regulation of hypothalamic somatostatin by glucocorticoids

Pergamon J. Steroid Biochem. Molec. Biol. Vol. 53, No. 1-6, pp. 277-282, 1995

Copyright ~: 1995 Elsevier Science Ltd 0960 - 0760 ( 95 ) 00065 - 8 Printed in Great Britain. All rights reserved

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Regulation of Hypothalamic Somatostatin by Glucocorticoids

Jest~s D e v e s a , 1. M 6 n i c a G a r c i a B a r r o s , 1 M i g u e l G o n d a r , 1 J. A. F. T r e s g u e r r e s 2 a n d V i c t o r A r c e 1

1Department of Physiology, School of Medicine, University of Santiago de Compostela and 2Department of Physiology, School of Medicine, University of Madrid, Spain

Glucocor t i co ids (GCs) p lay a key role in the phys io logy of the h y p o t h a l a m i c - s o m a t o t r o p h axis, since these s teroids enhance g rowth h o r m o n e (GH) gene t r a n s c r i p t i o n and increase G H R H r e c e p t o r synthesis . However , GC excess inhibi ts n o r m a l g rowth in all species s tudied. This is ma in ly due to the i m p a i r e d GH secre t ion obse rved du r ing hype rco r t i so l i sm , a s i tua t ion in which GH responses to a n u m b e r of s t imul i , inc luding GHRH, are b lun ted . The inh ib i to ry effect of GCs on GH secre t ion seems to be d e p e n d e n t on enhanced h y p o t h a l a m i c SS secre t ion. Since SS re lease is s t i m u l a t e d by ig-adrenergic agon i sm we tes ted the possibi l i ty tha t GC inh ib i t ion of GH secre t ion would depend on inc reased f l - a d r e n o c e p t o r ac t iv i ty in S S - p r o d u c i n g neurons . The e x p e r i m e n t a l design consis ted in eva lua t ing the GH response to G H R H in n o r m a l subjects a f t e r having induced hype rco r t i so l i sm , wi th DEX, and blocking jg -adrenoceptors with p r o p r a n o l o l (PRO). Moreove r , to inves t iga te the specif ici ty of this m e c h a n i s m , G H R H - i n d u c e d GH re lease was tes ted a f t e r induc ing h y p e r c o r t i s o l i s m and enhanc ing ~2-adrenergic or m u s c a r i n i c chol inergic tone, by giving c lonidine (CLO) or py r ido - s t igmine (PD), respect ive ly . As expected , n o c t u r n a l DEX a d m i n i s t r a t i o n inh ib i t ed the GH response to GHRH. In this s i tua t ion o f hype rco r t i so l i sm , bo th P R O and CLO, bu t not PD, were able to reverse the i nh ib i t o ry effect of DEX on GHRH-e l i c i t ed release. However , the po ten t i a t ing effect of these drugs on the G H R H - i n d u c e d GH secre t ion was only obse rved for PRO. These da ta c o n f i r m tha t GC excess inhibi ts GH release by increas ing h y p o t h a l a m i c SS secret ion, and tha t the m e c h a n i s m is m e d i a t e d by G C - i n d u c e d enhanced f l - ad rene rg ic responsiveness . T h e r e f o r e , the defect ive G H R H secre t ion obse rved in chron ic h y p e r c o r t i s o l i s m m u s t be a consequence of the con t inuous b lockade tha t SS excess exer t s on G H R H - p r o d u c i n g neurons . Our pos tu la te agrees with o the r da ta in the l i t e r a t u r e showing tha t GCs m o d u l a t e the secre t ion of some h y p o t h a l a m i c pept ides by changing the respons iveness of the p r o d u c i n g neu r ons f r o m ~2-adrenoceptors to tha t of j J -adrenoceptors .

J. Steroid Biochem. Molec. Biol., Vol. 53, No. 1-6, pp. 277-282, 1995

INTRODUCTION

Hypothalamic SS plays the main role in growth hormone (GH) control [1]. In fact, although hypothalamic GH releasing hormone (GHRH) must reach the pituitary somatotropes in order for GH secretion to be elicited, the release of this peptide seems to be modu- lated by SS [2], which otherwise counteracts the GH-releasing effect of G H R H at the somatotroph level. According to this hypothesis, the hypothalamic- somatotroph rhythm (HSR) [3] which establishes the episodic pattern of physiological GH secretion must have its main oscillator in SS-producing neurons. SS

Proceedings of the I X International Congress on Hormonal Steroids, Dallas, Texas, U.S.A., 24-29 September 1994.

