Low levels of endogenous anabolic androgenic steroids in females with severe asthma taking corticosteroids

Valentyna Yasinska^{1

2

3}, Cristina Gómez^{2

3

4}, Johan Kolmert^{2

3

4}, Magnus Ericsson^{5

6

7}, Anton Pohanka^{5

6}, Anna James^{2

3

4}, Lars I Andersson^{1

2

3}, Maria Sparreman-Mikus^{1

2

3}, Ana R Sousa⁸, John H Riley⁸, Stewart Bates⁸, Per S Bakke⁹, Nazanin Zounemat Kermani¹⁰, Massimo Caruso¹¹, Pascal Chanez¹², Stephen J Fowler^{13

14}, Thomas Geiser¹⁵, Peter H Howarth^{16

17}, Ildikó Horváth^{18

19}, Norbert Krug²⁰, Paolo Montuschi^{10

21}, Marek Sanak²², Annelie Behndig²³, Dominick E Shaw²⁴, Richard G Knowles²⁵, Barbro Dahlén^{1

2

3}, Anke-Hilse Maitland-van der Zee²⁶, Peter J Sterk²⁶, Ratko Djukanovic^{16

17}, Ian M Adcock¹⁰, Kian Fan Chung¹⁰, Craig E Wheelock^{2

3

4}, Sven-Erik Dahlén^{1

2

3

4}, Eva Wikström Jonsson^{5

6}; U-BIOPRED Study Group

Affiliations

¹ Clinical Lung and Allergy Research, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
² Department of Respiratory Medicine, Karolinska University Hospital, Stockholm, Sweden.
³ The Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
⁴ Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁵ Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
⁶ Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
⁷ Laboratoire AntiDopage Français, Université Paris-Saclay, Châtenay-Malabry, France.
⁸ Respiratory and Speciality Group, GSK, Clinical Sciences, Stockley Park, UK.
⁹ Institute of Clinical Science, University of Bergen, Bergen, Norway.
¹⁰ National Heart and Lung Institute and Data Science Institute, Imperial College London, London, UK.
¹¹ Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
¹² Assistance Publique des Hôpitaux de Marseille, Clinique des Bronches, Allergies et Sommeil, Aix Marseille Université, Marseille, France.
¹³ Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK.
¹⁴ Manchester Academic Health Science Centre and NIHR Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
¹⁵ Department of Pulmonary Medicine, University Hospital, University of Bern, Bern, Switzerland.
¹⁶ Faculty of Medicine, Southampton University, Southampton, UK.
¹⁷ NIHR Southampton Respiratory Biomedical Research Center, University Hospital Southampton, Southampton, UK.
¹⁸ Department of Public Health, Semmelweis University, Budapest, Hungary.
¹⁹ National Koranyi Institute for Pulmonology, Budapest, Hungary.
²⁰ Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
²¹ Department of Pharmacology, Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
²² Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland.
²³ Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
²⁴ Nottingham NIHR Biomedical Research Centre, University of Nottingham, Nottingham, UK.
²⁵ Knowles Consulting, Stevenage Bioscience Catalyst, Stevenage, UK.
²⁶ Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

PMID: 37868143
PMCID: PMC10588792
DOI: 10.1183/23120541.00269-2023

Low levels of endogenous anabolic androgenic steroids in females with severe asthma taking corticosteroids

Valentyna Yasinska et al. ERJ Open Res. 2023.

. 2023 Oct 2;9(5):00269-2023.

doi: 10.1183/23120541.00269-2023. eCollection 2023 Sep.

Authors

Affiliations

¹ Clinical Lung and Allergy Research, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
² Department of Respiratory Medicine, Karolinska University Hospital, Stockholm, Sweden.
³ The Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
⁴ Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁵ Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
⁶ Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
⁷ Laboratoire AntiDopage Français, Université Paris-Saclay, Châtenay-Malabry, France.
⁸ Respiratory and Speciality Group, GSK, Clinical Sciences, Stockley Park, UK.
⁹ Institute of Clinical Science, University of Bergen, Bergen, Norway.
¹⁰ National Heart and Lung Institute and Data Science Institute, Imperial College London, London, UK.
¹¹ Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
¹² Assistance Publique des Hôpitaux de Marseille, Clinique des Bronches, Allergies et Sommeil, Aix Marseille Université, Marseille, France.
¹³ Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK.
¹⁴ Manchester Academic Health Science Centre and NIHR Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
¹⁵ Department of Pulmonary Medicine, University Hospital, University of Bern, Bern, Switzerland.
¹⁶ Faculty of Medicine, Southampton University, Southampton, UK.
¹⁷ NIHR Southampton Respiratory Biomedical Research Center, University Hospital Southampton, Southampton, UK.
¹⁸ Department of Public Health, Semmelweis University, Budapest, Hungary.
¹⁹ National Koranyi Institute for Pulmonology, Budapest, Hungary.
²⁰ Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
²¹ Department of Pharmacology, Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
²² Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland.
²³ Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
²⁴ Nottingham NIHR Biomedical Research Centre, University of Nottingham, Nottingham, UK.
²⁵ Knowles Consulting, Stevenage Bioscience Catalyst, Stevenage, UK.
²⁶ Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

