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The effect of oral arginine hydrochloride on growth hormone levels, body composition, performance… Macintyre, James Gillis 1986

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THE EFFECT OF ORAL ARGININE HYDROCHLORIDE ON GROWTH HORMONE LEVELS, BODY COMPOSITION, PERFORMANCE AND BIOCHEMICAL PARAMETERS IN MALE RECREATIONAL RUNNERS By JAMES GILLIS MACINTYRE B.Sc. U n i v e r s i t y of T o r o n t o , 1974 M.D. The U n i v e r s i t y of Western O n t a r i o , 1978 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTERS OF PHYSICAL EDUCATION i n THE FACULTY OF GRADUATE STUDIES (PHYSICAL EDUCATION) We accept t h i s t h e s i s as conforming to the r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA A p r i l , 1986 © J a m e s G i l l i s M a c i n t y r e , 1986 ? 8 In presenting t h i s thesis i n p a r t i a l f u l f i l m e n t of the requirements for an advanced degree at the University of B r i t i s h Columbia, I agree that the Library s h a l l make i t f r e e l y a v a i l a b l e for reference and study. I further agree that permission for extensive copying of t h i s thesis for scholarly purposes may be granted by the head of my department or by h i s or her representatives. It i s understood that copying or pu b l i c a t i o n of t h i s thesis for f i n a n c i a l gain s h a l l not be allowed without my written permission. Department of The University of B r i t i s h Columbia 2075 Wesbrook Place Vancouver, Canada V6T 1W5 Date 1/l(Lr 3o , fife 1Q\ A B S T R A C T M a n y a t h l e t e s i n g e s t a m i n o a c i d s i n t h e b e l i e f t h a t t h e s e s u p p l e m e n t s w i l l r e s u l t i n i n c r e a s e d s e r u m g r o w t h h o r m o n e ( G H ) l e v e l s , w i t h a n a t t e n d a n t a n a b o l i c e f f e c t a n d i m p r o v e m e n t s i n a t h l e t i c p e r f o r m a n c e . I n o r d e r t o t e s t t h e s e h y p o t h e s e s t w e l v e m o d e r a t e l y f i t ( a v e r a g e V 0 2 m a x 5 1 . 2 m l / k g / m i n ) m a l e r e c r e a t i o n a l r u n n e r s ( a v e r a g e a g e 3 0 . 3 y e a r s ) i n a s t e a d y s t a t e o f t r a i n i n g i n g e s t e d 6 . 0 gm a r g i n i n e h y d r o c h l o r i d e ( A A ) o r l a c t o s e p l a c e b o ( P ) d a i l y o v e r t w o 7 w e e k p e r i o d s i n a d o u b l e b l i n d c r o s s - o v e r e x p e r i m e n t a l d e s i g n . C o m p r e h e n s i v e a n t h r o p o m e t r i c , p h y s i o l o g i c a l a n d b i o c h e m i c a l t e s t s w e r e p e r f o r m e d b e f o r e , a t t h e c r o s s o v e r , a n d a f t e r t h e a d m i n i s t r a t i o n o f t h e d r u g s . D a t a o n GH r e s p o n s e , p e r f o r m a n c e a n d b o d y c o m p o s i t i o n w a s a n a l y z e d b y M A N O V A , a n d r e p e a t e d A N O V A s w e r e u s e d f o r t h e b i o c h e m i c a l d a t a . A l t h o u g h GH l e v e l s w e r e i n c r e a s e d b y t h e A A , a n d t h e GH r e s p o n s e t o AA w a s g r e a t e r t h a n t h a t t o P , t h e i n c r e a s e s d i d n o t r e a c h s t a t i s t i c a l s i g n i f i c a n c e ( p = 0 . 1 3 ) . T h e GH r e s p o n s e t o AA w a s n e g a t i v e l y r e l a t e d t o % b o d y f a t ( r = - 0 . 6 0 , p < 0 . 0 5 ) a n d p o s i t i v e l y r e l a t e d t o m a x i m a l o x y g e n u p t a k e ( r = 0 . 6 9 , p < 0 . 0 5 ) . O r a l AA a d m i n i s t r a t i o n d i d n o t r e s u l t i n a n y s i g n i f i c a n t c h a n g e s i n b o d y c o m p o s i t i o n , m a x i m a l o x y g e n u p t a k e , a e r o b i c e n d u r a n c e , a n a e r o b i c c a p a c i t y , s t r e n g t h , o r b i o c h e m i c a l o r h e m a t o l o g i c a l p a r a m e t e r s . F i v e o f t h e s u b j e c t s r e p o r t e d s u b j e c t i v e i m p r o v e m e n t s i n t r a i n i n g w h i l e t a k i n g t h e A A . A r g i n i n e h y d r o c h l o r i d e i n g e s t i o n w a s a s s o c i a t e d w i t h n o s i g n i f i c a n t c h a n g e i n p l a s m a i m m u n o r e a c t i v e o r b i o a c t i v e i i growth hormone l e v e l s i n the 12 male r e c r e a t i o n a l a t h l e t e s t e s t e d . No s i g n i f i c a n t n e g a t i v e or p o s i t i v e b i o c h e m i c a l , h e m a t o l o g i c a l , s t r e n g t h , body c o m p o s i t i o n or performance changes were documented. KEY WORDS: ARGININE, GROWTH HORMONE, ATHLETIC PERFORMANCE, BODY COMPOSITION, OXYGEN UPTAKE i i i TABLE OF CONTENTS ABSTRACT i i LIST OF TABLES v i LIST OF FIGURES v i i ACKNOWLEDGEMENT v i i i INTRODUCTION 1 METHODS 3 S u b j e c t s 3 Study D e s i g n 3 T e s t i n g P r o t o c o l 4 S t a t i s t i c a l A n a l y s i s 8 RESULTS 10 S u b j e c t s 10 Hormonal Response 10 Body C o m p o s i t i o n 11 A e r o b i c and A n a e r o b i c F i t n e s s 11 S t r e n g t h 12 B i o c h e m i c a l and H e m a t o l o g i c a l P a r a m e t e r s 12 S u b j e c t i v e Changes 12 DISCUSSION 18 CONCLUSIONS 24 REFERENCES 26 i v APPENDIX: REVIEW OF LITERATURE 29 1- GROWTH HORMONE 30 1-1 STRUCTURE AND PRODUCTION 30 1-2 CONTROL OF SECRETION 30 1- 3 GH RELEASE 31 2- EFFECTS 37 2- 1 FUNCTION 37 2-2 METABOLIC 37 2-3 GROWTH 39 2-4 MUSCLE 40 2- 5 DISORDERS 46 3- GH AND ATHLETES 47 3- 1 INTRODUCTION 47 3-2 ADMINISTRATION 48 3-3 POTENTIAL USES 49 3-4 POTENTIAL PROBLEMS 51 v LIST OF TABLES TABLE 1: HORMONAL RESPONSES 13 TABLE 2: ANTHROPOMETRIC DATA 14 TABLE 3: PERFORMANCE DATA 15 TABLE 4: STRENGTH 16. TABLE 5: HEMATOLOGY / BIOCHEMICAL 17 v i L I S T OF F I G U R E S F I G U R E 1: E X P E R I M E N T A L D E S I G N / T E S T I N G P R O T O C O L . . 4 F I G U R E 2 : DATA A N A L Y S I S . . 9 v i i ACKNOWLEDGEMENT The author would l i k e to thank the S p o r t s M e d i c i n e C o u n c i l of Canada f o r f u n d i n g t h i s s t u d y . The p a r t i c i p a t i o n and c o - o p e r a t i o n of the s u b j e c t s was e s s e n t i a l , and t h e i r time and e f f o r t s are g r a t . e f u l l y acknowledged. Thanks are a l s o due to Dr. D.B. Clement, the t h e s i s committee chairman, as w e l l as committee members Dr. J.E. Taunton and Dr. D.C. McKenzie f o r p r o v i d i n g i n v a l u a b l e a s s i s t a n c e . A d d i t i o n a l thanks are due to Drs. P r i o r , Gordon, L i , and Schutz f o r t h e i r e x p e r t i s e and a s s i s t a n c e . A study of t h i s magnitude would be i m p o s s i b l e to perform w i t h o u t c o n s i d e r a b l e hands on h e l p , and e t e r n a l g r a t i t u d e i s due to Dr. W. Parkhouse, Dr. G. Matheson, Ms. Lynda F i l s i n g e r , Ms. Lynne Sawchuk, Ms. Y v e t t e V i g n a , Mr. B i l l H e a r s t and the s t a f f of the l a b o r a t o r y , pharmacy and r a d i o l o g y departments of the U.B.C. H e a l t h S c i e n c e s C e n t r e H o s p i t a l . F i n a l l y , thanks i s due to my w i f e Ginny, f o r her t o l e r a n c e , p a t i e n c e and a s s i s t a n c e . v i i i I N T R O D U C T I O N T h e d e s i r e o f a t h l e t e s t o i m p r o v e t h e i r p h y s i c a l p e r f o r m a n c e h a s l e d t o a n i n c r e a s e i n t h e u s e o f d r u g s a n d o t h e r e r g o g e n i c a i d s i n s p o r t . S t r i c t e r c o n t r o l o f a n a b o l i c s t e r o i d u s e h a s r e s u l t e d i n a t t e m p t s t o e l e v a t e e n d o g e n o u s g r o w t h h o r m o n e ( G H ) , w h i c h i s u n d e t e c t a b l e w i t h c u r r e n t l a b o r a t o r y t e c h n o l o g y . G r o w t h h o r m o n e i s a p o w e r f u l a n a b o l i c h o r m o n e , a n d i t s a d m i n i s t r a t i o n w i l l l e a d t o a p o s i t i v e n i t r o g e n b a l a n c e a n d a n i n c r e a s e i n l e a n b o d y m a s s i n h y p o p h y s e c t o m i z e d a n i m a l s ( 1 ) . T h e r e a r e t w o m e t h o d s o f GH s u p p l e m e n t a t i o n : i n j e c t i o n o f p u r e G H , o r t h e i n g e s t i o n o f v a r i o u s d r u g s a n d a m i n o a c i d s w h i c h c a u s e t h e r e l e a s e o f e n d o g e n o u s GH f r o m t h e p i t u i t a r y . T h e u s e o f p u r i f i e d GH i s r e l a t i v e l y u n c o m m o m d u e t o i t s c o s t a n d l i m i t e d a v a i l a b i l i t y . A m i n o a c i d s a r e i n e x p e n s i v e a n d e a s i l y a c c e s s i b l e , a n d a r e t h u s w i d e l y u s e d b y b o t h r e c r e a t i o n a l a n d e l i t e a t h l e t e s . I t h a s b e e n r e p o r t e d t h a t t h e o r a l a d m i n i s t r a t i o n o f a m i n o a c i d s w i l l l e a d t o i n c r e a s e s i n s e r u m GH l e v e l s ( 2 , 3 ) . T h e r e i s n o d o c u m e n t a t i o n , h o w e v e r , t h a t t h e s e i n c r e a s e s w i l l h a v e a n a n a b o l i c e f f e c t . F u r t h e r m o r e , t h e r e i s no e v i d e n c e t h a t t h e a n a b o l i c e f f e c t s o f GH w i l l r e s u l t i n i m p r o v e m e n t s i n a t h l e t i c p e r f o r m a n c e . I n h y p o p h y s e c t o m i z e d r a t s GH h a s l e d t o i n c r e a s e s i n m u s c l e m a s s , b u t n o t t o i n c r e a s e d p e r f o r m a n c e ( 4 ) . S u r g i c a l l y -i n d u c e d m u s c l e a t r o p h y i n r a t s w a s r e v e r s e d b y GH a d m i n i s t r a t i o n , h o w e v e r , c o n t r o l m u s c l e s i n t h e s a m e a n i m a l s h a d l e s s i n c r e a s e i n s i z e a n d no i m p r o v e m e n t s i n p e r f o r m a n c e ( 5 ) . P a t i e n t s w i t h a c r o m e g a l y a n d e x c e s s i v e GH l e v e l s o v e r p r o l o n g e d p e r i o d s o f t i m e d e v e l o p a m y o p a t h y i n w h i c h t h e m u s c l e s a p p e a r h y p e r t r o p h i e d b u t a r e i n f a c t f u n c t i o n a l l y w e a k e r ( 6 , 7 , 8 ) . - 1 -I t i s d i f f i c u l t to make a s s u m p t i o n s about the p o s s i b l e e f f e c t s of amino a c i d i n g e s t i o n on h e a l t h y a t h l e t e s based on s t u d i e s of u n t r a i n e d , h y p o p i t u i t a r y r a t s or c h r o n i c a l l y i l l , a c r o m e g a l i c humans. T h i s s t u d y was performed i n an attempt to answer t h r e e q u e s t i o n s . Does the o r a l a d m i n i s t r a t i o n of amino a c i d s cause s i g n i f i c a n t GH r e l e a s e ? Does a moderate change i n GH l e v e l s a f f e c t body c o m p o s i t i o n and performance? Are t h e r e any d e t r i m e n t a l b i o c h e m i c a l changes a s s o c i a t e d w i t h the i n g e s t i o n of amino a c i d s ? -2-METHODS  S u b j e c t s T w e l v e men v o l u n t e e r e d i n r e s p o n s e t o p o s t e d n o t i c e s a n d p e r s o n a l c o n t a c t s a n d a l l g a v e i n f o r m e d c o n s e n t a f t e r a d e t a i l e d e x p l a n a t i o n o f t h e e x p e r i m e n t . A l l s u b j e c t s w e r e r e c r e a t i o n a l r u n n e r s i n a s t e a d y s t a t e o f t r a i n i n g . T h e y w e r e f r e e o f m e d i c a l p r o b l e m s a n d n o t t a k i n g a n y m e d i c a t i o n s . P a r t i c i p a t i o n i n o t h e r a t h l e t i c a c t i v i t i e s w a s a l l o w e d i f i t h a d b e e n o n - g o i n g a n d w a s a t a l o w l e v e l . T h e y w e r e i n s t r u c t e d t o m a i n t a i n t h e i r d i e t a n d a c t i v i t y p a t t e r n s t h r o u g h o u t t h e p e r i o d o f t h e s t u d y a n d a s k e d t o k e e p a r e c o r d o f t h e i r a c t i v i t i e s . S t u d y D e s i g n T h e s t u d y w a s c o n d u c t e d o v e r t w o s e v e n w e e k p e r i o d s u s i n g a d o u b l e b l i n d c r o s s - o v e r d e s i g n . T h e s u b j e c t s w e r e g i v e n a m i n o a c i d ( A A ) ( 6 . 0 g r a m s o f L - A r g i n i n e m o n o h y d r o c h l o r i d e , BDH C h e m i c a l s , P o o l e , E n g l a n d ) d u r i n g o n e p e r i o d , a n d p l a c e b o ( P ) ( 6 . 0 g r a m s o f l a c t o s e ) d u r i n g t h e o t h e r . T h e s u b j e c t s i n g e s t e d t h e c o m p o u n d s e v e r y m o r n i n g o n a n e m p t y s t o m a c h . T h e d r u g s w e r e d i s p e n s e d i n i d e n t i c a l a p p e a r i n g g e l a t i n c a p s u l e s p r e p a r e d by a c l i n i c a l p h a r m a c i s t who r a n d o m l y a s s i g n e d t h e m e d i c a t i o n s a n d k e p t t h e c o d e u n t i l a l l s u b j e c t s h a d c o m p l e t e d t h e s t u d y . T e s t i n g o f t h e s u b j e c t s w a s c o n d u c t e d a t t h e b e g i n n i n g o f t h e e x p e r i m e n t , a t t h e 7 w e e k c r o s s o v e r p o i n t , a n d a t t h e c o n c l u s i o n o i t h e s e c o n d s t u d y p e r i o d ( F i g u r e 1 ) . A l l t e s t i n g w a s c o n d u c t e d a t t h e J . M . B u c h a n a n F i t n e s s a n d R e s e a r c h C e n t r e a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , w i t h e a c h t e s t i n g s e s s i o n t a k i n g p l a c e o v e r t w o c o n s e c u t i v e m o r n i n g s . On t h e f i r s t m o r n i n g , t e s t s -3-o f b o d y c o m p o s i t i o n , s t r e n g t h a n d m a x i m a l o x y g e n u p t a k e w e r e p e r f o r m e d . On t h e s e c o n d m o r n i n g , s u b j e c t s h a d a n a n a e r o b i c s p e e d t e s t , a c o m p u t e r i z e d t o m o g r a p h i c ( C . T . ) s c a n o f t h e i r t h i g h t o a s s e s s b o d y c o m p o s i t i o n , a n d p e r f o r m e d a n e n d u r a n c e r u n . B l o o d s a m p l e s a s d e s c r i b e d b e l o w w e r e t a k e n t o a s s e s s h o r m o n a l a n d m e t a b o l i c r e s p o n s e s t o t h e e x e r c i s e . F I G U R E 1 : E X P E R I M E N T A L D E S I G N / T E S T I N G P R O T I C O L T I M E GROUP 1 GROUP 2 0 WEEKS 7 WEEKS 14 WEEKS AA < P L A C E B O > < P L A C E B O > AA T e s t i n g P r o t o c o l H o r m o n a l R e s p o n s e B l o o d s a m p l e s w e r e t a k e n t o m o n i t o r h o r m o n a l l e v e l s , b i o c h e m i c a l a n d h e m a t o l o g i c a l p a r a m e t e r s . F a s t i n g b l o o d w o r k , i n c l u d i n g G H , w a s d r a w n v i a a v e n o u s p u n c t u r e o n t h e m o r n i n g o f t h e s e c o n d t e s t i n g d a y . T h e s u b j