Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe

doi:10.1530/EJE-21-0554

. 2022 Mar 23;186(5):K17-K24.

doi: 10.1530/EJE-21-0554.

Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe

Hanna Nowotny¹, Uta Neumann², Véronique Tardy-Guidollet³, S Faisal Ahmed⁴, Federico Baronio⁵, Tadej Battelino⁶, Jérôme Bertherat⁷, Oliver Blankenstein², Marco Bonomi^{8

9}, Claire Bouvattier^{10

11}, Aude Brac de la Perrière¹², Sara Brucker¹³, Marco Cappa¹⁴, Philippe Chanson¹⁵, Hedi L Claahsen-van der Grinten¹⁶, Annamaria Colao¹⁷, Martine Cools¹⁸, Justin H Davies¹⁹, Helmut-Günther Dörr²⁰, Wiebke K Fenske²¹, Ezio Ghigo²², Roberta Giordano²², Claus H Gravholt²³, Angela Huebner²⁴, Eystein Sverre Husebye^{25

26}, Rebecca Igbokwe²⁷, Anders Juul^{28

29}, Florian W Kiefer³⁰, Juliane Léger³¹, Rita Menassa³, Gesine Meyer³², Vassos Neocleous^{33

34}, Leonidas A Phylactou^{33

34}, Julia Rohayem³⁵, Gianni Russo³⁶, Carla Scaroni³⁷, Philippe Touraine³⁸, Nicole Unger³⁹, Jarmila Vojtková⁴⁰, Diego Yeste^{41

42

43}, Svetlana Lajic⁴⁴, Nicole Reisch¹

Affiliations

¹ Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany.
² Centre for Chronic Sick Children, Department of Paediatric Endocrinology and Diabetology, Charité Universitätsmedizin Berlin, Berlin, Germany.
³ Laboratoire de Biochimie et Biologie Moléculaire, Hospices Civils de Lyon, Centre National de Référence 'Développement Génital: du fœtus à l'adulte DEV-GEN' Université Lyon I, Lyon, France.
⁴ Developmental Endocrinology Research Group, University of Glasgow, Glasgow, UK.
⁵ Paediatric Endocrinology Unit, Department of Medical and Surgical Sciences, S.Orsola-Malpighi University Hospital, Bologna, Italy.
⁶ Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, University Children's Hospital, Ljubljana, Slovenia.
⁷ Service d'Endocinologie et Maladies Métaboliques, Hôpitaux Universitaires Paris-Centre, Assistance Publique - Hôpitaux de Paris, Paris, France.
⁸ Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
⁹ Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic Research, IRCSS Istituto Auxologico Italiano, Milan, Italy.
¹⁰ Service d'Endocrinologie de l'Enfant, GHU Paris-Sud, Hôpital de Bicêtre, Paris, France.
¹¹ Centre National de Référence 'Développement Génital: du fœtus à l'adulte DEV-GEN', Paris, France.
¹² Fédération d'Endocrinologie, de Diabétologie et des Maladies Métaboliques, Hospices Civils des Lyon, Centre National de Référence 'Développement Génital: du fœtus à l'adulte DEV-GEN', Lyon, France.
¹³ Department of Women's Health, University Women's Hospital, University of Tübingen, Tübingen, Germany.
¹⁴ Endocrinology Unit, Paediatric University Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹⁵ Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de Hypophyse, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
¹⁶ Department of Paediatric Endocrinology, Amalia Children's Hospital, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
¹⁷ Dipartimento Di Medicina Clinica E Chirurgia, Sezione Di Endocrinologia, Universita' Federico II di Napoli, Naples, Italy.
¹⁸ Department of Paediatric Endocrinology, Ghent University Hospital, University of Ghent, Ghent, Belgium.
¹⁹ Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
²⁰ Paediatric Endocrinology, Department of Paediatrics, Universitätsklinikum Erlangen, Erlangen, Germany.
²¹ Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.
²² Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Turin, Italy.
²³ Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
²⁴ Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Dresden, Technische Universität Dresden, Dresden, Germany.
²⁵ Department of Clinical Science and KG Jebsen Centre for Autoimmune Disorders, University of Bergen, Bergen, Norway.
²⁶ Department of Medicine, Haukeland University Hospital, Bergen, Norway.
²⁷ West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital NHS Foundation Trust, Birmingham, UK.
²⁸ Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
²⁹ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
³⁰ Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
³¹ Department of Paediatric Endocrinology and Diabetology and Reference Centre for Rare Diseases of Growth and Development, AP-HP Paris Nord Université de Paris, CHU Robert-Debre, Paris, France.
³² Division of Endocrinology, Department of Internal Medicine 1, Goethe University Frankfurt Faculty 16 Medicine, Frankfurt am Main, Germany.
³³ Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
³⁴ Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
³⁵ Centre of Reproductive Medicine and Andrology, Clinical and Operative Andrology, University of Münster, Münster, Germany.
³⁶ Department of Paediatrics, Endocrine Unit, Scientific Institute San Raffaele, Milan, Italy.
³⁷ Dipartimento di Medicina, U.O.C. Endocrinologia, Università di Padova, Padova, Italy.
³⁸ Department of Endocrinology and Reproductive Medicine, Centre for Rare Endocrine and Gynaecological Disorders, Sorbonne Université, Assistance Publique Hopitaux de Paris, Paris, France.
³⁹ Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, Essen, Germany.
⁴⁰ Department of Paediatrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, University Hospital in Martin, Martin, Slovakia.
⁴¹ Paediatric Endocrinology Service, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
⁴² Autonomous University of Barcelona, Bellaterra, Spain.
⁴³ CIBERER, ISCIII, Madrid, Spain.
⁴⁴ Department of Women's and Children's Health, Karolinska Institutet/Karolinska University Hospital, Paediatric Endocrinology Unit (QB83), Stockholm, Sweden.