PMID: 37868143
PMCID: PMC10588792
DOI: 10.1183/23120541.00269-2023

Abstract

Rationale: Patients with severe asthma are dependent upon treatment with high doses of inhaled corticosteroids (ICS) and often also oral corticosteroids (OCS). The extent of endogenous androgenic anabolic steroid (EAAS) suppression in asthma has not previously been described in detail. The objective of the present study was to measure urinary concentrations of EAAS in relation to exogenous corticosteroid exposure.

Methods: Urine collected at baseline in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcomes) study of severe adult asthmatics (SA, n=408) was analysed by quantitative mass spectrometry. Data were compared to that of mild-to-moderate asthmatics (MMA, n=70) and healthy subjects (HC, n=98) from the same study.

Measurements and main results: The concentrations of urinary endogenous steroid metabolites were substantially lower in SA than in MMA or HC. These differences were more pronounced in SA patients with detectable urinary OCS metabolites. Their dehydroepiandrosterone sulfate (DHEA-S) concentrations were <5% of those in HC, and cortisol concentrations were below the detection limit in 75% of females and 82% of males. The concentrations of EAAS in OCS-positive patients, as well as patients on high-dose ICS only, were more suppressed in females than males (p<0.05). Low levels of DHEA were associated with features of more severe disease and were more prevalent in females (p<0.05). The association between low EAAS and corticosteroid treatment was replicated in 289 of the SA patients at follow-up after 12-18 months.

Conclusion: The pronounced suppression of endogenous anabolic androgens in females might contribute to sex differences regarding the prevalence of severe asthma.

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Conflict of interest statement

Conflict of interest: V. Yasinska reports participation in advisory boards for AZ and GSK, and lecture honoraria from Sanofi and GSK. Conflict of interest: C. Gómez has nothing to disclose. Conflict of interest: J. Kolmert has nothing to disclose. Conflict of interest: M. Ericsson has nothing to disclose. Conflict of interest: A. Pohanka has nothing to disclose. Conflict of interest: A. James reports personal grant from Swedish Heart-Lung Foundation. Conflict of interest: L.I. Andersson has nothing to disclose. Conflict of interest: M. Sparreman-Mikus has nothing to disclose. Conflict of interest: A.R. Sousa reports employment and stocks or stock options from GSK. Conflict of interest: J.H. Riley has nothing to disclose. Conflict of interest: S. Bates has nothing to disclose. Conflict of interest: P.S. Bakke reports lecture honoraria from AstraZeneca and Boehringer Ingelheim. Conflict of interest: N. Zounemat Kermani has nothing to disclose. Conflict of interest: M. Caruso has nothing to disclose. Conflict of interest: P. Chanez reports participation in advisory boards, honoraria for consultancy, lectures fees and support for attending and/or travel from ALK, Almirall, AZ, Chiesi, GSK, Menarini, Novartis and Sanofi. Conflict of interest: S.J. Fowler has nothing to disclose. Conflict of interest: T. Geiser has nothing to disclose. Conflict of interest: P.H. Howarth reports employment and stocks or stock options from GSK. Conflict of interest: I. Horváth reports participation on an advisory board for AZ and Chiesi, honoraria for lectures from Chiesi and Roche, and support for attending and/or travel from Roche. Conflict of interest: N. Krug has nothing to disclose. Conflict of interest: P. Montuschi has nothing to disclose. Conflict of interest: M. Sanak has nothing to disclose. Conflict of interest: A. Behndig has nothing to disclose. Conflict of interest: D.E. Shaw has nothing to disclose. Conflict of interest: R.G. Knowles has nothing to disclose. Conflict of interest: B. Dahlén reports grant from GSK and Novartis. Conflict of interest: A-H. Maitland-van der Zee reports grants from BI, Vertex Innovation Award, Dutch Lung Foundation, Stichting Astma Bestrijding, IMI/3TR, EU grant ONELAB and EUROSTARS grant with Respiq, consulting fees from AZ and BI, and lecture honoraria from GSK. Conflict of interest: P.J. Sterk reports a grant from the Innovative Medicines Initiative. Conflict of interest: R. Djukanovic reports consulting fees from Synairgen, lecture honoraria from Regeneron, GSK and Kymab, and an advisory board for Synairgen. Conflict of interest: I.M. Adcock reports grant from EU-IMI, grants from GSK, MRK, EPSRC and Sanofi, consulting fees from GSK, Sanofi, Chiesi and Kinaset, lecture honoraria from AZ, Sanofi and Eurodrug, and payment for an educational event from Sunovion. Conflict of interest: K.F. Chung reports lectures honoraria from Novartis, AZ and Merck, advisory boards for GSK, AZ, Novartis, Roche, Merck, Rickett-Beckinson, Nocion and Shionogi, the Scientific Advisory Board of the Clean Breathing Institute supported by Haleon, grants from GSK, MRC and EPSRC, and support for travel from AZ. Conflict of interest: C.E. Wheelock has nothing to disclose. Conflict of interest: S-E. Dahlén reports research grants, consulting fees or lecture honoraria from AZ, Cayman Chemicals, GSK, Regeneron, Sanofi and Teva. Conflict of interest: E. Wikström Jonsson reports a research grant and expert assignment by Region Stockholm, and an expert appointment by the Swedish Medical Product Agency.

