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Free cortisol is likely to be a better guide to cortisolemia in systemic infection because it corresponds more closely to illness severity. The attenuated cortisol increment after tetracosactrin in RAI is not due to low cortisol-binding proteins. Free cortisol levels can be determined reliably using total cortisol and CBG levels.

Our study demonstrated elevations in total plasma cortisol and CBG concentrations during pregnancy and with low-dose OCP use. Pregnancy was also associated with significant increases in plasma free cortisol and UFC, suggesting that the rise in total plasma cortisol is contributed to by up-regulation of the maternal hypothalamic-pituitary-adrenal axis in addition to elevated CBG.

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Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30–60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that <1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding α1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.

BackgroundGlucocorticoid replacement is essential in patients with primary and secondary adrenal insufficiency, but many patients remain on higher than recommended dose regimens. There is no uniformly accepted method to monitor the dose in individual patients. We have compared cortisol concentrations in plasma, saliva and urine achieved following “physiological” and “stress” doses of hydrocortisone as potential methods for monitoring glucocorticoid replacement.MethodsCortisol profiles were measured in plasma, saliva and urine following “physiological” (20 mg oral) or “stress” (50 mg intravenous) doses of hydrocortisone in dexamethasone-suppressed healthy subjects (8 in each group), compared to endogenous cortisol levels (12 subjects). Total plasma cortisol was measured half-hourly, and salivary cortisol and urinary cortisol:creatinine ratio were measured hourly from time 0 (between 0830 and 0900) to 5 h. Endogenous plasma corticosteroid-binding globulin (CBG) levels were measured at time 0 and 5 h, and hourly from time 0 to 5 h following administration of oral or intravenous hydrocortisone. Plasma free cortisol was calculated using Coolens’ equation.ResultsPlasma, salivary and urine cortisol at 2 h after oral hydrocortisone gave a good indication of peak cortisol concentrations, which were uniformly supraphysiological. Intravenous hydrocortisone administration achieved very high 30 minute cortisol concentrations. Total plasma cortisol correlated significantly with both saliva and urine cortisol after oral and intravenous hydrocortisone (P <0.0001, correlation coefficient between 0.61 and 0.94). There was no difference in CBG levels across the sampling period.ConclusionsAn oral dose of hydrocortisone 20 mg is supraphysiological for routine maintenance, while stress doses above 50 mg 6-hourly would rarely be necessary in managing acute illness. Salivary cortisol and urinary cortisol:creatinine ratio may provide useful alternatives to plasma cortisol measurements to monitor replacement doses in hypoadrenal patients.

Summary Objective  To measure and contrast maternal cortisol and corticosteroid‐binding globulin (CBG) levels in pregnancies with normal outcomes, pre‐eclampsia, intrauterine growth restriction (IUGR) and in gamete recipients. Study design  Prospective study of 93 women at high risk of pre‐eclampsia, including gamete recipients (n = 22) and 33 controls. Plasma total and free cortisol and CBG were measured every 2 weeks from 16 weeks’ gestation until delivery. Results  Forty‐two per cent of the high‐risk group had complications, including pre‐eclampsia (n = 11), gestational hypertension (n = 16) and small‐for‐gestational‐age (SGA) neonates (n = 12). There were no complications in the controls. In all groups, plasma CBG concentrations increased progressively across gestation (P < 0·05), in parallel to total cortisol, but fell significantly from 36 weeks’ gestation onwards, with a corresponding rise in free cortisol concentrations. In pre‐eclampsia and gestational hypertension, plasma CBG, and total and free cortisol concentrations were lower from 36 weeks onwards (P < 0·05). In IUGR, plasma CBG concentrations were suppressed from 28 weeks’ gestation until delivery (P < 0·05), but with no significant difference in plasma total and free cortisol. Gamete recipients had significantly lower plasma CBG from 20 weeks’ gestation onwards, and plasma total and free cortisol were reduced at 24 and 32 weeks onwards, respectively. Conclusions  Maternal plasma CBG, total and free cortisol concentrations are reduced in pre‐eclampsia/gestational hypertension, and markedly reduced in gamete recipients. Low CBG may be due to reduced synthesis or enhanced inflammation‐driven degradation. Low maternal cortisol may be due to a lack of placental corticotropin‐releasing hormone or reduced maternal ACTH, driving cortisol production. Low maternal cortisol may influence the foetal hypothalamic–pituitary–adrenal axis and disease patterns later in life following complicated pregnancy.

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