Effect of synthetic atrial natriuretic polypeptide on hemorrhage-induced adrenocorticotropin secretion of the rat

The effect of synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) on the in vivo and in vitro release of ACTH and corticosterone was examined. In the in vivo study ACTH and corticosterone responses to rapid 2-ml/rat hemorrhage were measured in sixteen conscious rats after alpha-hANP administration. The hemorrhage increased plasma ACTH and corticosterone concentrations in the control group of rats (p greater than 0.01). ANP inhibited hemorrhage-induced ACTH secretion (p less than 0.05), but the plasma corticosterone response was not affected. In the in vitro study a high concentration of ANP (1 microM) reduced basal corticosterone secretion from the isolated rat adrenal gland (p less than 0.05), but the response to ACTH (10 ng/ml) and dibutyryl cyclic AMP (0.5 mM, 5.0 mM) was not affected. Our data suggest that ANP inhibits hemorrhage-induced ACTH secretion from the anterior pituitary but inhibits corticosterone secretion from the adrenal gland very weakly.     

Repeated handling, restraint, or chronic crowding impair the hypothalamic-pituitary-adrenocortical response to acute restraint stress.

The purpose of the present study was to assess whether, and to what extent prior handling, restraint or social crowding stress during 3-10 days affects the hypothalamic-pituitary-adrenocortical (HPA) response to an acute short-lasting restraint stress. Also the effect of a feedback inhibitory mechanism of corticosterone in the impairment of HPA axis by these stressors was investigated. Male Wistar rats were pretreated with handling 1 min/day for 3-10 days, restraint 2 times daily for 3-7 days and crowding stress for 7 days before exposure to acute restraint stress in metal tubes for 10 min. Some group of rats received exogenous s.c. corticosterone either once 25 mg/kg or 2 times daily 10 mg/kg for 3-10 days before restraint stress. After the last restraint the rats were decapitated and their trunk blood was collected for the measurement of plasma ACTH and serum corticosterone levels. Handling for 3-7 days, restraint for 3-7 days, and crowding for 7 days and a single pretreatment with corticosterone--all significantly and to a similar extent inhibited the restraint stress-induced increase in ACTH and corticosterone secretion. Chronic pretreatment with corticosterone blunted the restraint stress-induced increase in HPA axis activity. These results indicate that repeated short-lasting stress induced by handling, restraint, or crowding potently attenuates the acute restraint stress-induced stimulatory action of the HPA axis. They also indicate adaptive action of moderate stress on the HPA axis response to acute stress. The results also suggest that a short-lasting hypersecretion of corticosterone during psychological stress may induce a prolonged feedback inhibition of the HPA axis activity. The attenuation of HPA axis response by prior handling has also obvious methodological implications.     

A single corticosterone pretreatment inhibits the hypothalamic-pituitary-adrenal responses to adrenergic and cholinergic stimulation.

The purpose of the present study was to determine whether an increased plasma corticosterone or dexamethasone levels induced by a single corticosterone or dexamethasone injection to conscious rats affects the hypothalamic-pituitary-adrenocortical (HPA) activity induced by adrenergic and cholinergic agonists. Male Wistar rats were pretreated subcutaneously (s.c.) with a single dose of dexamethasone (5 mg/kg) or corticosterone (25 mg/kg) 24 or 48 h before intraperitoneal (i.p.) administration of adrenergic agonists: phenylephrine, an alpha1-adrenergic receptor agonist, clenbuterol, a beta2-adrenergic agonist and noradrenaline acting predominantly on alpha1-adrenoreceptors, and cholinergic agonists: carbachol, a predominant muscarinic receptor agonist and nicotine, a nicotinic receptor agonist. Dexamethasone profoundly decreased the resting ACTH levels in control rats and given 24 h before each of the stimulatory agonist abolished the adrenergic- and cholinergic agonists-induced ACTH and corticosterone responses. Pretreatment with corticosterone of control rats did not substantially alter the resting plasma ACTH and serum corticosterone levels measured 24 and 48 h later. A single pretreatment with corticosterone abolished or powerfully inhibited, perhaps by a feedback mechanism, the ACTH and corticosterone responses induced 24 and 48 h later by all adrenergic and cholinergic agonists used in this study. These results indicate that prolonged administration of corticosterone is not necessary to induce almost complete suppression of the HPA responsiveness to adrenergic or cholinergic stimulation. Chronic treatment with corticosteroids to achieve glucocorticoid receptors desensitization does not seem to be required.     

