It has been obvious for at least 2 decades that there is a paradox that limits understanding of adrenocortical physiology. First, the hypothalamo-pituitary-adrenal (HPA) axis seems to be very sensitive to feedback inhibition by glucocorticoid hormones secreted from the adrenals. Second, stress, which causes ample adrenal steroid secretion, does not appear to inhibit subsequent activity in the HPA axis.Dallman and Jones worked on this problem in the 1970's (1). We showed that prolonged restraint stress of 90 min duration in rats did not inhibit the corticosterone (B) response to the subsequent mild stress of intraperitoneal injection. However, injection of adrenocorticotropin (ACTH) or B which mimicked the B response to restraint, did inhibit the B response to subsequent injection stress. We concluded that stress must induce a facilitatory effect on subsequent responses of the HPA axis to stress (1). Neither of us was satisfied with this entirely deductive approach, and in 1971, in collaboration with Vernikos, we filled a notebook with our unsuccessful attempts to show direct evidence for stressinduced facilitation, studying rats 1 to 2 days after bilateral adrenalectomy and bioassay of ACTH. The results were uninterpretable; we know now that this is because of the extreme disequilibrium in central components of the HPA axis that occurs during the first days after adrenalectomy with removal of the feedback signal.Recently, our laboratory has made considerable progress in making sense of the apparent paradox by reexamining all three aspects of this problem: the effect of chronic stress on function of the HPA axis (2-4); the sensitivity of the adrenocortical system of the intact rat to passive elevation in circulating B (5); and finding direct evidence for a facilitatory effect of stress on some aspects of subsequent activity in the HPA axis (6). The results of these studies have led us to a new understanding of the control of the HPA axis. It seems appropriate for the third Mortyn Jones Memorial Lecture to describe the highlights of these studies. The results of our work, and that of others, in rats, also appear to apply to man, and may be of utility to the understanding of adrenocortical function under normal circumstances as well as in disease . Some characteristics of the HPA axis and corticosteroid feedbackFour major characteristics of activity in the adrenocortical system are shown schematically in Fig. 1. Understanding of these, and the fact that they interact, is critical to the understanding of the whole HPA axis, the design of experiments, and the prediction of outcomes.There is a marked circadian rhythm in basal activity of the HPA axis which informs all other functional aspects of the system (Fig. 1~) . Mean 24 h basal plasma B levels in rats average -5 pg/dl (7). Basal activity during the trough of the rhythm results from constitutive secretory activity of the pituitary and adrenal components of the system without hypothalamic input; basal activity during the peak of the rhythm requires input from the h...
The responses of young rats to left adrenalectomy or left adrenal manipulation were compared to surgical sham adrenalectomy in which adrenals were observed but not touched. At 12 h right adrenal wet weight, dry weight, DNA, RNA, and protein content were increased (P less than 0.05) after the first two operations. Left adrenal manipulation resulted in increased right adrenal weight at 12 h but no change in left adrenal weight. Sequential manipulation of the left adrenal at time 0 and the right adreanl at 12 h resulted in an enlarged right adrenal at 12h (P less than 0.01), and an enlarged left adrenal at 24 h (P less than 0.05), showing that the manipulated gland was capable of response. Bilateral adrenal manipulation of the adrenal glands resulted in bilateral enlargement at 12 h (P less than 0.01). Taken together with previous results, these findings strongly suggest that compensatory adrenal growth is a neurally mediated reflex.