e c t s t h e n h a d a 2 0 g a u g e i n d w e l l i n g t e f l o n i n t r a v e n o u s c a t h e t e r p l a c e d i n t h e c e p h a l i c v e i n , w h i c h w a s m a i n t a i n e d p a t e n t f o r s u b s e q u e n t b l o o d s a m p l i n g b y i n t e r m i t t a n t s m a l l i n f u s i o n s o f h e p a r i n i z e d n o r m a l s a l i n e . T h e i n i t i a l GH s a m p l e w a s d r a w n w i t h a s e p a r a t e p u n c t u r e t o a v o i d t h e p o s s i b l e GH s u r g e a s s o c i a t e d w i t h t h e s t r e s s o f e s t a b l i s h i n g t h e i n t r a v e n o u s l i n e . I m m e d i a t e l y a f t e r t h e l i n e w a s e s t a b l i s h e d , t h e - 4 -t e s t d r u g ( A A o r P ) w a s a d m i n i s t e r e d b y m o u t h , a n d t h e GH r e s p o n s e w a s a s s e s s e d w i t h a n o t h e r s a m p l e a t 1 2 0 m i n u t e s . I n o r d e r t o m i n i m i z e o t h e r i n f l u e n c e s o n GH l e v e l s , t h e s u b j e c t s w e r e k e p t f a s t i n g d u r i n g t h i s i n t e r v a l , a n d t h e o n l y a c t i v i t y t h e y e n g a g e d i n w a s a s l o w f i v e m i n u t e w a l k t o t h e r a d i o l o g y d e p a r t m e n t f o r t h e C . T . s c a n . G r o w t h h o r m o n e r e s p o n s e t o e x e r c i s e w a s m e a s u r e d b y s a m p l i n g GH 10 m i n u t e s a f t e r t h e c o n c l u s i o n o f t h e 3 0 m i n u t e e n d u r a n c e r u n . I n o r d e r t o h a v e i n f o r m a t i o n o n c h a n g e s i n t h e GH r e s p o n s e t o t h e d r u g w i t h t i m e , a 1 2 0 m i n u t e s a m p l e w a s d o n e o n t h e f i r s t t e s t i n g d a y o f t h e s e c o n d t e s t i n g p e r i o d . A s w i t h t h e o t h e r s a m p l e s , i t w a s c o l l e c t e d i n t h e f a s t i n g , i n a c t i v e s t a t e . T h e b l o o d f o r t h e GH s a m p l e s w a s l a b e l l e d , a n d k e p t o n i c e . A t t h e c o n c l u s i o n o f t h e t e s t i n g s e s s i o n t h e y w e r e t r a n s p o r t e d t o t h e h o s p i t a l l a b o r a t o r y , w h e r e t h e y w e r e c e n t r i f u g e d , a n d t h e o s e r u m f r o z e n a t - 7 0 C . S a m p l e s w e r e s a v e d a n d a n a l y z e d i n t w o b a t c h e s w i t h a l l s a m p l e s f r o m a n y o n e s u b j e c t b e i n g d o n e a t t h e s a m e t i m e t o a v o i d i n t e r - a s s a y v a r i a t i o n . A l i q u o t s f r o m e a c h o f t h e 3 GH s a m p l e s ( b a s e l i n e , 1 2 0 m i n u t e s p o s t d r u g , a n d 10 m i n u t e s p o s t e x e r c i s e ) w e r e c o m b i n e d t o m a k e p o o l e d s a m p l e s f o r b o t h t h e AA a n d t h e P t i m e p e r i o d s . T h e i n d i v i d u a l a n d p o o l e d s a m p l e s w e r e a n a l y z e d f o r GH i n d u p l i c a t e , u s i n g a s t a n d a r d r a d i o - i m m u n o a s s a y ( R I A ) k i t ( K a l l e s t a d L t d , M i n n e a p o l i s , M i n n . ) . T h e p o o l e d s a m p l e s w e r e a l s o a n a l y z e d f o r b o t h GH a n d P r o l a c t i n ( P R L ) by R I A t e c h n i q u e ( 9 ) . A b i o a s s a y w a s p e r f o r m e d w h i c h a s s e s s e d t h e t o t a l l a c t o g e n a c t i v i t y o n t h e b a s i s o f s t i m u l a t i o n o f c e l l s o f N b - 2 l y m p h o c y t e l i n e ( 1 0 ) . A c t i v e GH w a s c a l c u l a t e d b y s u b t r a c t i n g t h e -5-R I A l e v e l o f P R L f r o m t h e t o t a l l a c t o g e n a c t i v i t y d e t e r m i n e d by b i o a s s a y . B o d y C o m p o s i t i o n B o d y c o m p o s i t i o n w a s a s s e s s e d r a d i o g r a p h i c a l l y , a n d t h r o u g h s k i n f o l d m e a s u r e m e n t s a n d h y d r o s t a t i c w e i g h i n g . C o m p u t e r i z e d t o m o g r a p h y w a s p e r f o r m e d o n t h e s u b j e c t s ' r i g h t t h i g h s 15 cm p r o x i m a l t o t h e f e m o r a l c o n d y l e s . T h e s c a n s w e r e a n a l y z e d u s i n g q u a n t i t a t i v e d e n s i o m e t r i c m e t h o d s t o s e p a r a t e t h e a r e a s o f f a t f r o m t h o s e o f m u s c l e . T h e t o t a l c r o s s - s e c t i o n a l a r e a a n d p e r c e n t a g e s o f f a t a n d m u s c l e w e r e t h e n c a l c u l a t e d a n d a v e r a g e d o v e r t w o s c a n s ( 1 1 ) . I n a d d i t i o n , a n e x p e r i e n c e d a n t h r o p o m e t r i s t m e a s u r e d s k i n f o l d s a t 8 s i t e s ( t r i c e p s , s u b s c a p u l a r , b i c e p s , s u p r a - i l i a c , s u p r a - s p i n a l e , a b d o m i n a l , a n t e r i o r t h i g h a n d m e d i a l c a l f ) , l i m b c i r c u m f e r e n c e a t 2 s i t e s ( t h i g h a n d c a l f ) , a n d t h e w i d t h o f b o n y l a n d m a r k s a t 2 s i t e s ( f e m o r a l c o n d y l e s a n d w r i s t ) . A l l m e a s u r e m e n t s w e r e r e p e a t e d 3 t i m e s , a n d t h e a v e r a g e w a s u s e d f o r c o m p u t a t i o n s . I n t h e e v e n t o f a b e r r a n t m e a s u r e m e n t s , t h e t w o c l o s e s t m e a s u r e s w e r e u s e d . D e n s i t y w a s m e a s u r e d u s i n g h y d r o s t a t i c w e i g h i n g , a n d t h e s e v a l u e s w e r e t h e n c o n v e r t e d t o p e r c e n t f a t ( 1 2 ) . A e r o b i c a n d A n a e r o b i c F i t n e s s M a x i m a l o x y g e n u p t a k e w a s d e t e r m i n e d u s i n g a c o n t i n u o u s t r e a d m i l l p r o t o c o l . A f t e r a w a r m up p e r i o d t h e s u b j e c t s r a n a t a n - 1 i n i t i a l r a t e o f 2 . 6 6 m . s e c w i t h t h e s p e e d i n c r e a s e d b y - 1 0 . 2 2 m . s e c e v e r y m i n u t e u n t i l v o l i t i o n a l f a t i g u e . E x p i r e d g a s e s w e r e c o n t i n u o u s l y s a m p l e d a n d a n a l y z e d b y a B e c k m a n M e t a b o l i c M e a s u r e m e n t C a r t i n t e r f a c e d i n t o a H e w l e t t P a c k a r d 3 0 5 2 A D a t a - 6 -A c q u i s i t i o n S y s t e m r e c o r d i n g r e s p i r a t o r y g a s e x c h a n g e v a r i a b l e s e v e r y f i f t e e n s e c o n d s . M a x i m a l o x y g e n c o n s u m p t i o n w a s d e t e r m i n e d a s t h e a v e r a g e o f t h e h i g h e s t f o u r c o n s e c u t i v e 15 s e c o n d v a l u e s . T h e v e n t i l a t o r y t h r e s h o l d w a s d e t e r m i n e d b y v i s u a l i n s p e c t i o n o f t h e c u r v e o f e x c e s s CO e l i m i n a t i o n ( 1 3 ) . H e a r t r a t e w a s 2 m o n i t e r e d u s i n g a S p o r t T e s t e r H e a r t R a t e M i c r o c o m p u t e r ( E s c o t e k K y , O u l u , F i n l a n d ) , w h i c h c a l c u l a t e s , s t o r e s i n m e m o r y , a n d r e c a l l s t h e a v e r a g e h e a r t r a t e f o r e v e r y 3 0 s e c o n d p e r i o d d u r i n g e x e r c i s e . T h i s a l l o w e d a c c u r a t e d e t e r m i n a t i o n o f t h e h e a r t r a t e a t t h e v e n t i l a t o r y t h r e s h o l d . A e r o b i c e n d u r a n c e w a s e v a l u a t e d t h r o u g h t h e s u b m a x i m a l h e a r t r a t e r e s p o n s e a n d b l o o d l a c t a t e l e v e l s a t 10 m i n u t e i n t e r v a l s d u r i n g a 3 0 m i n u t e r u n a t a c o n s t a n t s p e e d . T h e s a m e s p e e d w a s -1 u s e d f o r a l l t h r e e r u n s , a n d w a s i n d i v i d u a l l y s e t a t 0 . 4 4 m . s e c l e s s t h a n t h e s p e e d a t t h e v e n t i l a t o r y t h r e s h o l d t h a t h a d b e e n d e t e r m i n e d o n t h e f i r s t t e s t i n g s e s s i o n . S e r u m g l u c o s e w a s m e a s u r e d e v e r y 10 m i n u t e s a s a n i n d i c a t o r o f m e t a b o l i c s u b s t r a t e m o b i l i z a t i o n a n d u t i l i z a t i o n . A n a e r o b i c c a p a c i t y w a s d e t e r m i n e d u s i n g a n a n a e r o b i c s p e e d o t e s t . T h e t r e a d m i l l w a s e l e v a t e d t o a s l o p e o f 2 0 , w i t h t h e - 1 s p e e d s e t a t 3 . 5 4 m . s e c , a n d t h e s u b j e c t s r a n t o t h e p o i n t o f v o l i t i o n a l f a t i g u e ( 1 4 ) . T h e t i m e t o f a t i g u e w a s r e c o r d e d , a n d a b l o o d l a c t a t e d e t e r m i n a t i o n w a s m a d e 3 m i n u t e s a f t e r t h e c o m p l e t i o n o f t h e t e s t . S t r e n g t h S t r e n g t h o f t h e b i c e p , t r i c e p , q u a d r i c e p , a n d h a m s t r i n g m u s c l e s w e r e m e a s u r e d b i l a t e r a l l y u s i n g t h e C y b e x I I I s o k i n e t i c - 7 -D y n a m o m e t e r . A f t e r t h e s u b j e c t s h a d f a m i l i a r i z e d t h e m s e l v e s w i t h o - 1 t h e e q u i p m e n t , t e s t i n g w a s c a r r i e d o u t a t t w o s p e e d s , 3 0 . s e c o - 1 a n d 1 8 0 . s e c . Two r e p e t i t i o n s w e r e p e r f o r m e d a t e a c h s p e e d , w i t h t h e h i g h e s t r e s u l t c o n s i d e r e d t h e p e a k t o r q u e . B i o c h e m i c a l a n d H e m a t o l o g i c a l M o n i t o r i n g B i o c h e m i c a l a n d h e m a t o l o g i c a l v a r i a b l e s w e r e m o n i t o r e d d u r i n g e a c h o f t h e t e s t i n g p e r i o d s . B i o c h e m i c a l t e s t s i n c l u d e d : b l o o d u r e a n i t r o g e n , c r e a t i n i n e , g l u c o s e , b i l i r u b i n , c a l c i u m , p h o s p h a t e , u r i c a c i d , a l k a l i n e p h o s p h a t a s e , l a c t a t e d e h y d r o g e n a s e ( L D H ) , t o t a l p r o t e i n , a l b u m i n , c h o l e s t e r o l - t o t a l a n d h i g h d e n s i t y l i p o p r o t e i n ( H D L ) , t r i g l y c e r i d e s , f e r r i t i n , a n d g l y c o s y l a t e d h e m o g l o b i n ( H b A l c ) . A c o m p l e t e h e m a t o l o g y p r o f i l e w a s o b t a i n e d , i n c l u d i n g h e m o g l o b i n , h e m a t o c r i t , l e u k o c y t e c o u n t , p l a t e l e t c o u n t a n d c e l l m o r p h o l o g y . T h e s e t e s t s w e r e p e r f o r m e d u s i n g s t a n d a r d h o s p i t a l l a b o r a t o r y a n a l y t i c a l t e c h n i q u e s . S u b j e c t C o m p l i a n c e A t t h e c o n c l u s i o n o f t h e s t u d y t h e s u b j e c t s w e r e g i v e n a q u e s t i o n n a i r e t o a s s e s s t h e b l i n d n e s s o f t h e p r o t o c o l a n d a n y s u b j e c t i v e c h a n g e s t h a t h a d o c c u r r e d d u r i n g t h e t w o t i m e p e r i o d s . T h e y w e r e a l s o q u e s t i o n e d r e g a r d i n g a n y c h a n g e s i n t h e i r v o l u m e o f e x e r c i s e o r a l t e r a t i o n s i n d i e t . S t a t i s t i c a l A n a l y s i s A l l d a t a w a s e n t e r e d i n t o t h e U . B . C . m a i n f r a m e c o m p u t e r a n d a n a l y z e d u s i n g B . M . D . s t a t i s t i c a l s o f t w a r e p a c k a g e s . T h e c r o s s -o v e r d e s i g n w a s c o l l a p s e d t o a l l o w c o m p a r i s o n o f t h e p r e a n d p o s t t r e a t m e n t t e s t v a r i a b l e s f o r a l l 12 s u b j e c t s ( F i g u r e 2 ) . F I G U R E 2 : DATA A N A L Y S I S T I M E P R E T R E A T M E N T P O S T T R E A r p MENT GROUP 1 < AA > < — P L A C E B O > GROUP 2 < — P L A C E B O > < A A > M u l t i v a r i a t e a n a l y s i s o f v a r i a n c e f o r r e p e a t m e a s u r e s w a s u s e d t o a s s e s s c h a n g e s i n t h e s u b j e c t s ' b o d y c o m p o s i t i o n , s t r e n g t h a n d p e r f o r m a n c e o v e r t h e 7 w e e k s o f AA a d m i n i s t r a t i o n . T h e a c u t e h o r m o n a l r e s p o n s e s t o AA a n d P i n g e s t i o n w e r e c o m p a r e d u s i n g m u l t i v a r i a t e a n a l y s i s . B i o c h e m i c a l a n d h e m a t o l o g i c a l d a t a w a s a n a l y z e d u s i n g o n e w a y a n a l y s i s o f v a r i a n c e f o r r e p e a t e d m e a s u r e s . C o r r e l a t i o n c o e f f i c i e n t s w e r e c a l c u l a t e d i n o r d e r t o d e t e r m i n e t h e r e l a t i o n s h i p s b e t w e e n t h e h o r m o n a l r e s p o n s e s a n d b o d y c o m p o s i t i o n , s t r e n g t h a n d f i t n e s s . T h e s u b j e c t s ' s e n s i t i v i t y t o AA s t i m u l a t i o n w a s c a l c u l a t e d b y s u b t r a c t i n g t h e i r GH r e s p o n s e t o P f r o m t h e i r r e s p o n s e t o A A . T h e 4 s u b j e c t s w i t h t h e g r e a t e s t d i f f e r e n c e w e r e c l a s s i f i e d a s AA r e s p o n d e r s , a n d t h e 4 s u b j e c t s w i t h t h e l e a s t n e t d i f f e r e n c e w e r e l a b e l l e d n o n - r e s p o n d e r s . T h e t w o g r o u p s w e r e t h e n c o m p a r e d o n t h e b a s i s o f b o d y c o m p o s i t i o n a n d V 0 2 m a x u s i n g o n e w a y a n a l y s i s o f v a r i a n c e . T h e t w o r e s p o n s e g r o u p s w e r e a l s o c o m p a r e d f o r c h a n g e s i n b o d y c o m p o s i t i o n a n d p e r f o r m a n c e o v e r t h e s t u d y p e r i o d u s i n g a t w o b y t w o a n a l y s i s o f v a r i a n c e f o r r e p e a t e d m e a s u r e s . F o r a l l a n a l y s e s i n t h e s t u d y t h e l e v e l o f s i g n i f i c a n c e w a s s e t a t 0 . 0 5 . - 9 -RESULTS S u b j e c t s The s u b j e c t s had an average age of 30.08 y e a r s (range 23 4 1 ) , w i t h an average h e i g h t of 180.2 c m . and weight of 79.1 k.g.. They were m o d e r a t e l y f i t ( a v e r a g e V02 max 51.2 m l / k g / m i n ) , r e g u l a r r e c r e a t i o n a l r u n n e r s a v e r a g i n g 23.8 km per week. S e v e r a l were i n v o l v e d i n o t h e r a c t i v i t i e s , but d i d not a l t e r t h e i r a c t i v i t i e s over t i m e . One c y c l e d on a r e g u l a r b a s i s , two were r e g u l a r weight l i f t e r s , and one rowed once a week. One s u b j e c t s u f f e r e d a f r a c t u r e d c l a v i c l e p a r t way t h r o u g h the AA p e r i o d , and s u b s t i t u t e d an e q u a l d u r a t i o n and i n t e n s i t y of c y c l i n g u n t i l he was a b l e to resume r u n n i n g . The s u b j e c t s d i d not r e p o r t any major changes i n d i e t or a c t i v i t y . Hormonal Responses The growth hormone r e s p o n s e s were h i g h l y v a r i a b l e , and are l i s t e d i n T a b l e 1. There was an i n c r e a s e i n serum GH post AA a d m i n i s t r a t i o n . The net GH r e s p o n s e (GH a t 120 minutes - GH b a s e l i n e ) was g r e a t e r fox the AA than f o r p l a c e b o . N e i t h e r of t h e s e d i f f e r e n c e s , however, r e a c h e d s t a t i s t i c a l s i g n i f i c a n c e . The GH r e s p o n s e to the AA d i d not v a r y w i t h t i m e , and was no d i f f e r e n t a t the end of the t e s t p e r i o d than a t the b e g i n n i n g . There was an i n c r e a s e i n GH l e v e l s a f t e r e x e r c i s e . The r e s p o n s e post AA was g r e a t e r than t h a t post P, but not s i g n i f i c a n t l y d i f f e r e n t . A l t h o u g h the AA r e s p o n d e r s (n=4) had lower body f a t (16.6% v s . 