Figures

**FIGURE 1**
Overview of steroid metabolism with metabolites measured in the study shown in grey boxes.

**FIGURE 2**
Levels of endogenous steroids in the urine of female and male study participants. a) Cortisol; b) dehydroepiandrosterone sulfate (DHEA-S); c) androsterone-glucuronate (G); d) testosterone-G. Data are presented as median (interquartile range). The Mann–Whitney U-test was used to compare two groups and the Kruskal–Wallis test to compare three groups. All graphs have a logarithmic y-axis scale, although statistical analyses were performed on arithmetic data. The box plots for the three severe asthma (SA) groups in a) (cortisol) are elongated due to the large number of imputed values (0.5 ng·mL⁻¹) where levels were below limit of detection (LOD) (see also tables 2 and 3). HC: healthy controls; MMA: mild-to-moderate asthma; SA: all patients with severe asthma; SA ICS: severe asthma subgroup with no detectable metabolites of oral corticosteroids in the urine (OCS-neg); SA OCS-pos: severe asthma subgroup with detectable metabolites of oral corticosteroids in the urine.

**FIGURE 3**
Reported oral corticosteroid (OCS) use and presence of urinary prednisone metabolites (OCS detected) in patients with severe asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes study at baseline (n=403) and longitudinal follow-up 12–18 months later (n=289).

**FIGURE 4**
Clinical and biomarker variables for the lowest (25th percentile; n=119) and highest (75th percentile; n=118) quartiles of asthmatic patients stratified for urinary concentrations of dehydroepiandrosterone sulfate (DHEA-S). Data are presented as median (interquartile range) for a) forced expiratory volume in 1 s (FEV₁; % predicted), b) Asthma Control Questionnaire (ACQ)-5, c) exacerbations in past year, d) Asthma Quality-of-Life Questionnaire (AQLQ), e) Hospital Anxiety and Depression Scale (HADS) total score, f) high-sensitivity C-reactive protein (hCRP) and g) S-matrix metalloproteinase (MMP)-3 (low and high groups were compared by Mann–Whitney U-test); and h) the number of subjects with detectable urinary oral corticosteroid (OCS) metabolites (significance calculated according to the Chi-squared test).

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References

1. Cephus JY, Stier MT, Fuseini H, et al. Testosterone attenuates group 2 innate lymphoid cell-mediated airway inflammation. Cell Rep 2017; 21: 2487–2499. doi: 10.1016/j.celrep.2017.10.110 - DOI - PMC - PubMed
1. Fuseini H, Yung JA, Cephus JY, et al. Testosteron decreases house dust mite-induced type 2 and IL-17A-mediated airway inflammation. J Immunol 2018; 201: 1843–1854. doi: 10.4049/jimmunol.1800293 - DOI - PMC - PubMed
1. Koziol-White CJ, Goncharova EA, Cao G, et al. DHEA-S inhibits human neutrophil and human airway smooth muscle migration. Biochim Biophys Acta 2012; 1822: 1638–1642. doi: 10.1016/j.bbadis.2012.06.012 - DOI - PMC - PubMed
1. Zein JG, McManus JM, Sharifi N, et al. Benefits of airway androgen receptor expression in human asthma. Am J Respir Crit Care Med 2021; 204: 285–293. doi: 10.1164/rccm.202009-3720OC - DOI - PMC - PubMed
1. Wenzel SE, Robinson CB, Leonard JM, et al. Nebulized dehydroepiandrosterone-3-sulfate improves asthma control in the moderate-to-severe asthma results of a 6-week, randomized, double-blind, placebo-controlled study. Allergy Asthma Proc 2010; 31: 461–471. doi: 10.2500/aap.2010.31.3384 - DOI - PubMed

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Low levels of endogenous anabolic androgenic steroids in females with severe asthma taking corticosteroids

Affiliations

Low levels of endogenous anabolic androgenic steroids in females with severe asthma taking corticosteroids

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources