title: Analysis of baseline hypothalamic-pituitary-adrenal activity in late adolescence reveals gender specific sensitivity of the stress axis.
abstract: Dysfunctional regulation of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as an important biological mechanism underlying stress-related diseases; however, a better understanding of the interlinked neuroendocrine events driving the release of cortisol by this stress axis is essential for progress in preventing or halting irreversible development of adverse HPA-function. We aimed to investigate basal HPA-activity in a normal population in late adolescence, the time of life believed to overlap with HPA-axis maturation and establishment of a lasting set point level of HPA function. A total of 1258 participants (mean age 16.6 years) recruited from the Western Australian Pregnancy (Raine) Cohort provided fasting morning blood and saliva samples for basal HPA activity assessment. Irrespective of gender, linear regression modelling identified a positive correlation between the main components of the HPA-cascade of events, ACTH, total cortisol and free cortisol in saliva. Corticosteroid binding globulin (CBG) was inversely associated with free cortisol in saliva, an effect most clearly observed in boys. ACTH levels were lower, but cortisol levels were higher in girls than in boys. Girls may also be exposed to more bioactive cortisol, based on higher average free cortisol measured in saliva at awakening. These relatively higher female free cortisol levels were significantly reduced by oral contraceptive use, eliminating the gender specific difference in salivary cortisol. Free plasma cortisol, calculated from total circulating cortisol and CBG concentrations, was also significantly reduced in girls using oral contraceptives, possibly via an enhancing effect of oral contraceptives on blood CBG content. This study highlights a clear gender difference in HPA activity under non-stressful natural conditions. This finding may be relevant for research into sex-specific stress-related diseases with a typical onset in late adolescence.
authors.affiliation: Endocrinology Unit, University/BHF Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom. R.Reynolds@ed.ac.uk
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Reynolds
authors.forename: Hilary L
authors.initials: HL
authors.lastname: Hii
authors.forename: Craig E
authors.initials: CE
authors.lastname: Pennell
authors.forename: Ian W
authors.initials: IW
authors.lastname: McKeague
authors.forename: E Ron
authors.initials: ER
authors.lastname: de Kloet
authors.forename: Stephen
authors.initials: S
authors.lastname: Lye
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Stanley
authors.forename: Eugen
authors.initials: E
authors.lastname: Mattes
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Foster
mesh_terms: D000293:Adolescent; D041923:Adolescent Development / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D008297:Male; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D012016:Reference Values; D012463:Saliva / Q000378:metabolism; D012727:Sex Characteristics; D013315:Stress, Psychological / Q000378:metabolism*; D014156:Transcortin / Q000378:metabolism*
chemical_list: D000324:Adrenocorticotropic Hormone; D014156:Transcortin; D006854:Hydrocortisone