20.2%, p=0.52), and h i g h e r V02max (53.2 v s . 51.8 ml/kg/min, p=0.82) than the n o n - r e s p o n d e r s (n=4), t h e s e d i f f e r e n c e s were not -10-s t a t i s t i c a l l y s i g n i f i c a n t . D u r i n g the t r e a t m e n t p e r i o d the r e s p o n d e r s ' body f a t d e c l i n e d (16.6% to 1 6 . 1 % ) , w h i l e t h a t of the n o n - r e s p o n d e r s i n c r e a s e d (20.2% to 2 1 . 8 % ) , but t h e s e d i f f e r e n c e s were not s t a t i s t i c a l l y s i g n i f i c a n t . The b i o a c t i v i t y of the GH was c a l c u l a t e d by s u b t r a c t i n g the RIA P r o l a c t i n from the t o t a l GH a c t i v i t y d e t e r m i n e d by b i o a s s a y . A l t h o u g h t h e r e was g r e a t e r b i o a c t i v i t y f o l l o w i n g AA than P, t h e r e was no s i g n i f i c a n t d i f f e r e n c e between the two. The net GH r e s p o n s e to AA was n e g a t i v e l y c o r r e l a t e d to %body f a t by CT scan (r=-0.6006, p<0.05), and p o s i t i v e l y c o r r e l a t e d to maximal oxygen uptake (r=.6966, p<0.05). The GH r e s p o n s e to P, however, was u n r e l a t e d t o e i t h e r f a c t o r (%body f a t by CT: r=.1842, p>0.05; V02 max: r=-.2582 p>0.05). Body C o m p o s i t i o n  There was no s i g n i f i c a n t change i n body c o m p o s i t i o n over the s t u d y p e r i o d ( T a b l e 2 ) . P e r c e n t a g e body f a t was unchanged when measured by CT s c a n n i n g , sum of s k i n f o l d s and h y d r o s t a t i c w e i g h i n g . T h i g h g i r t h was a l s o unchanged. A e r o b i c and A n a e r o b i c F i t n e s s N e i t h e r a e r o b i c nor a n a e r o b i c performance was s i g n i f i c a n t l y changed by the a d m i n i s t r a t i o n of the Amino A c i d ( T a b l e 3 ) . There was no d i f f e r e n c e i n the maximal oxygen uptake or the time to f a t i g u e i i the a n a e r o b i c speed t e s t . D u r i n g the endurance r u n , h e a r t r a t e and b l o o d l a c t a t e r o s e s i g n i f i c a n t l y w i t h t i m e , but t h e r e was no d i f f e r e n c e between pre and post AA. -11-S t r e n g t h A d m i n i s t r a t i o n of the AA d i d not s i g n i f i c a n t l y a l t e r any measurement of s t r e n g t h ( T a b l e 4 ) . There was no d i f f e r e n t i a l change i n s t r e n g t h between t r a i n e d and u n t r a i n e d muscle gr o u p s . The s t r e n g t h of d i s t a l m u s c u l a t u r e , as r e f l e c t e d by g r i p s t r e n g t h , was unchanged. B i o c h e m i c a l and H e m a t o l o g i c a l Measures B i o c h e m i c a l and h e m a t o l o g i c a l d a t a a l l remained w i t h i n the normal range t h r o u g h o u t the s t u d y ( T a b l e 5 ) . Hemoglobin, f e r r i t i n , c h o l e s t e r o l , H.D.L. c h o l e s t e r o l , t r i g l y c e r i d e s , and hemoglobin Al-C were s p e c i f i c a l l y a n a l y z e d , and no s i g n i f i c a n t changes o c c u r r e d . S u b j e c t i v e Changes There were no u n i f o r m s u b j e c t i v e changes r e p o r t e d on the q u e s t i o n n a i r e . F i v e s u b j e c t s n o t i c e d no d i f f e r e n c e s and were unable t o t e l l w h ich compound was g i v e n d u r i n g which p e r i o d . Two s u b j e c t s thought they were r e c e i v i n g AA when they were i n f a c t r e c e i v i n g P. F i v e s u b j e c t s were a b l e to i d e n t i f y the p e r i o d i n which the a c t i v e drug was t a k e n . They r e p o r t e d s u b j e c t i v e i n c r e a s e s i n performance and d e c r e a s e d f a t i g u e a f t e r w o r k o u t s . -12-T A B L E 1 : HORMONAL R E S P O N S E S F A C T O R AM INO A C I D ( m e a n + S D ) P L A C E B O ( m e a n +_ S D ) GH B A S E L I N E 0 M I N . ( n g / m l ) 1 . 7 (± 1 . 9 ) 2 . 6 (± 2 . 0 ) 0 . 3 5 1 4 GH 1 2 0 M I N . P O S T DRUG 2 . 6 (± 2 . 3 ) 1 . 8 (± l . D 0 . 2 4 2 3 GH N E T ( 1 2 0 - 0 ) 0 . 8 4 (+ 2 . 0 ) - 0 . 7 3 (+ 1 - 5 ) 0 . 1 3 5 9 GH P O S T E X E R C I S E 1 6 . 6 (± 9 . 7 ) 1 3 . 5 (+ 1 1 . 6 ) 0 . 3 9 1 1 E X E R C I S E NET ( P o s t e x . - 1 2 0 ) 1 4 . 1 (+ 1 0 . 5 ) 1 1 . 7 (+ 1 0 . 5 ) 0 . 5 2 2 8 GH P O O L E D 6 . 3 (+ 3 . 6 ) 5 . 8 (+ 2 . 0 ) 0 . 5 6 7 9 P R O L A C T I N P O O L E D ( n g / m l ) 1 0 . 6 (± 3 . 5 ) 1 2 . 2 (± 4 . 5 ) 0 . 2 8 2 5 L A C T O G E N T O T A L ( n g / m l ) 1 1 . 5 (± 5 . 5 ) 1 1 . 5 (+ 4 . 4 ) 0 . 9 5 7 5 GH A C T I V E ( l a c t o g e n - P R O ) 0 . 8 5 (+ 4 . 3 ) - 0 . 7 1 (+ 2 . 7 ) 0 . 2 1 0 7 - 1 3 -TABLE 2: ANTHROPOMETRIC DATA FACTOR PRE (mean + SD) POST (mean + SD) HEIGHT (cm) 180.3 (± 3.7) 180.3 (+ 3.7) WEIGHT (kg) 78.5 (+ 7.6) 79.3 (± 7.9) 0.141 %FAT by CT 19.1 (± 7.3) 19.7 (± 7.8) 0.209 %FAT by U/WW 15.3 (+ 4.5) 15.5 (± 5.4) 0.705 SUM SKINFOLDS (mm) 83.0 (+ 25.7) 87.9 (+ 29.3) 0.082 THIGH GIRTH (cm) 59.6 (+ 4.5) 60.3 (± 4.5) 0. 107 -14-T A B L E 3 : P E R F O R M A N C E F A C T O R P R E ( m e a n + S D ) P O S T ( m e a n + S D ) V 0 2 MAX ( m l / k g ) 5 1 . 2 (± 5 . 6 ) 5 0 . 5 (± 7 . 8 ) 0 . 5 0 3 A S T T I M E ( s e c ) 4 8 . 0 (± H . 7 ) 5 0 . 2 (+ 1 3 . 4 ) 0 . 2 5 1 E N D U R A N C E RUN H E A R T R A T E : 10 M I N 1 6 4 . 6 (± 2 0 M I N 1 6 5 . 6 (± 1 1 - 9 ) 3 0 M I N 1 6 9 . 3 (+ 1 2 . 9 ) 1 6 5 . 5 (+ 1 0 . 5 ) 1 6 7 . 8 (+ 1 1 . 6 ) 1 7 1 . 5 (+ 1 1 . 8 ) H . R . v s T i m e p = 0 . 0 0 0 5 H . R . v s . P r e / P o s t p = 0 . 5 3 4 L A C T A T E ( m m o l / m l ) 0 M I N 10 M I N 1 . 3 3 (+ 0 . 7 6 ) 3 . 3 5 (+ 0 . 8 9 ) 0 . 5 3 (+ 0 . 1 6 ) 3 . 4 8 (+ 2 . 1 6 ) L a c t a t e v s . T i m e p = 0 . 0 0 1 5 20 M I N 3 0 M I N 3 . 5 5 (+ 2 . 2 0 ) 3 . 2 7 (+ 2 . 1 1 ) 3 . 0 1 (+ 1 . 9 7 ) 2 . 6 1 (+ 1 . 1 3 ) L a c t a t e v s . P r e / P o s t p = 0 . 3 6 1 4 - 1 5 -TABLE 4: STRENGTH FACTOR PRE POST (mean + SD) (mean + SD) GRIP 58.9 (± 5.8) RT. QUADRICEPS 128.3 ( f t . l b s a t (+ 21 .9) 30 d e g r e e s / s e c ) RT. QUADRICEPS 64.2 ( f o o t . l b s a t ( + 17.5) 180 d e g r e e s / s e c ) RT. HAMSTRINGS 50.7 ( f o o t . l b s a t (+ 14.4) 30 d e g r e e s / s e c ) RT. HAMSTRINGS 26.3 ( f o o t . l b s a t (+ 8.3) 180 d e g r e e s / s e c ) 60.4 (+ 6.6) 125.4 (+ 24.6) 65.9 (± 15.4) 48.7 (+ 14.4) 28.2 (+ 7.5) 0.192 0.6126 0.7427 0.3069 0.3112 -16-TABLE 5: HEMATOLOGY / BIOCHEMICAL FACTOR PRE (mean + SD) POST (mean + SD) HEMOGLOBIN ( g m / d l ) 15.1 (± 0.9) 15.1 (+ 0.8) 0.9156 FERRITIN (ng/ml) 135.0 (+ 56.6) 126.8 (+ 46.8) 0.4598 CHOLESTEROL ( m g / d l ) 176.8 (+ 32.2) 172.7 (+ 26.8) 0.5622 HDL CHOLESTEROL (mg/dl) 48.8 (+ 9.1) 47.1 (+ 10.7) 0.6505 CHOL : HDL RATIO 3.68 (+ 0.64) 3.79 (+ 0.91) 0.5362 TRIGLYCERIDES (mg/dl) 82.7 (± 39.6) 83.6 (+ 37.9) 0.9197 HEMOGLOBIN A l e (% of t o t a l ) 4.73 (+ 0.40) 4.72 (+ 0.38) 0.9182 -17-DISCUSSION The c o n t r o l of GH s e c r e t i o n i s a complex p r o c e s s t h a t i s not f u l l y u n d e r s t o o d . Growth hormone i s r e l e a s e d from the p i t u i t a r y under h y p o t h a l a m i c c o n t r o l . The d i r e c t p i t u i t a r y r e g u l a t i o n i s v i a two h y p o t h a l a m i c hormones, one s t i m u l a t o r y , GH r e l e a s i n g hormone (GHRH) and one i n h i b i t o r y , s o m a t o s t a t i n ( G H I F ) . The r e l e a s i n g f a c t o r s a r e i n t u r n c o n t r o l l e d by h y p o t h a l a m i c neurons, which a r e i n f l u e n c e d by a number of d i f f e r e n t n e u r o t r a n s m i t t e r s . GH r e l e a s e i s i n c r e a s e d by a l p h a a d r e n e r g i c , s e r o t o n i n e r g i c , d o p a m i n e r g i c , and c h o l i n e r g i c s t i m u l i , as w e l l as the b l o c k a d e of b e t a a d r e n e r g i c s t i m u l i ( 1 5 ) . The e f f e c t s of o t h e r s t i m u l i such as e x e r c i s e , amino a c i d s , and changes i n t e m p e r a t u r e and serum g l u c o s e are mediated t h r o u g h t h e s e n e u r o t r a n s m i t t e r s . I t i s thought t h a t the i n f l u e n c e s of a r g i n i n e and e x e r c i s e a r e both mediated t h r o u g h c h o l i n e r g i c n eurons, as a t r o p i n e w i l l b l o c k the GH r e s p o n s e to both s t i m u l i ( 1 6 ) . Other hormones i n f l u e n c e GH l e v e l s as d e m o n s t r a t e d by the h i g h e r GH l e v e l s i n f e m a l e s , and the f l u c t u a t i o n of t h o s e l e v e l s d u r i n g the m e n s t r u a l c y c l e ( 1 7 , 1 8 ) . I t i s t h u s a p p a r e n t t h a t the u l t i m a t e c o n t r o l of GH s e c r e t i o n i s m u l t i f a c t o r i a l and dependent on the b a l a n c e of a l a r g e number of i n f l u e n c e s . Pre v i o u s s t u d i e s have demonstrated t h a t amino a c i d s are a p o t e n t s t i m u l u s to GH r e l e a s e ( 2 ,3,16,17,20), and the GH response to an i n t r a v e n o u s i n f u s i o n of 30 grams of s r g i n i n e h y d r o c h l o r i d e i s used as a t e s t of p i t u i t a r y f u n c t i o n . O r a l a d m i n i s t r a t i o n of amino a c i d s can a l s o i n c r e a s e serum GH, and t h e r e are two d i f f e r e n t r e s ponse p a t t e r n s r e p o r t e d i n the l i t e r a t u r e . High doses of a r g i n i n e a s p a r t a t e (250-500 mg/kg: 17.5-35 gms f o r a 70 -18-kg a d u l t ) w i l l cause an immediate r i s e i n GH l e v e l s to 12 - 20 ng/ml ( 3 , 1 9 ) . Lower doses of a r g i n i n e a s p a r t a t e (100 mg/kg: 7 gms f o r a 70 kg a d u l t ) have no e f f e c t ( 2 0 ) , w h i l e low doses r e p e a t e d s e v e r a l t i m e s a day have no immediate e f f e c t , but cause an average 60% i n c r e a s e i n the l e v e l of the s l e e p r e l a t e d GH surge ( 3 ) . Acute a d m i n i s t r a t i o n of 1.2 gms a r g i n i n e p y r r o l i d o n e c a r b o x y l a t e and 1.2 gms l y s i n e have been r e p o r t e d to cause a 700% i n c r e a s e i n GH l e v e l s w i t h i n 90 minutes ( 2 ) . B e f o r e t h e main st u d y was p e r f o r m e d , a p i l o t s t u d y a s s e s s e d the GH r e s p o n s e s t o v a r i o u s dosages and c o m b i n a t i o n s of amino a c i d s . The p i l o t s t u d y was u n a b l e t o d u p l i c a t e the r e s u l t s of I s i d o r i et a l ( 2 ) , and found the c o m b i n a t i o n of a r g i n i n e and l y s i n e i n e f f e c t i v e i n c a u s i n g an i n c r e a s e i n GH. The GH r e s p o n s e was h i g h l y v a r i a b l e b oth between and w i t h i n s u b j e c t s . The s t u d y d i d show t h a t GH was i n c r e a s e d by o r a l a r g i n i n e , and t h a t h i g h e r doses produced h i g h e r GH r e s p o n s e s . U n p l e a s a n t g a s t r o i n t e s t i n a l s i d e e f f e c t s l i m i t e d the amount of AA t h a t c o u l d be i n g e s t e d a t any one time to l e s s than 8 grams. I t was thus d e c i d e d to conduct the main s t u d y u s i n g the s i n g l e d a i l y dose of 6 grams of a r g i n i n e h y d r o c h l o r i d e . The GH r e s p o n s e s found i n the main st u d y were s i m i l a r to t h o s e i n the p i l o t . Growth hormone was i n c r e a s e d by the AA, w i t h the r e s p o n s e to AA b e i n g g r e a t e r i n magnitude than t h a t to P. The l e v e l s were h i g h l y v a r i a b l e , however, and d i d not r e a c h s t a t i s t i c a l s i g n i f i c a n c e , p o s s i b l y due to the s m a l l number of s u b j e c t s i n the s t u d y . A second i n f l u e n c e i s the i n t e r - s u b j e c t v a r i a b i l i t y i n r e s p o n s e to AA, a phenomenon t h a t had been noted -19-i n the p i l o t s t u d y . T h i s may be due to the somatotype of the s u b j e c t s , as i t i s w e l l r e c o g n i z e d t h a t such f a c t o r s as f i t n e s s l e v e l and o b e s i t y can i n f l u e n c e GH r e s p o n s e s ( 1 5 , 1 7 ) . T h i s p o s s i b i l i t y i s s u p p o r t e d by the f i n d i n g of a s i g n i f i c a n t c o r r e l a t i o n between the GH r e s p o n s e to AA and p e r c e n t a g e body f a t and maximal oxygen u p t a k e . The d i f f e r e n c e s i n somatotype and V02max between the r e s p o n d e r s and n o n - r e s p o n d e r s were not s t a t i s t i c a l l y s i g n i f i c a n t , but the t r e n d may i n d i c a t e t h a t t h e s e f a c t o r s i n f l u e n c e d the o v e r a l l r e s u l t s . I t i s of note t h a t the s u b j e c t who had the l o w e s t body f a t and h i g h e s t oxygen uptake a l s o had the h i g h e s t GH r e s p o n s e to AA a d m i n i s t r a t i o n . There was no s i g n i f i c a n t change i n body c o m p o s i t i o n over the 7 week p e r i o d of AA a d m i n i s t r a t i o n . The r e s p o n d e r s tended to have a d e c r e a s e i n body f a t over the t r e a t m e n t p e r i o d , w h i l e the non-r e s p o n d e r s d i d n o t . One s u b j e c t showed a d e c r e a s e i n body f a t over the t r e a t m e n t p e r i o d as d e t e r m i n e d by a l l t h r e e methods of measurement. The s u b j e c t i n q u e s t i o n was the one w i t h the h i g h e s t GH r e s p o n s e to the AA. The CT scan showed c o n s i s t e n t l y h i g h e r v a l u e s f o r body f a t than were c a l c u l a t e d u s i n g h y d r o s t a t i c w e i g h i n g , but t h i s d i f f e r e n c e i s most l i k e l y r e l a t e d to the s e l e c t i o n of the t h i g h as the s i t e f o r the s c a n , as the r e s u l t s of the two