christeff dhea cortisol hiv 1997 (1)

8/12/2019 Christeff DHEA Cortisol HIV 1997 (1)

1/8

ergamon Ps y c h o n e u r o e n d r o c r i n o l o g y , Vo l. 2 2 ( Su p p l e m e n t I ) p p . S I 1 - S1 8 , 1 9 97( ~) 1 9 9 7 E l s e v i e r Sc i e n c e L t d . Al l r i g h t s r e s e r v e d .P r i n t e d i n Gr e a t Br i t a i n

P I I : S 0 3 0 6 - 4 5 3 0 ( 9 7 ) 0 0 0 1 5 . 2 0 3 0 6 - 4 5 3 0 / 9 7 $ 1 7 . 0 0 + 0 0 0

S E R U M C O R T I S O L A N D D H E A C O N C E N T R A T I O N SD U R I N G H I V I N F E C T I O NN r v r n a Chr i s t e f f, 1, Nora Ghe rb i , 1 O l iv i e r Ma mm es , 1

M a r i e - T h r r b s e D a l l e 1 S h a h i n G h a r a k h a n i a n ~ O l i v i e r L o r t h o la r y 3J e a n - C l a u d e M e l c h i o r 4 an d E m m a n u e l A . N u n e z 1

I L a b o r a t o ir e d e B i o c h i m i e E n d o c r i n i e n n e / B i o c h i m i e B , F a c u l t6 d e M r d e c i n e / H 6 p i t a l XBi c h a t , Pa r i s , F r a n c e

e Se r v i c e d e s M a l a d i e s I n f e c t i e u s e s d u P r . W . Ro z e n b a u m , H6 p i t a l Ro t h s c h i l d , Pa r i s, F r a n c e~ Se r v i c e d e M 6 d e c i n e I n t e r n e d u P r . Gu i l l e v i n , H6 p i t a l Av i c e n n e , Bo b i g n y , F r a n c e

"~ Serv ice de N ut r i t ion , H 6pi ta l X . Bicha t , Par i s , Franc e

S U M M A R YT h e p r o g r e s s i o n o f H I V i n f e c ti o n i s a c c o m p a n i e d b y s e v e r e i m m u n o d e p r e s s i o n a n d c a c h e x i a , p a r t ic u l a rl yd u r i n g a d v a n c e d s t a g e s . T h e i m m u n e d e p r e s s i o n i s d u e l a rg e l y to a d r a m a t i c d r o p i n t h e n u m b e r o fC D 4 c e l ls . T h e l o s s o f b o d y w e i g h t i s m a i n l y d u e t o a r e d u ce d f a t- f re e m a s s w i t h n o c h a n g e i n a d ip o s et i ss u e . W e d e t e rm i n e d t h e s e r u m c o n c e n t r a t io n s o f c o ~ i s o l a n d D H E A a n d t h e i r c o rr e l at i o n s w i t h a b s o l u t eC D 4 c e l l c o u n t s a n d c h a n g e s i n b o d y w e i g h t o f H I V - p o s i t i v e m e n . T h e r e s u l t s o f f i v e r e t r o s p e c t i v e a n dp r o s p e c t i v e s t u d i e s in d i c a t e t h a t t h e s e r u m c o n c e n t r a t i o n s o f c o rt i s o l a n d D H EA i n HI V- i n f e c t e d p a t i e n t swe r e d i f f e r e n t f r o m t h o s e o f H1 V- n e g a t i v e c o n t r o l s . Se r u m c o r t i s o l wa s e l e v a t e d a t a l l s t a g e s o f i n f e c t i o n( + 2 0 t o + 5 0 % , p < . 0 5 t o p < . 0 0 1 ) p a r t i c u la r l y i n A I D S p a t ie n t s ( st a g e I V C ) . I n c o n t ra s t , th e s e r u m D H E Ac o n c e n t r a t i o n s we r e c l o s e l y c o r r e l a t e d wi t h t h e s t a g e o f Hl V- i n f e c t i o n , b e i n g h i g h e r i n t h e e a r l y s t a g e s( s t a g e s I a n d I II o r > 5 0 0 C D 4 ) t h a n i n a d v a n c e d s t a g e s ( I V C o r < 5 0 0 C D 4 ) - - i n t h e l a tt e r b e i n g b e lo wt h o s e o f H I V - n e g a ti v e m e n - - o r i n c o n t r o l s ( + 4 0 to 1 0 0 % , p < . 0 1 t o p < . 0 0 1 ) . T h e r e w a s a n eg a t i v e l in e a rc o r r e l a t i o n b e t w e e n t h e C D 4 c e l l c o u n t s a n d c o r t i s o l ( r = - 0 . 4 , p < . 0 2 ) a n d a p o s i t i v e l i n e a r c o r r e l a t i o nw i t h D H E A ( r = + 0 . 3 6 , p < . 0 1 ) . T h e r e w a s n o s ig n i f ic a n t c o r r el a ti o n b e t w e e n A b o d y w e i g h t a n d s e r u mc o r t i s o l . I n c o n t r a s t , t h e r e wa s a n e g a t i v e c o r r e l a t i o n b e t we e n s e r u m DHEA a n d A b o d y we i g h t ( % )( r = - 0 . 6 9 , p < . 0 0 0 1 ) a n d a p o s i t i v e c o r r e l a t i o n w i t h t h e c o r t i s o l / D H E A r a t i o ( r = + 0 . 6 1 , p < . 0 0 0 1 ) .Th e r e i s t h u s a l in k b e t w e e n t h e c i r c u l a t i n g c o n c e n t r a t i o n s o f a d r e n a l s t e r o i d s a n d t h e p r o g r e s s i o n o fi m m u n o s u p p r e s s i o n a n d c a c h e x i a d u r i n g H I V - i n fe c t io n . T h i s r a i se s t h e q u e s t i o n o f w h e t h e r t h e re i s ac a u s e - a n d - e f f e c t r e l a t i o n s h i p b e t we e n c l i n i c a l p r o g r e s s i o n a n d c i r c u l a t i n g s t e r o i d c o n c e n t r a t i o n s . Fu r t h e ri n v e s ti g a ti o n s in t o t h e r e l a ti o n s h i p b e t w e e n t h e r a ti o c o r t i s o l /D H E A a n d t h e i m m u n e r e s p o n s e a n d c a c h e x i as h o u l d i n d i c a t e t h e c o n t r i b u t i o n s o f t h e s e s t e r o i d s t o t h e e t i o l o g y o f HI V i n f e c t i o n a n d l e a d t o t h ed e v e l o p m e n t o f n e w t h e r a p e u t ic s t r a t eg i e s . ( ~ 1 9 9 7 E l se v i e r S c ie n c e L t d

