospital of Padova, Padua, Italy
- Unit of Andrology and Reproductive Medicine, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Giuseppe Sergi
- Geriatrics Division, Department of Medicine (DIMED), University of Padua, Padua, Italy
- Regional Reference Center for Gender Incongruence (CRRIG) of the Veneto Region, University Hospital of Padova, Padua, Italy
| | - Andrea Garolla
- Regional Reference Center for Gender Incongruence (CRRIG) of the Veneto Region, University Hospital of Padova, Padua, Italy
- Unit of Andrology and Reproductive Medicine, Department of Medicine (DIMED), University of Padua, Padua, Italy
| |
Collapse
|
|
2
|
Kałużewski T, Pinkier I, Wysocka U, Sałamunia J, Kępczyński Ł, Piotrowicz M, Kałużewski B, Gach A. Expanding the Molecular Landscape of Androgen Insensitivity Syndrome Through Next-Generation Sequencing. Appl Clin Genet 2024; 17:205-214. [PMID: 39722830 PMCID: PMC11669279 DOI: 10.2147/tacg.s498338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 11/27/2024] [Indexed: 12/28/2024] Open
Abstract
Androgen insensitivity syndrome (AIS) is an X-linked genetic disorder caused by mutations in the androgen receptor gene (AR), leading to impaired androgen signaling and resulting in varying degrees of undermasculinization in individuals with a 46,XY karyotype. This study aimed to expand the molecular landscape of AIS by identifying and characterizing pathogenic variants in the AR gene via next-generation sequencing (NGS). Molecular diagnostics revealed eight distinct variants within the AR gene, two of which had not been previously described. These include the following novel variants: c.3G>A, and c.1344_1345insTA. This study broadens the spectrum of known AR gene mutations associated with AIS and highlights the critical role of molecular diagnostics in the accurate classification of variants. These findings will aid in enhancing the clinical management and genetic counseling of individuals affected by AIS.
Collapse
Affiliation(s)
- Tadeusz Kałużewski
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, 93-338, Poland
- R&D Division, Laboratory of Medical Genetics, GENOS Sp. z o.o., Lodz, 91-033, Poland
| | - Iwona Pinkier
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, 93-338, Poland
| | - Urszula Wysocka
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, 93-338, Poland
| | - Jordan Sałamunia
- R&D Division, Laboratory of Medical Genetics, GENOS Sp. z o.o., Lodz, 91-033, Poland
| | - Łukasz Kępczyński
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, 93-338, Poland
- R&D Division, Laboratory of Medical Genetics, GENOS Sp. z o.o., Lodz, 91-033, Poland
| | - Małgorzata Piotrowicz
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, 93-338, Poland
| | - Bogdan Kałużewski
- R&D Division, Laboratory of Medical Genetics, GENOS Sp. z o.o., Lodz, 91-033, Poland
| | - Agnieszka Gach
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, 93-338, Poland
| |
Collapse
|
|
3
|
Hsu SH, Chen LR, Chen KH. Primary Osteoporosis Induced by Androgen and Estrogen Deficiency: The Molecular and Cellular Perspective on Pathophysiological Mechanisms and Treatments. Int J Mol Sci 2024; 25:12139. [PMID: 39596206 PMCID: PMC11593909 DOI: 10.3390/ijms252212139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 11/02/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
Primary osteoporosis is closely linked to hormone deficiency, which disrupts the balance of bone remodeling. It affects postmenopausal women but also significantly impacts older men. Estrogen can promote the production of osteoprotegerin, a decoy receptor for RANKL, thereby preventing RANKL from activating osteoclasts. Furthermore, estrogen promotes osteoblast survival and function via activation of the Wnt signaling pathway. Likewise, androgens play a critical role in bone metabolism, primarily through their conversion to estrogen in men. Estrogen deficiency accelerates bone resorption through a rise in pro-inflammatory cytokines (IL-1, IL-6, TNF-α) and RANKL, which promote osteoclastogenesis. In the classic genomic pathway, estrogen binds to estrogen receptors in the cytoplasm, forming a complex that migrates to the nucleus and binds to estrogen response elements on DNA, regulating gene transcription. Androgens can be defined as high-affinity ligands for the androgen receptor; their combination can serve as a ligand-inducible transcription factor. Hormone replacement therapy has shown promise but comes with associated risks and side effects. In contrast, the non-genomic pathway involves rapid signaling cascades initiated at the cell membrane, influencing cellular functions without directly altering gene expression. Therefore, the ligand-independent actions and rapid signaling pathways of estrogen and androgen receptors can be harnessed to develop new drugs that provide bone protection without the side effects of traditional hormone therapies. To manage primary osteoporosis, other pharmacological treatments (bisphosphonates, teriparatide, RANKL inhibitors, sclerostin inhibitors, SERMs, and calcitonin salmon) can ameliorate osteoporosis and improve BMD via actions on different pathways. Non-pharmacological treatments include nutritional support and exercise, as well as the dietary intake of antioxidants and natural products. The current study reviews the processes of bone remodeling, hormone actions, hormone receptor status, and therapeutic targets of primary osteoporosis. However, many detailed cellular and molecular mechanisms underlying primary osteoporosis seem complicated and unexplored and warrant further investigation.
Collapse
Affiliation(s)
- Shao-Heng Hsu
- Department of Medical Education, Taipei Tzu-Chi Hospital, The Buddhist Tzu-Chi Medical Foundation, New Taipei City 231, Taiwan;
| | - Li-Ru Chen
- Department of Physical Medicine and Rehabilitation, Mackay Memorial Hospital, Taipei 104, Taiwan;
- Department of Mechanical Engineering, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Kuo-Hu Chen
- Department of Obstetrics and Gynecology, Taipei Tzu-Chi Hospital, The Buddhist Tzu-Chi Medical Foundation, New Taipei City 231, Taiwan
- School of Medicine, Tzu-Chi University, Hualien 970, Taiwan
| |
Collapse
|
|
4
|
Lengyel K, Rudra M, Berghof TVL, Leitão A, Frankl-Vilches C, Dittrich F, Duda D, Klinger R, Schleibinger S, Sid H, Trost L, Vikkula H, Schusser B, Gahr M. Unveiling the critical role of androgen receptor signaling in avian sexual development. Nat Commun 2024; 15:8970. [PMID: 39419984 PMCID: PMC11487053 DOI: 10.1038/s41467-024-52989-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 09/24/2024] [Indexed: 10/19/2024] Open
Abstract
Gonadal hormone activities mediated by androgen and estrogen receptors, along with cell-autonomous mechanisms arising from the absence of sex-chromosome dosage compensation, are key factors in avian sexual development. In this study, we generate androgen receptor (AR) knockout chickens (AR-/-) to explore the role of androgen signaling in avian sexual development. Despite developing sex-typical gonads and gonadal hormone production, AR-/- males and females are infertile. While few somatic sex-specific traits persist (body size, spurs, and tail feathers), crucial sexual attributes such as comb, wattles and sexual behaviors remain underdeveloped in both sexes. Testosterone treatment of young AR-/- males fails to induce crow behavior, comb development, or regression of the bursa of Fabricius, which are testosterone-dependent phenotypes. These findings highlight the significance of androgen receptor mechanisms in fertility and sex-specific traits in chickens, challenging the concept of a default sex in birds and emphasizing the dominance of androgen signaling in avian sexual development.
Collapse
Affiliation(s)
- Kamila Lengyel
- Department of Behavioural Neurobiology, Max Planck Institute for Biological Intelligence, Seewiesen, Germany
- Reproductive Biotechnology, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Mekhla Rudra
- Department of Behavioural Neurobiology, Max Planck Institute for Biological Intelligence, Seewiesen, Germany
| | - Tom V L Berghof
- Reproductive Biotechnology, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Albertine Leitão
- Department of Behavioural Neurobiology, Max Planck Institute for Biological Intelligence, Seewiesen, Germany
| | - Carolina Frankl-Vilches
- Department of Behavioural Neurobiology, Max Planck Institute for Biological Intelligence, Seewiesen, Germany
| | - Falk Dittrich
- Department of Behavioural Neurobiology, Max Planck Institute for Biological Intelligence, Seewiesen, Germany
| | - Denise Duda
- Reproductive Biotechnology, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Romina Klinger
- Reproductive Biotechnology, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Sabrina Schleibinger
- Reproductive Biotechnology, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Hicham Sid
- Reproductive Biotechnology, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Lisa Trost
- Department of Behavioural Neurobiology, Max Planck Institute for Biological Intelligence, Seewiesen, Germany
| | - Hanna Vikkula
- Reproductive Biotechnology, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Benjamin Schusser
- Reproductive Biotechnology, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Manfred Gahr
- Department of Behavioural Neurobiology, Max Planck Institute for Biological Intelligence, Seewiesen, Germany.
| |
Collapse
|
|
5
|
Lee J, Yurkovetskiy LA, Reiman D, Frommer L, Strong Z, Chang A, Kahaly GJ, Khan AA, Chervonsky AV. Androgens contribute to sex bias of autoimmunity in mice by T cell-intrinsic regulation of Ptpn22 phosphatase expression. Nat Commun 2024; 15:7688. [PMID: 39227386 PMCID: PMC11372096 DOI: 10.1038/s41467-024-51869-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 08/21/2024] [Indexed: 09/05/2024] Open
Abstract
Autoimmune diseases such as systemic lupus erythematosus (SLE) display a strong female bias. Although sex hormones have been associated with protecting males from autoimmunity, the molecular mechanisms are incompletely understood. Here we report that androgen receptor (AR) expressed in T cells regulates genes involved in T cell activation directly, or indirectly via controlling other transcription factors. T cell-specific deletion of AR in mice leads to T cell activation and enhanced autoimmunity in male mice. Mechanistically, Ptpn22, a phosphatase and negative regulator of T cell receptor signaling, is downregulated in AR-deficient T cells. Moreover, a conserved androgen-response element is found in the regulatory region of Ptpn22 gene, and the mutation of this transcription element in non-obese diabetic mice increases the incidence of spontaneous and inducible diabetes in male mice. Lastly, Ptpn22 deficiency increases the disease severity of male mice in a mouse model of SLE. Our results thus implicate AR-regulated genes such as PTPN22 as potential therapeutic targets for autoimmune diseases.
Collapse
MESH Headings
- Animals
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/metabolism
- Male
- Female
- Autoimmunity
- Receptors, Androgen/metabolism
- Receptors, Androgen/genetics
- Mice
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Lupus Erythematosus, Systemic/immunology
- Lupus Erythematosus, Systemic/genetics
- Androgens/metabolism
- Mice, Knockout
- Lymphocyte Activation
- Mice, Inbred NOD
- Mice, Inbred C57BL
- Disease Models, Animal
- Signal Transduction
Collapse
Affiliation(s)
- Jean Lee
- Committee on Cancer Biology, The University of Chicago, Chicago, IL, 60637, USA
- Department of Pathology, The University of Chicago, Chicago, IL, 60637, USA
| | - Leonid A Yurkovetskiy
- Department of Pathology, The University of Chicago, Chicago, IL, 60637, USA
- Committee on Microbiology, The University of Chicago, Chicago, IL, 60637, USA
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA
| | - Derek Reiman
- Toyota Technological Institute at Chicago, Chicago, IL, 60637, USA
| | - Lara Frommer
- Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, 55101, Germany
| | - Zoe Strong
- Department of Pathology, The University of Chicago, Chicago, IL, 60637, USA
| | - Anthony Chang
- Department of Pathology, The University of Chicago, Chicago, IL, 60637, USA
| | - George J Kahaly
- Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, 55101, Germany
| | - Aly A Khan
- Department of Pathology, The University of Chicago, Chicago, IL, 60637, USA.
- Toyota Technological Institute at Chicago, Chicago, IL, 60637, USA.
- Department of Family Medicine, The University of Chicago, Chicago, IL, 60637, USA.
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA.
| | - Alexander V Chervonsky
- Department of Pathology, The University of Chicago, Chicago, IL, 60637, USA.
- Committee on Microbiology, The University of Chicago, Chicago, IL, 60637, USA.
- Committee on Immunology, The University of Chicago, Chicago, IL, 60637, USA.
| |
Collapse
|
|
6
|
Dart DA, Bevan CL, Uysal-Onganer P, Jiang WG. Analysis of androgen receptor expression and activity in the mouse brain. Sci Rep 2024; 14:11115. [PMID: 38750183 PMCID: PMC11096401 DOI: 10.1038/s41598-024-61733-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 05/09/2024] [Indexed: 05/18/2024] Open
Abstract
Androgen deprivation therapy (ADT) is the core treatment for advanced prostate cancer (PCa), with a proven survival benefit. ADT lowers circulating testosterone levels throughout the body, but with it comes a variety of reported side effects including fatigue, muscle wastage, weight gain, hot flushes and importantly cognitive impairment, depression, and mood swings. Testosterone has a key role in brain masculinization, but its direct effects are relatively poorly understood, due both to the brain's extreme complexity and the fact that some of testosterone activities are driven via local conversion to oestrogen, especially during embryonic development. The exact roles, function, and location of the androgen receptor (AR) in the adult male brain are still being discovered, and therefore the cognitive side effects of ADT may be unrecognized or under-reported. The age of onset of several neurological diseases overlap with PCa, therefore, there is a need to separate ADT side effects from such co-morbidities. Here we analysed the activity and expression level of the AR in the adult mouse brain, using an ARE-Luc reporter mouse and immunohistochemical staining for AR in all the key brain regions via coronal slices. We further analysed our data by comparing to the Allen Mouse Brain Atlas. AR-driven luciferase activity and distinct nuclear staining for AR were seen in several key brain areas including the thalamus, hypothalamus, olfactory bulb, cerebral cortex, Purkinje cells of the cerebellum and the hindbrain. We describe and discuss the potential role of AR in these areas, to inform and enable extrapolation to potential side effects of ADT in humans.