methods had a h i g h c o r r e l a t i o n ( p r e : r=0.89, p o s t : r=0.94). The ab s o l u t e v a l u e s however, a r e l e s s i m p o r t a n t than the net change i n a s s e s s i n g the r e s p o n s e to AA. Body c o m p o s i t i o n would seem to be the most s e n s i t i v e i n d i c a t o r of a response to a c h r o n i c low l e v e l i n c r e a s e i n GH, i n a s t e a d y s t a t e s t u d y such as t h i s , where t h e r e i s no change i n s t r e n g t h or endurance t r a i n i n g . The s t u d y r e s u l t s i n d i c a t e t h a t a -20-s m a l l change i n GH l e v e l s does not l e a d t o any change i n body c o m p o s i t i o n . There have been no r e p o r t s of any human s t u d i e s s i m i l a r t o t h i s one, however, an a n i m a l s t u d y r e p o r t e d a p o s i t i v e n i t r o g e n b a l a n c e and net a n a b o l i c e f f e c t (p<0.01) when r a b b i t s were g i v e n l a r g e doses of a r g i n i n e a s p a r t a t e (1,500 mg/kg/day) ( 2 1 ) . A l t h o u g h the i n v e s t i g a t o r s d i d not measure GH l e v e l s i n the r a b b i t s , t h e i r p r e v i o u s work had demonstrated a l a r g e i n c r e a s e i n GH to t h a t dose of amino a c i d . W i s t a r r a t s f e d 500 mg/kg of a r g i n i n e a s p a r t a t e per day i n c r e a s e d t h e i r w e i g ht by an average of 35.1% compared to an average weight i n c r e a s e of o n l y 26.2% i n c o n t r o l a n i m a l s ( 2 2 ) . A e r o b i c and a n a e r o b i c performance was not a f f e c t e d by the a d m i n i s t r a t i o n of a r g i n i n e . The s u b j e c t s were i n a s t e a d y s t a t e of e x e r c i s e , and were s p e c i f i c a l l y i n s t r u c t e d to a v o i d any a t t e m p t s a t i n c r e a s i n g t h e i r f i t n e s s l e v e l s . S e v e r a l p r e v i o u s s t u d i e s i n a c t i v e l y t r a i n i n g a t h l e t e s have shown improvements i n performance t h r o u g h the a d m i n i s t r a t i o n of 1.0 gram of a r g i n i n e a s p a r t a t e t h r e e t i m e s a day (23,24,25,26). A doub l e b l i n d c o n t r o l s t u d y d e m o n s t r a t e d a 21.2% i n c r e a s e i n maximal oxygen uptake i n t r e a t e d s u b j e c t s , and a 6.5% i n c r e a s e i n c o n t r o l s (p<0.005) ( 2 3 ) . Another d o u b l e b l i n d s t u d y c l a i m e d an i n c r e a s e i n oxygen uptake i n t r e a t e d s u b j e c t s , but r e p o r t e d n e i t h e r a b s o l u t e v a l u e s nor l e v e l s of s i g n i f i c a n c e ( 2 4 ) . An u n c o n t r o l l e d s t u d y r e p o r t e d a more r a p i d h e a r t r a t e r e c o v e r y a f t e r a s t a n d a r d i z e d bout of e x e r c i s e however, the r e s u l t s c o u l d have been due to a t r a i n i n g e f f e c t a l o n e ( 2 5 ) . A double b l i n d s t u d y u s i n g 4 grams of a r g i n i n e a s p a r t a t e d a i l y showed an improvement i n c a r d i o v a s c u l a r f i t n e s s -21-as a s s e s s e d by the M a r t i n e t t e s t ( 2 6 ) . These e x p e r i m e n t s were a l l c o n d ucted i n a c t i v e l y t r a i n i n g e l i t e a t h l e t e s who had low body f a t s and h i g h maximal oxygen u p t a k e s , and were thus l i k e l y t o have h i g h e r GH r e s p o n s e s t o the amino a c i d . The d i f f e r e n c e s i n s u b j e c t somatotype and t r a i n i n g programs may e x p l a i n the l a c k of s i g n i f i c a n t changes i n the p r e s e n t s t u d y . There was no s i g n i f i c a n t i n c r e a s e i n s t r e n g t h i n the t e s t s u b j e c t s . The h i g h i n t e r and i n t r a s u b j e c t v a r i a b i l i t y f o r the Cybex t e s t would have made s i g n i f i c a n c e u n l i k e l y even i f t h e r e had been net i n c r e a s e s . F i v e s u b j e c t s found t h a t t r a i n i n g was s u b j e c t i v e l y e a s i e r and r e c o v e r y was improved d u r i n g the a d m i n i s t r a t i o n of the AA. Two s u b j e c t s t hought they were r e c e i v i n g AA d u r i n g the time they r e c e i v e d P. One of t h e s e thought he had more energy d u r i n g the P p e r i o d , w h i l e the o t h e r found a s l i g h t d e c r e a s e i n work c a p a c i t y i n the AA p e r i o d . S u b j e c t i v e r e s p o n s e s a r e o f t e n r e g a r d e d w i t h s k e p t i c i s m , e s p e c i a l l y i f they a re not s u p p o r t e d by o b j e c t i v e changes. The s u b j e c t i v e f i n d i n g s i n t h i s s t u d y however, are i n agreement w i t h the European s t u d i e s u s i n g a r g i n i n e a s p a r t a t e . In one double b l i n d s t u d y ( 2 7 ) , 25 of 30 s u b j e c t s r e l a t e d a d e c r e a s e i n f a t i g u e , an improvement i n r e c o v e r y t i m e , and a g e n e r a l improvement i n w e l l b e i n g w h i l e on a r g i n i n e . Only 18 of 28 c o n t r o l s u b j e c t s r e l a t e d the same improvements, and t h e i r s e n s a t i o n s of improvement were g e n e r a l l y l e s s than those e x p e r i e n c e d by the t r e a t m e n t group. Another double b l i n d study ( 2 3 ) , r e p o r t e d improvraents i n s l e e p i n g , g e n e r a l s t a t e of w e l l b e i n g , and r a t e of r e c o v e r y f o r t h o s e on a r g i n i n e as compared w i t h t h o s e r e c e i v i n g p l a c e b o . Other s t u d i e s a l s o r e p o r t -22-s u b j e c t i v e improvements i n t r a i n i n g w h i l e on a r g i n i n e ( 2 4 , 2 5 , 2 6 ) . B i o c h e m i c a l and h e m a t o l o g i c a l v a r i a b l e s remained i n the normal range d u r i n g the c o u r s e of the s t u d y . A l t h o u g h a 7 week stud y may not p r e d i c t l o n g terra e f f e c t s , t h i s s u g g e s t s t h a t amino a c i d i n g e s t i o n i s not l i k e l y to be h a r m f u l i n s u b j e c t s w i t h a s i m i l a r GH r e s p o n s e . No changes had been p r e d i c t e d , and t h u s t h i s low l e v e l i n c r e a s e i n GH does not seem to a f f e c t g l u c o s e or l i p i d m e t a b o l i s m or e r y t h r o p o e s i s . A l t h o u g h no u r i n a l y s i s was done i n t h i s s t u d y , o t h e r a u t h o r s have r e p o r t e d i n c r e a s e s i n the u r i n a r y e x c r e t i o n of 17 K e t o s t e r o i d s f o l l o w i n g o r a l a r g i n i n e a s p a r t a t e ( 2 8 ) . That s t u d y , however was c o nducted on h o s p i t a l i z e d p a t i e n t s , and i t s r e l a t i o n s h i p to a t h l e t e s i s u n c l e a r . T o x i c o l o g i c a l s t u d i e s of h i g h dose, o r a l a r g i n i n e a s p a r t a t e i n r a t s and mice r e v e a l e d no m a c r o s c o p i c or m i c r o s c o p i c a b n o r m a l a t i e s i n any t i s s u e s a t a u t opsy ( 2 2 ) . -23-CONCLUSIONS The d a i l y a d m i n i s t r a t i o n of 6.0 grams of a r g i n i n e h y d r o c h l o r i d e over a 7 week p e r i o d d i d not cause s i g n i f i c a n t GH e l e v a t i o n s i n t h i s group of m o d e r a t e l y f i t , male r e c r e a t i o n a l r u n n e r s . There were no changes i n body c o m p o s i t i o n , s t r e n g t h or performance as a r e s u l t of the AA i n g e s t i o n . There were i n t e r -s u b j e c t d i f f e r e n c e s i n the GH re s p o n s e t o the AA, w i t h some h a v i n g a much g r e a t e r r e s p o n s e than o t h e r s . There was a t r e n d towards b o t h a h i g h e r i n i t i a l V02max and a lower body f a t i n the r e s p o n d i n g group, and they a l s o tended towards a change i n body c o m p o s i t i o n . One s u b j e c t i n p a r t i c u l a r d e monstrated a marked GH re s p o n s e to the AA, and he a l s o d e c r e a s e d h i s body f a t and had a s t r o n g s u b j e c t i v e improvement i n t r a i n i n g . A p l a c e b o e f f e c t c o u l d a c c o u n t f o r a l l of t h e s e changes. P r e v i o u s s t u d i e s w i t h a r g i n i n e a s p a r t a t e , however, s u g g e s t t h a t AA a d m i n i s t r a t i o n can a l t e r body c o m p o s i t i o n i n a n i m a l s , i n c r e a s e maximal oxygen uptake i n humans, and cause s u b j e c t i v e changes t h a t i n c l u d e reduced f a t i g u e and more r a p i d r e c o v e r y . Moreover, t h e s e changes o c c u r r e d i n e l i t e a t h l e t e s who may be more l i k e l y t o have a GH response to AA a d m i n i s t r a t i o n because of t h e i r low body f a t and h i g h f i t n e s s l e v e l s . I t i s p o s s i b l e t h a t h i g h e r d a i l y doses of AA would have caused a GH r e s p o n s e and e f f e c t i n t h i s p o p u l a t i o n . The same AA dose i n a d i f f e r e n t s u b j e c t p o p u l a t i o n ( h i g h V02max, low body f a t ) might have y i e l d e d p o s i t i v e r e s u l t s . A c t i v e t r a i n i n g to i n c r e a s e s t r e n g t h or f i t n e s s might have changed the response to amino a c i d i n g e s t i o n . F u r t h e r i n v e s t i g a t i o n s , i n c l u d i n g t r a i n i n g s t u d i e s i n h i g h l y c o n d i t i o n e d a t h l e t e s a r e n e c e s s a r y b e f o r e amino a c i d i n g e s t i o n can be s a i d t o i n c r e a s e GH l e v e l s or cause changes -24-i n f i t n e s s l e v e l , performance or body c o m p o s i t i o n . T h i s study suggests t h a t the o r a l i n g e s t i o n of amino a c i d s by r e c r e a t i o n a l a t h l e t e s i s u n l i k e l y to cause e i t h e r harm or magic performance improvements. - 2 5 -KOSTYO, J . L . and REAGAN, C R . The B i o l o g y of Growth Hormone Pharraac. Ther. (1976) 2:591-604. ISIDORI, A., Lo MONACO, A. and CAPPA, M. A Study of Growth Hormone R e l e a s e i n Man A f t e r O r a l A d m i n i s t r a t i o n of Amino A c i d s . C u r r e n t M e d i c a l R e s e a r c h O p i n i o n s , (1981) 7:475-481. BESSET, A.,BONARDET, A., R0ND0UIN, G., DESCOMPS, B., and PASSOUANT, P.. I n c r e a s e i n S l e e p R e l a t e d GH and P r l . S e c r e t i o n a f t e r C h r o n i c A r g i n i n e A s p a r t a t e A d m i n i s t r a t i o n i n Man. A c t a . E n d o c r i n o l o g i c a , (1982) 99:18-23. BIGLAND, B. and JEHRING, B. M u s c l e P e r formance i n R a t s , Normal, and T r e a t e d With Growth Hormone. J . P h y s i o l . , ( 1 9 5 2 ) , 116:129-136. APOSTOLAKIS, M., DELIGIANNIS, A. and MADENA-PYRGAKI, A. The E f f e c t s of Human Growth Hormone A d m i n i s t r a t i o n on the F u n c t i o n a l S t a t u s of Rat A t r o p h i e d M u s c l e F o l l o w i n g I m m o b i l i z a t i o n . The P h y s i o l o g i s t , ( 1 9 8 0 ) , 2 3 ( S u p p l ) : S I 1 1 - 1 1 2 . PICKETT, J.B., LAYZER, R.B., LEVIN, S.R., SCHNEIDER, V. CAMPBELL, M.J. and SUMNER, A . J . Neuromuscular c o m p l i c a t i o n s of Acromegaly. N e u r o l o g y , ( 1 9 7 5 ) , 25:638-645. LEWIS, P.D.: Neuromuscular I n v o l v e m e n t i n P i t u i t a r y G i g a n t i s m . B r i t i s h M e d i c a l J o u r n a l , ( 1 9 7 2 ) , 2:499-500. NAUGELSPAREN, M., TRICKEY, R., DAVIES, M.J. and JENKINS, J.S. M u s c l e Changes i n Acromegaly. B r i t i s h M e d i c a l J o u r n a l , ( 1 9 7 6 ) , 2:914-915. WHITAKER, M.D., PRIOR, J . C , SCHUTHAUER, B., DOLMAN, L. , DURITY,F. and PUDECK, M. G o n a d o t r o p h i n - S e c r e t i n g P i t u i t a r y Tumor: Repo r t and Review. C l i n i c a l E n d o c r i n o l o g y , ( 1 9 8 5 ) , 22:43-48. RENNIE, P.S., PRIOR, J . C , BRUCHOVSKY, N. and GOUT, P.W. B i o a c t i v e Form of Serum L a c t o g e n : E f f e c t s of Treatment of P r o l a c t i n o m a P a t i e n t s W i t h B r o m o c r i p t i n e . C l i n i c a l E n d o c r i n o l o g y , ( 1 9 8 5 ) , 22:65-73. GORDON, P., L i , D., M a c i n t y r e , J.G. and P r i o r , J.C. Assessment of Body C o m p o s i t i o n U s i n g C o m p u t e r i z e d Tomography. M a n u s c r i p t P r e p a r a t i o n . ( 1 9 8 6 ) . S I R I , W.E. Gross C o m p o s i t i o n of the Body. I n : Advances i n  B i o l o g i c a l and M e d i c a l P h y s i c s , Volume IV, ( 1956). Lawrence, J.H. and T o b i a s , C.A. ( E d i t o r s ) . Academic P r e s s , I n c . , New York. -26-13 VOLKOV, N.I., SHIRKOVETS, E.A. and BORILKEVICH, V.E. Assessment of A e r o b i c and A n a e r o b i c C a p a c i t y of A t h l e t e s i n T r e a d m i l l Running T e s t s . European J o u r n a l of A p p l i e d P h y s i o l o g y , ( 1 9 7 5 ) , 34:121-130. 14 CUNNINGHAM, D.A. and FAULKNER, J.A. The E f f e c t of T r a i n i n g on A e r o b i c and A n a e r o b i c M e t a b o l i s m D u r i n g a S h o r t E x h a u s t i v e Run. M e d i c i n e and S c i e n c e i n S p o r t s and E x e r c i s e , ( 1 9 6 9 ) , l ( 2 ) : 6 5 - 6 9 . 15 GALBO, H. Hormonal and M e t a b o l i c A d a p t a t i o n s to E x e r c i s e , ( 1 9 8 3 ) . Georg Thieme V e r l a g , New Y o r k . 16 CASANUEVA, F.F., VILLANUEVA, L., CABRANES, J.A., CABEZAS-CERRATO, J . , AND FERNANDEZ-CRUZ, A. C h o l i n e r g i c M e d i a t i o n of Growth Hormone S e c r e t i o n E l i c i t e d by A r g i n i n e , C l o n i d i n e , and P h y s i c a l E x e r c i s e i n Man. J . C l i n . E n d o c r i n o l o g y and M e t a b o l i s m , ( 1 9 8 4 ) , 59(3):526-530. 17 SHEPHARD, R.J., AND SIDNEY, K.H. E f f e c t s of P h y s i c a l E x e r c i s e on Plasma Growth Hormone and C o r t i s o l L e v e l s i n Human S u b j e c t s . I n : E x e r c i s e and S p o r t S c i e n c e s Reviews, ( 1 9 7 5 ) , J.H. Wilmore and J . F . Keough, ( E d i t o r s ) . Academic P r e s s , New Y o r k . 18 LINF00T, J.A.: Acromegaly and G i a n t i s m . I n : E n d o c r i n e  C o n t r o l of Growth, ( 1 9 8 1 ) . W.H. Daugheday ( E d i t o r ) . E l s e v i e r N o r t h H o l l a n d I n c . , New York. 19 ELSAIR, J . , POEY, J . , R0CHICCI0LI, P., DENINE, R., MERAD, R. and BENOUNICHE, N. E f f e t s de L ' A d m i n i s t r a t i o n "Per 0 s " a Doses V a r i a b l e s , D ' A s p a r t a t e D ' A r g i n i n e e t de C h l o r h y d r a t e D ' A r g i n i n e s u r l e s Taux D'Hormone de C r o i s s a n c e e t D'Acides Gras L i b r e s du Plasma Chez L ' E n f a n t Normal a J e u n . P a t h o l o g i e B i o l o g i e , ( 1 9 8 0 ) , 28(10):639-644. 