K e y w o r d s - ~ 2 o r t i s o l ; D H E A ; C o r t i so l - D H E A r at io ; H l V - i nf e ct e d m e n ; C D 4 l y m p h o c y t e s ; C a c h e x i a

I N T R O D U C T I O NT h e p r o g r e ss i o n o f H I V i n f e c t io n i s a c c o m p a n i e d b y s e v e re i m m u n o d e p r e s s i o n a n d c a c h e x i a ,

pa r t i cu l a r l y du r ing advanced s t ages . The immune dep re s s ion i s ma in ly due t o t he s e l ec t i ve de -

* Ad d r e s s c o r r e s p o n d e n c e t o : Nr v d n a C h r i s t e f f , La b o r a t o i r e d e B i o c h i m i e B , H6 p i t al Xa v i e r B i c h a t , 4 5 r u e He n r iHu c h a r d , 7 5 8 7 7 Pa r i s Ce d e x 1 8 , F r a n c e ( Tel : 3 3 1 4 0 2 5 8 5 5 1 ; Fa x : 3 3 I 4 2 2 9 7 9 9 7 ) .

S I I


2/8

S 1 2 N 6 v 6 n a C h r i s t e f f e t a l .

Sfo c o c o R c o o s l

IMMUNODEFICIENCY~D I

~ f a t f r e e b o d y m a s sA r e s e r u m g l u c o c o r t i c o i d a n d a n d r o g e nconcentra t ions re la ted to immunodef ic iency and cachexia

Fig. 1. Link between serum glucocorticoid and androg en concen trations and imm unodeficiency and cachexia.

p l e t i on o f CD 4 lym phoc y te s . Th e d rop i n bod y w e igh t i s due l a rge ly to a l o s s o f f a t -f r ee mass ,wh i l e t he ad ipose t i s sue r ema ins unchanged . The na tu r a l h i s t o ry o f HIV in f ec t i on beg ins w i ththe p r imary H IV in f ec t i on , cha rac t e r i z ed by de t ec t ab l e hum ora l and ce l l u l a r imm une r e spon sesto t he v i ru s , pa r t i cu l a rl y an i nc r ea se i n CD8 lym phoc y te s . Th i s i s f o l l owed by a p ro long ed pe -r i od (m ed ian 10 yea r s ) o f c li n i cal l a t ency , du r ing w h ich t he pa t i en t is u sua l l y a sy mp toma t i c , andthe re a r e no s ign i fi c an t changes i n t he CD 4 and C D8 T-ce l l coun t s . Th e re i s l it t le w e igh t l o s s du r -i ng t hi s pe r iod , gene ra l l y l e ss t han 10 . The p rog re s s ion t o AID S i s a cco m pan ie d by a g r adua ldec rea se i n t he num ber o f CD 4 ce l ls and t he appea rance o f cons t i tu t i ona l s igns and sym ptoms .F ina l ly , advanced H IV in f ec t i on i s a s soc i a t ed w i th d r ama t i c dec rea se i n the nu mb er o f CD4 Tlym pho cy te s and those t ha t r ema in a r e func t i ona l l y abno rma l . AID S pa t ien t s l o se ove r 10 o fthe i r body we igh t .

T h e a d r e n a l s te r o id h o r m o n e s , c o r ti s o l an d d e h y d r o e p i a n d r o s t e r o n e ( D H E A ) m o d u l a t e t h e i m -m une sys t em and i n f luence denu t r i t i on (Gros sm an , 1984 ; Ho mo -De la r che e t a l. , 1991 ; Nu nez &Chr i s t e f f, 1994 ). Cor t i so l dec rea se s T -ce l l p ro l i f e r a t i on and func t i on , by i nh ib i t i ng t he p roduc t iono f cy tok ines (Hom o-D e la r che , 1988 ). The ad rena l and rogen D HE A s t imu la t e s he lpe r T -ce l l f unc -t i on , enhanc ing t he capac i t y o f a c t iva t ed T -ce ll s to p ro duce i n t e r l euk in ( IL ) -2 , and cou n te r ac t s t heinh ib i t ion o f t h i s impor t an t l ymph ok in e by g luc oco r t i co id s (Day nes e t a l. , 1990 ) . These s t e ro idh o r m o n e s a l so a f f e ct t h e m u s c l e a m i n o - a c i d m e t a b o l i s m i m p l ic a t e d in H I V - c a c h e x i a ( N u n e z &Chr i s t e f f, 1994 ) . G luc oco r t i co id s s timu la t e am ino -ac id ca t abo l i sm by i n f luenc ing t he enzy me s o famino ac id ca t abo l i sm ( t r ansaminase , t r yp toph ane py ro l a se ) . By con t r a st , the an d rogens i nc r ea seamino -ac id anabo l i sm, p r inc ipa l l y i n bone musc l e s and s t imu la t e t he syn thes i s o f bone p ro t e in s(Koch ak ian , 1964 ). The d ec rea se i n and rogen sec r e t i on is the p r inc ipa l c ause o f mus cu l a r a t rophyand sen i l e o s t eopo ros i s . The e f f ec t s o f g lucoco r t i co id s and and rogens on t he immune r e sponseand p ro t e in m e tabo l i sm r a i s e t he ques t i on o f w he the r t he se s t e ro id s i n f l uence t he deve lopm en t o fthe imm une dep re s s ion and cache x i a tha t a r e d i s t inc t i ve f ea tu r e s o f HIV in f ec t i on (F ig . 1 ).