Collapse
Affiliation(s)
- D Alwyn Dart
- UCL (University College London) Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6DD, UK.
- Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, W12 0NN, UK.
- Cardiff China Medical Research Collaborative, School of Medicine, Cardiff University, Cardiff, CF14 4YS, UK.
| | - Charlotte L Bevan
- Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, W12 0NN, UK
| | - Pinar Uysal-Onganer
- Cancer Mechanisms and Biomarkers Research Group, School of Life Sciences, College of Liberal Arts and Sciences, University of Westminster, 115 New Cavendish Street, London, W1W 6UW, UK
| | - Wen Guo Jiang
- Cardiff China Medical Research Collaborative, School of Medicine, Cardiff University, Cardiff, CF14 4YS, UK
| |
Collapse
|
|
7
|
Jia JY, Chen GH, Shu TT, Lou QY, Jin X, He JY, Xiao WH, Zhai G, Yin Z. Androgen signaling inhibits de novo lipogenesis to alleviate lipid deposition in zebrafish. Zool Res 2024; 45:355-366. [PMID: 38485505 PMCID: PMC11017085 DOI: 10.24272/j.issn.2095-8137.2023.324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 01/15/2024] [Indexed: 03/19/2024] Open
Abstract
Testosterone is closely associated with lipid metabolism and known to affect body fat composition and muscle mass in males. However, the mechanisms by which testosterone acts on lipid metabolism are not yet fully understood, especially in teleosts. In this study, cyp17a1-/- zebrafish ( Danio rerio) exhibited excessive visceral adipose tissue (VAT), lipid content, and up-regulated expression and activity of hepatic de novo lipogenesis (DNL) enzymes. The assay for transposase accessible chromatin with sequencing (ATAC-seq) results demonstrated that chromatin accessibility of DNL genes was increased in cyp17a1-/- fish compared to cyp17a1+/+ male fish, including stearoyl-CoA desaturase ( scd) and fatty acid synthase ( fasn). Androgen response element (ARE) motifs in the androgen signaling pathway were significantly enriched in cyp17a1+/+ male fish but not in cyp17a1-/- fish. Both androgen receptor ( ar)-/- and wild-type (WT) zebrafish administered with Ar antagonist flutamide displayed excessive visceral adipose tissue, lipid content, and up-regulated expression and activity of hepatic de novo lipogenesis enzymes. The Ar agonist BMS-564929 reduced the content of VAT and lipid content, and down-regulated acetyl-CoA carboxylase a ( acaca), fasn, and scd expression. Mechanistically, the rescue effect of testosterone on cyp17a1-/- fish in terms of phenotypes was abolished when ar was additionally depleted. Collectively, these findings reveal that testosterone inhibits lipid deposition by down-regulating DNL genes via Ar in zebrafish, thus expanding our understanding of the relationship between testosterone and lipid metabolism in teleosts.
Collapse
Affiliation(s)
- Jing-Yi Jia
- College of Fisheries, Huazhong Agriculture University, Wuhan, Hubei 430070, China
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, China
| | - Guang-Hui Chen
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, China
| | - Ting-Ting Shu
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
- Hubei Key Laboratory of Three Gorges Project for Conservation of Fishes, Chinese Sturgeon Research Institute, China Three Gorges Corporation, Yichang, Hubei 443100, China
| | - Qi-Yong Lou
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, China
| | - Xia Jin
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, China
| | - Jiang-Yan He
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, China
| | - Wu-Han Xiao
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, China
| | - Gang Zhai
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
- Hubei Hongshan Laboratory, Huazhong Agriculture University, Wuhan, Hubei 430070, China. E-mail:
| | - Zhan Yin
- College of Fisheries, Huazhong Agriculture University, Wuhan, Hubei 430070, China
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei 430072, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
- Hubei Hongshan Laboratory, Huazhong Agriculture University, Wuhan, Hubei 430070, China
- Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing 100049, China. E-mail:
| |
Collapse
|
|
8
|
Yin L, Qi S, Zhu Z. Advances in mitochondria-centered mechanism behind the roles of androgens and androgen receptor in the regulation of glucose and lipid metabolism. Front Endocrinol (Lausanne) 2023; 14:1267170. [PMID: 37900128 PMCID: PMC10613047 DOI: 10.3389/fendo.2023.1267170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 09/28/2023] [Indexed: 10/31/2023] Open
Abstract
An increasing number of studies have reported that androgens and androgen receptors (AR) play important roles in the regulation of glucose and lipid metabolism. Impaired glucose and lipid metabolism and the development of obesity-related diseases have been found in either hypogonadal men or male rodents with androgen deficiency. Exogenous androgens supplementation can effectively improve these disorders, but the mechanism by which androgens regulate glucose and lipid metabolism has not been fully elucidated. Mitochondria, as powerhouses within cells, are key organelles influencing glucose and lipid metabolism. Evidence from both pre-clinical and clinical studies has reported that the regulation of glucose and lipid metabolism by androgens/AR is strongly associated with the impact on the content and function of mitochondria, but few studies have systematically reported the regulatory effect and the molecular mechanism. In this paper, we review the effect of androgens/AR on mitochondrial content, morphology, quality control system, and function, with emphases on molecular mechanisms. Additionally, we discuss the sex-dimorphic effect of androgens on mitochondria. This paper provides a theoretical basis for shedding light on the influence and mechanism of androgens on glucose and lipid metabolism and highlights the mitochondria-based explanation for the sex-dimorphic effect of androgens on glucose and lipid metabolism.
Collapse
Affiliation(s)
- Lijun Yin
- School of Sport, Shenzhen University, Shenzhen, China
| | - Shuo Qi
- School of Sport Health, Shandong Sport University, Jinan, China
| | - Zhiqiang Zhu
- School of Sport, Shenzhen University, Shenzhen, China
| |
Collapse
|
|
9
|
Shindo S, Kakizaki S, Sakaki T, Kawasaki Y, Sakuma T, Negishi M, Shizu R. Phosphorylation of nuclear receptors: Novelty and therapeutic implications. Pharmacol Ther 2023; 248:108477. [PMID: 37330113 DOI: 10.1016/j.pharmthera.2023.108477] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 05/20/2023] [Accepted: 06/06/2023] [Indexed: 06/19/2023]
Abstract
Nuclear receptors (NR) collectively regulate several biological functions in various organs. While NRs can be characterized by activation of the transcription of their signature genes, they also have other diverse roles. Although most NRs are directly activated by ligand binding, which induces cascades of events leading to gene transcription, some NRs are also phosphorylated. Despite extensive investigations, primarily focusing on unique phosphorylation of amino acid residues in different NRs, the role of phosphorylation in the biological activity of NRs in vivo has not been firmly established. Recent studies on the phosphorylation of conserved phosphorylation motifs within the DNA- and ligand-binding domains confirmed has indicated the physiologically relevance of NR phosphorylation. This review focuses on estrogen and androgen receptors, and highlights the concept of phosphorylation as a drug target.
Collapse
Affiliation(s)
- Sawako Shindo
- Department of Environmental Toxicology, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
| | - Satoru Kakizaki
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki, Gunma 370-0829, Japan
| | - Toshiyuki Sakaki
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan
| | - Yuki Kawasaki
- Laboratory of Public Health, Faculty of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaourui-machi, Takasaki, Gunma 370-0033, Japan
| | - Tsutomu Sakuma
- School of Pharmaceutical Sciences, Ohu University, Koriyama, Fukushima 963-8611, Japan
| | - Masahiko Negishi
- Reproductive and Developmental Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
| | - Ryota Shizu
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
| |
Collapse
|
|
10
|
Poznyak AV, Sukhorukov VN, Guo S, Postnov AY, Orekhov AN. Sex Differences Define the Vulnerability to Atherosclerosis. CLINICAL MEDICINE INSIGHTS-CARDIOLOGY 2023; 17:11795468231189044. [PMID: 37529084 PMCID: PMC10387777 DOI: 10.1177/11795468231189044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Accepted: 07/03/2023] [Indexed: 08/03/2023]
Abstract
For several decades, atherosclerosis has attracted the attention of researchers around the world. Even being a major cause of serious cardiovascular disease and events, atherosclerosis is still not fully understood. Despite the fact that the main players in the pathogenesis of atherosclerosis are well known, many mechanisms of their implementation and interactions remain unknown. The same can be said about the risk factors for atherosclerosis. Many of them are known, but exactly how they work remains to be seen. The main objective of this review is to summarize the latest data on sex as a biological variable in atherosclerosis in humans and animals; to determine what we do not still know about how sex affects the process of growth and complications of atherosclerosis. In this review, we summarized data on sex differences at 3 atherosclerotic aspects: inflammation, vascular remodeling, and plaque morphology. With all overviewed data, we came to the conclusion on the atheroprotective role of female sex.
Collapse
Affiliation(s)
| | - Vasiliy N Sukhorukov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Shuzhen Guo
- Diabetes Research Center, School of Traditional Chinese Medicine, Beijing University of Chinese, Beijing, China
| | - Anton Y Postnov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Federal State Budgetary Scientific Institution «Petrovsky National Research Centre of Surgery» (FSBSI “Petrovsky NRCS”), Moscow, Russia
| | - Alexander N Orekhov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Moscow, Russia
| |
Collapse
|
|
11
|
Conte C, Antonelli G, Melica ME, Tarocchi M, Romagnani P, Peired AJ. Role of Sex Hormones in Prevalent Kidney Diseases. Int J Mol Sci 2023; 24:ijms24098244. [PMID: 37175947 PMCID: PMC10179191 DOI: 10.3390/ijms24098244] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/29/2023] [Accepted: 05/03/2023] [Indexed: 05/15/2023] Open
Abstract
Chronic kidney disease (CKD) is a constantly growing global health burden, with more than 840 million people affected worldwide. CKD presents sex disparities in the pathophysiology of the disease, as well as in the epidemiology, clinical manifestations, and disease progression. Overall, while CKD is more frequent in females, males have a higher risk to progress to end-stage kidney disease. In recent years, numerous studies have highlighted the role of sex hormones in the health and diseases of several organs, including the kidney. In this review, we present a clinical overview of the sex-differences in CKD and a selection of prominent kidney diseases causing CKD: lupus nephritis, diabetic kidney disease, IgA nephropathy, and autosomal dominant polycystic kidney disease. We report clinical and experimental findings on the role of sex hormones in the development of the disease and its progression to end-stage kidney disease.
Collapse
Affiliation(s)
- Carolina Conte
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
- Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, 50139 Florence, Italy
| | - Giulia Antonelli
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
- Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, 50139 Florence, Italy
| | - Maria Elena Melica
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Mirko Tarocchi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| | - Paola Romagnani
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
- Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS, 50139 Florence, Italy
| | - Anna Julie Peired
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134 Florence, Italy
| |
Collapse
|
|
12
|
Yokobori K, Negishi M. Ser815 Phosphorylation stabilizes the androgen receptor homodimer and stimulates ER-stress induced cell death. Biochem Biophys Res Commun 2023; 639:54-61. [PMID: 36470072 PMCID: PMC9805519 DOI: 10.1016/j.bbrc.2022.11.083] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 11/26/2022] [Indexed: 11/29/2022]
Abstract
Androgen receptor, which regulates diverse biological processes for cell fate decisions, forms a homodimer in the cytoplasm and is monomerized by activation for nuclear translocation. Ser815 phosphorylated AR is expressed in mature prostates, with levels decreased by castration in mice or prostate cancer progression in humans. Here, we have examined the functional and biological roles of phosphorylation. AR phosphorylation at Ser815 stabilized homodimer formation in the cytoplasm, interrupting DHT-response nuclear translocation. cDNA microarray studies in castrated mouse prostates implied castration attenuates ER stress responses, suggesting AR phosphorylation acts on ER stress responses. In addition, AR Ser815Asp phospho-mimetic mutant expression augmented ER stress-induced death in PC-3 cells. These results suggested that phosphorylation at AR Ser815 modulates AR functions for maintaining the prostate.
Collapse
Affiliation(s)
- Kosuke Yokobori
- Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.
| | - Masahiko Negishi
- Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.
| |
Collapse
|
|
13
|
Kurapaty SS, Hsu WK. Sex-Based Difference in Bone Healing: A Review of Recent Pre-clinical Literature. Curr Rev Musculoskelet Med 2022; 15:651-658. [PMID: 36378466 PMCID: PMC9789279 DOI: 10.1007/s12178-022-09803-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/12/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE OF REVIEW Recent literature has sought to understand differences in fusion failure, specifically considering how patient sex may play a role. Overall, there exists inconclusive data regarding any sex-based differences in bone healing. RECENT FINDINGS In vitro studies examining the roles of sex hormones, 5-LO, IGF-1, VEGF, osteoclasts, and OPCs seem to show sexually dimorphic actions. Additionally, donor characteristics and stem cell environment seem to also determine osteogenic potential. Building on this biomolecular basis, in vivo work investigates the aforementioned elements. Broadly, males tend to have a more robust healing compared to females. Taking these findings together, differences in sex hormones levels, their timing and action, and composition of the inflammatory milieu underlie variations in bone healing by sex. Clinically, a robust understanding of bone healing mechanics can inform care of the transgender patient. Transgender patients undergoing hormone therapy present a clinically nuanced scenario for which limited long-term data exist. Such advances would help inform treatment for sports-related injury due to hormonal changes in biomechanics and treatment of transgender youth. While recent advances provide more clarity, conclusive answers remain elusive.
