The hormonal response to intravenous 5-hydroxytryptophan in bulimia nervosa

Journal of Psychosomatic Research, Vol. 40, No. 3, pp. 289-297, 1996 Copyright © 1996 Elsevier Science lnc. All rights reserved. 0022-3999/96 $15.00 + .00

ELSEVIER

0022-3999(95)00640-0

THE HORMONAL RESPONSE TO INTRAVENOUS 5 - H Y D R O X Y T R Y P T O P H A N IN BULIMIA NERVOSA D A V I D S. G O L D B L O O M , * ~ t P A U L E. G A R F I N K E L , * R A N D Y KATZI" and G R E G O R Y M. B R O W N * (Received 22 June 1995) Abstract-In recent years evidence has accumulated to implicate a disturbance in serotonin function in

the eating disorder bulimia nervosa. This study employs a neuroendocrine technique to assess the effect of intravenous 5-hydroxytryptophan, the immediate precursor to serotonin, on peripheral hormones in bulimia nervosa subjects and controls. Blunted prolactin and growth hormone responses were observed among bulimia nervosa subjects; the possible pathophysiology and implications of the findingsare discussed. Keywords:

Bulimia nervosa; Eating disorders; Neuroendocrine; Prolactin; 5-Hydroxytryptophan;

Serotonin. INTRODUCTION Since Russell's description o f bulimia nervosa (BN) in 1979 [1], this disorder has been the subject o f neurobiological scrutiny [2, 3] within the larger context o f a multidetermined psychosomatic illness [4]. In recent years, attention has focused on disturbances in brain serotonin (5-HT) activity in BN [5, 6]. The rationale for such investigation stems f r o m three independent lines o f inquiry. First, research on neural regulation o f appetitive behavior implicates 5-HT in the control o f both satiety and macronutrient selection in the medial h y p o t h a l a m u s [7, 8]; in animal models, reduction o f h y p o t h a l a m i c 5-HT activity impairs expression o f satiety and increases carbohydrate intake [7]. Clinically, these disturbances o f eating behavior are seen in BN patients [9, 10]. A second rationale emanates f r o m evidence that aberrations in dietary intake affect brain neurotransmitter activity, as indicated by such diverse parameters o f 5-HT function as platelet 5-HT receptors [11] and the neuroendocrine response to a 5-HT precursor [12]; further, this latter effect is seen in w o m e n , but not in men [12]. This suggests a gender-specific biological difference in response to dieting behavior that m a y play a role in the predominance o f this disorder a m o n g women. Finally, disturbances in brain 5 - H T have been implicated in the neurobiology o f diverse disorders such as depression, anxiety, suicidality, alcoholism, aggression, and impulsivity [13-16]; these disorders frequently co-exist with BN [17, 18] and are overrepresented a m o n g the families o f BN p r o b a n d s [19]. Evidence for 5-HT disturbances in BN emanates f r o m diverse peripheral measures * Department of Psychiatry, The Clarke Institute and 1 The Toronto Hospital, University of Toronto. :[:Address correspondence to: David S. Goldbloom, M.D., F.R.C.P.(C), Clarke Institute of Psychiatry, 250 College Street, Toronto, Ontario, Canada M5T 1R8. Fax: 416-979-6932. 289

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o f 5 - H T a c t i v i t y , all o f w h i c h are l i m i t e d by v i r t u e o f b e i n g i n d i r e c t . T h e s e i n c l u d e l o w levels o f t h e 5 - H T m e t a b o l i t e 5 - h y d r o x y i n d o l e a c e t i c a c i d in c e r e b r o s p i n a l fluid [20, 21], i n c r e a s e d p l a t e l e t 5 - H T u p t a k e [22], a r e l a t i o n s h i p b e t w e e n c h a n g e s in 5 - H T p r e c u r s o r levels in p l a s m a a n d b i n g e i n g b e h a v i o r [23], a n d a t h e r a p e u t i c effect o f selective 5 - H T - p r o m o t i n g d r u g s [24-26]. F u r t h e r , n e u r o e n d o c r i n e s t r a t e g i e s u s i n g a 5-HT precursor and a 5-HT postsynaptic receptor agonist have demonstrated a blunted p r o l a c t i n r e s p o n s e in B N s u g g e s t i v e o f a l t e r e d 5 - H T a c t i v i t y [6]. T h i s l a t t e r a p p r o a c h b o r r o w s a m o d e l a p p l i e d t o m o o d [27, 28] a n d a n x i e t y d i s o r d e r s [29, 30], a n d w h i l e it m a y g e n e r a t e p a r a l l e l d a t a , t h e results m u s t be v i e w e d w i t h t h e c a v e a t o f t h e k n o w n effects o f n u t r i t i o n a l d i s t u r b a n c e o n n e u r o e n d o c r i n e f u n c t i o n [31, 32]. T h e p u r p o s e o f this s t u d y was to i n v e s t i g a t e 5 - H T f u n c t i o n in B N u s i n g a n e u r o e n d o crine m o d e l . T h e i m m e d i a t e p r e c u r s o r o f 5 - H T , 5 - h y d r o x y t r y p t o p h a n ( 5 - H T P ) , was u s e d to s t i m u l a t e 5 - H T synthesis, a n d t h e effect o f this w a s d e t e r m i n e d by s a m p l i n g o f p r o l a c t i n , g r o w t h h o r m o n e , a n d c o r t i s o l - h o r m o n e s t h a t are, in p a r t , u n d e r serot o n e r g i c c o n t r o l [33]. W h i l e the 5 - H T P n e u r o e n d o c r i n e c h a l l e n g e has b e e n a p p l i e d to affective d i s o r d e r s [27], to o u r k n o w l e d g e it has n o t b e e n e m p l o y e d in t h e s t u d y o f 5 - H T f u n c t i o n in B N . W e h y p o t h e s i z e d t h a t this t e c h n i q u e w o u l d d e m o n s t r a t e b l u n t i n g o f h o r m o n a l r e s p o n s e s in B N s u b j e c t s reflective o f d e c r e a s e d 5 - H T activity.