We hav e t he r e fo re mea su red t he s e rum co ncen t r a t i ons o f co r t iso l and DH EA in HIV-pos i t i ve


3/8

Serum Cortisol and D HE A in H IV-positiveMenT ab l e 1 . S e ru m co r t i so l co n cen t r a t i o n s (nM / 1) i n H / V -p o s i t i v e m e n *

Controls ARC A ID S- AID S- IIChristeff et al ., 1988a 34 1+ 28 47 1_ +3 4 537.5_+32 516.6_+44Controls A IDS-II,-III AID S-IV C2 AID S-IVCtChristeff et al. , 1992a 375_+39 510_ +51 5 0 2 -+ 5 5 577_+66Controls AID S-II,-IIi AIDS-IV CLortholary et al ., 1996 338-+19 38 0- +2 4 472_+30

*Statistical significances are p resen ted in the RESU LTS section.

s13

m e n a n d a n a l y s e d t h e s e d a ta w i t h t he r e f e r e n c e t o th e s t a g e o f in f e c ti o n a n d t he C D 4 l y m p h o c y t ec o u n t. T h e r e l a ti o n s h i p b e t w e e n t h e s e r u m c o r ti s o l an d D H E A c o n c e n t r a t i o n s a n d t he c h a n g e inC D 4 co u n t an d t h e l o s s o f b o d y w e i g h t (% ) w as a l so i n v es ti g a t ed .

M E T H O S

T h e d a t a a r e t ak en f ro m f i v e r e t ro sp ec t i v e an d p ro sp ec t i v e s t u d i e s c a r r ied o u t o n m en w i t hW es t e rn -b l o t co n f i rm e d H IV -1 in f ec t i o n b e t w een 1 9 8 7 an d 1 99 2 a t C l au d e B e rn a rd H o sp i t a l , P a r i s(C h r i s t e f f e t a l. , 1 9 8 8 a ) , R o t h sch i l d H o s p i t a l , P a r is (C h r i s t e f f e t al ., 1 9 9 2 a , 1 9 9 5 ), an d A v i cen n eU n i v e r s i t y H o s p i t a l , B o b i g n y an d C o m p i ~ g n e H o sp i t a l (C h r i s t e f f e t a l. , 1 9 96 ; L o r t h o l a ry e t a l. .1 9 9 6 ). D y n am i c h o rm o n e - s t i m u l a t i n g te s t s w i t h co sy n t ro p i n ( sy n t h e t i c A C T H I_ 24 ) an d o v i n e C R H( c o r t i c o t r o p i n - r e l e a s i n g h o r m o n e ) w e r e p e r f o r m e d i n s t a g e I V C A I D S p a t i e n t s ( L o r t h o l a r y e ta l . , 1 9 9 6 ) . B l o o d sam p l e s w e re co l l e c t ed b e t w een 0 8 0 0 h an d 1 0 0 0 h an d a l l o w ed t o co ag u l a t eb e f o r e s e p a r a t io n o f s e ru m b y c e n t r if u g a t io n . T h e s t e ro i d h o r m o n e s w e r e e x t ra c t ed f r o m s e r u ms a m p l e s b y o r g a n i c s o l v e n t a n d f r a c t i o n a t e d b y c h r o m a t o g r a p h y o n S e p h a d e x L H 2 o . H o r m o n a lc o n c e n t r a t i o n s w e r e d e t e r m i n e d b y r a d i o i m m u n o a s s a y . T h e d a t a w e r e a n a l y z e d u s i n g d i f f e r e n ts t a t i s t i ca l t es t s appropr i a t e t o t he ind iv idua l s tud ies . The work adhered to condi t i ons se t ou t i nt h e H e l s i n k i D ec l a r a t i o n .

R E S U L T SSerum cor t i so l concen t ra t i ons in H lV-pos i t i v e men Tab le 1)

T h e se ru m co r t i so l co n ce n t r a t i o n s w e re s i g n i f i c an t l y h ig h e r i n H IV -p o s i t i v e m e n t h an H IV -s e r o n e g a t i v e m e n . T h e y w e r e + 3 5 % in th e A R C ( A I D S - r e l a t e d c o m p l e x ) su b j e c ts ( p < . 0 1 ) ; + 6 0 %in A I D S - I ( p a ti e n ts w i t h e a r ly A I D S ) s u b j e c t s ( p < . 0 0 1 ) ; a n d + 5 0 % in A I D S - I I ( p a ti e n ts w i t ha d v a n c e d A I D S ) s u b j e c ts ( p < . 0 0 1 ) ( C h r i s t e ff e t a l., 1 9 8 8 a ).

T h e f i g u re s fo r H IV -p o s i t i v e m en , c la s s i f ied acco rd i n g t o th e C D C 1 9 8 7 C r i t e r i a w e re + 3 5 %in s t ag es I I an d I I I , IV C 2 an d IV D p a t i en t s (p < . 0 1 ) an d + 5 5 % in s tag e IV C 1 p a t i en ts (p < . 0 1 )(C hr i s t e f f e t a l ., 1 992a , 1995; Lo r tho lary e t a l ., 1996) .

