Blood-brain barrier transport and brain sequestration of steroid hormones

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Abstract
Gonadal steroids are concentrated several-fold in brain relative to plasma, but brain corticosterone levels are only 30% of plasma values; differences may exist between the kinetics of brain sequestration of the gonadal steroids vs. corticosterone. The rate of brain sequestration of the sex steroid hormones (progesterone, 17-hydroxyprogesterone, dihydrotestosterone, testosterone, estradiol) vs. corticosterone was investigated in this study with a carotid-injection technique in anesthetized adult rats and newborn rabbits. The rate constants for steroid association (k3) and dissociation (k4) reactions with brain-binding systems were quantitated on the basis of a 2-compartment model. In adult rats, the k3/k4 ratio for the gonadal steroids ranged from 0.33 (17-hydroxyprogesterone) to 0.96 (dihydrotestosterone), but this ratio was immeasurably low for corticosterone. No brain sequestration of testosterone or estradiol was observed for the newborn rabbit, suggesting a developmental modulation of the putative gonadal steroid-binding protein. The low rate of corticosterone sequestration was also observed for the adrenalectomized rat; the absence of [3H]corticosterone sequestration was not due to high levels of endogenous hormone. No correlation was found between the k3/k4 ratio and the 1-octanol/Ringer partition coefficient (r [correlation coefficient] = 0.20, P < 0.40), suggesting that the steroids were not being sequestered by brain lipid. TLC analysis of brain [3H]progesterone radioactivity at 3 min after carotid injection indicated that progesterone was unmetabolized; the basis of the sequestration of steroid radioactivity during the 4 min period was tissue binding and not metabolism. The turnover rate of brain sequestration of blood-borne sex steroids (half-life .apprx. 1 min) is much higher than for corticosteroids, a finding that correlates with the much higher volume of distribution of the gonadal steroids in brain relative to corticosterone.