Neuroendocrine responses to cocaine do not exhibit sensitization following repeated cocaine exposure.

Cocaine-induced enhancement of motor activity and extracellular dopamine concentrations exhibits sensitization upon repeated exposure. In this study, the neuroendocrine responses to cocaine were examined following cocaine pretreatment regimens which have been shown to produce behavioral sensitization. Adult male rats were injected with cocaine (15 mg/kg, IP) once daily for 14 days, followed by a dose-response challenge with cocaine (1-15 mg/kg, IP) either 18 hours or 7 days after the final pretreatment injection. Blood was collected 15 minutes following injections for radioimmunoassay of ACTH, corticosterone, prolactin, and renin. Cocaine increased plasma ACTH and corticosterone, while it decreased prolactin and renin concentrations. Pretreatment with cocaine for 2 weeks did not alter any of these endocrine responses after either the 18 hour or 7 day interval between pretreatment and challenge injections. In contrast, sensitization to the locomotor stimulant effects of cocaine was observed on the final day of pretreatment injections, and 7 days later. These data suggest that these endocrine effects of cocaine do not exhibit sensitization following repeated cocaine exposure.     

The influence of indomethacin on the acth secretion induced by central stimulation of adrenergic receptors.

We had previously demonstrated that indomethacin affected the corticosterone secretion induced by central stimulation of alpha-but not beta-adrenergic receptors in conscious rats. In the present study we investigated whether hypothalamic and/or pituitary prostaglandins (PGs) were involved in the central adrenergic stimulation of ACTH secretion. Indomethacin, 2 mg/kg ip or 10 microg intracerebroventricularly (icv), was administered 15 min before phenylephrine (30 microg icv), an alpha-adrenergic agonist, clonidine (10 microg), an alpha2-adrenergic agonist, and isoprenaline (20 microg) or clenbuterol (10 microg), a beta1- or beta2-adrenergic agonist. One hour after the last injection the rats were decapitated and plasma levels of ACTH were measured. The present results show that the ACTH responses induced by icv administration of phenylephrine and clonidine were considerably impaired by icv or ip pretreatment with indomethacin, an inhibitor of prostaglandin synthesis. Indomethacin given by either route only slightly diminished the isoprenaline-induced ACTH response and did not substantially alter the clenbuterol-induced response. The adrenergic-induced ACTH responses were more potently inhibited by ip than by icv pretreatment with indomethacin, which may result from a stronger inhibition of PGs synthesis in the median eminence and anterior pituitary by ip pretreatment with indomethacin than in hypothalamic structures by its icv administration. These results indicate a significant involvement of PGs in central stimulation of the hypothalamic-pituitary adrenal (HPA) axis by alpha1- and alpha2- but not beta-adrenergic receptors.     

The role of alpha-2u-globulin in corticosteroidogenesis in male rats

Administration of estradiol-17 beta for 7 days to the adult male rat results in adrenal hyperplasia, decreased serum corticosterone along with elevation in serum ACTH and inhibition of adrenal 5-ene-3 beta-hydroxysteroid dehydrogenase activity (5-ene-3 beta-HSD). Treatment with alpha 2u-globulin for following 14 days of estrogen-treated rats reversed the effects of estrogen while in normal rats alpha 2u-globulin treatment increased adrenal 5-ene-3 beta-HSD activity and serum corticosterone level while causing a fall in serum ACTH. It is concluded that alpha 2u-globulin may play a role in ACTH secretion by inducing corticosterone synthesis.     