Collapse
Affiliation(s)
- Steven S. Kurapaty
- Department of Orthopaedic Surgery, Feinberg School of Medicine, Northwestern University, 676 North St. Clair Street, Suite 1350, Chicago, IL 6061 USA ,Simpson Querrey Institute, Center for Regenerative Nanomedicine, Northwestern University, Chicago, IL USA
| | - Wellington K. Hsu
- Department of Orthopaedic Surgery, Feinberg School of Medicine, Northwestern University, 676 North St. Clair Street, Suite 1350, Chicago, IL 6061 USA ,Simpson Querrey Institute, Center for Regenerative Nanomedicine, Northwestern University, Chicago, IL USA
| |
Collapse
|
|
14
|
高山 賢. [Recent advances in the sex steroid hormone action involved in the development of dementia and frailty]. Nihon Ronen Igakkai Zasshi 2022; 59:430-445. [PMID: 36476689 DOI: 10.3143/geriatrics.59.430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- 賢一 高山
- 東京都健康長寿医療センター研究所老化機構研究チームシステム加齢医学
| |
Collapse
|
|
15
|
Li Z, Fan Y, Xie C, Liu J, Guan X, Li S, Huang Y, Zeng R, Chen H, Su Z. High-fidelity reprogramming into Leydig-like cells by CRISPR activation and paracrine factors. PNAS NEXUS 2022; 1:pgac179. [PMID: 36714877 PMCID: PMC9802085 DOI: 10.1093/pnasnexus/pgac179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 09/02/2022] [Indexed: 02/01/2023]
Abstract
Androgen deficiency is a common medical conditions that affects males of all ages. Transplantation of testosterone-producing cells is a promising treatment for male hypogonadism. However, getting a cell source with the characteristics of Leydig cells (LCs) is still a challenge. Here, a high-efficiency reprogramming of skin-derived fibroblasts into functional Leydig-like cells (LLCs) based on epigenetic mechanism was described. By performing an integrated analysis of genome-wide DNA methylation and transcriptome profiling in LCs and fibroblasts, the potentially epigenetic-regulating steroidogenic genes and signaling pathways were identified. Then by using CRISPR/dCas9 activation system and signaling pathway regulators, the male- or female-derived fibroblasts were reprogrammed into LLCs with main LC-specific traits. Transcriptomic analysis further indicated that the correlation coefficients of global genes and transcription factors between LLCs and LCs were higher than 0.81 and 0.96, respectively. After transplantation in the testes of hypogonadal rodent models, LLCs increased serum testosterone concentration significantly. In type 2 diabetic rats model, LLCs which were transplanted in armpit, have the capability to restore the serum testosterone level and improve the hyperglycemia status. In conclusion, our approach enables skin-derived fibroblasts reprogramming into LLCs with high fidelity, providing a potential cell source for the therapeutics of male hypogonadism and metabolic-related comorbidities.
Collapse
Affiliation(s)
| | | | | | - Jierong Liu
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Xiaoju Guan
- Key Laboratory of Children Genitourinary Diseases of Wenzhou City, Department of Pediatric Urology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China
| | - Shijun Li
- Institute of Life Sciences, Wenzhou University, Wenzhou 325035, China
| | - Yadong Huang
- Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology, Jinan University, Guangzhou 510632, China
| | - Rong Zeng
- To whom correspondence should be addressed:
| | | | - Zhijian Su
- To whom correspondence should be addressed:
| |
Collapse
|
|
16
|
Sato K, Takayama KI, Hashimoto M, Inoue S. Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein (APP ) mRNA. FRONTIERS IN AGING 2022; 2:721579. [PMID: 35822056 PMCID: PMC9261399 DOI: 10.3389/fragi.2021.721579] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 07/28/2021] [Indexed: 01/01/2023]
Abstract
Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder characterized by progressive impairment of memory, thinking, behavior, and dementia. Based on ample evidence showing neurotoxicity of amyloid-β (Aβ) aggregates in AD, proteolytically derived from amyloid precursor protein (APP), it has been assumed that misfolding of Aβ plays a crucial role in the AD pathogenesis. Additionally, extra copies of the APP gene caused by chromosomal duplication in patients with Down syndrome can promote AD pathogenesis, indicating the pathological involvement of the APP gene dose in AD. Furthermore, increased APP expression due to locus duplication and promoter mutation of APP has been found in familial AD. Given this background, we aimed to summarize the mechanism underlying the upregulation of APP expression levels from a cutting-edge perspective. We first reviewed the literature relevant to this issue, specifically focusing on the transcriptional regulation of APP by transcription factors that bind to the promoter/enhancer regions. APP expression is also regulated by growth factors, cytokines, and hormone, such as androgen. We further evaluated the possible involvement of post-transcriptional regulators of APP in AD pathogenesis, such as RNA splicing factors. Indeed, alternative splicing isoforms of APP are proposed to be involved in the increased production of Aβ. Moreover, non-coding RNAs, including microRNAs, post-transcriptionally regulate the APP expression. Collectively, elucidation of the novel mechanisms underlying the upregulation of APP would lead to the development of clinical diagnosis and treatment of AD.
Collapse
Affiliation(s)
- Kaoru Sato
- Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Ken-Ichi Takayama
- Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Makoto Hashimoto
- Department of Basic Technology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Satoshi Inoue
- Department of Systems Aging Science and Medicine, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| |
Collapse
|
|
17
|
Abstract
Androgens are essential sex steroid hormones for both sexes. Testosterone (T) is the predominant androgen in males, while in adult females, T concentrations are about 15-fold lower and androgen precursors are converted to estrogens. T is produced primarily in testicular Leydig cells in men, while in women precursors are biosynthesised in the adrenal cortex and ovaries and converted into T in the periphery. The biosynthesis of T occurs via a series of enzymatic reactions in steroidogenic organs. Notably, the more potent androgen, dihydrotestosterone, may be synthesized from T in the classic pathway, however, alternate metabolic pathways also exist. The classic action of androgens on target organs is mediated through the androgen receptor, which regulates nuclear receptor gene transcription. However, the androgen-androgen receptor complex may also interact directly with membrane proteins or signaling molecules to exert more rapid effects. This review summarizes the current knowledge of androgen biosynthesis, mechanisms of action and endocrine effects in human biology, and relates these effects to respective human congenital and acquired disorders.
Collapse
Affiliation(s)
- Rawda Naamneh Elzenaty
- Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Bern University Hospital, University of Bern, Switzerland; Department of Biomedical Research, University of Bern, Switzerland; Graduate School of Cellular and Biomedical Sciences, University of Bern, Switzerland.
| | - Therina du Toit
- Department of Biomedical Research, University of Bern, Switzerland.
| | - Christa E Flück
- Division of Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Bern University Hospital, University of Bern, Switzerland; Department of Biomedical Research, University of Bern, Switzerland.
| |
Collapse
|
|
18
|
Venkatesh VS, Grossmann M, Zajac JD, Davey RA. The role of the androgen receptor in the pathogenesis of obesity and its utility as a target for obesity treatments. Obes Rev 2022; 23:e13429. [PMID: 35083843 PMCID: PMC9286619 DOI: 10.1111/obr.13429] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 01/09/2022] [Accepted: 01/09/2022] [Indexed: 11/27/2022]
Abstract
Obesity is associated with hypothalamic-pituitary-testicular axis dysregulation in males. Here, we summarize recent evidence derived from clinical trials and studies in preclinical animal models regarding the role of androgen receptor (AR) signaling in the pathophysiology of males with obesity. We also discuss therapeutic strategies targeting the AR for the treatment of obesity and their limitations and provide insight into the future research necessary to advance this field.
Collapse
Affiliation(s)
- Varun S Venkatesh
- Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria
| | - Mathis Grossmann
- Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria.,Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia
| | - Jeffrey D Zajac
- Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria.,Department of Endocrinology, Austin Health, Heidelberg, Victoria, Australia
| | - Rachel A Davey
- Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria
| |
Collapse
|
|
19
|
Feng M, Divall S, Jones D, Ubba V, Fu X, Yang L, Wang H, Yang X, Wu S. Comparison of Reproductive Function Between Normal and Hyperandrogenemia Conditions in Female Mice With Deletion of Hepatic Androgen Receptor. Front Endocrinol (Lausanne) 2022; 13:868572. [PMID: 35757434 PMCID: PMC9218244 DOI: 10.3389/fendo.2022.868572] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 05/05/2022] [Indexed: 11/13/2022] Open
Abstract
Obesity, altered glucose homeostasis, hyperinsulinism, and reproductive dysfunction develops in female humans and mammals with hyperandrogenism. We previously reported that low dose dihydrotestosterone (DHT) administration results in metabolic and reproductive dysfunction in the absence of obesity in female mice, and conditional knock-out of the androgen receptor (Ar) in the liver (LivARKO) protects female mice from DHT-induced glucose intolerance and hyperinsulinemia. Since altered metabolic function will regulate reproduction, and liver plays a pivotal role in the reversible regulation of reproductive function, we sought to determine the reproductive phenotype of LivARKO mice under normal and hyperandrogenemic conditions. Using Cre/Lox technology, we deleted the Ar in the liver, and we observed LivARKO female mice have normal puberty timing, cyclicity and reproductive function. After DHT treatment, like control mice, LivARKO experience altered estrous cycling, reduced numbers of corpus lutea, and infertility. Liver Ar is not involved in hyperandrogenemia-induced reproductive dysfunction. The reproductive dysfunction in the DHT-treated LivARKO lean females with normal glucose homeostasis indicates that androgen-induced reproductive dysfunction is independent from metabolic dysfunction.
Collapse
Affiliation(s)
- Mingxiao Feng
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Sara Divall
- Department of Pediatrics, Seattle’s Children’s Hospital, University of Washington, Seattle, WA, United States
| | - Dustin Jones
- Department of Cellular and Molecular Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Vaibhave Ubba
- Department of Cardiovascular Sciences/Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States
| | - Xiaomin Fu
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Endocrinology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Ling Yang
- Medical Genetics and Molecular Biochemistry, Temple University School of Medicine, Philadelphia, PA, United States
| | - Hong Wang
- Department of Cardiovascular Sciences/Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States
| | - Xiaofeng Yang
- Department of Cardiovascular Sciences/Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States
| | - Sheng Wu
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Cardiovascular Sciences/Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA, United States
- *Correspondence: Sheng Wu,
| |
Collapse
|
|
20
|
Yokobori K, Kawasaki Y, Sekine Y, Nobusawa S, Sakaki T, Negishi M, Kakizaki S. Androgen receptor phosphorylated at Ser815: The expression and function in the prostate and tumor-derived cells. Biochem Pharmacol 2021; 194:114794. [PMID: 34715066 DOI: 10.1016/j.bcp.2021.114794] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 10/13/2021] [Accepted: 10/13/2021] [Indexed: 12/29/2022]
Abstract
Androgen is beneficial for the prostate with normal functions but creates a risk for prostate cancer progression. How androgen receptor (AR) mediates these various androgen actions remains elusive. AR conserves a phosphorylation motif within its ligand-binding domain throughout species. Here, we have found AR phosphorylated at Ser815 (P-AR) is expressed in normal tissues of both human and mouse prostates. P-AR begins expression in association with prostatic development and castration decreases its expression levels in the mouse prostate. Functional analysis of AR in prostate cancer PC-3 cells showed ligand-induced AR nuclear translocation and transactivation were disturbed by its phosphorylation at Ser815. Moreover, P-AR suppressed oncogenic AKT signaling suggesting a suppressive function for prostate cancer development. In fact, AR phosphorylation levels progressively decrease in human prostates as cancer worsens. These findings showed androgen might utilize P-AR to self-antagonize oncogenic signals and cancer progression believed to be regulated by non-phosphorylated AR (NonP-AR). By differing its target genes and signal regulations from those of NonP-AR, P-AR co-expression with NonP-AR may be the molecular basis for androgen to balance its actions and to control disease developments.
