J Clin Pathol 1987;40:1098-1107

Effects of catecholamines on secretion ofadrenocorticotrophic hormone (ACTH) in manS AL-DAMLUJI, L H REESFrom the Department ofEndocrinology, St Bartholomew's Hospital, London

SUMMARY The hypothalamus receives a rich supply of adrenergic and noradrenergic nerve fibresfrom the brain stem, terminating in many hypothalamic regions, including the paraventricularnucleus, which is the site of the cell bodies of corticotrophin releasing factor (CRF) neurones inman. Experimental evidence has shown that an a, adrenoceptor mechanism stimulates adreno-corticotrophic hormone (ACTH) secretion in man. The site of action of this mechanism seems to bewithin the blood brain barrier, presumably modulating the secretion of the CRF complex. Thismechanism is important in the control of ACTH secretion in some physiological conditions inhealthy subjects.

The pioneering work of Harris' postulated theexistence of a hypothalamic corticotrophin releasingfactor (CRF) that is transported in the hypothalamo-hypophyseal portal system to the anterior pituitarygland, and which stimulates the secretion of adre-nocorticotrophic hormone (ACTH). This work wascrowned by Vale et al, who isolated and synthesised2a 41 amino acid peptide from ovine hypothalami withspecific CRF bioactivity. Equivalent peptides havebeen identified in other species, including man.Immunohistochemical studies have shown this pep-tide to be widely distributed in the central nervoussystem, but within the hypothalamus it is localisedmostly in the parvocellular neurones of the para-ventricular nucleus. The axons extend to the zonaexterna of the median eminence, which is the site ofthe first capillary bed in the hypothalamo-hypophyseal portal system.3-5

Further investigations have shown that other pep-tides may possess CRF activity. Prominent amongthese is vasopressin, which has a weak direct stimu-lant effect on ACTH secretion; but more importantly,it strongly enhances the activity of CRF-41 6 It there-fore seems that the hypothalamus secretes a CRF"complex" the constituents of which may vary underdifferent circumstances. The paraventricular nucleuscontains high concentrations of catecholamineswhich may influence the activity of the hypothalamo-pituitary adrenal axis (HPAA). In theory peripheralcirculating catecholamines may also influence ACTHsecretion as activation of the sympathoadrenal system

often accompanies that of the HPAA.In this review, we summarise the relation of

catecholamine systems to the hypothalamus and thepituitary gland and discuss the evidence from humanexperiments for a regulatory role of these amines inACTH secretion.

Catecholamine systems, the hypothalamus, and thepituitary glandThe hypothalamus contains the highest concen-trations of noradrenaline in the brain.7-9 The originof this noradrenaline is almost all extrinsic as surgicalisolation of the hypothalamus results in a drasticreduction of its noradrenaline content.'0" The nor-adrenergic innervation of the hypothalamus isderived from parts of the reticular formation in theventral and dorsal medulla oblongata and the locusceruleus at the junction of the pons and the midbrain.The axons ascend in the medial forebrain bundle, andsome cross the midline.12 -16 Noradrenergic nerveterminals can be identified in every hypothalamicnucleus, but two of the most densely innervated arethe paraventricular and supraoptic nuclei12 14 17 andthe median eminence.'4 17-lg The noradrenergicinnervation of the paraventricular nucleus is derivedlargely from the ventral medulla.2' By simultaneouslyusing catecholamine histofluorescence and neu-ropeptide immunocytochemistry, catecholaminergicneurones were observed with their terminals on thecell bodies of peptidergic neurones in hypothalamicnuclei,2022 suggesting a monosynaptic contact.

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The hypothalamus also contains high concen-trations of adrenaline.7 The cell bodies of adrenergicneurones lie within the reticular formation in theupper medulla23 24 and project to various parts of thebrain, including the diencephalon, in which the high-est concentrations are found in the paraventricularand arcuate nuclei and the median eminence.23-27Using combined immunocytochemistry Mezey et a!28showed that adrenergic neurones lie in close prox-imity to CRF-41 cell bodies in the paraventricularnucleus of rats.The dopaminergic innervation of the hypo-

thalamus is almost all intrinsic; surgical isolation ofthe hypothalamus results in little reduction ofdopamine content.'0 '" In the hypothalamus thetuberoinfundibular dopaminergic tract has its cellbodies in the arcuate nucleus, near the inferior end ofthe third ventricle. The axons project to the zonaexterna of the median eminence where they are inclose proximity to the first capillary bed of thehypothalamo-hypophyseal portal system, into whichdopamine is secreted. Dopaminergic neurones alsosupply the neural and the intermediate lobes of the ratpituitary.'2 18 The incerto-hypothalamic tract has itscell bodies mainly in the zona incerta and partlyinnervates the paraventricular nucleus.29The mammalian adenohypophysis does not receive

a catecholaminergic innervation.30 31 The neural andintermediate lobes of the rat contain considerablequantities of dopamine and smaller amounts of nor-adrenaline.30 The dopaminergic innervation isderived from neurones with their cell bodies in thearcuate nucleus,32 but the noradrenergic innervationseems to be from peripheral sympathetic nervesaccompanying blood vessels.32Dopamine is secreted into hypophyseal portal

plasma,33 and its role in the tonic inhibition of pro-lactin secretion is well established. There is contro-versy, however, as to whether adrenaline and nor-adrenaline are secreted into hypophyseal portalplasma. Several studies in rats have reported the con-centrations of adrenaline and noradrenaline inhypophyseal portal plasma to be no greater thanthose in peripheral plasma.33 More recently, someinvestigators38-40 have found that the concentrationof adrenaline in plasma from the transected pituitarystalk of anaesthetised rats was 60-90% higher thanthe adrenaline concentrations in peripheral venousplasma, and interpreted this as indicating a centralsource of adrenaline secretion into the portal circu-lation. The source of adrenaline in those experimentsmay have been partly derived from the severed stalknerves containing adrenergic fibres innervating theposterior and intermediate lobes, as the concentrationof adrenaline in plasma from a single portal vessel inthe intact stalk is lower than that in peripheral

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plasma.37 Nevertheless, whichever of these viewsconcerning the rat prevails, as the mammalian adeno-hypophysis does not receive a catecholaminergicinnervation31 32 it is unlikely that the anterior pitu-itary is exposed to much higher concentrations ofadrenaline than those found in peripheral plasma.The distribution of adrenoceptors in the hypo-

thalamus has been studied using autoradiographyand radioligand binding studies on homogenised ratbrain membranes. Within the hypothalamus, a, anda2 adrenoceptors are found in several nuclei, includ-ing the paraventricular nucleus.4" The median emi-nence has a high density of a2 adrenoceptors but nohigh al binding.4' The density of,-adrenoceptorbinding sites is lower in the hypothalamus than in thecerebral cortex, and even lower densities are foundin the adenohypophysis, about 10% of the densityin the cortex.42 Roughly equal densities of the twoP-adrenoceptor subtypes are found in the hypo-thalamus, but only 2 adrenoceptors are found in therat adenohypophysis.42 The paraventricular nucleushas an intermediate density of /-adrenoceptorbinding sites.4' Within the hypothalamus dopaminer-gic receptors are found in highest densities in themedian eminence (mostly D-l subtype), but the para-ventricular nucleus has an intermediate density ofboth D-l and D-2 binding sites.4' In the adeno-hypophysis only the D-2 receptor subtype is foundand helps to regulate prolactin secretion.43

Effects of adrenoceptor stimulation on ACTHsecretionThe early studies that assessed the interaction of cate-cholamines and the HPAA in man examined theeffects of administration of adrenaline on variousindirect indices of HPAA activity, such as theblood eosinophil count,44 -46 1 7-hydroxycortico-steroids,45-48 and various early ACTH bio-assays,49 50 but the results were conflicting. Morerecently, intravenous infusions of adrenaline5' 52 andnoradrenaline53 54 have been reported to have nostimulatory effect on basal plasma cortisol concen-trations in man. Muller-Hess et al5' suggested thatadrenaline may attenuate the cortisol response tohypoglycaemia induced by insulin, but this is proba-bly attributable to the attenuation of the hypo-glycaemic effect of insulin by adrenaline. Other evi-dence from man includes the observations thatamphetamines stimulate the secretion of ACTH andcortisol and that the effect is blocked by thymoxaminebut not propranolol, which suggests that it is medi-ated by a, adrenoceptors.55 56 Amphetamines havecomplex pharmacological actions and cause a gener-alised arousal effect that is correlated with the heightof the cortisol peak,55 57 so the mechanism by whichthey stimulate ACTH secretion is uncertain.

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In our current investigations of a-adrenergic ago-nists we have chosen methoxamine, a highly selectiveagonist at post-synaptic a, adrenoceptors58 59 that isfree of behavioural arousal effects when injectedintracerebroventricularly in experimental animals.60Like Nakai et al,6" we found that intravenousinfusions of methoxamine stimulate the secretion ofACTH and cortisol in man (fig 1).62 The stimulanteffects of methoxamine on ACTH and cortisol secre-tion were dose dependent and were accompanied byan increase in blood pressure, as may be expectedfrom an oa, adrenoceptor agonist.62 The effects ofmethoxamine were abolished by concomitant admin-istration of the highly selective a, adrenoceptorantagonist thymoxamine,59 confirming that they weremediated by a, adrenoceptors (fig 1).62 When given inlarge doses in experimental animals, methoxaminemay have P-adrenoceptor antagonist activity,63 butthis is not the mechanism by which it stimulates theHPAA in man: the effect was abolished by concomi-tant administration of thymoxamine, which lacksactivity at fl-adrenoceptors.64 Thymoxamine hasweak H-l antihistaminic action on the guinea pigileum in vitro,64 but we have found that thymox-amine does not attenuate the bronchoconstrictoraction of intravenously injected histamine,65 sug-gesting that thymoxamine has no H-i antihistaminicactivity in the doses used in man.To examine whether methoxamine stimulates

ACTH secretion by a central effect or by a peripheralaction, such as vasoconstriction or an increasein blood pressure, we compared the effects ofmethoxamine to those of the more hydrophilicnoradrenaline.66 Noradrenaline is a potent a,adrenoceptor agonist58 that reaches the pituitarygland and the median eminence after a systemic injec-tion but does not cross the blood brain barrier.67-69The noradrenaline infusions were designed to raisesystolic blood pressure by amounts equivalent tothose produced by methoxamine, so that equivalentperipheral a, adrenoceptor activation by the twodrugs could be compared.62 Fig 2 shows that thenoradrenaline infusions were not followed by arise in plasma cortisol above the mean control value,suggesting that the stimulation of the HPAA bymethoxamine is exerted by a central rather than aperipheral mechanism. As the pituitary gland and themedian eminence are outside the blood brain barrierand are accessible to circulating noradrenaline,6769our inability to stimulate the HPAA with noradren-aline suggests that the site of the stimulant a1 adreno-ceptors is within the blood brain barrier, presumablymodulating the secretion of the CRF complex.

In addition to its hydrophilic properties, nor-adrenaline differs from methoxamine in its ,B and a2adrenoceptor agonist actions. These receptor

Al-Damluji, Rees

activities of noradrenaline, however, do not accountfor the differences from methoxamine, as we foundthat fJ and f2 adrenoceptor agonists (prenalterol andsalbutamol, respectively), do not have a direct actionon ACTH secretion in man; and an U2 antagonist(yohimbine) does not modify cortisol secretion duringnoradrenaline infusions.62The noradrenaline infusions caused a slight

inhibition of cortisol secretion compared with saline(fig 2),62 as had been described by Wilcox et al."3 Themechanism of this inhibitory effect of peripheral

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Fig 1 Effects ofinfusions ofsaline and methoxamine(0-22 mg/minute) with and without thymoxamine (0.2 mg/kgbolus + 2-2 pg/kg/minute) on plasma ACTH,immunoreactive f endorphin (C-terminal LPH), cortisol,heart rate (HR), and bloodpressure (BP) in nine normalsubjects. Open circles, saline; closed circles, methoxamine;triangles, methoxamine and thymoxamine. (Reproduced bypermission ofthe publishers ofNeuroendocrinology,SKarger AG, Basel.)

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Fig 2 Comparison ofeffects ofmethoxamine andnoradrenaline on plasma cortisol and systolic bloodpressure(expressed as percentage changefrom mean control+ SEM). Noradrenaline infusions were given to increaseSBP by about 10 and 25% ofthe mean control value, similarto changes after methoxamine. (Reproduced by permission ofthe publishers ofNeuroendocrinology, SKarger AG, Basel.)

adrenoceptor activation on the HPAA is unclear, butit may be caused by the known inhibitory effect ofintravenous infusions of noradrenaline on the secre-

tion of vasopressin,70 which is a constituent of theCRF complex.

In another experiment a different approach was

used to examine the site of action of o1 adrenoceptorsin stimulating ACTH secretion. We studied a group

of patients with hypopituitarism caused by diseases ofthe hypothalamus or the pituitary stalk, such as crani-opharyngiomas. These patients respond to an intra-venous injection of synthetic ovine CRF-41 by an

increase in ACTH and cortisol secretion but they donot respond to hypoglycaemia induced by insulinwith a rise in plasma cortisol. This indicates that thecause of their hypoadrenalism is a failure of the syn-thesis or delivery of CRF, rather than a primarydefect in ACTH reserve. If the site of action of thestimulant a, adrenoceptors in stimulating ACTHsecretion is on the hypothalamus or its centralconnections-that is, within the blood barrier-thenthese patients would be expected to have no ACTH or

cortisol response to an infusion of methoxamine. Fig3 shows the result of a study in one such patient whoshows no cortisol response to hypoglycaemia inducedby insulin or methoxamine but responds normally tosynthetic ovine CRF-41. This is consistent with theview that the site of action of the stimulant a, adreno-ceptors is likely to be on the hypothalamus or itscentral connections, rather than directly on thepituitary gland.Some data from experimental animals are consis-

tent with the view that central adrenergic mechanismsstimulate the HPAA. Thus in cats corticosteroidsecretion is stimulated by the implantation of nor-

adrenaline into hypothalamic areas but not into thepituitary gland.7" In rats the depletion of hypo-thalamic noradrenaline by stereotaxic injection of theneurotoxin 6-hydroxydopamine into the medial fore-brain bundle is followed by a reduction of ACTHsecretion.72 Other experimental evidence, however,has been collected on the rat and the dog and has beeninterpreted as showing an inhibitory effect of central aadrenoceptors on ACTH secretion." The systemicadministration of P-adrenoceptor agonists stimulatesACTH secretion in the rat.74 Most of these appar-

ently conflicting data may be explained on the basis ofthe technical approaches and the pharmacologicalproperties of the compounds used.

Adrenaline has been reported to enhance the stimu-lant effect of synthetic ovine CRF-41 on ACTHsecretion by cultured rat adenohypophyseal cells invitro.7576 We therefore investigated the effects ofincreases in plasma concentrations of adrenalinewithin the normal range on the activity of CRF-41 inman in vivo.77 Intravenous infusions of adrenalinethat increased plasma adrenaline concentrations to4.33 (SEM 0.82) nmol/l had no stimulant effect on

ACTH or cortisol secretion basally or after the injec-tion of oCRF-41 (fig 4). The plasma adrenaline con-centrations during the adrenaline infusions were atthe upper limit of the range that has been observed innormal subjects and patients in a variety ofphysiological and pathological situations, such as

o-o Insulin 0-15 (u/kg)700 o Corticotrophin releasing factor

Methoxamine (20 mg)600-

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Fig 3 Effects on plasma cortisol ofhypoglycaemia inducedby insulin (blood glucose nadir < 22 mmol/l), synthetic ovineCRF-41 (100 ug bolus at 0 minutes), and methoxamine(20mg intravenouslyfrom 0 to 90 minutes) in patient withcraniopharyngioma causing hypothalamic deficiency. Shadedareas are 95% confidence limits ofplasma cortisol responseto identical dose ofmethoxamine in 11 normal subjects.

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Fig 4 Dose-response relation ofplasma ACTH to bolusdoses ofsynthetic ovine CRF-41 during infusions ofsaline(open circles) and adrenaline (3 ug/minute, closed circles) insix normal subjects. Mean SEM values are shown.(Reproduced by permission of the publishers of The JournalofEndocrinology.)

cold exposure,78 near maximal exercise,79 acutemyocardial infarction8O in patients in an intensivecare unit8i and in septicaemic patients who arenot shocked.82 Higher concentrations of plasmaadrenaline are observed only in extremes of patholo-gical situations, such as impending death8i or severesepticaemia with shock,82 and after the pharma-cological stimulus of hypoglycaemia induced byinsulin. It was therefore concluded that circulatingadrenaline has no physiological role in stimulatingACTH secretion either basally or in the presence ofCRF-41. This conclusion is compatible with the pre-vious findings that peripheral adrenergic stimulationwith noradrenaline, prenalterol, and salbutamol wasnot associated with activation of the pituitary adrenalaxis. The possibility that hypophyseal portal plasmamay contain somewhat higher concentrations ofadrenaline derived from a central source is contro-versial and has been discussed here. Milsom et a183studied the effects of adrenaline, noradrenaline, andclonidine and found no enhancement of the action ofsynthetic ovine CRF-41 by any of these substances.

In our investigation of the interaction of adrenalineand CRF-41 the adrenaline infusions were associatedwith a transient inhibition ofACTH secretion basallyand a slowing of the rate of rise of ACTH secretionafter the injection of CRF-41. This is compatiblewith the previously described inhibition of cortisol

Al-Damluji, Reessecretion by noradrenaline described above, andlocalises the site of action of this effect to the pituitarygland.The effects of clonidine on the activity of the

HPAA have also been examined, with conflictingresults: the drug has been reported both to inhibit84 85and to have no effect86 87 on corticotroph activity.This may perhaps be due to the drug's complex phar-macology, as it stimulates both tx, and a2 adreno-ceptors, the latter having the effect of inhibition ofnoradrenaline release from nerve endings. Clonidinealso causes hypotension, which is a potent stimulus toACTH secretion,8889 and sedation,60 which wouldbe expected to depress the HPAA.

The physiological importance of the stimulant a;adrenoceptors

I THE ROLE OF a, ADRENOCEPTORS INDETERMINING THE 24 HOUR CORTISOLSECRETORY PATTERN90A group of normal subjects were given 24 hour intra-venous infusions of the a, adrenoceptor agonistmethoxamine, the a, antagonist thymoxamine, andsaline under double blind conditions. During wakinghours, the methoxamine infusion was accompaniedby higher concentrations of plasma cortisol thansaline, while the converse held with thymoxamine(fig 5). In contrast, the nocturnal surge in cortisolsecretion was unaffected by these adrenergic manipu-lations. The results suggest than an cxl adrenoceptormechanism maintains cortisol secretion duringwaking hours but not at night. There is evidence fromexperimental animals that the nocturnal activity ofthe HPAA may be mediated by serotonergic andcholinergic mechanisms.

2 THE ROLE OF (XI ADRENOCEPTORS INCORTISOL SECRETION AFTER FOODFood ingestion stimulates cortisol secretion in man byan unknown mechanism.9' In rats feeding increasesthe turnover of noradrenaline in the hypothalamus,92so we investigated the role of a, adrenoceptors in themediation ofcortisol secretion after eating.93 A groupof normal subjects was given three hour intravenousinfusions of saline, methoxamine, and thymoxamine,and a standard meal was eaten 60 minutes after thestart of the intravenous infusions. Methoxamineenhanced and thymoxamine attenuated the ACTHand cortisol responses to the meal without affectingnutrient absorption (fig 6). ACTH is found in the gas-trointestinal tract as well as in the pituitarygland.9495 To determine whether the source of thisACTH secretion is the pituitary gland or the gastro-intestinal tract four patients with recent onset ofACTH deficiency and normally responsive adrenal

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Fig 5 Effects ofintravenous infusions ofmethoxamine (triangles), thymoxamine (open circles), and saline (closedcircles) on 24 hour pattern ofplasma cortisol in six normal subjects. C, coffee; L, lunch; T, tea; S, supper; D, drink;B, breakfast. (Reproduced by permission ofthe publishers ofClinical Endocrinology, Oxford: Blackwell ScientificPublications.)

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Fig 6 Effects ofmethoxamine (I jig/kg/minute), thymoxamine (0 15 mg/kg bolus + 2-5 jig/kg/minute),and saline on ACTH and cortisol responses tofood ingestion in six normal subjects. Infusions were givencontinuously throughout study and lunch was given at 60 minutes. Triangles, methoxamine; closed circles,saline; and open circles, thymoxamine. (Reproduced by permission ofthe publishers ofClinicalEndocrinology, Oxford: Blackwell Scientific Publications.)

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Fig 7 Effect oflunch on plasma cortisol in six normal subjects (shaded area mean + 2 SD) andfour patients with pituitaryACTH deficiency and responsive adrenal glands. Left panel shows plasma cortisol responses to physiological dose ofACTH infour patients. (Reproduced by permission ofthe publishers ofClinical Endocrinology, Oxford: Blackwell ScientificPublications.)

glands were given the same standard meal. There wasno ACTH or cortisol response in any of thesepatients, indicating that the source of the secretionwas the pituitary gland (fig 7).93 In conclusion, corti-sol secretion after the ingestion of food is mediated bycentral stimulant al adrenoceptors which modulatethe secretion of pituitary ACTH.

3 THE CORTISOL RESPONSE TOHYPOGLYCAEMIAHypoglycaemia is not physiological in man, butseveral studies have examined the effects of a andfi-adrenoceptor antagonists on the cortisol responseto this pharmacological stimulus. Nakai et al6'reported that phentolamine blunted the cortisolresponse to hypoglycaemia induced by insulin, buttheir findings could not be confirmed by several othergroups.96-99 It therefore seems at this stage that theHPAA response to hypoglycaemia, like the nocturnalsurge of cortisol secretion, is not mediated by aoeadrenoceptors.Nakai et a16' reported that propranolol enhanced

the pituitary-adrenal response to hypoglycaemiainduced by insulin but their results were notconfirmed by other investigators.97 98 100 Asdescribed above, we found no stimulant effect ofperipheral ,B-adrenoceptor activation on ACTHsecretion basally or after CRF-41 injection in man.As yet no clear evidence exists for a role of,-adren-ergic mechanisms in the control ofACTH secretion inman. In rats, however, P2 adrenoceptors stimulate thesecretion of the pro-opiocortin-derived peptides fromthe intermediate lobe,101 which is a vestigial organ inman. 102

The effects of dopaminergic mechanisms on thesecretion ofACTHDopamine inhibits the secretion of pro-opiocortin-derived peptides from the rat intermediate lobe.'03The effect may be of physiological relevance, asdopaminergic antagonists stimulate the secretion ofthe pro-opiocortin-derived peptides in rats and dogsin vivo,104'106 suggesting the existence of a tonicinhibitory dopaminergic mechanism. In mandopamine has no effect on the secretion of the pro-opiocortin-derived peptides by anterior pituitarytissue in vitro.'07 In healthy subjects dopamine hasno important effect on the secretion ofACTH or cor-tisol under basal conditions53 108 -110 or duringhypoglycaemia induced by insulin.'08 Recently wefound that dopamine has no major effect on theACTH response to CRF-41 (Al-Damluji et al,unpublished observations), but a slight inhibitoryaction was evident, presumably resulting from the riseof plasma noradrenaline concentrations during thedopamine infusions. This is similar to the inhibitoryeffect of peripheral adrenoceptor stimulationdescribed above. Dopamine does not cross the bloodbrain barrier after systemic administration."' Itsprecursor, 1-dopa, does but may produce ambiguousresults as it is converted to noradrenaline andadrenaline as well as dopamine and may interferewith the synthesis of other neurotransmitters such asserotonin."12 A useful substitute is bromocriptine, adopamine agonist that exerts strong central dopami-nergic effects when administered systemically."13Metoclopramide is a dopamine antagonist that hasprominent central effects when given parenterally."14Neither bromocriptine nor metoclopramide had any

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Effects of catecholamines on ACTH secretion 1105effect on basal plasma cortisol15 in normal subjects,and bromocriptine has no effect on the cortisolresponse to hypoglycaemia.116 On the basis of theavailable evidence dopaminergic mechanisms do notseem to have a role in the control ofACTH secretionin man.

ConclusionAn anatomical relation seems to exist between thecentral adrenergic and noradrenergic systems and thehypothalamo-pituitary adrenal axis. It is possible toshow by pharmacological means that a, adreno-ceptors stimulate ACTH secretion in man. The site ofaction of these stimulant a, adrenoceptors isprobably within the blood brain barrier, and theypresumably act by modulating the secretion of theCRF complex. This mechanism is important in thecontrol ofACTH secretion under some circumstancesin man. There is no evidence as yet of importantf- adrenergic or dopaminergic effects on ACTHsecretion in man.

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