Adrenomedullary and glycemic responses to ACTH, corticosterone, aldosterone, epinephrine and norepinephrine administrations in the soft-shelled turtle

The aim of the current investigation was to ascertain the role of ACTH and adrenal hormones on adrenomedullary and glycemic functions in soft-shelled turtles, Lissemys punctata punctata. All the experiments were carried out on sexually immature animals. Findings revealed that: (1) ACTH administration (0.5 IU/1.0 IU/2.0 IU per 100 g body wt. daily for 10 days) in all doses stimulated adrenomedullary function by increasing medullary cell nuclear diameter with elevations of norepinephrine, epinephrine and blood sugar levels. Only moderate and higher doses (50 microg/100 microg per 100 g body wt. daily for 10 days) of dexamethasone suppressed adrenomedullary activity and blood sugar level by reversing the changes to those of ACTH; the responses were dose-dependent. But these changes were no longer observed after ACTH treatment in dexamethasone (DMS) recipients (DMS: 100 microg/ 100 g body wt daily for the first 10 days and ACTH: 0.5 IU / 100 g body wt daily for the next 10 days); (2) Only moderate and higher doses (50 microg/100 microg per 100 g body wt daily for 10 days) of corticosterone increased adrenomedullary activity and blood sugar level and the responses were also dose-dependent. But aldosterone treatment in all doses (same as for corticosterone) had no significant effect on the adrenal medulla or blood sugar level; (3) Only moderate and higher doses of norepinephrine or epinephrine (same as for corticosterone) caused adrenomedullary atrophy with depletions of norepinephrine and epinephrine levels but elevated the glycemic level. The findings are briefly discussed.     

Involvement of GABAB receptors in the regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis in rats

Previous experiments have shown that the GABA_B receptor agonist -baclofen given subcutaneously to male rats significantly enhanced plasma concentrations of adrenocorticotropic hormone (ACTH) and the adrenocortical hormones corticosterone and aldosterone. The goal of the present study was to investigate whether the stimulatory effects on adrenocortical steroids elicited by -baclofen in vivo could be reversed by the selective GABA_B antagonist CGP 35 348. One hour before subcutaneous administration of 3 mg/kg -baclofen, a dose of 600 mg/kg CGP 35 348 or saline was administered intraperitoneally. The stimulatory effect of -baclofen on ACTH, corticosterone and aldosterone was significantly reduced by 60% after pretreatment with CGP 35 348. The GABA_B antagonist CGP 35 348 by itself had no effect on ACTH or the adrenocortical hormones. These results indicate that GABA_B receptors are involved in the -baclofen-induced activation of the HPA axis in rats. In vitro, however, neither -baclofen nor CGP 35 348 had any effects on corticosterone and aldosterone release from perifused adrenal cells. These results suggest that the participation of GABA_B receptors in the activation of the HPA axis induced by -baclofen in vivo does not occur at the level of the adrenal gland, and therefore must occur at the level of the pituitary or the brain.     

ACTH increases adrenal medullary PNMT activity in neonatal rats

Levels of plasma corticosterone and the activities of adrenomedullary dopamine-beta-hydroxylase (DBH) and phenylethanolamine-N-methyltransferase (PNMT) were measured in the 7-day-old rat following the administration of adrenocorticotropic hormone (ACTH) for 7 consecutive days beginning with day 1. ACTH led to significant adrenal hypertrophy and a concomitant elevation (10 to 15 fold) of plasma corticosterone concentration. Whereas DBH activity remained unchanged, adrenal PNMT activity was increased significantly following ACTH-induced elevation of plasma corticosterone levels. These results indicate that the pituitary-adreno-cortical-adrenomedullary axis is functional in the neonatal rat. Furthermore, since the transsynaptic control mechanisms are known to be non-functional or immature in the 7-day-old rat, our data suggest that neonatal rat adrenal catecholamine biosynthesis may be largely controlled by the pituitary-adrenocortical axis via glucocorticoids.     

ACTH and corticosterone response to naloxone and morphine in normal, hypophysectomized and dexamethasone-treated rats

The effect of opiate receptors blocker naloxone on ACTH and corticosterone secretion in normal, dexamethasone-treated and hypophysectomized rats was studied. A dose-related increase in plasma corticosterone level was found at 45 min after s.c. injection of naloxone in a dose range of 0.25-2.0 mg kg-1. The rise in plasma corticosterone was preceded by a slight increase in plasma ACTH. Acute morphine administration in a relatively low dose (6 mg kg-1 s.c.) induced a significant rise in both plasma ACTH and corticosterone levels. Dexamethasone treatment was followed by low basal corticosterone level, by total inhibition of the stress response and response to morphine injection, while the response to ACTH administration was normal. Under these circumstances as well as in rats 6 days after hypophysectomy, naloxone failed to increase plasma corticosterone levels. It is concluded that a direct stimulation of corticosteroid biosynthesis in adrenal cortex is not involved in the mechanism of naloxone-induced activation of pituitary-adrenocortical function.     