Collapse
Affiliation(s)
- Kosuke Yokobori
- Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
| | - Yuki Kawasaki
- Laboratory of Public Health, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Gunma 370-0033, Japan
| | - Yoshitaka Sekine
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Sumihito Nobusawa
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan
| | - Toshiyuki Sakaki
- Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama 939-0398, Japan
| | - Masahiko Negishi
- Pharmacogenetics Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan; Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Takasaki, Gunma 370-0829, Japan
| |
Collapse
|
|
21
|
Barbagallo F, Cannarella R, Bertelli M, Crafa A, La Vignera S, Condorelli RA, Calogero AE. Complete Androgen Insensitivity Syndrome: From the Relevance of an Accurate Genetic Diagnosis to the Challenge of Clinical Management. A Case Report. Medicina (B Aires) 2021; 57:medicina57111142. [PMID: 34833359 PMCID: PMC8624150 DOI: 10.3390/medicina57111142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 10/13/2021] [Accepted: 10/19/2021] [Indexed: 11/16/2022] Open
Abstract
Introduction: Androgen insensitivity syndrome (AIS), an X-linked recessive disorder of sex development (DSD), is caused by variants of the androgen receptor (AR) gene, mapping in the long arm of the X chromosome, which cause a complete loss of function of the receptor. Case presentation: We report a patient diagnosed with complete AIS (CAIS) at birth due to swelling in the bilateral inguinal region. Transabdominal ultrasound revealed the absence of the uterus and ovaries and the presence of bilateral testes in the inguinal region. The karyotype was 46,XY. She underwent bilateral orchiectomy at 9 months and was given estrogen substitutive therapy at the age of 11 years. Genetic analysis of the AR gene variants was requested when, at the age of 20, the patient came to our observation. Methods: The genetic testing was performed by next-generation sequence (NGS) analysis. Results: The genetic analysis showed the presence of the c.2242T>A, p.(Phe748Ile) variant in the AR gene. To the best of our knowledge, this variant has not been published so far. Furthermore, the patient has a heterozygous c.317A>G, p.(Gln106Arg) variation of the gonadotropin-releasing hormone receptor (GNRHR) gene, a heterozygous c.2273G>A, p.Arg758His variation of the chromodomain helicase DNA binding protein 7 (CHD7) gene, and compound heterozygous c.875A>G, p.Tyr292Cys, and c.8023A>G, p.Ile2675Val variations of the Dynein Axonemal Heavy Chain 11 (DNAH11) gene. Conclusions: The case herein reported underlines the importance of an accurate genetic analysis that has to include karyotype and AR gene variant analysis. This is useful to confirm a clinical diagnosis and establish the proper management of patients with CAIS. Numerous variants of the AR gene have not yet been identified. Moreover, several pitfalls are still present in the management of these patients. More studies are needed to answer unresolved questions, and common protocols are required for the clinical follow-up of patients with CAIS.
Collapse
Affiliation(s)
- Federica Barbagallo
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy; (F.B.); (A.C.); (S.L.V.); (R.A.C.); (A.E.C.)
| | - Rossella Cannarella
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy; (F.B.); (A.C.); (S.L.V.); (R.A.C.); (A.E.C.)
- Correspondence:
| | | | - Andrea Crafa
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy; (F.B.); (A.C.); (S.L.V.); (R.A.C.); (A.E.C.)
| | - Sandro La Vignera
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy; (F.B.); (A.C.); (S.L.V.); (R.A.C.); (A.E.C.)
| | - Rosita A. Condorelli
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy; (F.B.); (A.C.); (S.L.V.); (R.A.C.); (A.E.C.)
| | - Aldo E. Calogero
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy; (F.B.); (A.C.); (S.L.V.); (R.A.C.); (A.E.C.)
| |
Collapse
|
|
22
|
Andrisse S, Feng M, Wang Z, Awe O, Yu L, Zhang H, Bi S, Wang H, Li L, Joseph S, Heller N, Mauvais-Jarvis F, Wong GW, Segars J, Wolfe A, Divall S, Ahima R, Wu S. Androgen-induced insulin resistance is ameliorated by deletion of hepatic androgen receptor in females. FASEB J 2021; 35:e21921. [PMID: 34547140 DOI: 10.1096/fj.202100961r] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/23/2021] [Accepted: 08/31/2021] [Indexed: 12/16/2022]
Abstract
Androgen excess is one of the most common endocrine disorders of reproductive-aged women, affecting up to 20% of this population. Women with elevated androgens often exhibit hyperinsulinemia and insulin resistance. The mechanisms of how elevated androgens affect metabolic function are not clear. Hyperandrogenemia in a dihydrotestosterone (DHT)-treated female mouse model induces whole body insulin resistance possibly through activation of the hepatic androgen receptor (AR). We investigated the role of hepatocyte AR in hyperandrogenemia-induced metabolic dysfunction by using several approaches to delete hepatic AR via animal-, cell-, and clinical-based methodologies. We conditionally disrupted hepatocyte AR in female mice developmentally (LivARKO) or acutely by tail vein injection of an adeno-associated virus with a liver-specific promoter for Cre expression in ARfl/fl mice (adLivARKO). We observed normal metabolic function in littermate female Control (ARfl/fl ) and LivARKO (ARfl/fl ; Cre+/- ) mice. Following chronic DHT treatment, female Control mice treated with DHT (Con-DHT) developed impaired glucose tolerance, pyruvate tolerance, and insulin tolerance, not observed in LivARKO mice treated with DHT (LivARKO-DHT). Furthermore, during an euglycemic hyperinsulinemic clamp, the glucose infusion rate was improved in LivARKO-DHT mice compared to Con-DHT mice. Liver from LivARKO, and primary hepatocytes derived from LivARKO, and adLivARKO mice were protected from DHT-induced insulin resistance and increased gluconeogenesis. These data support a paradigm in which elevated androgens in females disrupt metabolic function via hepatic AR and insulin sensitivity was restored by deletion of hepatic AR.
Collapse
Affiliation(s)
- Stanley Andrisse
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Physiology and Biophysics, Howard University, Washington, District of Columbia, USA
| | - Mingxiao Feng
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Zhiqiang Wang
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Olubusayo Awe
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Cellular and Molecular Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Lexiang Yu
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Haiying Zhang
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Sheng Bi
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Hongbing Wang
- Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, USA
| | - Linhao Li
- Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland, USA
| | - Serene Joseph
- Department of Cardiovascular Sciences/Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
| | - Nicola Heller
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Franck Mauvais-Jarvis
- Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.,Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, Louisiana, USA.,VA Medical Center, New Orleans, Louisiana, USA
| | - Guang William Wong
- Department of Cellular and Molecular Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - James Segars
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Andrew Wolfe
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Sara Divall
- Department of Pediatrics, Seattle's Children's Hospital, University of Washington, Seattle, Washington, USA
| | - Rexford Ahima
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Sheng Wu
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Cellular and Molecular Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Department of Cardiovascular Sciences/Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.,Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
23
|
Metformin reduces oxandrolone- induced depression-like behavior in rats via modulating the expression of IL-1β, IL-6, IL-10 and TNF-α. Behav Brain Res 2021; 414:113475. [PMID: 34280460 DOI: 10.1016/j.bbr.2021.113475] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/15/2021] [Accepted: 07/15/2021] [Indexed: 01/22/2023]
Abstract
Oxandrolone (OXA) is an androgen and anabolic steroid (AAS) that is used to reverse weight loss associated with some medical conditions. One of the side effects of OXA is its potential to induce depressive symptoms. Growing evidence suggested that neuroinflammation and cytokines play crucial roles in sickness behavioral and associated mood disturbances. Previous studies showed that metformin attenuated neuroinflammation. This study investigated the potential protective role of metformin against OXA-induced depression-like behavior and neuroinflammation. Twenty- four Wistar male rats were randomly grouped into four groups: the control group (Control) received only vehicle; the oxandrolone group (OXA) received oxandrolone (0.28 mg/kg, i.p); the metformin group (MET) received metformin (100 mg/kg, i.p); and the oxandrolone / metformin group (OXA + MET) received both oxandrolone (0.28 mg/kg, i.p) and metformin (100 mg/kg, i.p). These treatments were administered for fourteen consecutive days. Behavioral tests to measure depression-like behavior were conducted before and after treatments. qRT-PCR was used to measure the relative expression of proinflammatory and anti-inflammatory cytokines in the hippocampus and hypothalamus. The results showed that oxandrolone induced depression-like behavior and dysregulated pro-/anti-inflammatory cytokines, while metformin attenuated these effects. These findings suggest that metformin is a potential treatment to reverse the depressive effects induced by oxandrolone that involve neuroinflammatory effects.
Collapse
|
|
24
|
Slominski RM, Raman C, Elmets C, Jetten AM, Slominski AT, Tuckey RC. The significance of CYP11A1 expression in skin physiology and pathology. Mol Cell Endocrinol 2021; 530:111238. [PMID: 33716049 PMCID: PMC8205265 DOI: 10.1016/j.mce.2021.111238] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 02/25/2021] [Accepted: 02/27/2021] [Indexed: 12/14/2022]
Abstract
CYP11A1, a member of the cytochrome P450 family, plays several key roles in the human body. It catalyzes the first and rate-limiting step in steroidogenesis, converting cholesterol to pregnenolone. Aside from the classical steroidogenic tissues such as the adrenals, gonads and placenta, CYP11A1 has also been found in the brain, gastrointestinal tract, immune systems, and finally the skin. CYP11A1 activity in the skin is regulated predominately by StAR protein and hence cholesterol levels in the mitochondria. However, UVB, UVC, CRH, ACTH, cAMP, and cytokines IL-1, IL-6 and TNFα can also regulate its expression and activity. Indeed, CYP11A1 plays several critical roles in the skin through its initiation of local steroidogenesis and specific metabolism of vitamin D, lumisterol, and 7-dehydrocholesterol. Products of these pathways regulate the protective barrier and skin immune functions in a context-dependent fashion through interactions with a number of receptors. Disturbances in CYP11A1 activity can lead to skin pathology.
Collapse
Affiliation(s)
- R M Slominski
- Department of Medicine, Division of Rheumatology, USA; Department of Dermatology, USA
| | - C Raman
- Department of Medicine, Division of Rheumatology, USA; Department of Dermatology, USA
| | - C Elmets
- Department of Dermatology, USA; Comprehensive Cancer Center, Cancer Chemoprevention Program, University of Alabama at Birmingham, USA
| | - A M Jetten
- Cell Biology Section, Immunity, Inflammation, Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
| | - A T Slominski
- Department of Dermatology, USA; VA Medical Center, Birmingham, AL, USA.
| | - R C Tuckey
- School of Molecular Sciences, The University of Western Australia, Perth, WA, Australia.
| |
Collapse
|
|
25
|
Tomas D, McLeod VM, Chiam MDF, Wanniarachchillage N, Boon WC, Turner BJ. Dissociation of disease onset, progression and sex differences from androgen receptor levels in a mouse model of amyotrophic lateral sclerosis. Sci Rep 2021; 11:9255. [PMID: 33927243 PMCID: PMC8085012 DOI: 10.1038/s41598-021-88415-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 03/30/2021] [Indexed: 01/14/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder caused by loss of motor neurons. ALS incidence is skewed towards males with typically earlier age of onset and limb site of onset. The androgen receptor (AR) is the major mediator of androgen effects in the body and is present extensively throughout the central nervous system, including motor neurons. Mutations in the AR gene lead to selective lower motor neuron degeneration in male spinal bulbar muscular atrophy (SBMA) patients, emphasising the importance of AR in maintaining motor neuron health and survival. To evaluate a potential role of AR in onset and progression of ALS, we generated SOD1G93A mice with either neural AR deletion or global human AR overexpression. Using a Cre-LoxP conditional gene knockout strategy, we report that neural deletion of AR has minimal impact on the disease course in SOD1G93A male mice. This outcome was potentially confounded by the metabolically disrupted Nestin-Cre phenotype, which likely conferred the profound lifespan extension observed in the SOD1G93A double transgenic male mice. In addition, overexpression of human AR produced no benefit to disease onset and progression in SOD1G93A mice. In conclusion, the disease course of SOD1G93A mice is independent of AR expression levels, implicating other mechanisms involved in mediating the sex differences in ALS. Our findings using Nestin-Cre mice, which show an inherent metabolic phenotype, led us to hypothesise that targeting hypermetabolism associated with ALS may be a more potent modulator of disease, than AR in this mouse model.
Collapse
Affiliation(s)
- Doris Tomas
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia
| | - Victoria M McLeod
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia
| | - Mathew D F Chiam
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia
| | - Nayomi Wanniarachchillage
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia
| | - Wah C Boon
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia
| | - Bradley J Turner
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia.
- Perron Institute for Neurological and Translational Science, Queen Elizabeth Medical Centre, Nedlands, WA, 6150, Australia.
| |
Collapse
|
|
26
|
Sakakibara I, Yanagihara Y, Himori K, Yamada T, Sakai H, Sawada Y, Takahashi H, Saeki N, Hirakawa H, Yokoyama A, Fukada SI, Sawasaki T, Imai Y. Myofiber androgen receptor increases muscle strength mediated by a skeletal muscle splicing variant of Mylk4. iScience 2021; 24:102303. [PMID: 33870126 PMCID: PMC8041868 DOI: 10.1016/j.isci.2021.102303] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 02/16/2021] [Accepted: 03/10/2021] [Indexed: 12/14/2022] Open
Abstract
Androgens have a robust effect on skeletal muscles to increase muscle mass and strength. The molecular mechanism of androgen/androgen receptor (AR) action on muscle strength is still not well known, especially for the regulation of sarcomeric genes. In this study, we generated androgen-induced hypertrophic model mice, myofiber-specific androgen receptor knockout (cARKO) mice supplemented with dihydrotestosterone (DHT). DHT treatment increased grip strength in control mice but not in cARKO mice. Transcriptome analysis by RNA-seq, using skeletal muscles obtained from control and cARKO mice treated with or without DHT, identified a fast-type muscle-specific novel splicing variant of Myosin light-chain kinase 4 (Mylk4) as a target of AR in skeletal muscles. Mylk4 knockout mice exhibited decreased maximum isometric torque of plantar flexion and passive stiffness of myofibers due to reduced phosphorylation of Myomesin 1 protein. This study suggests that androgen-induced skeletal muscle strength is mediated with Mylk4 and Myomesin 1 axis.