20 CAMPISTRON, G. Approche P h a r m a c o l o g i q u e de L ' A r g i n i n e et de L ' A c i d e A s p a r t i q u e . Etude P h a r m a c o c i e n e t i q u e e t Pharmacodynamique. T h e s i s No. 112, ( 1 9 8 0 ) , F a c u l t e des S c i e n c e s P h a r m a c e u t i q u e s , T o u l o s e . c i t e d i n B e s s e t e t a l . , o p . c i t . 21 ELSAIR, J . , KHELFAT, M., TABET A0UL, M. and IKLEF, F. E f f e t s de L ' A s p a r t a t e D ' A r g i n i n e , A d m i n i s t r e ' par V o i e O r a l , Sur l e B i l a n D'Azote du L a p i n Normal ou T r a i t e par L ' H y d r o c o r t i s o n e . P a t h . B i o l . , ( 1 9 8 2 ) , 30(4):206-210. 22 CASTAGNOU, R., E x p e r t i s e T o x i c o l o g i q u e de Sargenor S o l u t e ' B u v a b l e , a 10% de L - A s p a r t a t e de L - A r g i n i n e . Med. I n t . , ( 1 9 6 8 ) , 3(11):811-817. -27-23 TRANCIOVEANU, M., DRAGAN, I . , PLOESTEANU, N. e t CORNEANU, I . Etude de L ' I n f l u e n c e du Sargenor Sur l e s P r o c e s s u s de R e c u p e r a t i o n Chez l e s S p o r t i f s de P e r f o r m a n c e . C i n e s i o l o g i e , ( 1 9 7 1 ) , 10:137-145. 24 DRAGAN, I . , VASILIU, A. and LAZAR, N. R e s e a r c h e s C o n c e r n i n g the I n f l u e n c e of " S a r g e n o r " on H i g h - P e r f o r m a n c e Sportsmen. P r o c e e d i n g s of t h e T h i r d European Congress of S p o r t s M e d i c i n e , Budapest, September, 1974. 25 L'EGLISE, M. U t i l i s a t i o n de L ' A s p a r t a t e de L ' A r g i n i n e chez 50 Jeunes S p o r t i f ( E s p o i r s N a t i o n a u x ) . C i n e s i o l o g i e , ( 1970), 9:337-355. 26 SELLIER, J . I n t e r e t de L ' A s p a r t a t e D ' A r g i n i n e " S a r g e n o r " chez des A t h l e t e s de C o m p e t i t i o n en P e r i o d e D'Entrainement I n t e n s i f . Rev. Med. T o u l o u s e , ( 1 9 6 9 ) , 8:879-881. 27 STREICHER, M., CHAURAND, J . , TIXIER, P., DUBARRY, J.P., BERDEIL, S., BENECH, A. e t PONTAGNIER, H. Etudes B i o c h i m i q u e et C l i n i q ^ u e de L ' A c t i o n de L ' A s p a r t a t e D ' A r g i n i n e s u r l e s R e a c t i o n s de F a t i g u e de 58 A t h l e t e s . C i n e s i o l o g i e , ( 1 9 7 4 ) , 13:342-373. 28 MARTIN, M.P., VINCENEUX, M. e t HATOY, M.D. Etude C l i n i q u e et B i o l o g i q u e de L ' A s p a r t a t e D ' a r g i n i n e chez l e s S u j e t s de Moin de 50 Ans. J . des Med. du Nord e t de L ' E s t , ( 1 9 6 7 ) , 4:54-55. -28-APPENDIX A LITERATURE REVIEW -29-GROWTH HORMONE: REVIEW OF LITERATURE 1-GROWTH HORMONE 1-1 STRUCTURE AND PRODUCTION Human growth hormone (GH) i s a p o l y p e p t i d e hormone composed of 191 amino a c i d s , and h a v i n g a m o l e c u l a r w e i g h t of about 21,500 ( 1 ) . The a n t e r i o r p i t u i t a r y c o n t a i n s a t o t a l of 5 t o 10 mg of GH, which i s s y n t h e s i z e d and s t o r e d i n the somatotroph c e l l s ( 2 ) . GH p r o d u c t i o n i s i n f l u e n c e d by bo t h age and sex , and has been e s t i m a t e d a t between 0.4 and 1.0 rag per day i n a d u l t males, w i t h h i g h e r r a t e s i n a d o l e s c e n t s and fem a l e s ( 2 , 3 ) . Serum GH l e v e l s f l u c t u a t e d u r i n g the day but a r e g e n e r a l l y i n the range of 0.5 -3.0 ng/ml i n the a d u l t male ( 2 , 3 ) . L e v e l s r e f l e c t p r o d u c t i o n r a t e s , w i t h f e m a l e s and a d o l e s c e n t s h a v i n g h i g h e r l e v e l s ( 2 , 4 ) , and f e m a l e s t a k i n g e s t r o g e n s h a v i n g s t i l l h i g h e r l e v e l s ( 4 ) . GH i s m e t a b o l i z e d i n the l i v e r , w i t h a plasma h a l f - l i f e of 17 to 45 minutes ( 5 ) . 1-2 CONTROL OF GH SECRETION Growth hormone r e l e a s e from the p i t u i t a r y i s c o n t r o l l e d t h r o u g h a feedback system i n v o l v i n g two hormones, one e x c i t a t o r y , growth hormone r e l e a s i n g hormone (GHRH), and one i n h i b i t o r y , s o m a t o s t a t i n . A l t h o u g h the r e l e a s e mechanisms a re complex and i n c o m p l e t e l y u n d e r s t o o d , i t i s thought t h a t s o m a t o s t a t i n c o n t r o l o r i g i n a t e s from the a n t e r i o r h y p o t h a l a m i c p e r i v e n t r i c u l a r system, w h i l e t h a t of GHRH i s m a i n l y from the v e n t r o m e d i a l and a r c u a t e n u c l e i of the hypothalamus, and the l i m b i c system ( 6 , 7 , 8 ) . GHRH a t t a c h e s t o r e c e p t o r s i t e s on the GH s e c r e t o r y g r a n u l e s and -30-s t i m u l a t e s GH r e l e a s e t h r o u g h a c t i v a t i o n of membrane cAMP ( 8 ) . S o m a t o s t a t i n a c t s at a s e p a r a t e r e c e p t o r s i t e and i n h i b i t s GH r e l e a s e i n a n o n - c o m p e t i t i v e f a s h i o n ( 8 , 9 ) . The s e n s i t i v i t y of the p i t u i t a r y t o GHRH i s i n f l u e n c e d by a number of f a c t o r s , and may d i m i n i s h w i t h age ( 7 , 8 ) . 1-3 GH RELEASE There a re many p h y s i o l o g i c and p h a r m a c o l o g i c s t i m u l i t o GH r e l e a s e , w i t h each a c t i n g on a s p e c i f i c a r e a of the b r a i n and mediated t h r o u g h pathways c o n t r o l l e d by d o p a m i n e r g i c , a d r e n e r g i c , c h o l i n e r g i c and s e r o t o n e r g i c neurons ( 6 , 7 ) . There i s a g r e a t d e a l of i n t e r a c t i o n between the s t i m u l i , w i t h c o m b i n a t i o n s m o d u l a t i n g each o t h e r i n e i t h e r a s y n e r g i s t i c or c o m p e t i t i v e manner ( 6 , 7 ) . There a r e hormonal i n f l u e n c e s on GH r e s p o n s e , as women have h i g h e r b a s a l GH l e v e l s , d e m o n s t r a t e f l u c t u a t i o n s i n GH l e v e l s d u r i n g the m e n s t r u a l c y c l e and have a g r e a t e r r e s p o n s i v e n e s s to GH r e l e a s e s t i m u l i ( 5 ) . These d i f f e r e n c e s are p r o b a b l y on the b a s i s of e s t r o g e n l e v e l s , as r e s p o n s e s a re d e c r e a s e d i n menopausal women, and the r e s p o n s e s of men t r e a t e d w i t h e s t r o g e n s are s i m i l a r t o , but s l i g h t l y l e s s than those of women ( 5 , 1 0 ) . T e s t o s t e r o n e does not seem to i n f l u e n c e GH r e l e a s e , as i t s a d m i n i s t r a t i o n to 8 women d i d not r e s u l t i n a s i g n i f i c a n t change i n t h e i r GH response to a r g i n i n e i n f u s i o n ( 1 0 ) . There a re e p i s o d i c GH s u r g e s d u r i n g the day, w i t h the l a r g e s t o c c u r r i n g 60 to 90 minutes a f t e r s l e e p o n s e t , at the b e g i n n i n g of slow wave s l e e p ( 2 , 3 , 7 , 1 1 ) . I t i s thought t h a t s l e e p r e l a t e d GH s u r g e s a re i n i t i a t e d by the l i m b i c system and mediated by s e r o t o n e r g i c neurons ( 6 , 7 ) , and t h a t t h e y are d e c r e a s e d i n -31-magnitude i n both the e l d e r l y and obese ( 2 , 1 1 ) . The n o c t u r n a l s e c r e t i o n of GH may be i n c r e a s e d i n t r a i n e d a t h l e t e s w i t h i n c r e a s e d a c t i v i t y l e v e l s ( 1 2 ) . P s y c h o l o g i c a l and p h y s i c a l s t r e s s e s can i n c r e a s e GH s e c r e t i o n ( 1 , 2 , 3 , 5 , 6 , 7 ) . A l t h o u g h the e x a c t mechanism and c e n t r e of c o n t r o l i s unknown, i t i s p o s s i b l e t h a t i t a c t s t h r o u g h i n c r e a s e d c e n t r a l c a t e c h o l a m i n e r e l e a s e ( 1 ) . GH r e l e a s e i s i n c r e a s e d i n r e s p o n s e to h y p o g l y c e m i a and i n h i b i t e d by a r i s i n g b l o o d g l u c o s e . The GH r e s p o n s e i s s t i m u l a t e d by both a b s o l u t e h y p o g l y c e m i a , and a r a p i d d e c r e a s e i n b l o o d g l u c o s e even i n the p r e s e n c e of normal serum l e v e l s ( 3 , 1 3 ) . The r e s p o n s e to h y p o g l y c e m i a i s mediated i n p a r t t h r o u g h a l p h a a d r e n e r g i c neurons a t the l e v e l of the v e n t r o m e d i a l n u c l e u s ( 6 , 7 , 1 1 ) , and can be i n c r e a s e d by b e t a a d r e n e r g i c b l o c k a d e and d e c r e a s e d by a l p h a a d r e n e r g i c b l o c k a d e and s e r o t o n i n a n t a g o n i s t s ( 1 1 ) . I n s u l i n i n d u c e d h y p o g l y c e m i a i s employed as a t e s t of p i t u i t a r y f u n c t i o n , and r e s u l t s i n a GH r i s e i n 85 to 100 p e r c e n t of normal i n d i v i d u a l s ( 1 1 ) . E x e r c i s e i s a p o t e n t s t i m u l u s f o r GH r e l e a s e , w i t h 20 minutes of e x e r c i s e a t 75 to 90% of V02max r e s u l t i n g i n a GH response e q u i v a l e n t i n magnitude to t h a t i n d u c e d by i n s u l i n h y p o g l y c e m i a and g r e a t e r t h a n t h e r e s p o n s e s to s l e e p , a r g i n i n e and L-Dopa ( 1 4 ) . The GH r e s p o n s e i s i n f l u e n c e d by the e x e r c i s e ( t y p e , i n t e n s i t y and d u r a t i o n ) , the c h a r a c t e r i s t i c s of the i n d i v i d u a l (age, sex, body c o m p o s i t i o n , f i t n e s s l e v e l ) , e n v i r o n m e n t a l f a c t o r s , and p r e - t r e a t m e n t w i t h v a r i o u s d r u g s . The i n t e r a c t i o n s between e x e r c i s e and GH have been e x t e n s i v e l y -32-s t u d i e d , and the r e s u l t s are summarized i n r e v i e w a r t i c l e s ( 5 , 1 5 ) . The c e n t r a l c o n t r o l mechanisms of e x e r c i s e r e l a t e d GH r e l e a s e have not been d e f i n i t e l y e s t a b l i s h e d . B l o c k a d e of a l p h a a d r e n e r g i c , s e r o t o n e r g i c , c h o l i n e r g i c and d o p a m i n e r g i c neurons i n h i b i t s GH r e l e a s e ( 1 5 , 1 6 ) , w h i l e r e l e a s e i s i n c r e a s e d by b e t a a d r e n e r g i c b l o c k a d e ( 1 5 ) , and p y r i d o x i n e i n f u s i o n , which p r o b a b l y a c t s t h r o u g h i n c r e a s e d c e n t r a l d o p a m i n e r g i c a c t i v i t y ( 1 7 ) . Serum GH l e v e l s i n c r e a s e d u r i n g e x e r c i s e , w i t h the o nset of t h e i n c r e a s e e a r l i e r w i t h more i n t e n s e e x e r c i s e ( 5 ) . Peak l e v e l s a r e found 15 to 30 m i n u tes f o l l o w i n g e x e r c i s e ( 1 4 , 1 8 ) , and d e c r e a s e w i t h a h a l f - l i f e of 16 t o 23 m i n u tes ( 5 , 1 8 ) . I n e x e r c i s e of l o n g e r d u r a t i o n GH l e v e l s may r e a c h a peak and then d e c l i n e ( 5 ) , a l t h o u g h they were found to be e l e v a t e d i n 7 s u b j e c t s i m m e d i a t e l y f o l l o w i n g a 100 km u l t r a m a r a t h o n ( 1 9 ) . The t y p e of e x e r c i s e i s i m p o r t a n t i n d e t e r m i n i n g the GH r e s p o n s e , w i t h i n t e r m i t t a n t p r o d u c i n g h i g h e r l e v e l s than c o n t i n u o u s e x e r c i s e ( 2 0 ) , even when the t o t a l amount of work i s e q u a l ( 2 1 , 2 2 ) . Arm work has been shown to cause a g r e a t e r GH r e s p o n s e than l e g work at an e q u i v a l e n t oxygen uptake ( 2 3 ) , a l t h o u g h the arm work was a l s o a s s o c i a t e d w i t h h i g h e r h e a r t r a t e s , b l o o d p r e s s u r e , and plasma n o r e p i n e p h e r i n e and l a c t a t e l e v e l s . In c y c l e e r g o m e t r y , GH r e l e a s e has been shown to be p r o p o r t i o n a l to the i n t e n s i t y of the work and i n d e p e n d a n t of changes i n b l o o d pH and l a c t a t e ( 2 4 ) . Other a u t h o r s have found t h a t the GH r e s p o n s e i s g r e a t e s t w i t h moderate e x e r c i s e , and d e c r e a s e d towards b a s a l l e v e l s i n maximal e x e r c i s e ( 2 5 , 2 6 ) . S t i l l -33-o t h e r a u t h o r s have f a i l e d t o show any r e l a t i o n s h i p between e x e r c i s e i n t e n s i t y and the magnitude of the GH r e s p o n s e ( 2 7 ) . One a u t h o r d e m o n s t r a t e d a GH r e s p o n s e to a s h o r t bout of i n t e n s e s t a i r c l i m b i n g , but no r e s p o n s e to w a l k i n g a t moderate speed (4 m.p.h.) f o r 1.5 h o u r s , a l t h o u g h a GH r e s p o n s e o c c u r r e d w i t h w a l k i n g f o l l o w i n g p r e - t r e a t m e n t w i t h a p r o t e i n d r i n k ( 2 8 ) . A h i g h l o a d , low r e p e t i t i o n w e i g h t . l i f t i n g p r o t o c o l produced a GH i n c r e a s e , w h i l e a low l o a d , h i g h r e p e t i t i o n p r o t o c o l of e q u i v a l e n t t o t a l l o a d and d u r a t i o n had no e f f e c t ( 2 9 ) . GH r e l e a s e f o l l o w i n g e x e r c i s e i s thought to be d e t e r m i n e d by the s u b j e c t ' s f i t n e s s l e v e l , w i t h a g r e a t e r r e s p o n s e d e m o n s t r a t e d i n u n f i t than i n f i t i n d i v i d u a l s , even a t e q u i v a l e n t w o r k l o a d s ( 1 5 ) . One s t u d y , however, d e m o n s t r a t e d no d i f f e r e n c e i n r e s p o n s e between f i t and u n f i t s u b j e c t s i n e x e r c i s e to e x h a u s t i o n ( 3 0 ) , a l t h o u g h i t i s p o s s i b l e t h a t s t r e s s c o n t r i b u t e d to the r e s p o n s e to e x h a u s t i v e e x e r c i s e . L o n g i t u d i n a l t r a i n i n g s t u d i e s have shown t h a t the GH r e s p o n s e to an e q u i v a l e n t i n t e n s i t y of e x e r c i s e i s lower f o l l o w i n g t r a i n i n g , a l t h o u g h the d i f f e r e n c e s were not s t a t i s t i c a l l y s i g n i f i c a n t ( 2 5 , 2 6 ) . Other a u t h o r s , however, have noted no t r a i n i n g i n d u c e d change i n the GH r e s p o n s e to e x e r c i s e ( 3 1 ) . T r a i n i n g has been shown to reduce the d e c l i n e towards b a s a l GH l e v e l s found d u r i n g i n t e n s e e x e r c i s e ( 2 5 , 2 6 ) . Women have h i g h e r GH r e s p o n s e s to e x e r c i s e , p o s s i b l y on the b a s i s of e s t r o g e n l e v e l s ( 5 ) , a l t h o u g h i t has been p o s t u l a t e d t h a t the i n c r e a s e may be due to l o w e r f i t n e s s l e v e l s ( 5 ) , or a h i g h e r p s y c h o l o g i c a l s t r e s s r e s p o n s e to e x e r c i s e ( 1 5 ) . Body