Verapamil inhibits proliferation but not steroidogenesis of regenerating rat adrenal cortex

The effect of verapamil, a calcium channel antagonist, on proliferation and steroidogenesis was investigated in regenerating rat adrenal cortex. Verapamil was given subcutaneously in two doses (1 and 5 mg/kg) to male Wistar rats subjected to adrenal enucleation combined with contralateral adrenalectomy. It was found that verapamil inhibited the mitotic activity of adrenocortical cells on the 4th and 8th day after surgery in a dose-dependent manner. However, no changes in corticosterone secretion were observed.     

Effect of dexamethasone on steroidogenesis and on adrenocortical cyclic AMP and cyclic GMP responses to ACTH

The inhibitory action of dexamethasone on the adrenal steroidogenic response to ACTH was confirmed by im administration of graded doses (5, 10 and 30 ng) of synthetic beta 1-24 ACTH to young adult male rats which had received dexamethasone (0.1 mg/100 g bw) 4 hr prior to sacrifice. Following this, kinetic studies were performed by measuring plasma corticosterone, adrenocortical cyclic AMP and cyclic GMP before and 4, 12 and 30 min after administration of either 10 or 30 ng of ACTH. These doses were selected because their effects could be either completely or partially inhibited by dexamethasone. In rats without dexamethasone all the doses of ACTH which were checked induced an increase in both corticosterone and cyclic AMP and a decrease in cyclic GMP. With the smallest dose of ACTH the earlier administration of dexamethasone resulted in complete suppression of both the steroidogenic response and the cyclic AMP response. With the largest dose of ACTH both responses were diminished. In dexamethasone-treated rats the decrease in cyclic GMP was significantly less pronounced 4 min after ACTH than it was in non-treated rats. These results support the view that cyclic AMP and cyclic GMP might both be concerned with the mechanism of acute adrenal steroidogenesis.     

Effect of adrenergic antagonists and cyclooxygenase inhibitors on the nicotine-induced hypothalamic-pituitary-adrenocortical activity.

Nicotine is a potent stimulus for the hypothalamic-pituitary-adrenal (HPA) axis. Systemic nicotine acts via central mechanisms to stimulate by multiple pathways the release of ACTH from the anterior pituitary corticotrops and corticosterone from the adrenal cortex. Nicotine may stimulate indirectly the hypothalamic paraventricular nucleus, the site of the corticotropin-releasing hormone (CRH) neurons which activates ACTH release. In the present studies an involvement of adrenergic system and prostaglandins synthesized by constitutive cyclooxygenase (COX-1) and inducible cyclooxygenase (COX-2) in the nicotine-induced HPA response in rats was investigated. Nicotine (2.5-5 mg/kg i.p.) significantly increased plasma ACTH and corticosterone levels measured 1 hr after administration. Adrenergic receptor antagonists or COX inhibitors were injected i.p. 15 min prior to nicotine and the rats were decapitated 1 hr after the last injection. Prazosin (0.01-0.1 mg/kg), an alpha1-adrenergic antagonist, significantly decreased the nicotine-evoked ACTH and corticosterone secretion. Yohimbine (0.1-1.0 mg/kg), an alpha2-adrenergic antagonist, moderately diminished ACTH response, and propranolol (0.1-10 mg/kg), a beta-adrenergic antagonist, did not significantly alter the nicotine-induced hormones secretion. Pretreatment with piroxicam (0.2-2.0 mg/kg), a COX-1 inhibitor, considerably impaired the nicotine-induced ACTH and corticosterone secretion. Compound NS-398 (0.2-5.0 mg/kg), a selective COX-2 blocker did not markedly alter these hormones secretion, and indomethacin (2 mg/kg), a non-selective COX inhibitor significantly diminished ACTH response. These results indicate that systemic nicotine stimulates the HPA axis indirectly, and both adrenergic system and prostaglandins are significantly involved in this stimulation. Noradrenaline, stimulating postsynaptic alpha1-adrenergic receptors, and prostaglandins, synthesized by COX-1 isoenzyme, are of crucial significance in the nicotine-induced ACTH and corticosterone secretion.     