*Correspondence to J. Devesa.

secretion, by blocking both GHRH release and the secretagogue effect of the peptide, interrupts pituitary GH secretion. The rhythmic lack of SS release, most likely governed by suprahypothalamic structures, will allow GHRH to be secreted and therefore induce GH release to the blood. These concepts are shown schematically in Fig. 1.

On these bases, the factors involved in GH control would mainly act by affecting hypothalamic SS secretion. Therefore, in order to ascertain how GH is regulated, the putative effect of each factor studied on hypothalamic SS release must first be investigated [1]. Such an investigation would take into account that adrenergic inputs to SS-producing neurons play the main role in SS control, it now being clear that while ct2-adrenergic stimulation inhibits SS release in all

277

278 Jest~s Devesa et al.

GHRH

~2 g

} I' I L-.-SS

I I

I GH _.. I

PITUITARY SOMATOTROPES

Fig. 1. H y p o t h a l a m i c g r o w t h h o r m o n e control . SS i nh ib i t s GH secret ion by counteract ing the effect of G H R H at the s o m a t o t r o p e s level a n d d i rec t ly i n h i b i t i n g the h y p o t h a l a m i c re lease of the peptide. In t u r n , SS secret ion is m a i n l y d e p e n - den t on the b a l a n c e b e t w e e n a2-adrenerg ic ( i nh ib i t o ry ) a n d ~ - a d r e n e r g i c ( s t i m u l a t o r y ) act ivi t ies at the S S - p r o d u c i n g n e u r o n s . GH direct ly s t imula te s SS release . > s t i m u l a t i o n .

- - - --, inh ib i t ion .

species in which it has been studied [4], fl-adrenergic agonism stimulates the secretion of this inhibitory peptide.

G L U C O C O R T I C O I D S A N D G R O W T H H O R M O N E S E C R E T I O N

Glucocorticoids (GCs) are a key component for the physiological functioning of the hypothalamic- somatotroph axis [1]. These steroids enhance G H gene transcription [5] and increase G H R H receptor synthesis [6]; consequently, it seems to be logical that a synthetic GC such as dexamethasone (DEX) stimulates both GHR H- induced G H release [7] and spontaneous secretion of the hormone [8]. In line with this, an adequate GC replacement is needed to restore a normal G H secretion in patients with idiopathic A C T H deficiency [9]. However, it is well known that GC excess inhibits normal growth in all species studied [10]. Although this results from the conjunc- tion of a number of peripheral alterations, chronic hypercortisolism is associated with impaired G H secretion [11]. Either the spontaneous secretion of the hormone or its release in response to a number of stimuli, including G H R H , are blunted in situations of GC excess. Therefore paradoxically GCs seem to play two opposite roles in G H control: facilitatory, exerted at the pituitary level; and inhibitory, most likely exerted on the hypothalamic structures. The former, a physiological effect, must be associated with the permissive role that these steroids play in the organism [1]; however, when trying to provide a physiological explanation for the inhibitory action that GCs exert on G H secretion, a number of questions arise. Tha t is, why does this effect occur? Where and

how does the inhibition take place? What is the physiological meaning of this effect?

In order to provide an adequate answer to these questions, we must first know how G H secretion occurs (for review see Ref. [1]). G H is released into peripheral blood episodically. This episodic pattern is necessary for the optimal induction of physiologic effects at the peripheral level. The rhythm, most likely established by suprahypothalamic structures, is basically modu- lated by the S S - G H relationships. G H release stimulates SS secretion [12], which in turn interrupts the secretory activity in somatotropes. Interestingly, the lack of G H does not appear to affect the rhythmic secretion of SS [4], while in the absence of this peptide a tonic G H secretion can be observed. According to this, as pointed out in the Introduction, SS plays the main role in G H control. The rhythmic interruption of SS release allows G H R H to be secreted; then G H R H induces a rapid, dose-dependent, release of G H somatotropes, but also the transcription of the G H gene. In turn, increased G H would represent a positive signal to SS-producing neurons (Fig. 1). Thei r response would optimize, by blocking G H R H secretion and action, the amount of G H released and consequently the pituitary stores in the hormone.

A number of reports suggested a primary GC- induced G H R H blockade as the mechanism directly responsible for the lack of G H seen in hypercortisolism [13, 14]. However, we hypothesized that the inhibitory effect of GCs on G H secretion had to be exerted by stimulating SS secretion [1, 15]. In our hypothesis, SS excess being the primary event, SS-dependent G H R H blockade would therefore take place [2]. In fact, in rats, the administration of pharmacological doses of DEX for 3 days increases the hypothalamic content of SS [16], whereas the administration of SS antiserum enhances the blunted G H response to G H R H observed in animals given DEX for 4 days [17].

Th e possibility that hypercortisolism led to increased SS secretion was tested according to our recent model indicative of how the G H responses to physiological or pharmacological challenges should be interpreted [1]. Moreover, since SS control is mainly exerted by inhibitory ~2-adrenergic pathways and stimulatory fl-adrenergic pathways, our experimental model was based on the possibility that an increased SS tone would be dependent on enhanced fl-adrenoceptor responsiveness (Fig. 1). The support for such a hypothesis proceeds from several findings demonstrating that, at the peripheral level, GCs increase fl-agonist- stimulated adenyl cyclase activity and fl-adrenoceptor number [18]. In fact, the sequence homologous to glucocorticoid-responsive elements has been identified in the 3' flanking region of the fl2-adrenoceptor gene [19, 20].

Our study [15], in normal humans, basically con- sisted of the evaluation of the G H response to G H R H after inducing hypercortisolism with DEX, and then

Glucocorticoids and Somatostatin 279

DEX.

P

23OO

CONTROL STUDY

P GI4RH

P, or PRO, or CLO, or PD - O ~

Blood sam#es for GH analysis

0800 0900 Day time

DEX PRO, or CLO, or PD - - G H R H

HYPERCORTISOLISM I t Blood samples for GH analysis

2300 0800 0900 Day time

Fig. 2. This d i a g r a m schemat ica l ly shows the exper imen ta l protocol followed. In a control study, the GH r e s p o n s e t o G H R H was analyzed af ter giving dexamethasone (DEX) or placebo (P) 10h before. The GH response t o G H R H w a s then tes ted under ~ -ad rene rg ic blockade with p roprano lo l (PRO), o r ~ t 2 - a d r e n e r g i c

a g o n i s m w i t h e l o n i d i n e ( C L O ) , o r c h o l i n e r g i c a g o n i s m with pyr idos t igmine (PD), These studies were repea ted u n d e r hypercor t i so l i sm elicited by giving DEX 10 h before t h e G H R H challenge.

blocking /3-adrenoceptors with propranolol (PRO) (Fig. 2). With this experimental design we attempted to ascertain whether /?-adrenoceptor blockade would be able to counteract the inhibitory effect of GCs on the G H response to G H R H . In such a case, a logical conclusion would be that the mechanism postulated for GCs at the peripheral level [18] would also be operative on the SS-producing neurons. In addition, and to better elucidate the specificity of this putative mechanism of action, we also tested the GHRH- induced G H release in the same subjects after inducing hypercortisolism and enhancing e2-adrenergic or muscarinic cholinergic tone, by giving clonidine (CLO) or pyridostigmine (PD), respectively (Fig. 2). The rationale for this was based on (1) the direct SS-release inhibiting effect found for C L O by our group [21]; and (2) the fact that while cholinergic pathways play an important role in SS control [22], their effects seem to be mediated by catecholamines [23], as it occurs in the periphery. On these bases, it would be expected that CLO, acting at

the post-synaptic level in the SS-producing neurons, would be able to counteract the inhibitory effect of D EX on the G H response to G H R H , while this would not occur with PD, acting proximal to adrenergic neurons.