METHODS Subjects

All BN patients (n = 8) and female control subjects (n = 8) provided written informed consent for participation in this study. BN patients were recruited from clinical referrals to the Eating Disorders Programme of The Toronto Hospital; healthy controls were recruited from the University of Toronto. All BN patients met DSM-III-R [34] criteria for BN based on a semistructured interview. In addition, all subjects were evaluated for current and lifetime psychiatric disorder using the Diagnostic Interview Schedule (DIS) [35]. Other baseline measures for all subjects included demographics, current and lifetime weight history, the Eating Attitudes Test (EAT) [36], the Eating Disorder Inventory (EDI) [37], and the Hamilton Rating Scale for Depression (HAM-D) [38]. All subjects were free of psychotropic medications for at least 4 weeks prior to the study. All subjects were admitted to the Clinical Investigation Unit (CIU) of The Toronto Hospital for 3 days to allow nutritional and psychiatric evaluation as well as acclimatization to the experimental milieu. All subjects kept food diaries that were reviewed with the CIU nutritionist to determine kilocalorie and macronutrient intake for the 2 days prior to the neuroendocrine testing; all reasonable efforts were made to prohibit bingeing and purging behavior by the BN patients during this time. A strict serotonergic diet with regard to availability of dietary tryptophan and other amino acids was not enforced; all subjects were asked to abstain from alcohol for the period of the study. In the 2 days prior to the neuroendocrine challenge, all subjects were treated with the peripheral decarboxylase inhibitor carbidopa 100 mg po tid. The purpose of this was to block the peripheral conversion of 5-HTP to 5-HT and thus minimize the toxicity of increased peripheral 5-HT activity [39]. N e u r o e n d o c r i n e test

On the third day of hospitalization in the CIU, after an overnight fast, all subjects had two intravenous lines inserted for infusion and sampling at 0800 h. After an hour of acclimatization to this procedure, two baseline blood samples were drawn 30 minutes apart for prolactin, cortisol, growth hormone, 5-HTP, and 5-HT. At 0930 h, an intravenous infusion of 0.4 mg/kg L-SHTP was initiated and ran for 30 minutes. L-SHTP was dissolved in a solution of 250 mL of normal saline. The dose of 0.4 mg/kg was selected on the basis of dosing studies, which suggested that this was the minimal effective dose to stimulate prolactin secretion [40]. Starting at 1000 h, plasma hormone levels were drawn every 30 minutes for 5 sampling points. Subjects were awake but reclining throughout the procedure. Blood samples for L-5HTP and 5-HT were drawn in tubes containing heparin and EDTA; 15 mg of ascorbic acid was added, the tubes were centrifuged, and then samples were stored at - 20°C until assay. Samples for prolactin, growth hormone, and cortisol were drawn with no additive, and serum was frozen at - 2 0 ° C until assay.

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Table I.-Subjects BN (.~ + SEM) n=8 Age (years) BMI (kg/m 2) Current weight (kg) Maximum weight (kg) Minimum weight (kg) No. of years of BN Current no. binges/week Current no. vomits/week EAT total score HAM-D Current MDE (DIS) Past MDE (DIS) Past AN (definite)

23.6 + 1.5 23.1 + 0.7 62.5 _+ 1.9 66.5 _ 2.7 50.1 _+ 1.5 4.4 +_ 0.9 11.5 11.5 34.7 + 3.5 11.0 + 1.7 2 subjects 5 subjects 4 subjects (4-12 years earlier)

NC (~ + SEM) n=8 24.7 22.0 62.1 65.5 54.7

_+ 1.1 NS _+ 0.6 NS +_ 1.5 NS _ 3.1 NS + 2.3 NS 0 0 0 4.5 + 1.5" 1.0 + 1.0"* 0 0 0

*p < 0.0001; **p < 0.001.