Hormone mediated changes in monoamine stores and regulation of enzymes of biosynthesis and metabolism in the rat adrenal gland. Influence of progesterone, estradiol, ACTH and testosterone administration

The influence of daily injections, for 7 days, of 17-hydroxyprogesterone caproate (8 mg/100 g body weight pro die), of estradiol-17 beta 17-undecylate (1.2 mg/100 g body weight pro die) of testosterone enanthate (2 mg/100 g body weight pro die) and of ACTH (4 IU/100 g body weight pro die) to male Wistar rats, weighing 200 g, were investigated. Monamine storage and regulation of enzymes phenylethanolamine N-methyl transferase (PNMT), monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) were studied in the adrenal glands. Results from testosterone treated rats were especially significant : the hormone administration decreased the stores of dopamine and norepinephrine (epinephrine precursors), stimulated PNMT and decreased metabolism of epinephrine by MAO and COMT. However, the adrenal content of epinephrine remained in the normal range. These findings suggest that uptake of epinephrine is accelerated in peripheral tissues by testosterone.     

Pituitary cyclic AMP and plasma hormone responses to epinephrine administration in vivo

The present study was conducted to characterize the in vivo effects of epinephrine administration on levels of pituitary cyclic AMP and plasma hormones. Rats were injected with saline or epinephrine bitartrate (1 mg/kg lP) and sacrificed by decapitation 1, 5, 15, 30 or 60 min post-injection. Levels of pituitary cyclic AMP and plasma ACTH, beta-endorphin, beta-LPH, corticosterone and prolactin were determined by radioimmunoassays. The injection procedure itself was somewhat stressful as demonstrated by increased levels of plasma prolactin and ACTH 5 min following either saline or epinephrine injection. This "stress" response was rapid and short-lasting for the pituitary hormones. The response of the adrenal hormone, corticosterone, to saline injection was slower in onset and longer in duration. Pituitary cyclic AMP levels did not increase following saline injection. Epinephrine-injected animals displayed markedly elevated plasma levels of ACTH, beta-endorphin and beta-LPH at 15, 30 and 60 min as compared to control or saline-injected rats. In addition, levels of pituitary cyclic AMP were increased over 10 fold at these times. Levels of plasma prolactin, a stress-responsive hormone, were not significantly increased in epinephrine-injected animals as compared to saline-injected rats indicating that these later responses seem to be specific to epinephrine rather than to stress.     

Secretion of aldosterone and corticosterone by the adrenals of Brattleboro rats in response to ACTH administration

The secretions of aldosterone and corticosterone in response to administration of 0,5 mUI of (1,24) ACTH (synacthène-Ciba) were measured in the adrenal venous blood of 15 Brattleboro female rats genetically lacking vasopressin and in 15 Long-Evans female rats, pretreated with dexamethasone. The secretions of aldosterone and corticosterone increased according to a similar profile in the two groups of animals: maximum values were 20-30 min. after ACTH injection; however the steroidogenic secretion of the adrenal cortex was always about 50% less in the Brattleboro female rats than in Long-Evans female rats. This result suggests mainly that vasopressin may be involved in the mechanisms which control the in vivo production of aldosterone by the adrenal glomerulosa cells.     

Effects of adrenal medullectomy and passive immunization with an anti-CRF antiserum on the corticotropin secretion in response to stress in Long-Evans rats

Ether stress-induced ACTH and corticosterone secretion is similar in 60 days adrenal medullectomized and intact Long-Evans Rats. Passive immunisation with a 41-CRF antiserum impairs corticotropic function after stress. This decrease is more pronounced in adrenal medullectomized than in intact animals. These results suggest that epinephrine plays a minor role on the stress induced ACTH secretion. This role can be demonstrated only after immunoneutralisation of endogenous 41-CRF.     

Serotoninergic stimulation of aldosterone secretion in vivo: role of the hypothalamo-pituitary adrenal axis.