Results from this study [15] confirmed the experimental hypothesis. Nocturnal D EX administration induced the existence of a refractory phase [3] in all the subjects at the time of G H R H tests, 9 h later. This indicated a high amount of SS inputs reaching the somatotropes. In this situation, and as previously described in other studies, G H R H challenge was not able to evoke a significant G H release. Both PRO and CLO, but not PD, were able to reverse the inhibitory effect of DEX on the GHRH-el ic i ted G H response. However, while the PRO-enhanced G H RH - in duced G H secretion remained unaffected by hypercorti- sol±sin, this was no longer observed with CLO. From these data, summarized in Table 1, we concluded that the inhibitory effect of GC excess on G H release

Table 1. Plasma G H peaks (pg/l; mean +' SEM) elicited by G H R H in the different experimental situations. In the control study the GH response to G H R H was significantly (P < 0.01) enhanced after pretreatment with propranolol (PRO), clonidine (CLO) or pyridostigmine (PD). Nocturnal dexamethasone administration significantly (P < 0.05) reduced the GH response to GHRH. This blunted GH response was totally or partially restored after [I-adrenergic blockade, with PRO, or o~2-adrenergic agonism, with CLO, respectively, but unaffected by cholinergic agonism with

PD

P or DEX PRO CLO PD

Control 20.3 ± 5.5* 43 ± 4.6** 55.6 ± 5.6** 51.2_+ 7** Hypercortisolism 10.7 ± 3.9 39 ± 5.5** 25.9 ± 3.9* 12.9 ± 3.1

*P <0.05 vs control study under hypercortisolism (DEX). **P < 0.01 vs placebo study (P, control).

280 Jesus Devesa et al.

11 n

1.- GC c,o _ PRO

I I m l

I I ' I

PITUITARY SOMATOTROPES

Fig. 3. GCs inh ib i t G H sec re t i on by e n h a n c i n g SS re lease . Th i s effect s e e m s to be due to i n c r e a s e d ~8-adrenergic ac t iv i ty in SS n e u r o n s (1). the defect ive G H R H sec re t i on o b s e r v e d in h y p e r c o r t i s o l i s m m u s t occu r as a consequence of the tonic i n h i b i t i o n t h a t SS exe r t s on G H R H n e u r o n s (2). G H sec re t ion is t h e n b l u n t e d (2). / / - a d r e n e r g i c b lockade wi th P R O i m p e d e s SS to be secre ted . CLO ac t ing d i rec t ly on ~2-ad renocep to r s wou ld a l low a certain degree of SS inh ib i t ion , therefore leading to a GH r e s p o n s e to G H R H chal lenge.

s t i m u l a t i o n . - - - --, inh ib i t ion .

is due to increased hypothalamic SS secretion which appears to be dependent on DEX-induced enhanced fl-adrenergic responsiveness [15] (Fig. 3). Moreover, the study allowed us to confirm our postulate regarding the major role that central adrenergic pathways play in SS, and therefore in GH, control. In effect, the lack of action of the enhancement of cholingeric tone, with PD, under hypercortisolism, compared to that of C LO in the same experimental situation, would be related to the different site of action of these drugs [23]. PD acting proximal to adrenergic neurons would be unable to antagonize fl-adrenergic- induced SS release, whereas C L O directly stimulating ~2-adrenoceptors in SS neurons would partially counteract the DEX-induced increased fl-adrenergic activity (Fig. 3). Since CLO is a rather selective ~t2-adrenergic agonist, it is likely that the opposing effects of endogenously enhanced fl-adrenergic responsiveness and exogenously induced ~2-adrenergic stimulation could account for the G H responses to G H R H seen after giving DEX + CLO. Tha t is, those subjects in which the effect of DEX on fl-adrenoceptors had been low; or those in which this effect had partially disappeared at the time of CLO administration, exhib- ited the normal CLO-enhanced GHRH- induced G H release [21]. This is consistent with the fact that the cellular responses of many tissues to N E depend on the relative availability of its receptor subtypes (~1, ~2, #).

Our postulate that glucocorticoids increase SS release by enhancing fl-adrenoceptor responsiveness is also supported by a recent study by Huang et a l . [24]. These authors described that GCs modulate i rANP secretion in hypothalamic neurons by changing the

responsiveness of the cells from ~2-adrenoceptors to that of fl-adrenoceptors.

Th e possibility of enhanced SS tone being responsible for the inhibitory effect of GC on G H release seems to dispute data indicating that it is the lack of G H R H which accounts for the blunted G H secretion seen in chronic hypercortisolism. This argument is based on the finding that pyridostigmine administration is unable to restore G H release in Cushing's patients, whereas priming with G H R H partially re- instated the G H response to cholinergic agonism in these patients [25]. However, G H R H administration does not elicit G H release in the presence of elevated SS inputs to the pituitary, and PD is not able to block /%adrenergic dependent SS-enhanced release [15]. Therefore, although it is likely that a G H R H defective secretion exists during chronic hypercortisolism, it must be due to the tonic inhibitory effect that SS hypertone exerts on G H R H neurons (Fig. 3). A G H R H challenge after a few days fl-adrenergic blockade in Cushing's patients would clarify this aspect.