DHT increases muscle strength through myofiber AR Myofiber AR increases a fast-type muscle-specific novel splicing variant of Mylk4 MYLK4 regulates muscle strength and muscle stiffness MYLK4 induces phosphorylation of MYOM1
Collapse
Affiliation(s)
- Iori Sakakibara
- Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.,Department of Pathophysiology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.,Department of Nutritional Physiology, Institute of Medical Nutrition, Tokushima University Graduate School, Tokushima 770-8503, Japan
| | - Yuta Yanagihara
- Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.,Division of Laboratory Animal Research, Advanced Research Support Center, Ehime University, Toon, Ehime 791-0295, Japan
| | - Koichi Himori
- Graduate School of Health Sciences, Sapporo Medical University, Sapporo, Hokkaido 060-8558, Japan
| | - Takashi Yamada
- Graduate School of Health Sciences, Sapporo Medical University, Sapporo, Hokkaido 060-8558, Japan
| | - Hiroshi Sakai
- Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.,Department of Pathophysiology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Yuichiro Sawada
- Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.,Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Hirotaka Takahashi
- Division of Cell-Free Sciences, Proteo-Science Center (PROS), Ehime University, Matsuyama, Ehime 790-8577, Japan
| | - Noritaka Saeki
- Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.,Division of Laboratory Animal Research, Advanced Research Support Center, Ehime University, Toon, Ehime 791-0295, Japan
| | - Hiroyuki Hirakawa
- Department of Physiology and Cell Biology, Tokyo Medical and Dental University (TMDU), Graduate School, Tokyo 113-8510, Japan
| | - Atsushi Yokoyama
- Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - So-Ichiro Fukada
- Project for Muscle Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan
| | - Tatsuya Sawasaki
- Division of Cell-Free Sciences, Proteo-Science Center (PROS), Ehime University, Matsuyama, Ehime 790-8577, Japan
| | - Yuuki Imai
- Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.,Department of Pathophysiology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.,Division of Laboratory Animal Research, Advanced Research Support Center, Ehime University, Toon, Ehime 791-0295, Japan.,Research Unit for Skeletal Health and Diseases, Ehime University, Toon, Ehime 791-0295, Japan
| |
Collapse
|
|
27
|
Jin S, An H, Zhou T, Li T, Xie M, Chen S, Chen C, Ying B, Xu Z, Li X, Li M. Sex- and age-specific clinical and immunological features of coronavirus disease 2019. PLoS Pathog 2021; 17:e1009420. [PMID: 33770147 PMCID: PMC8026060 DOI: 10.1371/journal.ppat.1009420] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 04/07/2021] [Accepted: 02/22/2021] [Indexed: 01/22/2023] Open
Abstract
To simultaneously determine clinical and immunological responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old females and males, 681 coronavirus disease 2019 (COVID-19) patients and 369 normal controls (NCs) were analyzed based on age and sex classifications using multiple linear regression analysis. Compared to the age-matched NCs, both young and old male and female non-comorbid COVID-19 patients had lower lymphocyte counts and alanine aminotransferase (ALT) concentration, and only young male and female patients had lower neutrophil counts. Compared to young patients, both old males and females had significantly higher plasma ALT and AST concentrations. Compared to young and old females, age-matched males had higher plasma ALT and AST concentrations, but only young males had higher C-reactive protein (CRP) concentration. Compared to females, old males, but not young males, showed higher incidence of critical illness. Compared to young patients, old females had more leukocyte and neutrophil counts above the normal upper limit and B cell count below the normal lower limit (NLL), while old males had more lymphocyte and natural killer (NK) cell counts below the NLL. No sex or age associations with B cell and NK cell counts were observed. However, there were age-dependent decreases in CD8+ T-cell counts in both male and female COVID-19 patients. Age was negatively associated with CD8+ T cell counts but positively associated with neutrophil count, CRP, ALT, and AST concentrations, and sex (females) was negatively associated with neutrophil count, CRP, ALT, and AST concentrations. The present study suggests that SARS-CoV-2 infection mainly induced 1) beneficial sex (female)-related differences regarding reduced COVID-19 disease severity and negative associations with inflammatory responses and liver damage, and 2) harmful age-related differences relating to negative associations with CD8+ T cell count and positive associations with inflammatory responses and liver damage. Thus, sex and age are biological variables that should be considered in the prevention and treatment of COVID-19.
Collapse
Affiliation(s)
- Shengwei Jin
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, China
| | - Hui An
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, China
| | - Tong Zhou
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ting Li
- Department of Anesthesia and Critical Care, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, China
| | - Mengzhen Xie
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China
| | - Saijing Chen
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China
| | - Chengshui Chen
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University; Wenzhou, China
| | - Binyu Ying
- Department of Critical Care Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhangye Xu
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaokun Li
- School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ming Li
- School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China
| |
Collapse
|
|
28
|
Tyutyusheva N, Mancini I, Baroncelli GI, D’Elios S, Peroni D, Meriggiola MC, Bertelloni S. Complete Androgen Insensitivity Syndrome: From Bench to Bed. Int J Mol Sci 2021; 22:ijms22031264. [PMID: 33514065 PMCID: PMC7865707 DOI: 10.3390/ijms22031264] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/07/2021] [Accepted: 01/22/2021] [Indexed: 12/13/2022] Open
Abstract
Complete androgen insensitivity syndrome (CAIS) is due to complete resistance to the action of androgens, determining a female phenotype in persons with a 46,XY karyotype and functioning testes. CAIS is caused by inactivating mutations in the androgen receptor gene (AR). It is organized in eight exons located on the X chromosome. Hundreds of genetic variants in the AR gene have been reported in CAIS. They are distributed throughout the gene with a preponderance located in the ligand-binding domain. CAIS mainly presents as primary amenorrhea in an adolescent female or as a bilateral inguinal/labial hernia containing testes in prepubertal children. Some issues regarding the management of females with CAIS remain poorly standardized (such as the follow-up of intact testes, the timing of gonadal removal and optimal hormone replacement therapy). Basic research will lead to the consideration of new issues to improve long-term well-being (such as bone health, immune and metabolic aspects and cardiovascular risk). An expert multidisciplinary approach is mandatory to increase the long-term quality of life of women with CAIS.
Collapse
Affiliation(s)
- Nina Tyutyusheva
- Pediatric and Adolescent Endocrinology, Division of Paediatrics, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy; (N.T.); (G.I.B.); (S.D.); (D.P.)
| | - Ilaria Mancini
- Gynecology and Human Reproduction Physiopathology Unit, IRCCS Policlinico di Sant’Orsola, DIMEC, University of Bologna, 40138 Bologna, Italy; (I.M.); (M.C.M.)
| | - Giampiero Igli Baroncelli
- Pediatric and Adolescent Endocrinology, Division of Paediatrics, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy; (N.T.); (G.I.B.); (S.D.); (D.P.)
| | - Sofia D’Elios
- Pediatric and Adolescent Endocrinology, Division of Paediatrics, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy; (N.T.); (G.I.B.); (S.D.); (D.P.)
| | - Diego Peroni
- Pediatric and Adolescent Endocrinology, Division of Paediatrics, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy; (N.T.); (G.I.B.); (S.D.); (D.P.)
| | - Maria Cristina Meriggiola
- Gynecology and Human Reproduction Physiopathology Unit, IRCCS Policlinico di Sant’Orsola, DIMEC, University of Bologna, 40138 Bologna, Italy; (I.M.); (M.C.M.)
| | - Silvano Bertelloni
- Pediatric and Adolescent Endocrinology, Division of Paediatrics, Azienda Ospedaliero-Universitaria Pisana, 56126 Pisa, Italy; (N.T.); (G.I.B.); (S.D.); (D.P.)
- Correspondence: ; Tel.: +39-050-992743; Fax: +39-050-992641
| |
Collapse
|
|
29
|
Yin L, Luo M, Wang R, Ye J, Wang X. Mitochondria in Sex Hormone-Induced Disorder of Energy Metabolism in Males and Females. Front Endocrinol (Lausanne) 2021; 12:749451. [PMID: 34987473 PMCID: PMC8721233 DOI: 10.3389/fendo.2021.749451] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 11/24/2021] [Indexed: 01/01/2023] Open
Abstract
Androgens have a complex role in the regulation of insulin sensitivity in the pathogenesis of type 2 diabetes. In male subjects, a reduction in androgens increases the risk for insulin resistance, which is improved by androgen injections. However, in female subjects with polycystic ovary syndrome (PCOS), androgen excess becomes a risk factor for insulin resistance. The exact mechanism underlying the complex activities of androgens remains unknown. In this review, a hormone synergy-based view is proposed for understanding this complexity. Mitochondrial overactivation by substrate influx is a mechanism of insulin resistance in obesity. This concept may apply to the androgen-induced insulin resistance in PCOS. Androgens and estrogens both exhibit activities in the induction of mitochondrial oxidative phosphorylation. The two hormones may synergize in mitochondria to induce overproduction of ATP. ATP surplus in the pancreatic β-cells and α-cells causes excess secretion of insulin and glucagon, respectively, leading to peripheral insulin resistance in the early phase of type 2 diabetes. In the skeletal muscle and liver, the ATP surplus contributes to insulin resistance through suppression of AMPK and activation of mTOR. Consistent ATP surplus leads to mitochondrial dysfunction as a consequence of mitophagy inhibition, which provides a potential mechanism for mitochondrial dysfunction in β-cells and brown adipocytes in PCOS. The hormone synergy-based view provides a basis for the overactivation and dysfunction of mitochondria in PCOS-associated type 2 diabetes. The molecular mechanism for the synergy is discussed in this review with a focus on transcriptional regulation. This view suggests a unifying mechanism for the distinct metabolic roles of androgens in the control of insulin action in men with hypogonadism and women with PCOS.
Collapse
Affiliation(s)
- Lijun Yin
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Man Luo
- Metabolism Research Center, Zhengzhou University Affiliated Zhengzhou Central Hospital, Zhengzhou, China
| | - Ru Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Jianping Ye
- Metabolism Research Center, Zhengzhou University Affiliated Zhengzhou Central Hospital, Zhengzhou, China
- Center for Advanced Medicine, College of Medicine, Zhengzhou University, Zhengzhou, China
- Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- *Correspondence: Jianping Ye, ; Xiaohui Wang,
| | - Xiaohui Wang
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
- *Correspondence: Jianping Ye, ; Xiaohui Wang,
| |
Collapse
|
|
30
|
Peng Y, Zhu H, Han B, Xu Y, Liu X, Song H, Qiao J. Identification of Potential Genes in Pathogenesis and Diagnostic Value Analysis of Partial Androgen Insensitivity Syndrome Using Bioinformatics Analysis. Front Endocrinol (Lausanne) 2021; 12:731107. [PMID: 34867780 PMCID: PMC8637961 DOI: 10.3389/fendo.2021.731107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 10/25/2021] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND Androgen insensitivity syndrome (AIS) is a rare X-linked genetic disease and one of the causes of 46,XY disorder of sexual development. The unstraightforward diagnosis of AIS and the gender assignment dilemma still make a plague for this disorder due to the overlapping clinical phenotypes. METHODS Peripheral blood mononuclear cells (PBMCs) of partial AIS (PAIS) patients and healthy controls were separated, and RNA-seq was performed to investigate transcriptome variance. Then, tissue-specific gene expression, functional enrichment, and protein-protein interaction (PPI) network analyses were performed; and the key modules were identified. Finally, the RNA expression of differentially expressed genes (DEGs) of interest was validated by quantitative real-time PCR (qRT-PCR). RESULTS In our dataset, a total of 725 DEGs were captured, with functionally enriched reproduction and immune-related pathways and Gene Ontology (GO) functions. The most highly specific systems centered on hematologic/immune and reproductive/endocrine systems. We finally filtered out CCR1, PPBP, PF4, CLU, KMT2D, GP6, and SPARC by the key gene clusters of the PPI network and manual screening of tissue-specific gene expression. These genes provide novel insight into the pathogenesis of AIS in the immune system or metabolism and bring forward possible molecular markers for clinical screening. The qRT-PCR results showed a consistent trend in the expression levels of related genes between PAIS patients and healthy controls. CONCLUSION The present study sheds light on the molecular mechanisms underlying the pathogenesis and progression of AIS, providing potential targets for diagnosis and future investigation.
Collapse
Affiliation(s)
- Yajie Peng
- Department of Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Zhu
- Department of Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bing Han
- Department of Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yue Xu
- Department of Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuemeng Liu
- Department of Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huaidong Song
- Research Centre for Clinical Medicine, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jie Qiao, ; Huaidong Song,
| | - Jie Qiao
- Department of Endocrinology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jie Qiao, ; Huaidong Song,
| |
Collapse
|
|
31
|
Maseroli E, Vignozzi L. Testosterone and Vaginal Function. Sex Med Rev 2020; 8:379-392. [DOI: 10.1016/j.sxmr.2020.03.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 03/08/2020] [Accepted: 03/10/2020] [Indexed: 01/04/2023]
|
|
32
|
Gu S, Dai H, Zhao X, Gui C, Gui J. AKT3 deficiency in M2 macrophages impairs cutaneous wound healing by disrupting tissue remodeling. Aging (Albany NY) 2020; 12:6928-6946. [PMID: 32291381 PMCID: PMC7202485 DOI: 10.18632/aging.103051] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 03/04/2020] [Indexed: 12/14/2022]
Abstract
AKT signaling and M2 macrophage-guided tissue repair are key factors in cutaneous wound healing. A delay in this process threatens human health worldwide. However, the role of AKT3 in delayed cutaneous wound healing is largely unknown. In this study, histological staining and transcriptomics demonstrated that prolonged tissue remodeling delayed wound healing. This delay was accompanied by defects in AKT3, collagen alpha-1(I) chain (COL1A1), and collagen alpha-1(XI) chain (COL11A1) expression and AKT signaling. The defect in AKT3 expression was M2 macrophage-specific, and decreased AKT3 protein levels were observed in CD68/CD206-positive macrophages from delayed wound tissue. Downregulation of AKT3 in M2 macrophages did not influence cell polarization but impaired collagen organization by inhibiting COL1A1 and COL11A1 expression in human skin fibroblasts (HSFs). Moreover, a co-culture model revealed that the downregulation of AKT3 in the human monocytic cell line (THP-1)-derived M2 macrophages impaired HSF proliferation and migration. Finally, cutaneous wound healing in AKT3-/- mice was much slower than that of AKT3+/+ mice, and F4/80 macrophages from the AKT3-/- mice had an impaired ability to promote wound healing. Thus, the downregulation of AKT3 in M2 macrophages prolonged tissue remodeling and delayed cutaneous wound healing.