The control of aldosterone secretion in vivo by serotonin was studied in conscious rats. Serial blood samples were taken from indwelling arterial cannulae before and after i.p. administration of 1 ml (4 g/l) 5-hydroxytryptophan (5-HTP), the precursor of serotonin (5-HT), or saline, and analysed for 5-HTP, serotonin, 5-hydroxyindoleacetic acid, plasma renin activity (PRA), corticosterone, aldosterone, sodium and potassium concentration. The relative contribution of the hypothalamo-pituitary adrenal axis was investigated in animals pretreated with the synthetic glucocorticoid dexamethasone. 5-HTP caused a significant increase in all parameters within 45 min except for plasma sodium and potassium. Saline administration showed no significant effect. Dexamethasone pretreatment significantly impaired the corticosterone and aldosterone response to 5-HTP, although the aldosterone response was merely attenuated. No other parameter was affected by dexamethasone pretreatment. The results show that administration of 5-HTP, which increases serum serotonin levels, stimulates PRA, corticosterone and aldosterone secretion. Dexamethasone pretreatment inhibits the aldosterone response, though not completely, suggesting that the stimulatory action of 5-HTP involves the release of ACTH, which stimulates corticosterone and aldosterone secretion by the adrenal cortex. The failure of dexamethasone to block the aldosterone response completely, suggests the involvement of other mechanisms such as the renin-angiotensin system or a direct action of serotonin on the adrenal zona glomerulosa.     

Effects of (D-ala2, met5)-enkephalinamide and naloxone on ACTH and corticosterone secretion

An intravenous administration of (D-ala2, met5)-enkephalinamide (DALA) caused a significant elevation of plasma ACTH and corticosterone at 10 to 20 min after injection in unanesthetized freely moving rats. An intraperitoneal administration of cyproheptadine tended to reduce plasma ACTH and corticosterone levels at 60 min after injection, but it did not attenuate the DALA-induced ACTH and corticosterone elevation. A large dose of naloxone (1-10 mg/kg body weight) caused a significant elevation in plasma corticosterone, but naloxone at 10 mg/kg body weight reduced the basal ACTH level and DALA-induced ACTH elevation. When both DALA and naloxone were injected, the steroidogenic effect was attenuated. Neither DALA nor naloxone affected the basal ACTH release and CRF-induced ACTH stimulation in rat anterior pituitary cell cultures. These results suggest that DALA acts at the extra-hypophyseal level to stimulate ACTH and corticosterone and that the naloxone stimulatory effect on steroidogenesis acts on the adrenal gland or is mediated by stimulating corticosterone stimulating factors other than ACTH.     

Effect of subdiaphragmatic vagotomy and cholinergic agents in the hypothalamic-pituitary-adrenal axis activity.

In the present study, we examined whether the vagus nerve is involved in mediating the stimulation of hypothalamic-pituitary-adrenal (HPA) axis by cholinergic muscarinic and nicotinic agonists, carbachol and nicotine. The site of HPA axis muscarinic stimulation was determined using peripheral (i.p.) and intracerebroventricular (i.c.v.) administration of carbachol, atropine sulphate (AtrS) and atropine hydrobromide (AtrBr). The i.p. carbachol-(0.5 mg/kg)-induced corticosterone response was significantly reduced by i.p. pretreatment with AtrBr (0.1 mg/kg), but was not diminished by i.c.v. AtrS (0.1 mug). The increase in corticosterone secretion induced by i.c.v. carbachol (2 microg) was totally abolished by i.c.v. pretreatment with AtrS (0.1 microg) but was not altered by i.p. AtrBr. Subdiaphragmatic vagotomy performed 2 weeks earlier substantially decreased the i.p. carbachol (0.2 mg/kg)-induced ACTH response and markedly augmented ACTH and corticosterone response to a higher dose of carbachol (0.5 mg/kg) in comparison with the responses in sham operated rats. Vagotomy abolished the stimulatory effect of i.p. nicotine in a low dose (1 mg/kg) on ACTH and corticosterone secretion; the ACTH response to higher dose (2.5 mg/kg) was considerably reduced, while corticosterone response remained unaffected. These results suggest that carbachol given i.c.v. evokes considerable corticosterone response by stimulation of central cholinergic muscarinic receptors. A major part of the i.p. carbachol-induced corticosterone secretion results from peripheral cholinergic muscarinic receptor stimulation. Subdiaphragmatic vagotomy moderately intensified the carbachol-induced ACTH and corticosterone secretion. Vagotomy significantly reduced the nicotine-induced ACTH secretion, possibly by the involvement of vagal afferents. The nicotine-induced corticosterone secretion is not exclusively regulated by circulating ACTH but by various intra-adrenal regulatory components.