PMID: 35235536
PMCID: PMC9010809
DOI: 10.1530/EJE-21-0554

Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe

Hanna Nowotny et al. Eur J Endocrinol. 2022.

. 2022 Mar 23;186(5):K17-K24.

doi: 10.1530/EJE-21-0554.

Authors

Affiliations

¹ Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany.
² Centre for Chronic Sick Children, Department of Paediatric Endocrinology and Diabetology, Charité Universitätsmedizin Berlin, Berlin, Germany.
³ Laboratoire de Biochimie et Biologie Moléculaire, Hospices Civils de Lyon, Centre National de Référence 'Développement Génital: du fœtus à l'adulte DEV-GEN' Université Lyon I, Lyon, France.
⁴ Developmental Endocrinology Research Group, University of Glasgow, Glasgow, UK.
⁵ Paediatric Endocrinology Unit, Department of Medical and Surgical Sciences, S.Orsola-Malpighi University Hospital, Bologna, Italy.
⁶ Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, University Children's Hospital, Ljubljana, Slovenia.
⁷ Service d'Endocinologie et Maladies Métaboliques, Hôpitaux Universitaires Paris-Centre, Assistance Publique - Hôpitaux de Paris, Paris, France.
⁸ Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
⁹ Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic Research, IRCSS Istituto Auxologico Italiano, Milan, Italy.
¹⁰ Service d'Endocrinologie de l'Enfant, GHU Paris-Sud, Hôpital de Bicêtre, Paris, France.
¹¹ Centre National de Référence 'Développement Génital: du fœtus à l'adulte DEV-GEN', Paris, France.
¹² Fédération d'Endocrinologie, de Diabétologie et des Maladies Métaboliques, Hospices Civils des Lyon, Centre National de Référence 'Développement Génital: du fœtus à l'adulte DEV-GEN', Lyon, France.
¹³ Department of Women's Health, University Women's Hospital, University of Tübingen, Tübingen, Germany.
¹⁴ Endocrinology Unit, Paediatric University Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹⁵ Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de Hypophyse, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
¹⁶ Department of Paediatric Endocrinology, Amalia Children's Hospital, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
¹⁷ Dipartimento Di Medicina Clinica E Chirurgia, Sezione Di Endocrinologia, Universita' Federico II di Napoli, Naples, Italy.
¹⁸ Department of Paediatric Endocrinology, Ghent University Hospital, University of Ghent, Ghent, Belgium.
¹⁹ Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
²⁰ Paediatric Endocrinology, Department of Paediatrics, Universitätsklinikum Erlangen, Erlangen, Germany.
²¹ Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.
²² Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Turin, Italy.
²³ Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
²⁴ Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Dresden, Technische Universität Dresden, Dresden, Germany.
²⁵ Department of Clinical Science and KG Jebsen Centre for Autoimmune Disorders, University of Bergen, Bergen, Norway.
²⁶ Department of Medicine, Haukeland University Hospital, Bergen, Norway.
²⁷ West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital NHS Foundation Trust, Birmingham, UK.
²⁸ Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
²⁹ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
³⁰ Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
³¹ Department of Paediatric Endocrinology and Diabetology and Reference Centre for Rare Diseases of Growth and Development, AP-HP Paris Nord Université de Paris, CHU Robert-Debre, Paris, France.
³² Division of Endocrinology, Department of Internal Medicine 1, Goethe University Frankfurt Faculty 16 Medicine, Frankfurt am Main, Germany.