Collapse
Affiliation(s)
- Song Gu
- Department of Sports Medicine and Joint Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, P.R. China.,Trauma Center, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China
| | - Hanhao Dai
- Department of Sports Medicine and Joint Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, P.R. China
| | - Xilian Zhao
- Department of Sports Medicine and Joint Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, P.R. China
| | - Chang Gui
- Department of Biomedical Engineering, Washington University in St. Louis, MO 63130, USA
| | - Jianchao Gui
- Department of Sports Medicine and Joint Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, P.R. China
| |
Collapse
|
|
33
|
Harada N, Hanada K, Minami Y, Kitakaze T, Ogata Y, Tokumoto H, Sato T, Kato S, Inui H, Yamaji R. Role of gut microbiota in sex- and diet-dependent metabolic disorders that lead to early mortality of androgen receptor-deficient male mice. Am J Physiol Endocrinol Metab 2020; 318:E525-E537. [PMID: 32017595 DOI: 10.1152/ajpendo.00461.2019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The gut microbiota is involved in metabolic disorders induced by androgen deficiency after sexual maturation in males (late-onset hypogonadism). However, its role in the energy metabolism of congenital androgen deficiency (e.g., androgen-insensitive syndrome) remains elusive. Here, we examined the link between the gut microbiota and metabolic disease symptoms in androgen receptor knockout (ARKO) mouse by administering high-fat diet (HFD) and/or antibiotics. HFD-fed male, but not standard diet-fed male or HFD-fed female, ARKO mice exhibited increased feed efficiency, obesity with increased visceral adipocyte mass and hypertrophy, hepatic steatosis, glucose intolerance, insulin resistance, and loss of thigh muscle. In contrast, subcutaneous fat mass accumulated in ARKO mice irrespective of the diet and sex. Notably, all HFD-dependent metabolic disorders observed in ARKO males were abolished after antibiotics administration. The ratios of fecal weight-to-food weight and cecum weight-to-body weight were specifically reduced by ARKO in HFD-fed males. 16S rRNA sequencing of fecal microbiota from HFD-fed male mice revealed differences in microbiota composition between control and ARKO mice. Several genera or species (e.g., Turicibacter and Lactobacillus reuteri, respectively) were enriched in ARKO mice, and antibiotics treatment spoiled the changes. Furthermore, the life span of HFD-fed ARKO males was shorter than that of control mice, indicating that androgen deficiency causes metabolic dysfunctions leading to early death. These findings also suggest that AR signaling plays a role in the prevention of metabolic dysfunctions, presumably by influencing the gut microbiome, and improve our understanding of health consequences in subjects with hypogonadism and androgen insensitivity.
Collapse
Affiliation(s)
- Naoki Harada
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan
| | - Kazuki Hanada
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan
| | - Yukari Minami
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan
| | - Tomoya Kitakaze
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan
| | - Yoshiyuki Ogata
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan
| | - Hayato Tokumoto
- Division of Biological Science, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka, Japan
| | - Takashi Sato
- Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan
| | - Shigeaki Kato
- Graduate School of Science and Engineering, Iryo Sosei University, Iwaki, Fukushima, Japan
| | - Hiroshi Inui
- Department of Nutrition, College of Health and Human Sciences, Osaka Prefecture University, Habikino, Osaka, Japan
| | - Ryoichi Yamaji
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan
| |
Collapse
|
|
34
|
Small B, Millard CEF, Kisanga EP, Burman A, Anam A, Flannery C, Al-Hendy A, Whirledge S. The Selective Progesterone Receptor Modulator Ulipristal Acetate Inhibits the Activity of the Glucocorticoid Receptor. J Clin Endocrinol Metab 2020; 105:5609012. [PMID: 31665442 PMCID: PMC7112983 DOI: 10.1210/clinem/dgz139] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 10/22/2019] [Indexed: 12/19/2022]
Abstract
CONTEXT The selective progesterone modulator ulipristal acetate (ulipristal) offers a much-needed therapeutic option for the clinical management of uterine fibroids. Although ulipristal initially passed safety evaluations in Europe, postmarketing analysis identified cases of hepatic injury and failure, leading to restrictions on the long-term use of ulipristal. One of the factors potentially contributing to significant side effects with the selective progesterone modulators is cross-reactivity with other steroid receptors. OBJECTIVE To determine whether ulipristal can alter the activity of the endogenous glucocorticoid receptor (GR) in relevant cell types. DESIGN Immortalized human uterine fibroid cells (UtLM) and hepatocytes (HepG2) were treated with the synthetic glucocorticoid dexamethasone and/or ulipristal. Primary uterine fibroid tissue was isolated from patients undergoing elective gynecological surgery and treated ex vivo with dexamethasone and/or ulipristal. In vivo ulipristal exposure was performed in C57Bl/6 mice to measure the effect on basal gene expression in target tissues throughout the body. RESULTS Dexamethasone induced the expression of established glucocorticoid-target genes period 1 (PER1), FK506 binding protein 51 (FKBP5), and glucocorticoid-induced leucine zipper (GILZ) in UtLM and HepG2 cells, whereas cotreatment with ulipristal blocked the transcriptional response to glucocorticoids in a dose-dependent manner. Ulipristal inhibited glucocorticoid-mediated phosphorylation, nuclear translocation, and DNA interactions of GR. Glucocorticoid stimulation of PER1, FKBP5, and GILZ was abolished by cotreatment with ulipristal in primary uterine fibroid tissue. The expression of glucocorticoid-responsive genes was decreased in the lung, liver, and uterus of mice exposed to 2 mg/kg ulipristal. Interestingly, transcript levels of Fkbp5 and Gilz were increased in the hippocampus and pituitary. CONCLUSIONS These studies demonstrate that ulipristal inhibits endogenous glucocorticoid signaling in human fibroid and liver cells, which is an important consideration for its use as a long-term therapeutic agent.
Collapse
Affiliation(s)
- Benjamin Small
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Charles E F Millard
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Edwina P Kisanga
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Andreanna Burman
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
| | - Anika Anam
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
- Department of Internal Medicine, Endocrinology, Yale School of Medicine, New Haven, Connecticut
| | - Clare Flannery
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
- Department of Internal Medicine, Endocrinology, Yale School of Medicine, New Haven, Connecticut
| | - Ayman Al-Hendy
- Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois
| | - Shannon Whirledge
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut
- Correspondence and Reprint Requests: Shannon Whirledge, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 310 Cedar St, Office LSOG 204C, New Haven, CT, 06510. E-mail:
| |
Collapse
|
|
35
|
Fulare S, Deshmukh S, Gupta J. Androgen Insensitivity Syndrome: A rare genetic disorder. Int J Surg Case Rep 2020; 71:371-373. [PMID: 32493623 PMCID: PMC7322742 DOI: 10.1016/j.ijscr.2020.01.032] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 01/23/2020] [Accepted: 01/30/2020] [Indexed: 12/30/2022] Open
Abstract
Androgen Insensitivity Syndrome is a rare X-linked recessive genetic disorder caused by mutation in Androgen Receptor (AR) gene. Individuals with Complete Androgen Insensitivity Syndrome have 46XY karyotype and present as female appearance and bilateral undescended testis. 17 year old patient, presented with swelling in bilateral inguinal region and primary amenorrhea. Karyotype was mapped as 46 XY, elevated serum testosterone level. Bilateral orchidectomy was performed and patient was advised hormonal substitution therapy and provided psychological counselling. Background Androgen Insensitivity Syndrome (AIS) is a rare X-linked recessive androgen receptor (AR) disorder with 46XY karyotype. Partial AIS affects 5–7 per 1,000,000 genetically male individuals whereas Complete AIS affects 2–5 per 100,000 genetically male individuals. CAIS CAIS is characterized by complete resistance to the action of androgens. Presentation of case 17-year patient presented with swelling in bilateral inguinal region. Patient also complained of primary amenorrhea with serum FSH and LH levels being raised, serum testosterone level much above normal range. MRI Pelvis revealed agenesis of vagina, uterine body, both ovaries and cervix. Bilateral testes were noted in bilateral superficial inguinal ring. Bilateral orchidectomy was done and the patient was advised estrogen substitution therapy. Discussion CAIS is usually diagnosed at puberty, when the patient presents with primary amenorrhea. Karyotype has to be mapped in order to differentiate from other genetic disorders. Orchidectomy should be done to avoid risk of malignancy of undescended intra-abdominal testes (3.6 % at 25 years old, and 33 % at 50 years old, reported by various studies). Hormonal substitution therapy should be administered. Comprehensive psychiatric assessment and intervention go a long way in alleviating distress and enhancing quality of life. Conclusion Androgen Insensitivity Syndrome requires expert and sympathetic handling. Close collaboration between surgeon, gynaecologist and psychologist is essential for proper management of complete androgen insensitivity syndrome.
Collapse
Affiliation(s)
| | | | - Jyoti Gupta
- NKP Salve Institute of Medical Sciences, Nagpur, India
| |
Collapse
|
|
36
|
Lagunin AA, Ivanov SM, Gloriozova TA, Pogodin PV, Filimonov DA, Kumar S, Goel RK. Combined network pharmacology and virtual reverse pharmacology approaches for identification of potential targets to treat vascular dementia. Sci Rep 2020; 10:257. [PMID: 31937840 PMCID: PMC6959222 DOI: 10.1038/s41598-019-57199-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 12/21/2019] [Indexed: 02/07/2023] Open
Abstract
Dementia is a major cause of disability and dependency among older people. If the lives of people with dementia are to be improved, research and its translation into druggable target are crucial. Ancient systems of healthcare (Ayurveda, Siddha, Unani and Sowa-Rigpa) have been used from centuries for the treatment vascular diseases and dementia. This traditional knowledge can be transformed into novel targets through robust interplay of network pharmacology (NetP) with reverse pharmacology (RevP), without ignoring cutting edge biomedical data. This work demonstrates interaction between recent and traditional data, and aimed at selection of most promising targets for guiding wet lab validations. PROTEOME, DisGeNE, DISEASES and DrugBank databases were used for selection of genes associated with pathogenesis and treatment of vascular dementia (VaD). The selection of new potential drug targets was made by methods of NetP (DIAMOnD algorithm, enrichment analysis of KEGG pathways and biological processes of Gene Ontology) and manual expert analysis. The structures of 1976 phytomolecules from the 573 Indian medicinal plants traditionally used for the treatment of dementia and vascular diseases were used for computational estimation of their interactions with new predicted VaD-related drug targets by RevP approach based on PASS (Prediction of Activity Spectra for Substances) software. We found 147 known genes associated with vascular dementia based on the analysis of the databases with gene-disease associations. Six hundred novel targets were selected by NetP methods based on 147 gene associations. The analysis of the predicted interactions between 1976 phytomolecules and 600 NetP predicted targets leaded to the selection of 10 potential drug targets for the treatment of VaD. The translational value of these targets is discussed herewith. Twenty four drugs interacting with 10 selected targets were identified from DrugBank. These drugs have not been yet studied for the treatment of VaD and may be investigated in this field for their repositioning. The relation between inhibition of two selected targets (GSK-3, PTP1B) and the treatment of VaD was confirmed by the experimental studies on animals and reported separately in our recent publications.
Collapse
Affiliation(s)
- Alexey A Lagunin
- Pirogov Russian National Research Medical University, Department of Bioinformatics, Moscow, 117997, Russia.
- Institute of Biomedical Chemistry, Department of Bioinformatics, Moscow, 119121, Russia.
| | - Sergey M Ivanov
- Pirogov Russian National Research Medical University, Department of Bioinformatics, Moscow, 117997, Russia
- Institute of Biomedical Chemistry, Department of Bioinformatics, Moscow, 119121, Russia
| | - Tatyana A Gloriozova
- Institute of Biomedical Chemistry, Department of Bioinformatics, Moscow, 119121, Russia
| | - Pavel V Pogodin
- Institute of Biomedical Chemistry, Department of Bioinformatics, Moscow, 119121, Russia
| | - Dmitry A Filimonov
- Institute of Biomedical Chemistry, Department of Bioinformatics, Moscow, 119121, Russia
| | - Sandeep Kumar
- Punjabi University, Department of Pharmaceutical Sciences and Drug Research, Patiala, 147002, India
| | - Rajesh K Goel
- Punjabi University, Department of Pharmaceutical Sciences and Drug Research, Patiala, 147002, India.
| |
Collapse
|
|
37
|
Hu C, Fang D, Xu H, Wang Q, Xia H. The androgen receptor expression and association with patient's survival in different cancers. Genomics 2019; 112:1926-1940. [PMID: 31759122 DOI: 10.1016/j.ygeno.2019.11.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 11/04/2019] [Accepted: 11/11/2019] [Indexed: 01/04/2023]
Abstract
To understand the androgen receptor (AR) in different human malignancies, we conducted a pan-cancer analysis of AR in different tumor tissues and association with patient survival and obtained AR expression data from The Cancer Genome Atlas. Pan-Cancer Analysis of AR indicated that 12 tumor types had decreased AR expression in the tumor, while glioblastoma multiforme has overexpressed AR. The survival analysis showed that high AR mRNA is associated with poor survival of stomach adenocarcinoma and low-grade glioma, but better survival of adrenocortical carcinoma, kidney renal clear cell carcinoma, acute myeloid leukemia, liver hepatocellular carcinoma, ovarian serous cystadenocarcinoma, and skin cutaneous melanoma based on AR mRNA, protein or AR-score. AR was associated with different clinical characteristics and AR correlated genes enriched in cancer-related pathways. These data indicate that AR signaling may be strongly associated with some cancer development and patients' survival, which is promising for potential treatment using antiandrogen therapies.
