Abstract
The regulation of reproductive function by glucocorticoids occurs at all levels of the hypothalamo-pituitary-gonadal axis. Within the pituitary, glucocorticoids have been shown to directly alter gene expression in gonadotrophs, indicating that these cell types are sensitive to regulation by the glucocorticoid receptor. Whilst the major glucocorticoid metabolising enzymes, 11β-hydroxysteroid dehydrogenase (11βHSD; HSD11B1 and HSD11B2), have been described in human pituitary adenomas, the activity of these enzymes within different pituitary cell types has not been reported. Radiometric conversion assays were performed in αT3-1, LβT2 (gonadotrophs), AtT-20 (corticotrophs) and GH3 (somatolactotrophs) anterior pituitary cell lines, using tritiated cortisol, corticosterone, cortisone or 11-dehydrocorticosterone as substrates. The net oxidation of cortisol/corticosterone and net reduction of cortisone/11-dehydrocorticosterone were significantly higher in the two gonadotroph cells lines compared with the AtT-20 and GH3 cells after 4 h. Whilst these enzyme activities remained the same in αT3-1 and LβT2 cells over a 24 h period, there was a significant increase in glucocorticoid metabolism in both AtT-20 and GH3 cells over this same period, suggesting cell-type specific activity of the 11βHSD enzyme(s). Stimulation of both gonadotroph cell lines with either 100 nM GnRH or PACAP (known physiological regulators of gonadotrophs) resulted in significantly increased 11β-dehydrogenase (11βDH) and 11-ketosteroid reductase (11KSR) activities, over both 4 and 24 h. These data reveal that gonadotroph 11βHSD enzyme activity can act to regulate local glucocorticoid availability to mediate the influence of the HPA axis on gonadotroph function.
Highlights
The phenomenon of stress-related infertility, observed in many distinct species of mammals and lower vertebrates, reflects multiple endocrine interactions between the reproductive and stress axes
Comparative 11βHSD Activities in Pituitary Cell Lines. Both 11β-dehydrogenase and 11-ketosteroid reductase activities could be measured in all four anterior pituitary cell lines irrespective of the radiometric conversion assay duration or the steroid substrate (Figures 1 and 2)
The net levels of lower in the gonadotroph cell lines compared with the AtT-20 and GH3 cells
Summary
The phenomenon of stress-related infertility, observed in many distinct species of mammals and lower vertebrates, reflects multiple endocrine interactions between the reproductive (hypothalamo-pituitary-gonadal) and stress (hypothalamo-pituitary-adrenal) axes. Several studies by independent research teams have established that both pharmacological and physiological glucocorticoids (corticosterone in myomorph rodents, i.e., rats and mice; cortisol in most other mammals) can exert direct effects to suppress reproduction at the level of the hypothalamus, anterior pituitary, gonads and reproductive tract [1,2,3,4,5]. These members of the short-chain alcohol dehydrogenase enzyme superfamily catalyze the inter-conversion of active glucocorticoids (cortisol and corticosterone) with their inert. The first cloned isoenzyme, type 1 11βHSD (HSD11B1), is a bidirectional, low-affinity enzyme that predominantly catalyzes the reduction of cortisone to cortisol (and 11-dehydrocorticosterone to corticosterone) using reduced nicotinamide adenine dinucleotide phosphate (NADPH) as the preferred pyridine dinucleotide cosubstrate [8,9,10]. The direction of HSD11B1 activity is determined by the redox state of NADP+/NADPH in the lumen of the smooth endoplasmic reticulum that is, in turn, dependent upon the activity of the microsomal hexose-6-phosphate dehydrogenase enzyme (H6PDH) [11,12,13,14,15,16,17]
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