³³ Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
³⁴ Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
³⁵ Centre of Reproductive Medicine and Andrology, Clinical and Operative Andrology, University of Münster, Münster, Germany.
³⁶ Department of Paediatrics, Endocrine Unit, Scientific Institute San Raffaele, Milan, Italy.
³⁷ Dipartimento di Medicina, U.O.C. Endocrinologia, Università di Padova, Padova, Italy.
³⁸ Department of Endocrinology and Reproductive Medicine, Centre for Rare Endocrine and Gynaecological Disorders, Sorbonne Université, Assistance Publique Hopitaux de Paris, Paris, France.
³⁹ Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, Essen, Germany.
⁴⁰ Department of Paediatrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, University Hospital in Martin, Martin, Slovakia.
⁴¹ Paediatric Endocrinology Service, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
⁴² Autonomous University of Barcelona, Bellaterra, Spain.
⁴³ CIBERER, ISCIII, Madrid, Spain.
⁴⁴ Department of Women's and Children's Health, Karolinska Institutet/Karolinska University Hospital, Paediatric Endocrinology Unit (QB83), Stockholm, Sweden.

PMID: 35235536
PMCID: PMC9010809
DOI: 10.1530/EJE-21-0554

Abstract

Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.

Design and methods: A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN.

Results: Pdex treatment is currently provided by 36% of the surveyed centres. The treatment is initiated by different specialties, that is paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23% stated to initiate therapy at 4-5 weeks postconception (wpc), 31% at 6 wpc and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 µg/kg/day is used. Dose distribution among the centres varies from once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72% of the responding centres. Cases treated per country and year vary between 0.5 and 8.25. Registries for long-term follow-up are only available at 46% of the centres that are using Pdex treatment. National registries are only available in Sweden and France.

Conclusions: This study reveals a high international variability and discrepancy in the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence-based guidelines on prenatal diagnostics, treatment and follow-up of pregnancies at risk for CAH.

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Figures

**Figure 1**
Use of Pdex treatment and prenatal diagnostics to prevent virilization in girls with CAH. (A) Pie chart depicting the percentage of included centres using or not using Pdex treatment (n = 36). (B) Selected disciplines providing Pdex treatment in the corresponding country. Multiple selections were possible (n = 31; 5 NA). (C) Daily dosing distribution of Pdex. Only centres using Pdex treatment were included (n = 13). (D) Types of prenatal diagnostics for CAH used in each corresponding country (n = 25). CVS (*CYP21A2* GT + ST): *CYP21A2* genotyping and sextyping between 1012 wpc; treatment is discontinued for male foetuses or notaffected females. AC (*CYP21A2* GT + ST): *CYP21A2* genotyping and sextyping between 1516 wpc; treatment is discontinued for male foetuses or notaffected females. *SRY* + CVS: *SRY*typing from maternal blood (cfDNA); treatment of females only; CVS for *CYP21A2* GT between 1012 wpc; treatment only continued for affected females. NIPD: massively parallel sequencing using cfDNA from maternal blood; only affected females are treated. (E) Overview of important timepoints of development of external genitalia in females. Stars are marking the starting point of Pdex treatment as indicated by each centre (n = 13).