c o m p o s i t i o n i n f l u e n c e s the GH r e s p o n s e to a v a r i e t y of -34-s t i m u l i , i n c l u d i n g e x e r c i s e , w i t h obese i n d i v i d u a l s b e i n g l e s s r e s p o n s i v e ( 2 , 6 , 1 1 , 1 5 ) . Temperature i n c r e a s e s d u r i n g e x e r c i s e may be a s t i m u l u s to GH s e c r e t i o n , as e x e r c i s e i n a warm environment has been shown to r e s u l t i n a g r e a t e r GH r e s p o n s e than the same e x e r c i s e i n the c o l d ( 3 2 , 3 3 , 3 4 ) . Other a u t h o r s , however, d i s p u t e t h i s phenomenon, and c l a i m t h a t t h e r e i s a g r e a t d e a l of i n t e r - s u b j e c t v a r i a b i l i t y i n GH r e s p o n s e s t o h e a t i n g ( 2 0 ) . H e a t i n g a l o n e , i n the absence of e x e r c i s e , has r e s u l t e d i n a GH s u r g e g r e a t e r i n magnitude than t h a t r e s u l t i n g from t e m p e r a t u r e i n c r e a s e s d u r i n g e x e r c i s e ( 3 4 ) . C o l d ambient c o n d i t i o n s have r e s u l t e d i n v i r t u a l l y c o mplete i n h i b i t i o n of GH s e c r e t i o n i n r e s p o n s e to e x e r c i s e ( 3 3 , 3 4 ) , a l t h o u g h GH was found to i n c r e a s e d u r i n g the post e x e r c i s e r e c o v e r y p e r i o d ( 3 3 ) , which may merely r e f l e c t a d e l a y e d r e s p o n s e . I t i s p o s s i b l e t h a t the GH r e s p o n s e s to t e m p e r a t u r e may be p a r t of the g e n e r a l i z e d s t r e s s r e a c t i o n ( 3 2 ) , and t h i s mechanism may be e s p e c i a l l y i m p o r t a n t i n s t u d i e s where s u b j e c t s a r e a r t i f i c i a l l y h e a t e d . G l u c o s e i n g e s t i o n w i l l d e c r e a s e the GH r e s p o n s e to e x e r c i s e ( 5 ) , a l t h o u g h t h i s may be more pronounced i n m i l d than i n moderate or i n t e n s e e x e r c i s e ( 1 5 ) . D i a b e t i c s have h i g h e r GH r e s p o n s e s than normal c o n t r o l s to s i m i l a r e x e r c i s e bouts ( 5 , 3 5 ) . GH r e l e a s e i s i n f l u e n c e d by p h a r m a c o l o g i c agents i n c l u d i n g o t h e r hormones and drugs which a l t e r the l e v e l s of the c e n t r a l n e u r o t r a n s m i t t e r amines. GH i s r e l e a s e d i n r e s p o n s e to n o r a d r e n a l i n , c l o n i d i n e , L-dopa, b r o m o c r i p t i n e , p r o p r a n o l o l , apomorphine, v a s o p r e s s i n and g l u c a g o n , w h i l e i t s r e l e a s e i s i n h i b i t e d by i s o p r o t e r e n o l , p h e n t o l a r a i n e , raethysergide, -35-c y p r o h e p t a d i n e , morphine, c h l o r p r o m a z i n e , i m i p r a m i n e and g l u c o c o r t i c o i d s ( 2 , 6 , 7 , 1 1 ) . Amino a c i d s can s t i m u l a t e GH r e l e a s e . They a r e e f f e c t i v e both o r a l l y , t h r o u g h the i n g e s t i o n of s i m p l e amino a c i d s (36,37) and p r o t e i n r i c h d r i n k s ( B o v r i l ) ( 1 1 , 2 8 ) , and v i a i n t r a v e n o u s i n f u s i o n ( 2 , 6 , 7 , 1 0 , 1 1 ) , which can be used as a t e s t of p i t u i t a r y f u n c t i o n . Serum GH was i n c r e a s e d s e v e n - f o l d 90 mi n u t e s a f t e r the i n g e s t i o n of 1.2 gm of 1 - a r g i n i n e p y r r o l i d o n e c a r b o x y l a t e and 1.2 gm of 1 - l y s i n e h y d r o c h l o r i d e i n 15 males aged 15 t o 20 y e a r s ( 3 6 ) . No re s p o n s e was o b t a i n e d when e i t h e r of the amino a c i d s were a d m i n i s t e r e d a l o n e . A l t h o u g h the s u b j e c t s ' body c o m p o s i t i o n , f i t n e s s l e v e l s , and degree of m a t u r i t y can a l l i n f l u e n c e the GH r e s p o n s e , none of th e s e f a c t o r s a r e r e p o r t e d by the a u t h o r s . F i v e males aged 20 to 35 i n g e s t e d 250 mg/kg of a r g i n i n e a s p a r t a t e i n 3 d i v i d e d d o s e s , r e s u l t i n g i n a 60% i n c r e a s e i n s l e e p - r e l a t e d GH s e c r e t i o n as compared to p l a c e b o c o n t r o l , w i t h no change i n daytime GH v a l u e s ( 3 7 ) . A l t h o u g h t h i s low dose of a r g i n i n e a s p a r t a t e (83 rag/kg) does not s t i m u l a t e an a c u t e GH r e s p o n s e , o t h e r s t u d i e s have shown t h a t h i g h e r doses (250 mg/kg) w i l l r e s u l t i n an immediate, s i g n i f i c a n t GH re s p o n s e ( 3 8 ) . The mechanism of a r g i n i n e i n d u c e d GH r e l e a s e i s u n c l e a r , but a d r e n e r g i c (11) and c h o l i n e r g i c (16) neurons a r e i n v o l v e d . The r e s p o n s e to a r g i n i n e can be d e c r e a s e d by the i n f u s i o n of be t a e n d o r p h i n s ( 3 9 ) , p r i o r a d m i n i s t r a t i o n of a h i g h c a r b o h y d r a t e d i e t ( 6 ) , h y p e r g l y c e m i a ( 1 0 ) , i n c r e a s e d f r e e f a t t y a c i d s ( 1 1 ) , and clomi p h e n e ( 1 1 ) . I n c r e a s e d r e s p o n s e s o c c u r i n both men and women f o l l o w i n g e s t r o g e n a d m i n i s t r a t i o n ( 1 0 , 1 1 , 2 8 ) . Dopamine i n f u s i o n -36-has a d u a l e f f e c t on a r g i n i n e i n d u c e d GH r e l e a s e , i n c r e a s i n g the re s p o n s e i f a r g i n i n e i s g i v e n c o i n c i d e n t l y and e a r l y i n the i n f u s i o n , but b l u n t i n g t h e r e s p o n s e i f a r g i n i n e i s g i v e n a f t e r a l o n g e r p e r i o d of i n f u s i o n ( 4 0 ) . 2-EFFECTS 2-1 FUNCTION The most i m p o r t a n t f u n c t i o n of GH i s to i n c r e a s e s o m a t i c growth. A d m i n i s t r a t i o n t o h y p o p i t u i t a r y c h i l d r e n r e s u l t s i n a p o s i t i v e n i t r o g e n b a l a n c e and a s t i m u l a t i o n of s k e l e t a l and s o f t t i s s u e growth ( 2 ) . A l t h o u g h i t was once thought t h a t the r e g u l a t i o n of l i n e a r growth i n c h i l d h o o d was i t s s o l e f u n c t i o n , i t i s now a p p a r e n t t h a t i t s m e t a b o l i c e f f e c t s a re i m p o r t a n t i n day to day h o m e o s t a t i c f u n c t i o n i n g . 2-2 METABOLIC GH red u c e s g l u c o s e and p r o t e i n m e t a b o l i s m by s h i f t i n g o x i d a t i v e m e t a b o l i s m towards the u t i l i z a t i o n of f a t t y a c i d s , perhaps i n o r d e r to s p a r e p r o t e i n f o r a n a b o l i c pathways ( 2 , 4 1 , 4 2 ) . I n h y p o p i t u i t a r y a n i m a l s , GH i n d u c e s an immediate i n c r e a s e i n the c e l l u l a r uptake of g l u c o s e ( 2 , 4 1 ) , however, t h i s i n i t i a l i n s u l i n - l i k e e f f e c t i s m i n i m a l i n no r m a l , i n t a c t a n i m a l s and humans and i s thought to be of l i t t l e c l i n i c a l s i g n i f i c a n c e ( 2 ) . GH i n h i b i t s the c e l l u l a r uptake of g l u c o s e and has a net a n t i ' n s u l i n e f f e c t ( 1 , 2 , 6 , 4 1 ) . I n a d d i t i o n , g l u c o s e i s l i b e r a t e d from the l i v e r t h r o u g h g l u c o n e o g e n e s i s as w e l l as a g r e a t e r r e l e a s e from the i n c r e a s e d h e p a t i c g l y c o g e n s t o r e s ( 4 1 ) . I n s u l i n r e l e a s e i s i n c r e a s e d , both i n r e s p o n s e to h y p e r g l y c e m i a , and - 3 7 -through a d i r e c t e f f e c t on the b e t a c e l l s of the pancreas t h a t i n c r e a s e s i n s u l i n l e v e l s i n d e p e n d a n t of i t s e f f e c t on g l u c o s e ( 2 , 6 , 4 1 , 4 2 ) . T o t a l d a i l y i n s u l i n p r o d u c t i o n i s markedly i n c r e a s e d by GH ( 4 2 ) , and i t has been proposed t h a t the i n c r e a s e d u t i l i z a t i o n of i n s u l i n i s t h r o u g h enhanced a f f i n i t y f o r i n s u l i n by the enzyme systems f o r p r o t e i n s y n t h e s i s ( 4 2 ) . P r o l o n g e d h i g h l e v e l s of GH, such as t h o s e found i n a c r o m e g a l y , can r e s u l t i n d i a b e t e s . GH s t i m u l a t e s the m o b i l i z a t i o n of l i p i d s from a d i p o s e t i s s u e , and i n c r e a s e s t h e i r o x i d a t i o n , w i t h a r e s u l t a n t f a l l i n r e s p i r a t o r y q u o t i e n t (1,2,6,41,42,43). A d m i n i s t r a t i o n of GH l e a d s to a r e d u c t i o n of p e r i p h e r a l a d i p o s e s t o r e s , an i n c r e a s e i n h e p a t i c f a t s t o r e s and i n c r e a s e d plasma f r e e f a t t y a c i d s (FFA) (2,6,41,42,43). A l t h o u g h some s t u d i e s i n d i c a t e t h a t GH p l a y s a s i g n i f i c a n t r o l e i n the m o b i l i z a t i o n of FFA d u r i n g e x e r c i s e ( 4 4 ) , o t h e r i n v e s t i g a t o r s q u e s t i o n i t s i m p o r t a n c e . F o l l o w i n g e x e r c i s e f o r 60 m i n u t e s , FFA m o b i l i z a t i o n was demonstrated i n normal r a t s , however, t h e r e was no such FFA r e s p o n s e i n h y p o p h y s e c t o m i z e d r a t s ( 4 5 ) . Because the post e x e r c i s e GH l e v e l s were g r e a t l y reduced i n the normal r a t s , the a u t h o r s c o n c l u d e d t h a t GH had no r o l e i n the FFA m o b i l i z a t i o n . T h i s i n t e r p r e t a t i o n may have been e r r o n e o u s as the GH l e v e l s d u r i n g the e x e r c i s e were not known, and s e v e r e e x e r c i s e has p r e v i o u s l y been shown to d e c r e a s e GH l e v e l s . I t i s p o s s i b l e t h a t GH a c t s i n c o n j u n c t i o n w i t h g l u c o c o r t i c o i d s and o t h e r hormones to mediate the FFA r e s p o n s e ( 4 1 ) . P r o t e i n s y n t h e s i s i s g r e a t l y i n c r e a s e d by the a d m i n i s t r a t i o n of GH to h y p o p h y s e c t o m i z e d a n i m a l s ( 4 1 ) . The e x a c t mechanisms w i l l be d i s c u s s e d i n the s e c t i o n on the e f f e c t of GH on muscle. -38-2-3 GROWTH Somatic growth i s i n c r e a s e d by the a d m i n i s t r a t i o n of GH, a l t h o u g h t h e r e i s some c o n t r o v e r s y as to the e x a c t mechanism. E a r l y i n v e s t i g a t o r s were unable to s t i m u l a t e c h o n d r o c y t e growth i n v i t r o t h r o u g h the a d d i t i o n of GH to the c e l l c u l t u r e medium, and i t was o n l y a f t e r t hey added serum from i n t a c t a n i m a l s t h a t growth o c c u r r e d ( 2 , 4 1 , 4 6 ) . They l a t e r i s o l a t e d the somatomedins, a group of growth p r o m o t i n g p o l y p e p t i d e s t h a t a r e s y n t h e s i z e d i n the l i v e r and c i r c u l a t e i n the b l o o d f o l l o w i n g exposure to GH ( 4 6 ) . The somatomedins have been p u r i f i e d , w i t h the most p o w e r f u l a t growth s t i m u l a t i o n b e i n g Somatomedin C, a l s o c a l l e d i n s u l i n -l i k e growth f a c t o r 1 (IGF-1) ( 4 6 , 4 7 ) . Somatomedin l e v e l s a r e r e l a t i v e l y low i n i n f a n t s , r e a c h a d u l t l e v e l s by the age of 6 y e a r s , and d e c l i n e i n o l d e r i n d i v i d u a l s ( 4 6 , 4 7 ) . L e v e l s a re more dependant on the 24 hour i n t e g r a t e d GH l e v e l s than peak GH l e v e l s ( 4 6 , 4 7 ) . Some a u t h o r s s p e c u l a t e t h a t the c a t a b o l i s m of a g i n g r e s u l t s from a r e d u c t i o n i n somatomedin l e v e l s i n r e s p o n s e to an age r e l a t e d d e c l i n e i n GH s e c r e t i o n ( 4 7 ) . I n t r a u t e r i n e growth i s i n d e p e n d a n t of GH and somatomedin l e v e l s , w i t h g r a d u a l l y i n c r e a s i n g dependance t h r o u g h the p o s t n a t a l p e r i o d ( 4 7 , 4 8 ) . E s t r o g e n s i n h i b i t the p r o d u c t i o n of somatomedins, and i t i s s p e c u l a t e d t h a t t h i s feedback r e s u l t s i n the h i g h e r GH l e v e l s found i n f e m a l e s ( 4 6 ) . The i n v i t r o e f f e c t s of somatomedins are c h o n d r o g e n i c , s t i m u l a t i n g DNA, RNA, and p r o t e i n s y n t h e s i s , and i n c r e a s i n g the i n c o r p o r a t i o n of s u l f a t e i n t o p r o t e o g l y c a n s ( 4 6 ) . They a l s o have i n s u l i n l i k e e f f e c t s , i n c r e a s i n g c e l l u l a r uptake of g l u c o s e and -39-amino a c i d s , and en h a n c i n g g l y c o g e n and p r o t e i n s y n t h e s i s ( 4 6 ) . The i n v i v o e f f e c t s of the somatomedins a r e d i f f i c u l t to s e p a r a t e from t h o s e of GH i t s e l f , as c e l l p r o l i f e r a t i o n i s dependant, e i t h e r d i r e c t l y or i n d i r e c t l y , on the pr e s e n c e of GH ( 4 8 ) . C a r t i l a g e has r e c e p t o r s i t e s f o r both somatomedins ( 4 6 ) , and GH, which has been shown to d i r e c t l y s t i m u l a t e i t s growth ( 4 8 ) . I t i s ap p a r e n t t h a t f u r t h e r s t u d i e s a r e needed b e f o r e the i s s u e i s r e s o l v e d . 2-4 MUSCLE Muscle growth i s a c o m p l i c a t e d p r o c e s s t h a t i s a f u n c t i o n of both work and hormonal f a c t o r s ( 4 9 , 5 0 ) . M u s c l e grows both l o n g i t u d i n a l l y and c i r c u m f e r e n t i a l l y , w i t h l o n g i t u d i n a l growth o c c u r r i n g d u r i n g the l i n e a r growth phase, i n c h i l d h o o d t h r o u g h the a d d i t i o n of sarcomeres a t the rausculo-tendonous j u n c t i o n ( 5 0 , 5 1 ) . M u s c l e c e l l s i n c r e a s e i n d i a m e t e r t h r o u g h an i n c r e a s e i n the number of m y o f i b r i l s . The p r o t e i n s f o r f i b r e growth ( a c t i n , myosin and t r o p o r a y s i n ) a r e s y n t h e s i z e d i n l a r g e p o l y r i b o s o m e s t h a t l i e i n the s a r c o p l a s r a a d j a c e n t to e x i s t i n g m y o f i b r i l s . These p r o t e i n s then a g g r e g a t e to form f i l a m e n t s which a t t a c h t h e m s e l v e s to t he Z l i n e s ( 5 0 ) . T h i s mechanism i s common to both work and hormone i n d u c e d growth, even though the u n d e r l y i n g c o n t r o l mechanism a t the c e l l u l a r l e v e l appears to be d i f f e r e n t f o r the two t y p e s of growth. In both t y p e s of growth the f o r m a t i o n of new p r o t e i n s has many r e q u i r e m e n t s a t a c e l l u l a r l e v e l ( 5 2 ) . The mRNA t e m p l a t e must be produced from the n u c l e a r DNA, a r e a c t i o n c a t a l y z e d by RNA polymerase.