Collapse
Affiliation(s)
- Chao Hu
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, China; Department of Pathology, School of Basic Medical Sciences & The Affiliated Sir Run Run Hospital, Nanjing Medical University, Nanjing 21116, China
| | - Dan Fang
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, China; Department of Pathology, School of Basic Medical Sciences & The Affiliated Sir Run Run Hospital, Nanjing Medical University, Nanjing 21116, China
| | - Haojun Xu
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, China; Department of Pathology, School of Basic Medical Sciences & The Affiliated Sir Run Run Hospital, Nanjing Medical University, Nanjing 21116, China
| | - Qianghu Wang
- Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, 211116 Nanjing, China
| | - Hongping Xia
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Key Laboratory of Antibody Technique of National Health Commission, Nanjing Medical University, Nanjing 211166, China; Department of Pathology, School of Basic Medical Sciences & The Affiliated Sir Run Run Hospital, Nanjing Medical University, Nanjing 21116, China.
| |
Collapse
|
|
38
|
Harada N, Yotsumoto Y, Katsuki T, Yoda Y, Masuda T, Nomura M, Shiraki N, Inui H, Yamaji R. Fetal androgen signaling defects affect pancreatic β-cell mass and function, leading to glucose intolerance in high-fat diet-fed male rats. Am J Physiol Endocrinol Metab 2019; 317:E731-E741. [PMID: 31287713 DOI: 10.1152/ajpendo.00173.2019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
We previously demonstrated that androgen signaling expands pancreatic β-cell mass in the sexual maturation period (Am J Physiol Endocrinol Metab 314: E274-E286, 2018). The aim of this study was to elucidate whether fetal androgen signaling plays important roles in β-cell mass development and β-cell function in adulthood, defects of which are associated with type 2 diabetes mellitus. In the pancreas of male fetuses, androgen receptor (AR) was strongly expressed in the cytoplasm and at the cell membrane of Nkx6.1-positive β-cell precursor cells but was markedly reduced in insulin-positive β-cells. Administration of the anti-androgen flutamide to pregnant dams during late gestation reduced β-cell mass and Ki67-positive proliferating β-cells at birth in a male-specific manner without affecting body weight. The decrease of β-cell mass in flutamide-exposed male rats was not recovered when rats were fed a standard diet, whereas it was fully recovered when rats were fed a high-fat diet (HFD), at 6 and 12 wk of age. Flutamide exposure in utero led to the development of glucose intolerance in male rats due to a decrease in insulin secretion when fed HFD but not standard diet. Insulin sensitivity did not differ between the two groups irrespective of diet. These results indicated that the action of fetal androgen contributed to β-cell mass expansion in a sex-specific manner at birth and to the development of glucose intolerance by decreasing the secretion of insulin in HFD-fed male rats. Our data demonstrated the involvement of fetal androgen signaling in hypothesized sex differences in the developmental origins of health and disease by affecting pancreatic β-cell function.
Collapse
Affiliation(s)
- Naoki Harada
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan
| | - Yusuke Yotsumoto
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan
| | - Takahiro Katsuki
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan
| | - Yasuhiro Yoda
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan
| | - Tatsuya Masuda
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan
| | - Masayuki Nomura
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan
| | - Nobuaki Shiraki
- Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Kanagawa, Japan
| | - Hiroshi Inui
- Division of Clinical Nutrition, Department of Clinical Nutrition, Graduate School of Comprehensive Rehabilitation, Osaka Prefecture University, Habikino, Osaka, Japan
| | - Ryoichi Yamaji
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka, Japan
| |
Collapse
|
|
39
|
Chen JF, Lin PW, Tsai YR, Yang YC, Kang HY. Androgens and Androgen Receptor Actions on Bone Health and Disease: From Androgen Deficiency to Androgen Therapy. Cells 2019; 8:cells8111318. [PMID: 31731497 PMCID: PMC6912771 DOI: 10.3390/cells8111318] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Revised: 10/21/2019] [Accepted: 10/22/2019] [Indexed: 12/12/2022] Open
Abstract
Androgens are not only essential for bone development but for the maintenance of bone mass. Therefore, conditions with androgen deficiency, such as male hypogonadism, androgen-insensitive syndromes, and prostate cancer with androgen deprivation therapy are strongly associated with bone loss and increased fracture risk. Here we summarize the skeletal effects of androgens—androgen receptors (AR) actions based on in vitro and in vivo studies from animals and humans, and discuss bone loss due to androgens/AR deficiency to clarify the molecular basis for the anabolic action of androgens and AR in bone homeostasis and unravel the functions of androgen/AR signaling in healthy and disease states. Moreover, we provide evidence for the skeletal benefits of androgen therapy and elucidate why androgens are more beneficial than male sexual hormones, highlighting their therapeutic potential as osteoanabolic steroids in improving bone fracture repair. Finally, the application of selective androgen receptor modulators may provide new approaches for the treatment of osteoporosis and fractures as well as building stronger bones in diseases dependent on androgens/AR status.
Collapse
Affiliation(s)
- Jia-Feng Chen
- Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Kaohsiung Chang-Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 833, Taiwan;
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan; (P.-W.L.); (Y.-R.T.); (Y.-C.Y.)
| | - Pei-Wen Lin
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan; (P.-W.L.); (Y.-R.T.); (Y.-C.Y.)
- Center for Menopause and Reproductive Medicine Research, Department of Obstetrics and Gynecology, Kaohsiung Chang-Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 833, Taiwan
| | - Yi-Ru Tsai
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan; (P.-W.L.); (Y.-R.T.); (Y.-C.Y.)
- Center for Menopause and Reproductive Medicine Research, Department of Obstetrics and Gynecology, Kaohsiung Chang-Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 833, Taiwan
- An-Ten Obstetrics and Gynecology Clinic, Kaohsiung 802, Taiwan
| | - Yi-Chien Yang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan; (P.-W.L.); (Y.-R.T.); (Y.-C.Y.)
- Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
| | - Hong-Yo Kang
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan; (P.-W.L.); (Y.-R.T.); (Y.-C.Y.)
- Center for Menopause and Reproductive Medicine Research, Department of Obstetrics and Gynecology, Kaohsiung Chang-Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 833, Taiwan
- Correspondence: ; Tel.: +886-7-731-7123 (ext. 8898)
| |
Collapse
|
|
40
|
Effect of Moxibustion on Testosterone Secretion and Apoptosis of Spermatogenic Cells in Aging Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:5186408. [PMID: 31885650 PMCID: PMC6925733 DOI: 10.1155/2019/5186408] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 08/20/2019] [Accepted: 09/09/2019] [Indexed: 01/13/2023]
Abstract
Analysis of androgen secretion and sperm production was conducted in the testis to investigate the efficacy of moxibustion on testicular function in aging rats. Male Sprague–Dawley rats were randomly divided into the aging group (N = 8), the mild-warm moxibustion group (N = 8), and the youth control group (N = 8). Rats in the mild-warm moxibustion group (MWMG) were exposed to mild-warm moxibustion at the Zusanli (ST36) and Shenshu (BL23) acupuncture points daily, from the age of 12 months until the age of 24 months. After the intervention, testicular tissue was harvested from all rats across groups. Changes in testicular structure were examined by hematoxylin and eosin (H&E) stain. Detection of the apoptosis of spermatogenic cells was performed by the TUNEL assay. Testosterone level in the testis was analyzed by the ELISA assay, and the expression of Bax, Bcl-2, and androgen receptor (AR) in the testis was evaluated by immunohistochemistry. AR expression analysis was subsequently performed by the western blotting assay, and the detection of telomerase activity of the testis and the expression of Bax, Bcl-2, and AR mRNA were performed by real-time PCR. Compared with the youth controls, telomerase activity in the testis, testosterone levels, expression of AR, and expression of antiapoptosis factor Bcl-2 protein and mRNA were significantly decreased (P < 0.01) in the aging group. Spermatogenic cell apoptosis (P < 0.01) and proapoptotic factor Bax expression were significantly increased (P < 0.01) in the aging rats compared with the youth control group. The MWMG exhibited significant increases in testicular telomerase activity, testosterone level, AR expression, and antiapoptosis factor Bcl-2 expression (P < 0.05 or P < 0.01) compared with the aging group. In this experimental group, spermatogenic apoptosis was inhibited (P < 0.01) and proapoptotic factor Bax expression significantly reduced (P < 0.01). Mild-warm moxibustion can inhibit reproductive senescence by improving telomerase activity, improving AR expression, restoring testosterone, and inhibiting spermatogenic apoptosis via regulation of Bcl-2/Bax.
Collapse
|
|
41
|
Takayama K, Fujiwara K, Inoue S. Amyloid precursor protein, an androgen‐regulated gene, is targeted by RNA‐binding protein PSF/SFPQ in neuronal cells. Genes Cells 2019; 24:719-730. [DOI: 10.1111/gtc.12721] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 09/09/2019] [Accepted: 09/14/2019] [Indexed: 01/07/2023]
Affiliation(s)
- Ken‐ichi Takayama
- Department of Systems Aging Science and Medicine Tokyo Metropolitan Institute of Gerontology Tokyo Japan
| | - Kyoko Fujiwara
- Department of Medicine Nihon University School of Medicine Tokyo Japan
- Department of Anatomy Nihon University School of Dentistry Tokyo Japan
| | - Satoshi Inoue
- Department of Systems Aging Science and Medicine Tokyo Metropolitan Institute of Gerontology Tokyo Japan
- Division of Gene Regulation and Signal Transduction Research Center for Genomic Medicine Saitama Medical University Hidaka Saitama Japan
| |
Collapse
|
|
42
|
Sex and the kidneys: current understanding and research opportunities. Nat Rev Nephrol 2019; 15:776-783. [PMID: 31586165 DOI: 10.1038/s41581-019-0208-6] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2019] [Indexed: 12/22/2022]
Abstract
Concerns regarding sex differences are increasingly pertinent in scientific and societal arenas. Although biological sex and socio-cultural gender are increasingly recognized as important modulators of renal function under physiological and pathophysiological conditions, gaps remain in our understanding of the mechanisms underlying sex differences in renal pathophysiology, disease development, progression and management. In this Perspectives article, we discuss specific opportunities for future research aimed at addressing these knowledge gaps. Such opportunities include the development of standardized core data elements and outcomes related to sex for use in clinical studies to establish a connection between sex hormones and renal disease development or progression, development of a knowledge portal to promote fundamental understanding of physiological differences between male and female kidneys in animal models and in humans, and the creation of new or the development of existing resources and datasets to make them more readily available for interrogation of sex differences. These ideas are intended to stimulate thought and interest among the renal research community as they consider sex as a biological variable in future research projects.
Collapse
|
|
43
|
Giovannelli P, Di Donato M, Galasso G, Di Zazzo E, Medici N, Bilancio A, Migliaccio A, Castoria G. Breast cancer stem cells: The role of sex steroid receptors. World J Stem Cells 2019; 11:594-603. [PMID: 31616537 PMCID: PMC6789191 DOI: 10.4252/wjsc.v11.i9.594] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 05/06/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023] Open
Abstract
Breast cancer (BC) is the most common cancer among women, and current available therapies often have high success rates. Nevertheless, BC might acquire drug resistance and sometimes relapse. Current knowledge about the most aggressive forms of BC points to the role of specific cells with stem properties located within BC, the so-called “BC stem cells” (BCSCs). The role of BCSCs in cancer formation, growth, invasiveness, therapy resistance and tumor recurrence is becoming increasingly clear. The growth and metastatic properties of BCSCs are regulated by different pathways, which are only partially known. Sex steroid receptors (SSRs), which are involved in BC etiology and progression, promote BCSC proliferation, dedifferentiation and migration. However, in the literature, there is incomplete information about their roles. Particularly, there are contrasting conclusions about the expression and role of the classical BC hormonal biomarkers, such as estrogen receptor alpha (ERα), together with scant, albeit promising information concerning ER beta (ERβ) and androgen receptor (AR) properties that control different transduction pathways in BCSCs. In this review, we will discuss the role that SRs expressed in BCSCs play to BC progression and recurrence and how these findings have opened new therapeutic possibilities.