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References

1. Therrell BL.Newborn screening for congenital adrenal hyperplasia. Endocrinology and Metabolism Clinics of North America 20013015–30. (10.1016/s0889-8529(0870017-3) - DOI - PubMed
1. Reisch N, Willige M, Kohn D, Schwarz HP, Allolio B, Reincke M, Quinkler M, Hahner S, Beuschlein F. Frequency and causes of adrenal crises over lifetime in patients with 21-hydroxylase deficiency. European Journal of Endocrinology 201216735–42. (10.1530/EJE-12-0161) - DOI - PubMed
1. Zetterstrom RH, Karlsson L, Falhammar H, Lajic S, Nordenstrom A. Update on the Swedish newborn screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. International Journal of Neonatal Screening 20206 71. (10.3390/ijns6030071) - DOI - PMC - PubMed
1. Speiser PW.Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Endocrinology and Metabolism Clinics of North America 20013031–59, vi. (10.1016/s0889-8529(0870018-5) - DOI - PubMed
1. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SEet al.Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2010954133–4160. (10.1210/jc.2009-2631) - DOI - PMC - PubMed

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[1] Therrell BL.Newborn screening for congenital adrenal hyperplasia. Endocrinology and Metabolism Clinics of North America 20013015–30. (10.1016/s0889-8529(0870017-3) - DOI - PubMed

[2] Therrell BL.Newborn screening for congenital adrenal hyperplasia. Endocrinology and Metabolism Clinics of North America 20013015–30. (10.1016/s0889-8529(0870017-3) - DOI - PubMed

[3] Reisch N, Willige M, Kohn D, Schwarz HP, Allolio B, Reincke M, Quinkler M, Hahner S, Beuschlein F. Frequency and causes of adrenal crises over lifetime in patients with 21-hydroxylase deficiency. European Journal of Endocrinology 201216735–42. (10.1530/EJE-12-0161) - DOI - PubMed

[4] Reisch N, Willige M, Kohn D, Schwarz HP, Allolio B, Reincke M, Quinkler M, Hahner S, Beuschlein F. Frequency and causes of adrenal crises over lifetime in patients with 21-hydroxylase deficiency. European Journal of Endocrinology 201216735–42. (10.1530/EJE-12-0161) - DOI - PubMed

[5] Zetterstrom RH, Karlsson L, Falhammar H, Lajic S, Nordenstrom A. Update on the Swedish newborn screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. International Journal of Neonatal Screening 20206 71. (10.3390/ijns6030071) - DOI - PMC - PubMed

[6] Zetterstrom RH, Karlsson L, Falhammar H, Lajic S, Nordenstrom A. Update on the Swedish newborn screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. International Journal of Neonatal Screening 20206 71. (10.3390/ijns6030071) - DOI - PMC - PubMed

[7] Speiser PW.Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Endocrinology and Metabolism Clinics of North America 20013031–59, vi. (10.1016/s0889-8529(0870018-5) - DOI - PubMed

[8] Speiser PW.Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Endocrinology and Metabolism Clinics of North America 20013031–59, vi. (10.1016/s0889-8529(0870018-5) - DOI - PubMed

[9] Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SEet al.Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2010954133–4160. (10.1210/jc.2009-2631) - DOI - PMC - PubMed

[10] Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SEet al.Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2010954133–4160. (10.1210/jc.2009-2631) - DOI - PMC - PubMed

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Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe

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Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe

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