- The mRNA appears i n the c y t o p l a s m where i t -40-a t t a c h e s to ribosoraes and s u b s e q u e n t l y i n t e r a c t s w i t h the tRNA c a r r y i n g the s p e c i f i c amino a c i d s to be i n c o r p o r a t e d i n t o the f i n a l p r o t e i n . The e n t i r e p r o c e s s i s thus dependant on the s u p p l y of amino a c i d s , the number of r i b o s o m e s , and the p r e s e n c e and a c t i v i t y of s e v e r a l enzymes. When GH i s added to c e l l s i n v i t r o t h e r e i s no d e t e c t a b l e change f o r 20 to 30 m i n u t e s . A f t e r the i n i t i a l l a g phase t h e r e i s an i n c r e a s e d r a t e of amino a c i d uptake f o r one to two h o u r s . The r a t e then r e t u r n s t o normal and remains r e f r a c t o r y to the a d d i t i o n of more GH f o r s e v e r a l hours ( 4 1 , 5 3 ) , most l i k e l y t h r o u g h the s y n t h e s i s of an i n h i b i t o r p r o t e i n ( 5 3 , 5 4 ) . The i n c r e a s e d amino a c i d uptake i s b l o c k e d by i n h i b i t o r s of p r o t e i n s y n t h e s i s , i n d i c a t i n g t h a t i t r e q u i r e s a t r a n s p o r t p r o t e i n ( 4 1 ) . P r o t e i n s y n t h e s i s i s i n c r e a s e d subsequent to and i n d e p e n d a n t of the amino a c i d u p t a k e , o c c u r r i n g even when uptake i s i n h i b i t e d ( 5 3 ) . A l t h o u g h the r a t e of amino a c i d uptake i s o n l y i n c r e a s e d f o r a few hours and then becomes r e f r a c t o r y to a d d i t i o n a l GH, p r o t e i n s y n t h e s i s remains e l e v a t e d f o r a much l o n g e r time ( 5 4 ) . I n c r e a s e d p r o t e i n s y n t h e s i s i s a l s o i n d e p e n d a n t of the s y n t h e s i s of new RNA, and r e s u l t s from enhanced t r a n s l a t i o n of e x i s t i n g mRNA th r o u g h f a c i l i t a t i o n of i t s attachment to r i bosomes ( 4 1 , 5 3 ) . RNA s y n t h e s i s does i n c r e a s e , but not u n t i l 18 to 24 hours a f t e r GH i s a d m i n i s t e r e d to h y p o p h y s e c t o m i z e d r a t s ( 4 1 ) . T h i s r e s u l t s i n an i n c r e a s e i n the number and s i z e of r i b o s o m e s , and w i t h i n 24 hours the a b i l i t y of muscle to s y n t h e s i z e p r o t e i n i s d oubled ( 4 1 ) . There i s an i n c r e a s e i n the DNA c o n t e n t of muscles i f GH t r e a t m e n t i s c o n t i n u e d f o r 7 days ( 4 1 ) . I t i s -41-unknown whether t h i s r e p r e s e n t s an i n c r e a s e i n the number of n u c l e i t h a t a re a c t i v e i n s y n t h e s i z i n g muscle f i b r e s , or merely an i n c r e a s e d number of s a t e l l i t e c e l l n u c l e i ( 5 0 ) . The c o n t r o l of GH mediated growth d i f f e r s from work i n d u c e d growth i n s e v e r a l r e s p e c t s . I n s u l i n i s a r e q u i r e d c o - f a c t o r f o r GH i n d u c e d growth ( 5 5 , 5 6 ) , but i s u n n e c e s s a r y f o r work i n d u c e d muscle growth ( 5 6 ) . W h i l e GH mediated amino a c i d uptake r e q u i r e s the s y n t h e s i s of a t r a n s p o r t p r o t e i n ( 4 1 ) , uptake i s i n d e p e n d a n t of p r o t e i n s y n t h e s i s i n work i n d u c e d growth, and o c c u r s even i n the p r e s e n c e of i n h i b i t o r s ( 4 9 , 5 7 , 5 8 ) . T h i s i n d i c a t e s t h a t t h e r e are d i f f e r e n t mechanisms of amino a c i d uptake f o r the two p r o c e s s e s . The s y n t h e s i s of new RNA i s r e q u i r e d f o r work i n d u c e d muscle growth ( 4 9 , 5 7 , 5 8 ) , w h i c h d i f f e r s from hormonal i n d u c e d growth where GH enhances the r a t e of t r a n s l a t i o n of e x i s t i n g RNA and s t i m u l a t e s growth even i n the p r e s e n c e of i n h i b i t o r s of RNA s y n t h e s i s ( 4 1 , 5 3 ) . A l t h o u g h work and hormones can both cause muscle growth, t h e s e p r o c e s s e s can o c c u r i n d e p e n d a n t l y of one a n o t h e r ( 5 9 ) , which has been dem o n s t r a t e d t h r o u g h a number of e x p e r i m e n t s . Many of t h e s e e x p e r i m e n t s have been performed on h y p o p h y s e c t o m i z e d r a t s , which have no endogenous GH p r o d u c t i o n . T h i s a l l o w s c l o s e c o n t r o l of both the amount of work performed by the muscle, and the hormonal i n f l u e n c e s to which i t i s exposed. Muscle work can be i n c r e a s e d by p e r f o r m i n g a s u r g i c a l tenotomy on s y n e r g i s t i c m u s c l e s . The muscle most commonly c u t i s the g a s t r o c n e m i u s , the c u t t i n g of which l e a d s to a g r e a t i n c r e a s e i n the w o r k l o a d of both the s o l e u s and p l a n t a r i s . M u s c l e work can be d e c r e a s e d or a b o l i s h e d by i m m o b i l i z i n g i t t h r o u g h f i x a t i o n of the j o i n t on -42-which i t a c t s , or by s e c t i o n i n g i t s nerve s u p p l y . B o v i n e GH, which i s e f f e c t i v e i n p r o m o t i n g growth i n r a t s , can be a d m i n i s t e r e d i n c o n t r o l l e d doses t o s t i m u l a t e muscle growth. D i f f e r e n t c o m b i n a t i o n s of t h e s e t e c h n i q u e s have been used to d e t e r m i n e how work and GH i n t e r a c t i n p r o m o t i n g muscle growth. The independance of hormonal and work e f f e c t s on muscular growth were dem o n s t r a t e d by comparing the e f f e c t s of t e n o t o m i z i n g the g a s t r o c n e m i u s of both normal and h y p o p h y s e c t o m i z e d r a t s ( 5 9 ) . Compensatory growth of the p l a n t a r i s and s o l e u s o c c u r r e d , and the r a t i o of growth of the t e n o t o m i z e d muscles to the n o n - t e n o t o r a i z e d c o n t r a l a t e r a l c o n t r o l l i m b was the same i n both groups of a n i m a l s . T h i s would i n d i c a t e t h a t the degree of work i n d u c e d s t i m u l a t i o n of growth i s i n d e p e n d a n t of hormonal i n f l u e n c e s . Other e x p e r i m e n t s have examined the e f f e c t s of GH on both n o r m a l , h y p e r t r o p h i e d , and a t r o p h i e d muscles ( 6 0 , 6 1 , 6 2 ) . Normal, f u l l y grown r a t s were t r e a t e d w i t h GH d a i l y f o r 21 days, d u r i n g which time t h e i r food i n t a k e was kept e q u i v a l e n t to t h e i r p a i r -matched c o n t r o l s ( 6 0 ) . N e i t h e r group was g i v e n any s t r e n g t h t r a i n i n g regimen. At the end of the t e s t p e r i o d the GH t r e a t e d r a t s were 20% h e a v i e r , had a q u a d r i c e p s w e i g h t 26.2% g r e a t e r , and an i n c r e a s e i n muscle f i b r e c r o s s - s e c t i o n a l d i a m e t e r of 6-12% as compared to u n t r e a t e d c o n t r o l s . The q u a d r i c e p s , however, d e s p i t e i t s i n c r e a s e d s i z e , d i d not d e v e l o p any g r e a t e r t e n s i o n , and, when e x p r e s s e d as t e n s i o n per gram of muscle wei^.hl , they d i d not pe r f o r m as w e l l as tho s e of the c o n t r o l a n i m a l s . The r e s e a r c h e r s had two p o s s i b l e h y p o t h e s e s to e x p l a i n t h e s e f i n d i n g s . The f i r s t p o s s i b i l i t y was t h a t the new m a t e r i a l r e s p o n s i b l e f o r the -43-i n c r e a s e i n weight was n o t , i n f a c t , c o n t r a c t i l e p r o t e i n . A l t e r n a t i v e l y , the l a c k of t e n s i o n development may have been due to a d e f e c t i n ne u r o - m u s c u l a r t r a n s m i s s i o n or a change i n the p r o p o g a t i o n of the c o n t r a c t i l e i m p u l s e . I t i s unknown, however, whether t r a i n i n g t he r a t s or h a v i n g a l o n g e r a d a p t a t i o n p e r i o d from the time of c e s s a t i o n of GH t r e a t m e n t t o t e s t i n g would have changed the r e s u l t s . In a n o t h e r e x p e r i m e n t ( 6 1 ) , muscle w e i g h t , EMG a c t i v i t y , c o n t r a c t i l e c a p a c i t y and work performance were s t u d i e d t o de t e r m i n e the e f f e c t of GH on a t r o p h i e d muscle i n r a t s . The g a s t r o c n e m i u s of the c o n t r o l r a t s was a t r o p h i e d t h r o u g h i m m o b i l i z a t i o n , and weighed 62% of the the we i g h t of the c o n t r a l a t e r a l c o n t r o l muscle. GH a d m i n i s t r a t i o n i n c r e a s e d the wei g h t of the a t r o p h i e d muscles by 19% when compared to those of the u n t r e a t e d c o n t r o l a n i m a l s . T w i t c h and t e t a n i c t e n s i o n s d e v e l o p e d i n the g a s t r o c n e m i u s of the GH t r e a t e d a n i m a l s were i n c r e a s e d by 58% and 65% r e s p e c t i v e l y as compared to tho s e d e v e l o p e d i n the n o n - t r e a t e d c o n t r o l s . There was, however, no i n c r e a s e i n the t e n s i o n d e v e l o p e d i n the no r m a l , n o n - a t r o p h i e d c o n t r a l a t e r a l c o n t r o l m u s c l e s . An e l a b o r a t e s e r i e s of e x p e r i m e n t s compared the e f f e c t s of GH on a t r o p h i e d and h y p e r t r o p h i e d muscles ( 6 2 ) . Comparisons were made to both the muscles of the n o r m a l , c o n t r a l a t e r a l l i m b , and to the muscles of non-GH ( s a l i n e ) t r e a t e d r a t s . A t h i r d c o m p a r i s o n was made between the GH and the s a l i n e t r e a t e d r a t s i n which one h i n d l i m b was a t r o p h i e d and the o t h e r h y p e r t r o p h i e d . In a l l e x p e r i m e n t a l c o n d i t i o n s the GH t r e a t e d muscles i n c r e a s e d i n s i z e r e l a t i v e to the non GH t r e a t e d c o n t r o l s . With GH -44-s t i m u l a t i o n , the growth of both a t r o p h i e d and h y p e r t r o p h i e d muscles was always p r o p o r t i o n a l to the growth of the muscles of the c o n t r a l a t e r a l n o n - s u r g i c a l c o n t r o l l i m b . The a u t h o r s c o n c l u d e d t h a t GH i n c r e a s e d the b a s a l r a t e of p r o t e i n s y n t h e s i s which i n t u r n was d e t e r m i n e d by the amount of m u s c u l a r work. A l t h o u g h p r o t e i n s y n t h e s i s i s i n c r e a s e d by both GH and m u s c u l a r work, the a c t u a l p r o t e i n s s y n t h e s i z e d w i l l d i f f e r d epending on the s t i m u l u s . I s o m e t r i c s t r e n g t h t r a i n i n g t e n d s to i n c r e a s e the amount of m y o f i b r i l l a r p r o t e i n , w h i l e endurance t r a i n i n g i n c r e a s e s the s a r c o p l a s m i c and m i t o c h o n d r i a l p r o t e i n s ( 5 0 ) . Work i n d u c e d h y p e r t r o p h y has l e d to a 50% i n c r e a s e i n the c o l l a g e n c o n t e n t of muscle ( 4 9 ) , and GH can a l s o s t i m u l a t e c o l l a g e n s y n t h e s i s ( 1 , 5 3 ) . I t i s p o s s i b l e t h a t both the l a c k of improved performance and the d i s c r e p a n c y between the i n c r e a s e s i n muscle w e i g h t and f i b r e s i z e (26% v s . 6-12%) i n GH t r e a t e d r a t s were due to the p r e f e r e n t i a l s y n t h e s i s of c o l l a g e n i n the h y p e r t r o p h i e d muscles ( 6 0 ) . A l a r g e i n c r e a s e i n muscle c o l l a g e n i s found i n the myopathy of a c r o m e g a l y , a d i s e a s e which i s caused by c h r o n i c h y p e r s e c r e t i o n of GH and c h a r a c t e r i z e d by o u t w a r d l y h y p e r t r o p h i e d but f u n c t i o n a l l y weaker muscles ( 6 3 , 6 4 ) . A l t h o u g h t h e s e s t u d i e s i n d i c a t e t h a t GH a d m i n i s t r a t i o n may l e a d t o i n c r e a s e s i n muscular s i z e and improvements i n the performance of a t r o p h i e d m u s c l e s , i t remains d i f f i c u l t to p r e d i c t the a b i l i t y of GH to i n c r e a s e c o n t r a c t i l e elements and improve the performance of normal muscles i n normal humans. -45-2-5 DISORDERS Abnormal l e v e l s of GH a r e found i n two d i s e a s e s t a t e s . Low or absent l e v e l s are found i n p a t i e n t s w i t h p i t u i t a r y f a i l u r e , and they p r e s e n t w i t h growth r e t a r d a t i o n , r e l a t i v e o b e s i t y , d e l a y e d e a r l y motor development and premature a g i n g ( 6 5 ) . These changes a r e r e v e r s i b l e t o a c e r t a i n e x t e n t , and d e f i c i e n t c h i l d r e n a r e commonly t r e a t e d w i t h GH i n j e c t i o n s . P i t u i t a r y tumors can l e a d t o h y p e r s e c r e t i o n of GH, w i t h the age of onset d e t e r m i n i n g the c l i n i c a l p r e s e n t a t i o n . GH e x c e s s i n p r e p u b e r t a l i n d i v i d u a l s l e a d s t o i n c r e a s e d l i n e a r growth and g i g a n t i s m , w h i l e acromegaly r e s u l t s from GH e x c e s s e s o c c u r r i n g a f t e r e p i p h y s e a l c l o s u r e ( 2 ) . Acromegaly has an i n s i d i o u s o nset and i s c h a r a c t e r i z e d by g r a d u a l t h i c k e n i n g of bones and s o f t t i s s u e s , e v e n t u a l l y l e a d i n g t o c o a r s e n i n g and d e f o r m i t i e s of the s k u l l , f a c e , hands, and f e e t . I t i s not a benign d i s e a s e , w i t h a m o r t a l i t y of 50% by the age of 50 y e a r s and 89% by 60 y e a r s ( 4 ) . C o m p l i c a t i o n s i n c l u d e g l u c o s e i n t o l e r a n c e , d i a b e t e s raellitus, h y p e r t e n s i o n , a t h e r o s c l e r o t i c h e a r t d i s e a s e , c o n g e s t i v e h e a r t f a i l u r e , c a r d i o m y o p a t h y , n e u r o p a t h y , and myopathy ( 4 ) . The myopathy of acromegaly i s u n u s u a l i n t h a t the muscles o f t e n appear to be o u t w a r d l y h y p e r t r o p h i e d , but are a c t u a l l y f u n c t i o n a l l y i m p a i r e d , w i t h the v i c t i m s c o m p l a i n i n g of mu s c u l a r weakness, easy f a t i g u a b i l i t y , and d e c r e a s e d e x e r c i s e t o l e r a n c e ( 6 3,64,66,67). Some a u t h o r s have r e p o r t e d s t r e n g t h g a i n s e a r l y i n the c o u r s e of acromegaly ( 6 8 ) , w h i l e o t h e r s r e p o r t t h a t t h i s i s a v a r i a b l e and uncommon f i n d i n g ( 6 6 ) . The myopathy i s u s u a l l y p r o x i m a l i n d i s t r i b u t i o n ( 6 6 ) , which i s where the g r e a t e s t degree of muscle h y p e r t r o p h y o c c u r s ( 6 0 ) . B i o p s i e s of a f f e c t e d muscles -46-have r e v e a l e d v a r i a b l e changes, some showing normal (67) and o t h e r s h y p e r t r o p h y of Type I f i b r e s ( 6 3 , 6 4 ) . Type I I f i b r e s have been shown to be n o r m a l , a t r o p h i e d and h y p e r t r o p h i e d w i t h i n a s i n g l e b i o p s y from one i n d i v i d u a l ( 6 7 ) , w h i l e o t h e r s t u d i e s have r e p o r t e d more a t r o p h y , p a r t i c u l a r l y of l i b f i b r e s ( 6 3 , 6 4 ) . B i o p s i e s have a l s o d e m o n s t r a t e d o c c a s i o n a l n e c r o t i c f i b r e s , and a pronounced i n c r e a s e i n c o n n e c t i v e t i s s u e ( 6 3 , 6 4 ) . The myopathic changes appear to be more r e l a t e d to the d u r a t i o n of the acromegaly than the serum l e v e l s of GH ( 6 4 , 6 6 ) , a l t h o u g h some a u t h o r s f e e l t h a t the somatomedin l e v e l s c o r r e l a t e c l o s e l y t o the degree of i n v o l v e m e n t ( 4 6 ) . 