Assuming that GCs stimulate hypothalamic SS secretion, the observation that an acute effect of these steroids is to consistently induce a clear G H release [26] appears to be quite surprising. Thus , the administration of DEX (4 mg, i.v.) 3 h prior to a G H R H challenge increases basal plasma G H values and potentiates the G H response to G H R H . How can we con- ciliate this finding with the SS-mediated inhibitory effect described above?

Interestingly, the GH-releasing effect of GC is consistently observed 3 h after the steroid administration; it is not potentiated by SS-inhibiting drugs [26, 27], but its apparition is delayed by the induction of SS

Glucocorticoids and Somatostatin 281

release wi th atropine. T h e s e data indicate that the

secret ion of G H induced by D E X is media ted by

inh ib i t ed S S secretion. Moreover , a func t iona l ly intact h y p o t h a l a m i c - s o m a t o t r o p h axis is needed in order to observe the D E X - i n d u c e d G H secret ion [28]. T h e r e - fore, a direct effect of G C at the somatot ropic level as the factor respons ib le for the acute G H response may

be discarded. Cons ide r ing the above, and be ing aware of the

existence of a H S R modu la t ed by G H - S S re la t ion-

ships, these data lead us to speculate that D E X - i n d u c e d G H release is also a consequence of the DEX-e l i c i t ed SS secretion. T h a t is, the d i s rup t ion of the H S R by D E X admin i s t r a t i on would reset the rhy thmic i ty of the system. T h u s , in a first step D E X would increase SS release, therefore b locking G H secretion. T h e lack of

G H would in t u r n i n t e r rup t SS secret ion thus al lowing G H to be secreted. T h e r e are no exper imenta l data to suppor t the hypothes is that such a m e c h a n i s m would be respons ib le for the acute G H - r e l e a s i n g effect

of GCs ; however , the r e synchron iza t ion of the H S R fol lowing its r up t u r e by c lon id ine has been repor ted by our group [29]. There fo re , the fact that D E X

admin i s t r a t i on acutely synchronizes the r h y t h m of G H secret ion exactly 3 h af terwards [26] migh t be expla ined

as descr ibed above. T e s t i n g the G H response to G H R H at short t ime intervals after g iving D E X

and having induced or not f l -adrenerg ic blockade would demons t ra t e whe ther or not this hypothesis is correct.

I n s u m m a r y , the inh ib i to ry effect that GCs play on

G H secret ion is clearly media ted by f l -adrenerg ic - i nduced SS release. T h e lack of G H R H observed in chronic hypercor t i so l i sm is mos t likely depend e n t on

the c o n t i n u o u s blockade that SS hyper tone exerts on G H R H - p r o d u c i n g neurons . T h e acute, facil i tatory role that GCs play in G H control is most likely media ted by the s t imu la t ing effect of these steroids on SS release as well, resu l t ing in a r e synchron iza t ion of the H S R . T h i s is apart f rom the well k n o w n effects of these steroids on the n u m b e r of G H R H receptors [6] and on G H gene express ion [5].

These postulates agree wi th our exper imenta l data ind ica t ing that SS plays the most impor t an t role in G H control and that SS secret ion is ma in ly regula ted by the balance be tween c~ 2- and f l -adrenerg ic activity in SS- p r o d u c i n g neu rons [1].

T h e control of hypotha lamic SS secret ion by G C would be related to the regulatory role that these steroids play in the organism.

Acknowledgement--This study was supported by DGICYT (Madrid, Spain), grant PM88-0208 and grant PM90-0024.

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29. Lima L., Arce V., Diaz M. J., Tresguerres J. A. F. and Devesa J.: Clonidine pretreatment modifies the growth hormone secretory pattern induced by short term continuous GRF infu- sion in normal man. Ch'n. Endocr. (Oxf). 35 (1991) 129-135.

regulation of hypothalamic somatostatin by glucocorticoids

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