title: Can side effects of steroid treatments be minimized by the temporal aspects of delivery method?
abstract: BACKGROUND
  Glucocorticoids are commonly prescribed medications associated with significant mortality and morbidity, even when used at physiological dosages. The endogenous glucocorticoids are secreted in a complex rhythm consisting of both a daily circadian rhythm and a more rapid and dynamic ultradian rhythm that is highly conserved in nature. Current therapeutic options attempt to target the circadian aspects of this rhythm but do not take into account the oscillating ultradian pulsatility.
  
  
  METHODS
  This article analyzes English-language literature on Pubmed and discusses the physiology and evidence behind the importance of different patterns of glucocorticoid presentation on gene regulation, animal responses and clinical significance.
  
  
  CONCLUSIONS
  There is compelling evidence for pulsatility being an important factor in hypothalamic pituitary adrenal (HPA) axis regulation and tissue responses to glucocorticoids. Different patterns of gene regulation and neural and behavioral responses are seen dependent upon the pattern of glucocorticoid presentation. Disease states are associated with disordered HPA ultradian activity. Glucocorticoid treatments have significant risk/benefit issues. It is now time to go back to first principles and think about the physiology and patterns of drug presentation in glucocorticoid-based therapeutics.
authors.affiliation: University of Bristol, Henry Wellcome Laboratories for Integrative Neurosciences and Endocrinology , Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY , UK +44 0117 331 3123 ; +44 0117 331 3169 ; georgina.russell@bristol.ac.uk.
authors.forename: Georgina M
authors.initials: GM
authors.lastname: Russell
authors.forename: Stafford L
authors.initials: SL
authors.lastname: Lightman
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D055870:Drug Chronotherapy; D016503:Drug Delivery Systems; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000009:adverse effects* / Q000378:metabolism; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D005938:Glucocorticoids
keywords: gene pulsing; glucocorticoids; side effects; ultradian