3-GH AND ATHLETES 3-1 INTRODUCTION A t h l e t e s a r e c o n s t a n t l y s t r i v i n g t o improve t h e i r p h y s i c a l p e r f o r m a n c e . In a d d i t i o n to r e c e n t advances i n a t h l e t e t r a i n i n g , p r e p a r a t i o n and m o n i t o r i n g , t h e r e has been a d i s t r e s s i n g i n c r e a s e i n the use of drugs and a n a b o l i c a g e n t s i n the hope t h a t they w i l l g i v e the a t h l e t e an a d d i t i o n a l c o m p e t i t i v e edge. The i n t e r n a t i o n a l s p o r t community has become i n c r e a s i n g l y a l a rmed about the use of d r u g s , and a t t e m p t s have been made to curb t h e i r use. S p o r t Canada and the S p o r t s M e d i c i n e C o u n c i l of Canada share t h e s e c o n c e r n s , and have i n s t i t u t e d comprehensive d o p i n g c o n t r o l p r o c e d u r e s f o r major c o m p e t i t i o n s and c a r d e d a t h l e t e s . To d a t e , t h e s e measures have been p r i m a r i l y d i r e c t e d towards the e r a d i c a t i o n of a n a b o l i c s t e r o i d use, and s e v e r a l u s e r s have been d e t e c t e d and d i s c i p l i n e d . There i s a l s o i n c r e a s i n g p r e s s u r e a g a i n s t s t e r o i d use from o t h e r r e g u l a t o r y -47-b o d i e s . The U n i v e r s i t y of C a l g a r y has r e c e n t l y i n s t i t u t e d a p o l i c y of drug t e s t i n g f o r a l l i n t e r - c o l l e g i a t e a t h l e t e s . In the U n i t e d S t a t e s , the N.C.A.A. has a l s o i n v o k e d a n t i - d o p i n g r e g u l a t i o n s . As the p r o b a b i l i t y of d e t e c t i o n i n c r e a s e s , some a t h l e t e s have abandoned s t e r o i d s i n f a v o u r of o t h e r a n a b o l i c a g e n t s , and i t i s r e p o r t e d t h a t GH i s the c u r r e n t drug of c h o i c e f o r many a t h l e t e s (69,70,71,72,73,74). The p r e v a l e n c e of GH s u p p l e m e n t a t i o n i s unknown, however, e v i d e n c e of i t was r e p o r t e d l y found i n u r i n e specimens t e s t e d a t the World T r a c k and F i e l d Championships i n H e l s i n k i i n 1983 ( 7 5 ) , and i t i s thought to be w i d e l y used i n f o o t b a l l p l a y e r s ( 6 9 ) , and b o d y b u i l d e r s ( 7 1 , 7 3 , 7 6 ) . 3-2 ADMINISTRATION There a r e two p r i n c i p a l modes of GH s u p p l e m e n t a t i o n ; i n j e c t i o n of exogenous GH, or the o r a l a d m i n i s t r a t i o n of v a r i o u s drugs i n an attempt to s t i m u l a t e the r e l e a s e of endogenous GH from the p i t u i t a r y . U n t i l r e c e n t l y the o n l y exogenous GH a v a i l a b l e was t h a t r e c o v e r e d from human cada v e r p i t u i t a r i e s , which was i n r e l a t i v e l y l i m i t e d s u p p l y . W h i l e i t s i n t e n d e d use was i n the t r e a t m e n t of GH d e f i c i e n t c h i l d r e n , some s u p p l i e s were b e i n g d i v e r t e d to a t h l e t e s ( 7 0 ) . The use of human p i t u i t a r y GH has now been d i s c o n t i n u e d due to the f e a r of C r e u t z f e l d t - J a k o b d i s e a s e ( 7 7 , 7 8 , 7 9 ) . S e v e r a l companies are p r o d u c i n g b i o s y n t h e t i c GH t h r o u g h the use of recom b i n a n t DNA t e c h n o l o g y i n b a c t e r i a . The o n l y form c u r r e n t l y approved f o r use has an e x t r a m e t h i o n i n e group a t t a c h e d to i t , which has l e d to a n t i b o d y f o r m a t i o n i n about 30% of the c h i l d r e n -48-t r e a t e d ( 7 9 ) . I t i s not known what e f f e c t s t h e s e a n t i b o d i e s w i l l have, but t h e r e i s s p e c u l a t i o n t h a t they may i n t e r f e r e w i t h endogenous GH ( 7 7 , 7 9 ) . T h i s p o t e n t i a l consequence of b i o s y n t h e t i c m e thional-GH has caused some a u t h o r s to a d v i s e a t h l e t e s a g a i n s t i t s use ( 7 7 ) . Other companies are c u r r e n t l y t e s t i n g an e x a c t GH d u p l i c a t e and e x p e c t to market i t i n the near f u t u r e ( 7 9 ) . In a d d i t i o n to human p i t u i t a r y and b i o s y n t h e t i c GH, t h e r e are a l s o r e p o r t s of a t h l e t e s u s i n g a s u b s t a n c e r e f e r r e d to as " g o r i l l a j u i c e " , w hich i s r e p r e s e n t e d as p r i m a t e GH ( 7 0 ) , a l t h o u g h i n some ca s e s i t was a c t u a l l y found to be an a n a b o l i c s t e r o i d ( 7 0 , 7 7 ) . A t h l e t e s a l s o use drugs i n c l u d i n g p r o p r a n o l o l , v a s o p r e s s i n , c l o n i d i n e and L-Dopa to s t i m u l a t e the r e l e a s e of GH from the p i t u i t a r y . The most r e a d i l y a v a i l a b l e and commonly used s u b s t a n c e s , however, a r e the amino a c i d s , and t h e i r i n g e s t i o n has become w i d e s p r e a d i n both a t h l e t e s and the g e n e r a l p u b l i c . The use of the s i n g l e amino a c i d s a r g i n i n e , l y s i n e , o r n i t h i n e and t r y p t o p h a n as GH r e l e a s e r s has been p o p u l a r i z e d t h r o u g h a best s e l l i n g book ( 8 0 ) , and t h e i r use has been w i d e l y promoted i n v i t a m i n and h e a l t h food s t o r e s . In r e s p o n s e to the i n c r e a s e d use of amino a c i d s and c o n c e r n s about t h e i r p o s s i b l e e f f e c t s , the H e a l t h P r o t e c t i o n Branch of the F e d e r a l Government r e c e n t l y r e c l a s s i f i e d them as new drugs and suspended t h e i r d i s t r i b u t i o n p ending f u r t h e r t e s t i n g . 3-3 POTENTIAL USES There i s no p u b l i s h e d e v i d e n c e t h a t GH s u p p l e m e n t a t i o n w i l l l e a d to improvements i n p e r f o r m a n c e . There are numerous c l a i m s , however, m o s t l y i n l i f t e r s and b o d y b u i l d e r s , about the p o t e n t i a l -49-b e n e f i c i a l e f f e c t s of GH. There a r e r e p o r t s of l a r g e g a i n s (30-40 l b s . ) i n l e a n body weight (70,71,73,76) a f t e r GH use. One proponent c l a i m s "Wow, i s t h i s g r e a t s t u f f ! I t i s the bes t drug f o r permanent muscle g a i n s P e o p l e who use i t can exp e c t t o g a i n 30 to 40 l b s of muscle i n t e n weeks i f they can eat 10,000 c a l o r i e s per day T h i s i s the o n l y drug t h a t can remedy bad g e n e t i c s as i t w i l l make anybody grow. A few s i d e e f f e c t s can o c c u r , however..... Even w i t h a l l t h a t , ( p o t e n t i a l s i d e e f f e c t s ) we LOVE the s t u f f . " ( 8 1 ) . Other u s e r s a re not so i m p r e s s e d , and have s a i d t h a t the e f f e c t s of GH are o v e r r a t e d (70) and t h a t i t s use has not l e d to s p e c t a c u l a r changes ( 7 7 , 8 2 ) . Assessment of GH's i n f l u e n c e i s f u r t h e r c o m p l i c a t e d by the m i s r e p r e s e n t a t i o n of a n a b o l i c s t e r o i d s as i n j e c t a b l e GH ( 7 0 , 7 7 ) . The e v i d e n c e c u r r e n t l y a v a i l a b l e does not i n d i c a t e a c l e a r b e n e f i t from the use of GH i n a t h l e t i c s . Some of i t s e f f e c t s a r e u s e f u l i n b o d y - b u i l d i n g where low body f a t and good muscle d e f i n i t i o n and bu l k a re of prime i m p o r t a n c e . I t s i n f l u e n c e i n s t r e n g t h and power s p o r t s i s l e s s c e r t a i n . The ap p a r e n t enhancement of muscle b u l k may be due to i n c r e a s e s i n c o n n e c t i v e t i s s u e a l o n e , and not c o n t r a c t i l e e l e m e n t s . T h i s p o s s i b i l i t y i s s u p p o r t e d by the l a c k of performance improvements i n the muscles of a n i m a l s t r e a t e d w i t h GH, and i n the a c r o m e g a l i c s w i t h o u t w a r d l y h y p e r t r o p h i e d but f u n c t i o n a l l y weaker m u s c l e s . I t i s c l e a r t h a t the p o t e n t i a l e f f e c t s of GH on a t h l e t e s cannot be p r e d i c t e d w i t h o u t f u r t h e r s t u d y , however, i t i s e q u a l l y c l e a r t h a t the use of GH s u p p l e m e n t a t i o n i n a t h l e t e s i s a p r a c t i c e t h a t i s u n l i k e l y to d i s a p p e a r . -50-In a d d i t i o n to GH use i n h e a l t h y a t h l e t e s , t h e r e may be some p o t e n t i a l uses f o r GH as a t h e r a p u t i c a g e n t . I t has been r e p o r t e d t h a t GH can speed e x p e r i m e n t a l f r a c t u r e h e a l i n g i n a n i m a l s and i n humans w i t h d e l a y e d u n i o n ( 8 3 ) , however, some a u t h o r s r e p o r t t h a t i t s e f f i c a c y i n u n c o m p l i c a t e d f r a c t u r e s i s i n c o n c l u s i v e ( 8 3 ) , w h i l e o t h e r s f e e l t h a t i t s use i s of no b e n e f i t ( 8 4 ) . GH has a l s o been used to t r e a t p r i m a r y and s econdary o s t e o p o r o s i s w i t h p o t e n t i a l l y f a v o u r a b l e r e s u l t s ( 8 5 ) . I t i s p o s s i b l e t h a t GH w i l l one day be used to r e v e r s e some of the c a t a b o l i c changes a s s o c i a t e d w i t h d e b i l i t a t i n g d i s e a s e s and a g i n g . 3-4 POTENTIAL PROBLEMS There are s e r i o u s m e d i c a l and e t h i c a l problems a s s o c i a t e d w i t h GH s u p p l e m e n t a t i o n . Acromegaly i s an i n s i d i o u s , i r r e v e r s i b l e d i s e a s e t h a t may become a major h e a l t h problem i f GH s u p p l e m e n t a t i o n becomes w i d e s p r e a d . A l t h o u g h t h e r e are no documented c a s e s of acromegaly o c c u r r i n g i n GH u s e r s , t h e r e are numerous a n e c d o t a l a c c o u n t s of a t h l e t e s s u f f e r i n g from i t s e a r l y e f f e c t s such as c o a r s e n i n g of the f e a t u r e s and t h i c k e n i n g of the bones of the f a c e , hands and f e e t ( 70,71,73,81). P r o l o n g e d use may w e l l l e a d to o t h e r c o m p l i c a t i o n s i n c l u d i n g d i a b e t e s , a r t h r i t i s , myopathies and a s h o r t e n e d l i f e span. There i s a l s o the p o t e n t i a l problem of GH a n t i b o d i e s which may n e u t r a l i z e endogenous GH and cause a r e l a t i v e GH d e f i c i e n c y . In a d d i t i o n to the c o m p l i c a t i o n s of GH i t s e l f and the p o s s i b i l i t y of C r e u t z f e ^ l -Jacob D i s e a s e , t h e r e are the p o t e n t i a l problems of h e p a t i t i s and A c q u i r e d Immuno-Deficiency Syndrome (AIDS) i f n e e d l e s are shared and s t e r i l e i n j e c t i o n t e c h n i q u e s not employed. -51-The m e d i c a l problems p a l e i n co m p a r i s o n to the major e t h i c a l i s s u e s s u r r o u n d i n g GH use. The l a c k of s c i e n t i f i c s u p p o r t f o r i t s e f f i c a c y i n s p o r t s and the p o t e n t i a l h a z a r d s of i t s use w i l l not d e t e r the a t h l e t e who i s d e t e r m i n e d to win a t a l l c o s t s . The p r o s p e c t of an u n l i m i t e d s u p p l y of pure b i o s y n t h e t i c GH has l e d to c h i l l i n g p r e d i c t i o n s of GH t r e a t e d g i a n t s u n d e r m i n i n g the p r e s e n t s t r u c t u r e of o r g a n i z e d s p o r t ( 7 0 , 7 1 , 8 0 ) . The overwhelming d e s i r e of p a r e n t s to have t h e i r c h i l d r e n succeed i n a t h l e t i c s , and the v a s t f i n a n c i a l rewards of p r o f e s s i o n a l s p o r t s make GH abuse a d i s t i n c t p o s s i b i l i t y r e q u i r i n g s t r i c t r e g u l a t i o n of GH a v a i l a b i l i t y t o a v e r t p o t e n t i a l t r a g e d i e s . H i s t o r y has demonstrated t h a t e t h i c s and the concept of f a i r p l a y a re o f t e n l o s t i n the quest f o r v i c t o r y . The c o n t r o l of o t h e r drugs and e r g o g e n i c a i d s has been d i f f i c u l t t o e n f o r c e , and GH use may become a problem of tremendous magnitude. At p r e s e n t t h e r e remains much to be l e a r n e d about the uses and abuses of GH. I t i s p o s s i b l e t h a t i t w i l l become a f o r m i d a b l e t h e r a p u t i c agent to speed h e a l i n g and reduce the e f f e c t s of a g i n g , however, i t a l s o has the p o t e n t i a l to d r a m a t i c a l l y a l t e r the p a t t e r n s of modern a t h l e t i c s . At p r e s e n t , t r a i n i n g i s the o n l y proven way to improve p e r f o r m a n c e . The my s t i q u e s u r r o u n d i n g the p r o p e r t i e s and b e n e f i t s of GH w i l l t ake many s t u d i e s and many y e a r s t o d i s p e l l , e s p e c i a l l y i f f u r t h e r s t u d i e s c o n c l u d e t h a t i t i s of no p r a c t i c a l v a l u e i n s p o r t . -52-BIBLIOGRAPHY 1 GRODSKY, G.M. C h e m i s t r y and F u n c t i o n of the Horraones:IV P i t u i t a r y and Hypothalamus. I n : H a r p e r s Review of_ B i o c h e m i s t r y , ( 1 9 8 2 ) . 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