T h e i n c r e a s e s w e r e + 2 0 % t o + 4 0 % ( p < . 0 5 ) w h a t e v e r t h e C D 4 l y m p h o c y t e c o u n t ( C h r i s te f f e tal . , 1995).Respo nse o f A I D S pa t i en t s t o dyna mic cor t i so l s t imu la t ion t e s t s

S t i m u l a ti o n o f s t a g e I V C H I V - p o s i t i v e m e n w i t h c o s y n t r o p i n i n c re a s e d t h e ir s e r u m c o r ti s o lb y 7 5 % a t 3 0 m i n an d b y 1 0 0 % a t 6 0 ra i n i n a ll s t u d ied p a t i en t s . B y co n t r a s t , t h e ir r e sp o n se t oo v i n e C R H s t im u l a t i o n w a s d i f f er e n t. O n l y 3 7 % o f th e p a t ie n t s r e s p o n d e d n o r m a l l y w it h a 1 0 0 %i n c rea se i n b o t h A C T H an d co r t i so l ; 6 3 % h ad ab n o rm a l r e sp o n se s , w i t h l i t t l e o r n o ch an g e i n t h ec i r cu l a t i n g A C T H an d co r t i so l (L o r t h o l a ry e t a l . , 1 9 9 6 ) .


4/8

s14 N6vfna Christeff et al,T a b l e 2 . S e r u m D H E A c o n c e n t r a t io n s ( n M / l) i n H I V - p o s i t i v e m e n *

Cont rol s AIDS-I I ,q l l AIDS-IV Cz AID S-IV ClChr i st e ff e t a l . , 1992 a 18 .0+_1 .05 33 .3+ _5 .5 12 .5_ +1 .4 13 .5+_2 .4Controls AIDS -II ,- l ll AIDS -IV CCh risteff et al. , 1 9 96 15.6_+ .4 27.2+3 .5 13.0 + 1.6*Statistical significances are presented in the RESULTS section.

S eru m D H E A co n cen t ra t i o n s i n H IV -p o s i t iv e m en T a b l e 2 )T h e s e r u m D H E A c o n c e n t r a t i o n s a p p e a r e d t o b e c l o se l y c o r r e la t e d w i t h th e s ta g e o f H I V

i n fe c t i o n . D H E A w a s v e r y h ig h d u r i n g t h e e a r ly a s y m p t o m a t i c s t a g e s o f t h e d is e a s e a n d w a sb e l o w n o r m a l in t h e a d v a n c e d s ta g e s . T h e s e r u m D H E A w e r e e l e v a t e d b y + 6 0 t o + 8 5 , ( p < . 0 1 )in s ta g e s I I a n d I I I p a t ie n t s c o m p a r e d t o H I V - n e g a t i v e m e n . T h e D H E A c o n c e n t r a t io n s d e c r e a s e ds i g n if i c a n tl y i n I V C s t a g e p a t i e n t s t o - 1 5 t o - 3 0 , p < . 0 5 ( C h r i s t e f f e t a l. , 1 9 9 2 a , 1 9 9 6; N u n e z& C h r i s t e f f , 1 9 9 4 ) .

T h e D H E A c o n c e n t r a t i o n s in t h e p a t ie n t s w i t h C D 4 c e ll c o u n t s o f > 5 0 0 w e r e 6 5 t o 1 0 0 ,( p < . 0 0 1 ) h i g h e r t h a n i n p a t i e n t s w i t h C D 4 c e l l c o u n t s o f 5 0 0 - 2 0 0 o r o f < 2 0 0 C D 4 c e l ls . ( C h r i s t e f fe t a l . , 1 9 9 5 , 1 9 9 6 ) .

C o r r e l a t i o n b e t w e e n s e r u m c o r t i s o l a n d D H E A a n d C D 4 c e l l c o u n t sT h e r e w a s a s i g n i f ic a n t l y n e g a t i v e c o r r e l a ti o n b e t w e e n t h e l o g - t r a n s f o r m e d C D 4 c e l l c o u n t

a n d t h e s e r u m c o r t i s o l c o n c e n t r a t i o n ( r= -0 .4 , p < . 0 2 ) ( L o r t h o l a r y e t a l. , 1 9 9 6 ), b u t th e r e w a s as ig n i fi c an t ly p o s i t iv e c o r r e l a t i o n b e t w e e n t he s e r u m D H E A a n d t h e C D 4 l y m p h o c y t e c e ll c o u n t( r = 0 . 3 6 , p < . 0 1 ) ( C h r i s t e f f e t a l. , 1 9 9 6 ) .C o r r e l a t i o n b e t w e e n s e r u m c o r t i s o l a n d D H E A a n d t h e b o d y w e i g h t

T h e r e w a s n o s i g n i f ic a n t c o r r e l a t io n b e t w e e n t h e c h a n g e i n b o d y w e i g h t ( ) a n d s e r u m c o r t is o l .B y c o n t r a s t , t h e r e w a s a n e g a t i v e s i g n i f ic a n t c o r r e l a t i o n b e t w e e n t h e lo s s o f b o d y w e i g h t a n dt he s e r u m D H E A ( r = - - 0 . 6 9 , p < . 0 0 0 1 ) a n d a p o s i ti v e c o r r e l a ti o n w i t h th e c o r t is o l / D H E A r a ti o( r= -0 . 6 1 , p < . 0 0 0 1 ) .

D I S U S S I O N

T h e r e s u l t s o f o u r s t u d i e s a n d o t h e r s ( L a u d a t e t a l ., 1 9 9 5 ; P o r e t s k y e t a l ., 1 9 9 5 ; R a f f i e t a l. , 1 9 91 ;V i l le t te e t a l. , 1 9 9 0 ) s h o w t h a t t h e s e r u m c o r t i s o l a n d D H E A i n H I V - i n f e c t e d m e n a r e d i f fe r e n tf r o m t h o s e o f H I V - n e g a t i v e c o n t r o l s . T h e s e r u m c o r t i s o l is h i g h ( + 3 0 t o 5 0 ) i n a ll g r o u p s o f H I V -i n f e c t e d s u b j e c ts , b u t t h e s e r u m D H E A i s c l o s e l y c o r r e l a t e d w i t h t h e s ta g e o f H I V i n f e c t i o n , b e i n gh i g h e r (+ 6 0 t o 8 5 ) i n t h e e a r l y s t a g e s o f t he d is e a se , a n d b e l o w n o r m a l ( - 1 5 t o 3 0 ) in A I D Sp a t i e n ts . T h e i n c r e a s e d c o r t i so l c o n c e n t r a t i o n m a y b e d u e t o s ti m u l a t i o n o f t h e a d re n a l c o r t e x b ye n h a n c e d p r o d u c t i o n o f A C T H . B u t , t h e b a s a l s e r u m A C T H c o n c e n t r a t i o n w a s in c r e a s e d (V e r g e se t al ., 1 9 8 9 ) , u n c h a n g e d ( R a f f i e t a l ., 1 9 9 1 ) o r d e c r e a s e d ( V i l l e t te e t a l. , 1 9 9 0 ) i n t h e e a r l y s t a g e so f H I V i n f e c t io n , a n d n o r m a l ( L o r t h o l a r y e t ai ., 1 9 9 6 ; M e m b r a n o e t a l. , 1 9 8 7 ; R a f fi e t a l. , 1 9 9 1 ) o rd e c r e a s e d ( V i l le t te e t a l. , 1 9 9 0 ) d u r i n g t h e la t e r s t a g e s. T h e i n c r e a s e d s e r u m c o r t is o l c o n c e n t r a t i o no b s e r v e d i n H I V - i n f e c t e d m e n , m o s t o f t e n w i t h o u t c o n c o m i t a n t i n c r e a s e i n c i r c u l a t i n g A C T H ,s u g g e s t s t h a t th e a d r e n a l c o r t e x i s d i r e c t l y s t i m u l a t e d b y o t h e r f a c t o r s. C y t o k i n e s , s u c h a s I L - 1a n d i n t e r f e r o n a l p h a ( I F N o t ) , a c t in g i n d i r e c t ly o r d i re c t l y , c o u l d w e l l m o d u l a t e a d r e n a l s t e r o idp r o d u c t i o n v i a th e i r i n f lu e n c e o n t h e h y p o t h a l a m i c - p i t u i t a r y - a d r e n a l ( H P A ) a x is ( B e s e d o v s k y e ta l. , 1 9 9 1 ; M e y e r e t a l. , 1 9 8 7 ; W h i t c o m b e t al ., 1 9 8 8 ) . H o w e v e r , t h e a b n o r m a l r e s p o n s e o f A I D S


5/8

S e r u m C o r t is o l a n d D H E A i n H I V p o s it iv e M e n S I 5p a t i en t s t o th e o v i n e C R H t e s t i n d i ca t e s t h a t th e d i r ec t e f f ec t s o f cy t o k i n e s o n t h e H P A ax i s a r em o d i f i ed d u r i n g t h e ad v an ced s t ag es o f i n fec t i o n . T h e e l ev a t ed se ru m co r t i so l m ay a l so b e d u et o d ec rea sed co r t i so l c a t ab o l i sm cau se d b y an ab n o rm a l f a t t y a c i d p ro f i l e (C h r i s t e f f e t al., 1 9 8 8 a )an d a l t e r a t i o n s i n t h e co n cen t r a t i o n s an d b i n d i n g p ro p e r t i e s o f co r t i co s t e ro i d -b i n d i n g g l o b u l i n i nH IV - i n fec t ed p a t ien t s (M ar t i n e t a l. , 1 9 9 2 ). In d eed , t h e p r i m ary co r t i so l r e s i s t an ce (N o rb i a t o e ta l . , 1992) duc to abnormal g lucocor t i co id receptors (Norb ia to e t a l . , 1992; Val l e t t e e t a l . , 1992)m ay g i v e r i s e t o t h e h i g h se ru m co r t i so l t h a t o ccu r s d u r i n g H IV i n fec t i o n .

T h e d r o p in th e s e r u m D H E A c o n c o m i t a n t w it h th e H I V i n f e ct io n p r o g r e s s e s c o u ld b e b r o u g h tab o u t b y a m ech an i sm s i m i l a r t o t h a t u n d e r l y i n g t h e f a l l i n an d ro g en co n cen t r a t i o n s t h a t o ccu r sin h u m an sep t ic sh o ck (C h r i s t e f f e t a l. , 1 9 8 8 b , 1 9 9 2 b ) , ex p e r i m en t a l en d o t o x i n sh o ck in m a l e r a ls(Ch r i s t e f f e t a l ., 1987), and o ther s t ress s i t ua t ion (W ool f e t a l ., 1985) .

T h e re is a l so a s ig n i f i c an t r e l a t i o n sh i p b e t w e en t h e C D 4 ce l l co u n t , t h e d ev e l o p m e n t o f c ach e x i aa n d s e r u m c o r ti so l a n d D H E A . T h e d e c r e a s e i n th e n u m b e r o f C D 4 l y m p h o c y t e s is a c c o m p a n i e db y an i n c rea se i n s e ru m co r t i so l an d a d ec rea se i n D H E A . T h e a s so c i a t i o n s b e t w een co r t i so l ,D H E A an d a f a ll in t h e n u m b er o f C D 4 ce l l s su g g es t t h a t t h e se s t e ro i d s p l ay an i m p o r t an t ro l ei n t h e n o rm a l fu n c t i o n o f t h e i m m u n e sy s t em t h ro u g h t h e i r e f f ec t s o n cy t o k i n e s ec re t i o n an dl y m p h o cy t e p ro l i f e r a t i o n an d ac t i v i t y . T h e l o s s o f b o d y w e i g h t , p a r t i cu l a r l y t h e f a t - f r ee m ass i sa l so co r r e l a t ed w i t h t h e d ro p i n D H E A an d t h e i n c rea se i n t h e co r t i so l / D H E A ra t i o .

Th e da ta (Chr i s t e f f e t a l ., 1988a , 1992a , 1995 , 1996; Lo r tho lary e t a l ., 1996) show a l inkb e t w e e n t he c h a n g e s i n c i rc u l a t in g c o r t is o l a n d D H E A a n d t he p r o g r e s s i o n o f i m m u n o s u p p r e s s i o nan d cac h ex i a i n H IV -p o s i t i v e m e n . T h i s r a i s e s th e q u es t io n o f w h e t h e r t h e re is a c au se -an d -e f f ec tr e l a t i o n sh i p b e t w een c l in i ca l p ro g re s s i o n an d c i r cu l a t i n g s t e ro i d co n cen t r a t i o n s . F i g u re 2 o u t l in e st h e p o ss i b l e r e l a t i o n sh i p s b e t w een c i r cu l a t i n g co r t i so l , D H E A , i m m u n e d ep re s s i o n an d cach ex i ad u r i n g t he d e v e l o p m e n t o f H I V i n f e c t io n . T h e h i g h s e r u m D H E A t h at o c c u r s a t e a r ly s t ag e s o fH IV i n fec t i o n co u l d en h an ce IL -2 sy n t h e s i s (D ay n es e t a l . , 1 9 9 0 ) an d T -ce l l f u n c t i o n (P ad g e t t

L o r i a , 1 9 9 4 ) an d s t im u l a t e m u sc l e p ro t e i n an ab o l i sm t o o f f se t t h e i m m u n e d ep re s s i o n an d t h ei n c rea sed p ro t e i n ca t ab o l i sm ch a rac t e r i s t ic o f H I V i n fec t i o n an d / o r i n d u ced b y e l ev a t ed co r t iso l .T h e d ec rea se i n D H E A an d t h e m a i n t en an ce o f t h e i n c rea sed se ru m co r t i so l fo u n d d u r i n g t h ea d v a n c e d s t a g e s o f d is e a s e m a y t r i g g e r a n i m m u n e d e p r e s s i o n ( d r o p in C D 4 c e l ls ) a n d d e c r e a s e dm u s c l e p r o t e i n a n a b o l i s m , a s w e l l a s c a u s i n g a n i m b a l a n c e b e t w e e n a m i n o - a c i d a n a b o l i s m a n dca t ab o l i sm . D H E A co u l d t h e re fo re ac t a s an an t i g l u co co r t i co i d an d an t ag o n i ze t h e su p p re s s i v ee f f e c t o f d e x a m e t h a s o n e o n I L - 2 p r o d u c t i o n ( D a y n e s e t a l., 1 9 9 0) a n d l y m p h o c y t e p r o l if e r a ti o n(B l au e r e t al., 1 9 9 1 ). T h e h i g h c i r cu l a t in g D H E A co u l d o f f se t th e i m m u n o d ep re s s i o n an d p ro t e i nca t ab o l i sm i n d u ced b y e l ev a t ed co r t i so l . T h e l o w se ru m D H E A i n A ID S p a t i en t s i s n o l o n g e rsu f f i c i en t t o ex e rc i s e an t i g l u co co r t i co i d ac t i o n a l l o w i n g t h e e l ev a t ed co r t i so l t o co n t r i b u t e t oi m m u n o d ep re s s i o n (d ro p in C D 4 ce l l s ) an d i n c rea sed p ro t e in ca t ab o l i sm (d ec rea sed f a t - f r ee m ass ) .C o r t i so l an d D H E A a re t h e re fo re ac t i n g a s an ag o n i s t - an t ag o n i s t co u p l e (N u n ez C h r i s t e ff , 1 99 6 ).T h e c o r t i s o l /D H E A r a t io u n d o u b t e d l y h a s a p r o f o u n d i n fl u en c e o n t h e b o d y ' s p h y s i o l o g ic a l a n d / o rp a t h o p h y s i o l o g i ca l r e sp o n s e s . F u r t h e r i n v es t ig a t i o n o f t h e r e l a t i o n sh i p b e t w ee n t h e co r t i so l / D H E Ara t io an d i m m u n e r e s p o n se an d cac h ex i a sh o u l d i n d i ca te t h e ex ac t p o s i t i o n s o f t h e se s t e ro i d s int h e e t i o l o g y o f H IV i n fec t i o n an d p ro v i d e a so u n d b a s i s fo r t h e d ev e l o p m en t o f n ew t h e rap eu t i cs t ra t eg ies .A c k n o w l e d g e m e n t s : T h e a u t h o r s t h a n k D r. O w e n P a r k e s fo r c o r r e c ti n g t h e m a n u s c r i p t a n d M r s . C l a u d e t t e R e b o u lf o r s e c r e ta r i a l a s s i s t a n c e .


6/8

S16 N6v6na Christeff et al.S t a ge s o f H I V i n f e c t io n

e a r ly s ta g e s a dv a n c e d s ta g e s

C O R T I S O L l I I

W E I G H T L O S S < 5 > 1 0

amino acids

Fig. 2. Endocrine , immune and metabol ic changes during the progress ion of HIV infec t ion.

R E F E R E N C E SBesedovsky, HO, Del Rey, A, Klusman, L, Furukawa, H, Monge Ardit t , G and Kabiersch, A (1991)Cyt oki nes a s mo dul a t or s o f t he hyp ot ha l amo-p i t u i ta ry-adrena l ax is . J Steroid Biochem Mol Biol 40,613-618 .Blauer , KL, Poth, M, Ro gers , WM and Bernton, EW (1991) D ehyd roepiandro sterone antagonizes thesuppressive effec ts of dexam ethasone on lym pho cyte prol ife ra tion. Endocrinology 129, 3174--3179.Chris te ff , N, Aucla i r , MC, Benassayag, C, Carl i , A and Nunez , EA (1987) Endotoxin- induced changes insex steroid hormone levels in male rats. J Steroid Biochem 26 , 67-71 .Christeff, N, Michon, C, Goertz, G, Hassid, J, Matheron, S, Girard, PM, Coulaud, JP and Nunez, EA(1988a) Ab no rm al free fat ty acids and cortisol conc entrat ion s in the serum o f A ID S patients. Eur JCancer Clin Oncol 24(7) , 1179-1183.Christeff, N, Benassayag, C, Carl i-Viei l le , C, Carl i , A and Nunez, EA (1988b) Elevated oestrogen andredu ced testosterone levels in the serum o f ma le septic sho ck pat ients. J Steroid Biochem Mol Biol 29,

4 3 5 - 4 4 0 .Chris te ff, N, Gharak hanian, S, Tho bie , N, Ro zenba um , W and N unez , EA (1992a) E vidence for chang esin adrenal and testicular steroids durin g H IV infect ion. J AIDS 5 8 4 1 - 8 4 6 .Christeff, N, Carl i , A, Benassayag, C, Bleichner, G, Vaxelaire, JF and Nunez, EA (1992b) Relat ionship


7/8

Serum Cortisol and DH EA in HIV-positive Men SI7b e tween ch an g es in se r u m es t r o n e l ev e l s an d o u tco m e in h u m an m a le s w i th sep t i c sh o ck . Circ Shock3 6 , 2 4 9 - 2 5 5 .