Collapse
Affiliation(s)
- Pia Giovannelli
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Marzia Di Donato
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Giovanni Galasso
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Erika Di Zazzo
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Nicola Medici
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Antonio Bilancio
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Antimo Migliaccio
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| | - Gabriella Castoria
- Department of Precision Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy
| |
Collapse
|
|
44
|
Activation of PSGR with β-ionone suppresses prostate cancer progression by blocking androgen receptor nuclear translocation. Cancer Lett 2019; 453:193-205. [DOI: 10.1016/j.canlet.2019.03.044] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 03/17/2019] [Accepted: 03/23/2019] [Indexed: 01/10/2023]
|
|
45
|
Rubinow KB, Houston B, Wang S, Goodspeed L, Ogimoto K, Morton GJ, McCarty C, Braun RE, Page ST. Androgen receptor deficiency in monocytes/macrophages does not alter adiposity or glucose homeostasis in male mice. Asian J Androl 2019; 20:276-283. [PMID: 29205180 PMCID: PMC5952483 DOI: 10.4103/aja.aja_54_17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Androgen deprivation in men leads to increased adiposity, but the mechanisms underlying androgen regulation of fat mass have not been fully defined. Androgen receptor (AR) is expressed in monocytes/macrophages, which are resident in key metabolic tissues and influence energy metabolism in surrounding cells. Male mice bearing a cell-specific knockout of the AR in monocytes/macrophages (M-ARKO) were generated to determine whether selective loss of androgen signaling in these cells would lead to altered body composition. Wild-type (WT) and M-ARKO mice (12–22 weeks of age, n = 12 per group) were maintained on a regular chow diet for 8 weeks and then switched to a high-fat diet for 8 additional weeks. At baseline and on both the regular chow and high-fat diets, no differences in lean mass or fat mass were observed between groups. Consistent with the absence of differential body weight or adiposity, no differences in food intake (3.0 ± 0.5 g per day for WT mice vs 2.8 ± 0.4 g per day for M-ARKO mice) or total energy expenditure (0.6 ± 0.1 Kcal h−1 for WT mice vs 0.5 ± 0.1 Kcal h−1 for M-ARKO mice) were evident between groups during high-fat feeding. Liver weight was greater in M-ARKO than that in WT mice (1.5 ± 0.1 g vs 1.3 ± 0.0 g, respectively, P = 0.02). Finally, M-ARKO mice did not exhibit impairments in glucose tolerance or insulin sensitivity relative to WT mice at any study time point. In aggregate, these findings suggest that AR signaling specifically in monocytes/macrophages does not contribute to the regulation of systemic energy balance, adiposity, or insulin sensitivity in male mice.
Collapse
Affiliation(s)
- Katya B Rubinow
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Barbara Houston
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Shari Wang
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Leela Goodspeed
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Kayoko Ogimoto
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Gregory J Morton
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| | | | | | - Stephanie T Page
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
| |
Collapse
|
|
46
|
Walters KA, Gilchrist RB, Ledger WL, Teede HJ, Handelsman DJ, Campbell RE. New Perspectives on the Pathogenesis of PCOS: Neuroendocrine Origins. Trends Endocrinol Metab 2018; 29:841-852. [PMID: 30195991 DOI: 10.1016/j.tem.2018.08.005] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 08/13/2018] [Accepted: 08/14/2018] [Indexed: 11/25/2022]
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrine condition in reproductive-aged women. It is characterized by reproductive, endocrine, metabolic, and psychological features. The cause of PCOS is unknown, thus there is no cure and its management remains suboptimal because it relies on the ad hoc empirical management of symptoms only. We review here the strong support for PCOS having a neuroendocrine origin. In particular, we focus on the role of aberrant hypothalamic-pituitary function and associated hyperandrogenism, and their role as major drivers of the mechanisms underpinning the development of PCOS. This important information now provides a target site and a potential mechanism for the future development of novel, targeted, and mechanism-based effective therapies for the treatment of PCOS.
Collapse
Affiliation(s)
- Kirsty A Walters
- Fertility and Research Centre, School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia; https://research.unsw.edu.au/people/dr-kirsty-walters.
| | - Robert B Gilchrist
- Fertility and Research Centre, School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - William L Ledger
- Fertility and Research Centre, School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia
| | - Helena J Teede
- Monash Centre for Health Research and Implementation, Monash Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3168, Australia
| | - David J Handelsman
- Andrology Laboratory, ANZAC Research Institute, University of Sydney, Sydney, New South Wales 2139, Australia
| | - Rebecca E Campbell
- Centre of Neuroendocrinology and Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin 9054, New Zealand
| |
Collapse
|
|
47
|
Zhao M, Yuan L, Yuan MM, Huang LL, Su C, Chen YH, Yang YY, Hu Y, Xu DX. Maternal lipopolysaccharide exposure results in glucose metabolism disorders and sex hormone imbalance in male offspring. Mol Cell Endocrinol 2018; 474:272-283. [PMID: 29614340 DOI: 10.1016/j.mce.2018.03.019] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 03/16/2018] [Accepted: 03/31/2018] [Indexed: 12/31/2022]
Abstract
An adverse intrauterine environment may be an important factor contributing to the development of type 2 diabetes in later life. The present study investigated the longitudinal effects of maternal lipopolysaccharide (LPS) exposure during the third trimester on glucose metabolism and sex hormone balance in the offspring. Pregnant mice were intraperitoneally injected with LPS (50 μg/kg) daily from gestational day (GD) 15 to GD17. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were assessed at postnatal day (PND) 60 and PND120. Sex hormones, their receptors, and metabolic enzymes (aromatase) were measured in male offspring at different phases of development (PND14: juvenile; PND35: adolescence; PND60: adulthood; and PND120: middle age). LPS-exposed male offspring exhibited glucose intolerance and insulin resistance by GTT and ITT at middle age, accompanied by an increase in fasting blood glucose and reductions in serum insulin levels and hepatic phosphorylated (p) -AKT/AKT ratio. However, glucose intolerance and insulin resistance were not observed in LPS-exposed female offspring. Maternal LPS exposure upregulated hepatic aromatase proteins and mRNA levels in male offspring at all time points. At adolescence, the testosterone/estradiol ratio (T/E2) was markedly reduced in LPS-exposed male offspring. Moreover, maternal LPS exposure significantly increased hepatic estrogen receptor (ER) α expressions and decreased hepatic androgen receptor (AR) expressions in male offspring. At adulthood, maternal LPS exposure increased serum estradiol levels, decreased serum testosterone levels and elevated hepatic ERβ expressions in male offspring. In conclusion, maternal LPS exposure upregulated aromatase expressions, followed by a reduction in the T/E2 ratio and an alteration in sex hormone receptor activity, which might be involved in the development of glucose metabolism disorders in middle-aged male offspring. This study provides a novel clue and direction to clarify the pathogenesis of maternal infection-related diabetes in male offspring.
Collapse
Affiliation(s)
- Mei Zhao
- School of Nursing, Anhui Medical University, Hefei 230032, China; Anhui Provincial Key Laboratory of Population Health & Aristogenics, Hefei, 230032, China.
| | - Li Yuan
- School of Nursing, Anhui Medical University, Hefei 230032, China
| | - Man-Man Yuan
- School of Nursing, Anhui Medical University, Hefei 230032, China
| | - Li-Li Huang
- School of Nursing, Anhui Medical University, Hefei 230032, China
| | - Chang Su
- The Fourth Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Yuan-Hua Chen
- Anhui Provincial Key Laboratory of Population Health & Aristogenics, Hefei, 230032, China; Department of Histology and Embryology, Anhui Medical University, Hefei, 230032, China
| | - Yu-Ying Yang
- School of Nursing, Anhui Medical University, Hefei 230032, China
| | - Yan Hu
- School of Nursing, Anhui Medical University, Hefei 230032, China
| | - De-Xiang Xu
- Anhui Provincial Key Laboratory of Population Health & Aristogenics, Hefei, 230032, China; Department of Toxicology, Anhui Medical University, Hefei, 230032, China
| |
Collapse
|
|
48
|
Ying M, Zhao R, Jiang D, Gu S, Li M. Lifestyle interventions to alleviate side effects on prostate cancer patients receiving androgen deprivation therapy: a meta-analysis. Jpn J Clin Oncol 2018; 48:827-834. [PMID: 30053039 DOI: 10.1093/jjco/hyy101] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 07/04/2018] [Indexed: 12/30/2022] Open
Abstract
Background Prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT) are prone to suffer a series of potential side effects, including metabolic change, declining physical strength and worsening fatigue. Recent studies found that the change of lifestyle interventions can help to alleviate some adverse reactions, but the results were controversial. Therefore, the aim of this review was to comprehensively evaluate the effects of these lifestyle interventions on the side effects on PCa patients who received ADT. Methods We searched several electronic databases, including ScienceDirect, PubMed, Cochrane library, CNKI and Wanfang database, without language restrictions. Among the literature, such lifestyle interventions as dietary advice, exercise and physical activities were carried out in the way of randomized controlled trials (RCTs) on PCa patients taking ADT. Pooled estimates were performed using fixed-effects or random-effects model. Results Eleven RCTs involving 905 participants were included in this review. Compared with usual care group, exercise intervention could significantly improve the quality of life (QoL) of PCa patients undergoing ADT (P = 0.05, SMD = 0.17, 95% CI -0.00 to 0.34), but exercise plus dietary advice could not significantly improve the QoL (P = 0.15, SMD = 0.45, 95% CI -0.17 to 1.08). Moreover, lifestyle intervention could significantly change body composition (P = 0.03, SMD = -0.1, 95% CI -0.19 to -0.01). However, there showed no obvious difference in mitigating fatigue and depression (P = 0.46, SMD = 0.11, 95% CI -0.18 to 0.39; P = 0.31, SMD = -0.18, 95% CI -0.54 to 0.17). Conclusions The results of this meta-analysis from present study indicated that exercise interventions can better improve the QoL and alleviate treatment-related side effects on prostate cancer patients taking ADT, and better therapeutic regimens for PCa patients are likely to emerge in the process.
Collapse
Affiliation(s)
- Miaofa Ying
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - Rui Zhao
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - Deqi Jiang
- Department of Biopharmaceutical, Yulin Normal University, Yulin, China
| | - Shenglong Gu
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou
| | - Mingxing Li
- Department of Pharmacy, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou
| |
Collapse
|
|
49
|
Yang P, Liu X, Gao J, Qu S, Zhang M. Complete androgen insensitivity syndrome in a young woman with metabolic disorder and diabetes: A case report. Medicine (Baltimore) 2018; 97:e11353. [PMID: 30113450 PMCID: PMC6112890 DOI: 10.1097/md.0000000000011353] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
RATIONALE Androgen insensitivity syndrome (CAIS) is a rare X-linked recessive androgen receptor disorder characterized by complete resistance to the actions of androgen in an individual with 46,XY karyotype. Metabolic disorder and diabetes has been rarely reported in these patients. PATIENT CONCERNS A 22-year-old female patient was admitted to our center for the evaluation of high blood sugar. The central obesity, lipid dysfunction, and diabetes were found in the patient. The patient also presented as primary amenorrhea and poor secondary sex characteristics after puberty. DIAGNOSES The diagnosis of CAIS in this patient was established by infantile female genitalia, absence of ovary and uterus, history of gonadectomy, 46,XY karyotype, and carried a mutation c.2751C>G (p.917F > L) in androgen receptor gene. INTERVENTION The patient was treated by insulin, metformin, statins and estrogen. OUTCOMES After 6 months follow-up, blood sugar and lipid profiles were normal, but breast development and weight loss were not obvious. LESSONS We report a case of CAIS in a 22-year-old female accompanying central obesity, dyslipidemia, and diabetes mellitus. It is extremely important to recognize special type diabetes among the young-onset diabetic patients, and this case will provide further evidence of a link between impaired androgen receptor signaling and metabolic regulation.
Collapse
Affiliation(s)
- Peng Yang
- Department of Endocrinology & Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine
| | - Xiang Liu
- Department of Urology, Putuo District People's Hospital, Shanghai, China
| | - Jingyang Gao
- Department of Endocrinology & Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine
| | - Shen Qu
- Department of Endocrinology & Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine
| | - Manna Zhang
- Department of Endocrinology & Metabolism, Shanghai Tenth People's Hospital, Tongji University School of Medicine
| |
Collapse
|
|
50
|
Harada N. Role of androgens in energy metabolism affecting on body composition, metabolic syndrome, type 2 diabetes, cardiovascular disease, and longevity: lessons from a meta-analysis and rodent studies. Biosci Biotechnol Biochem 2018; 82:1667-1682. [PMID: 29957125 DOI: 10.1080/09168451.2018.1490172] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Testosterone is a sex hormone produced by testicular Leydig cells in males. Blood testosterone concentrations increase at three time-periods in male life-fetal, neonatal (which can be separated into newborn and infant periods), and pubertal stages. After peaking in the early 20s, the blood bioactive testosterone level declines by 1-2% each year. It is increasingly apparent that a low testosterone level impairs general physical and mental health in men. Here, this review summarizes recent systematic reviews and meta-analyses of epidemiological studies in males (including cross-sectional, longitudinal, and androgen deprivation studies, and randomized controlled testosterone replacement trials) in relation to testosterone and obesity, body composition, metabolic syndrome, type 2 diabetes, cardiovascular disease, and longevity. Furthermore, underlying mechanisms are discussed using data from rodent studies involving castration or androgen receptor knockout. This review provides an update understanding of the role of testosterone in energy metabolism. Abbreviations AR: androgen receptor; CV: cardiovascular; FDA: US Food and Drug Administration; HFD: high-fat diet; KO: knockout; MetS: metabolic syndrome; RCT: randomized controlled trial; SHBG: sex hormone binding globulin; SRMA: systematic review and meta-analysis; TRT: testosterone replacement therapy; T2DM:type 2 diabetes mellitus.
Collapse
Affiliation(s)
- Naoki Harada
- a Division of Applied Life Sciences , Graduate School of Life and Environmental Sciences, Osaka Prefecture University , Sakai , Osaka , Japan
| |
Collapse
|