A Duality in Mammalian Glucocorticoid Signaling

Abstract

I tested a prevalent assumption in glucocorticoid research that states that each species has a dominant glucocorticoid, and cortisol and corticosterone are interchangeable steroids. A comprehensive analysis of historical and current data failed to support this assumption and revealed evidence of drift away from exploration of cortisol and corticosterone as dual, important adrenal products to the exclusive quantification of one, dominant glucocorticoid. Originating approximately 30 years ago, the dominant glucocorticoid/ interchangeability assumption is now portrayed in textbook images used to represent adrenal steroid biosynthesis and is widespread throughout empirical research. Less than 1% of over 50,000 published papers relating to the glucocorticoids have considered the potential for independence in glucocorticoid signaling by quantifying both cortisol and corticosterone within a sample. A dispersed literature shows independent regulation of cortisol and corticosterone, extensive inter-species variation in glucocorticoid concentrations and cortisol: corticosterone ratios and adrenal synthesis of the non-dominant glucocorticoid during early development. We hypothesize that there is a functional duality in glucocorticoid signaling and use mass spectrometry to explore the glucocorticoid profile of the full-term human (n = 125) and guinea pig (n = 28) fetus (both cortisol-dominant species). The sample preparation method yielded poor steroid recoveries (~ 4-28%), which made quantification by mass spectrometry challenging, but in both species corticosterone concentrations were significantly higher in fetal blood compared to umbilical venous or umbilical mixed blood (p < 0.0001), suggesting fetal corticosterone enrichment. Within an individual, cortisol was not an accurate predictor of corticosterone for either species (human, r = 0.001, p > 0.05; guinea pig, r = 0.14, p > 0.05) and our data suggests independent glucocorticoid responses; in humans, cortisol was significantly higher in vaginal deliveries relative to elective Caesarian sections (p < 0.0001) but corticosterone was unaffected. Guinea pig fetal corticosterone was not affected by daily maternal stress during gestation but cortisol was significantly lower in stressed fetuses (p < 0.05). While these preliminary data require further investigation, we conclude that fetuses from the human and guinea pig actively secrete the non-dominant glucocorticoid in late gestation and suggest that there is a functional duality in glucocorticoid signaling.