Ch r i s t e f f , N , W in te r , C , Gh a r ak h an ian , S , T h o b ie , N , W i r b e l , E , Co s t ag l io l a , D , Nu n ez , E A an d Ro zen b au m ,W ( 19 9 5) D i f f e r en ces in t h e an d r o g en s o f HI V p o s i t i v e p a t i en t s w i th an d wi th o u t K ap o s i ' s sa r co m a . JClin Pathol 48 , 513-518 .Chr is te f f , N, Lor th o lary , O, Cas assu s , R Tho bie , N, Veyssier , E T or r i , O, G ui l lev in , L and Nu nez , EA( 1 9 9 6 ) Re la t io n sh ip b e tween sex s t e r o id h o r m o n e l ev e l s an d im m u n e f u n c t io n in H I V- in f ec t ed m en . ExpClin Endocrinol Diabetes 104 , 130 - I 36 .Day n es , RA, Du b ley , DJ an d Ar an eo , BA ( 1 9 9 0 ) Reg u la t io n o f m u r in e ly m p h o k in e p r o d u c t io n in v iv o1 I . D eh y d r o ep ian d r o s t e r o n e i s a n a tu r a l en h an ce r o f i n t e r l eu k in 2 sy n th es i s b y h e lp e r T - ce l ls . E u r Jbnmunol 2 0 , 7 9 3 - 8 0 2 .Gr o ssm an , C ( 1 9 8 4 ) Reg u la t io n o f t h e im m u n e sy s t em b y sex s t e r o id s . Endocrine Rev 5, 435--445.Ho m o - De la r ch e F ( 1 9 8 8 ) G lu c o co r t i co id s , l y m p h o k in es an d th e ce l l r e sp o n se . In : lm u r a , H , Sh izu m e , Kan d Yo sh id a S ( E d s ) P r o g r e ss i n E n d o c r in o lo g y . E l sev ie r , Am ste r d am , p p . 3 4 9 - 3 5 4 .Ho m o - De la r ch e , F , F i t zp a t r i ck , F , Bach , JE Dar d en n e , M , Ch r i s te f f , N an d Nu n ez , E A ( 19 9 1) Sex s t e r o id s,g lu co co r t i co id s , s tr e s s an d au to im m u n i ty . J Steroid Biochem Mol Biol 4 0 , 6 1 9 - 6 3 7 .Ko ch ak ian , CD ( 1 9 6 4 ) Mech an i sm o f an ab o l i c ac t io n o f an d r o g en s . Acta Endocrmol suppl 92, 192-213.L au d a t , A , B lu m , L , Gu ech o t , J , P i ca r d , O , Cab an e , J , I m b e r t , JC an d Gib o u d eau ( 1 9 9 5 ) Ch an g es insy s t em ic g o n ad a l an d ad r en a l s t e r o id s in a sy m p to m a t i c h u m an im m u n o d e f i c i en cy v i r u s - in f ec t ed m en :r e l a t io n sh ip wi th t h e C D4 ce l l co u n t . Eur J Endocrinol 133, 418--424.Lor tho lary , O, Ch r is te f f , N, Casa ssus , P , Thob ie , N, Veyssier, R T rogof f , B, Brauner , M and Nune z , EA( 19 9 6) Hy p o th a l am o - p i tu i t a r y - a d r en a l f u n c t io n in h u m an im m u n o d e f i c i en cy v i r u s - in f ec t ed m en . J ClinEndocrinol Metab 8 1 , 7 9 1 - 7 9 6 ,Mar t in , ME , B en assay ag , C , A m ie l , C , Can to n , P an d Nu n ez , E A ( 19 9 2) A l t e r a t io n in t h e co n cen t ra t io n s an db in d in g p r o p e r t i e s o f sex s t e r o id b in d in g p r o t e in an d co r t i co s t e r o id - b in d in g g lo b u l in i n H I V+ p a t ien t s .J L)ldocrinol h2vest 15 , 597-603 .Mem b r an o , L , I r on y , I, De r e , W , K le in , R , B ig l i e r i, E G an d Co b b , E ( 1 9 8 7 ) Ad r en o co r t i c a l f u n ct ion inacq u i r ed im m u n o d e f i c i en cy sy n d r o m e . J Clin Endocrinol Metab 65 , 482-487 .Mey e r , W J , Sm i th , E M , R ich a r d , GE , Cav a l lo , A , Mo r i l l , AC an d B la lo ck , JE ( 19 8 7) I n v iv o im m u n o r eac t iv ead r en o co r t i co t r o p in ( ACT H) p r o d u c t io n b y h u m an m o n o n u c lea r l eu k o cy te s f r o m n o r m a l an d ACT H-def ic ien t ind iv iduals . J Clin Endocrinol Metab 6 4 , 9 8 - 1 0 5 .No r b ia to , G , Bev i l acq u a , T , Vag o , T , Ba lb i , G , Ch eb a t , E , B e r to ra , R Mo r o n i , M, G a l l i , M an d Old en b u r g ,N ( 1 9 9 2 ) Co r t i so l r e s i s t an ce in acq u i r ed im m u n o d e f i c i en cy sy n d r o m e . J Clin Endocrinol Metab 74,6 0 8 - 6 1 3 .Nu n ez , E A an d Ch r i s t e f f, N ( 1 9 9 4 ) S t e r o id h o r m o n e , cy to k in e , li p id an d m e tab o l i c d i s tu r b an ces in HI VI n f ect io n . In : No r b ia to , G ( E d ) T h e E n d o c r in o lo g y an d M e tab o l i sm o f HI V I n f ec t io n . Baillielr s ClinicalEndocrinology and Metabolism, London, 8 (4) , 803-824 .Nu n ez , E A an d C h r i s t ef f , N ( 1 9 9 6 ) Reg u la t io n b y ag o n i s t i c - an tag o n i s t i c co u p le s o f r eac t io n to s t r e ss i nI h e s t e r o id n e two r k . I n : P r o ceed in g s o f t h e T h i r d E u r o p ean C o n g r e ss o n S y s t em s S c ien ce , Ro m e 1 -4Oc to b e r 1 9 9 6 . E d iz io n i Kap p a , Ro m a , p p . 6 7 5 - 6 8 0 .Pad g e t t , DA an d L o r i a , RM ( 1 9 9 4 ) I n v i t r o p o ten ti a t i o n o f l y m p h o cy te ac t iv a t io n b y d eh y d r o ep ian d r o s t e r o n e ,an d r o s t en ed io l an d an d r o s t en e t r io l . J lmmunol 153 , 1544-1552 .Po r e t sky , L , Can . S an d Z u m o f f , B ( 1 9 9 5 ) T es t i cu l a r d y s f u n c t io n in h u m an im m u n o d e f i c i en cy v i r u s - in f ec t edmen. Metabolism 4 4 , 9 4 6 - 9 5 3 .Raf fi , t Br isseau , JM, Plan chon , B , Rdm i, JR Bar r ie r , JH and Gro l le au , JY (1991) E ndoc r ine funct ion in98 HIV - infec ted pa t ien ts : a p ros pect iv e study . J AIDS 5, 7 2 9 - 7 3 3 .Va l l e tt e , O , S u m id a , C , T h o b ie , N an d Nu n ez , E A ( 19 9 2) Mo d u la t io n o f g lu co co r t i co id b in d in g to r a t l iv e rcy to so l r ecep to r b y l i p id - so lu b le ex t r ac t s f r o m th e se r u m o f AI D S p a t i en ts . J AIDS Res Hum Retroviruses8 , 1693-1697 .Verges , B, Chavanet , P , De sgres , Y, Vai l lau t , G, W aldner , A, Brun , Y M and Pute la t , R (1989) Ad renalf imct ion in HIV- infec ted pa t ien ts . Acta Endocrinol (Copenhagen) 121 , 633-637 .Vi l le t te , JM, Bou r in , P , Do inel , C, M ansour , 1 , Fie t , J , Boudou , R Dreu x , C, R oue , R , Deb ord , M and Levy ,F ( 1 99 0 ) Ci r cad ian v a r i a t io n in p l a sm a l ev e l s o f h y p o p h y sea l , ad r en o co r t i c a l an d t e s t i cu l a r h o r m o n es inm en in f ec t ed wi th h u m an im m u n o d e f i c i en cy v i r u s. J Clin Endocrinol Metab 70 , 572-577 .W h i t co m b , RW , Mas to n L in eh an , W , W ah l , L M an d K u azek , RA ( 19 8 8) M o n o cy te s s t im u la t e co rt i so lp r o d u c t io n b y cu l tu r ed h u m an ad r en o co r t i c a l c e l l s . J Clin Endocrinol Metab 6 6 , 3 3 - 3 8 .W o o l f , PD, Ham i l l , W , McD o n a ld , YV, L ee , L A an d K e l ly , M ( 1 9 8 5 ) T r an s i en t h y p o g o n ad o t r o p ic h y p o g -


8/8

S 18 N6v6na Christeff el al.onadism caused by critical illness. J lin Endocrinol Metab 60 444-450

christeff dhea cortisol hiv 1997 (1)

Documents