We have tested the hypothesis that unilateral adrenalectomy results in decreased glucocorticoid secretion, reflexly elevated ACTH secretion, and consequently, compensatory adrenal growth. Plasma ACTH and corticosterone and right adrenal weight were measured during the first 10 days after left adrenalectomy or sham adrenalectomy in young male rats. There is a decrease in plasma corticosterone after unilateral adrenalectomy compared to sham adrenalectomy that persists for 1 h. ACTH is elevated only at 2 h after unilateral adrenalectomy compared to shamoperated rats. Treatment with dexamethasone, shown to abolish the ACTH and corticosterone responses to laparotomy with intestinal traction, resulted in significantly increased adrenal weight after unilateral adrenalectomy by 6 h (wet or dry weight), and at 24 h. Compensatory adrenal growth also occurs after unilateral adrenalectomy in hypophysectomized rats (wet or dry weight). We conclude the compensatory adrenal growth after unilateral adrenalectomy requires neither a virtual decrease in circulating corticosterone levels nor elevated ACTH levels, and speculate that the phenomenon is neurally mediated.
We have shown that chronic cold stress strongly interacts with corticosterone (B) to determine subsequent regulation of the hypothalamo-pituitary-adrenal (HPA) axis responses to novel stress. These studies, using the same 2 sets of rats, show that chronic cold also interacts with B and testosterone on signals of energy balance. The two groups of rats differed in weight by 20% and in age by 2 weeks (44-59 days of age). Adrenalectomized rats, replaced with varying doses of B, were exposed to cold or served as controls. Food intake and body weight during the experiments and hormones, metabolites and fat depots were measured on day 5. B, but not cold, affected food intake in the younger rats; by contrast, cold, but not B, affected food intake in the older rats. Testosterone was higher in older control rats and was markedly depressed by cold; younger rats had lower testosterone that was minimally affected by cold. Weight gain decreased in all rats at room temperature with increasing B, whereas they all lost weight in cold independently of B. Cold stimulated and B inhibited interscapular brown adipose tissue DNA content (reflecting sympathetic stimulation of thermogenesis). B stimulated insulin, whereas cold inhibited leptin and insulin; B also increased white adipose tissue weight gain in controls and inhibited its loss in cold. Leptin was unrelated to white adipose tissue depots in older control rats but was strongly related to these stores in younger rats and in all rats in cold. We conclude that: 1. By decreasing signals that act centrally to inhibit food intake (insulin, leptin and testosterone) cold allows B to stimulate food intake; 2. B inhibits weight gain although it causes accrual of fat; 3. Cold, probably through sympathetic stimulation of white adipose tissue, causes fat loss which is modulated by the inhibitory effect of B on sympathetic outflow; and, 4. The slope of the relationship between fat depot size and leptin becomes flatter in cold, possibly because of increased sympathetic outflow to these depots.
Regeneration of rat adrenals was studied after bilateral enucleation to determine whether there is a neural component mediating this process as there is in compensatory adrenal growth after unilateral adrenalectomy. Regeneration was approximately 50% complete (based on criteria of wet weight and DNA content) by 10 days after enucleation; at this time circulating ACTH levels were twice as high in enucleates as in sham-operated controls, but corticosterone levels were normal. Regeneration was apparently complete at sometime between 3 and 6 weeks and circulating ACTH and corticosterone levels were normal at these times compared to controls. Unilateral adrenal enucleation resulted in compensatory growth of the opposite gland, not regeneration of the enucleated gland. Unilateral hypothalamic hemi-islands made with a Halász knife resulted in bilateral augmentation of adrenal regeneration at 10 days and 6 weeks. From these results we conclude that adrenal regeneration after bilateral enucleation occurs by different afferent and efferent mechanisms than compensatory adrenal growth after unilateral adrenalectomy. Additional studies were performed in rats 3 and 6 weeks after adrenal enucleation to test whether the adrenal medulla participates either in compensatory adrenal growth or in the augmented ACTH response to ether vapors observed in unilaterally adrenalectomized rats. Normal compensatory adrenal growth occurred 3 days after unilateral adrenalectomy in rats bilaterally enucleated 6 weeks earlier. Prior enucleation did not inhibit the increased ACTH response of unilaterally adrenalectomized rats to ether. Therefore, the adrenal medulla does not mediate compensatory adrenal growth or the augmented ACTH response of unilaterally adrenalectomized rats to ACTH-releasing stimuli.
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