Hormone measurement Prolactin, growth hormone, and cortisol levels were determined by radioimmunoassay. Prolactin was measured by the method of Hwang et al. [41], growth hormone according to Schalch and Parker [42], and cortisol as described by Brown et al. [43]. The intra-assay variations for prolactin, growth hormone, and cortisol were 8°70, 5070, and 2070, respectively; the corresponding interassay variations were 5%, 13070,and 12070.5-HTP and 5-HT levels were measured by high-performance liquid chromatography [44]. Individual samples were corrected for recovery by use of added 5-HTP. All assays were performed in the neurosciences laboratory of McMaster University under the supervision of one of the authors (GMB). Statistical analysis As the data for the 3 hormones, 5-HT, and 5-HTP were not normally distributed, nonparametric analysis by group with the Mann-Whitney test was performed for all measures. Response to the L-SHTP stimulus was determined for each hormone by examining mean hormone levels by group at each postinfusion sampling point, by comparing area under the curve (AUC) for each hormone between groups, and by comparing peak minus baseline responses for each hormone between groups. Where a significant difference existed between the two baseline measures (-30' and 00 for any hormone within subjects, the second measure (17), immediately prior to infusion of 5-HTP, was used for all analyses. Demographic, psychometric, and nutritional data were analyzed by t test for between-group differences.

RESULTS T h e clinical features o f the B N patients a n d c o n t r o l s (NC) ar e s u m m a r i z e d in T a b l e I; g r o u p s were w e l l - m a t c h e d f o r age, b o d y mass index, c u r r e n t weight, an d lifetime adult weight extremes. T h e B N patients h a d b o t h c h r o n i c a n d active disorders, with p s y c h o l o g i c a l as well as b e h a v i o r a l d i s t u r b a n c e s as reflected by the H a m i l t o n depression an d E A T scores; in a d d i t i o n , 4 B N subjects had h ad a r e m o t e h i s t o r y o f A N 4 to 12 years earlier. T w o B N subjects were c u r r e n t l y suffering f r o m a m a j o r depressive episode a c c o r d i n g to the DIS. N u t r i t i o n a l analysis did n o t reveal an y significant differences b e t w e e n g r o u p s o n either o f the days p r i o r to testing with regard to either kilocalories o r m a c r o n u t r i e n t s , as reflected in T a b l e II. P l a s m a levels o f 5 - H T P a n d 5 - H T are r e p r esen t ed in T a b l e III. T h e r e was no significant difference in th e m e a n dose o f I . -5 H TP a d m i n i s t e r e d to the t w o groups ( ~ + S E M : B N patients 2 4 . 7 + 6.5 rag, controls 2 4 . 9 + 0 . 8 mg). H o w e v e r , L - 5 H T P

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Table I I . - Nutritional status

Two days pretest kcal One day pretest kcal CHO (gm) Protein (gm) Fat (gm)

BN (-g + SEM)

NC (~ + SEM)

1,519.3 _ 254.8

1,824.5 ± 150.8 NS

1,383.2 180.2 58.1 58.4

1,808.0 + 246.2 193.2 +_ 11.2 81.6 +_ 10.7 78.2 _+ 19.8

+ 147.0 ± 22.2 ± 5.2 _+ 7.4

NS NS NS NS

plasma levels after the infusion revealed a significant difference between groups; L-5HTP plasma levels were elevated among BN subjects compared to controls at postinfusion times + 30 min (Z = 2.63, p <0.008), + 60 min (Z = 2.38, p<0.02), and + 90 min ( Z = 2.58, p < 0 . 0 1 ) . When the data were analyzed by calculating the area under the curve, postinfusion L-5HTP levels were significantly elevated in BN subjects ( Z = 2.36, p <0.02). Peak minus baseline analyses for L-5HTP, however, did not distinguish between the two groups. There were no reliable differences between groups for the measure of plasma 5-HT levels. The hormonal responses to T.-5HTP are illustrated in Table IV. Because of significant differences between the two baseline samples (-30' and 0"), which may have reflected an ongoing adaptation to the test environment, the second baseline sample (0") was employed. Following the infusion of L-5HTP, prolactin and growth hormone secretion increased in BN patients and controls. There was a significant blunting o f the prolactin response a m o n g BN subjects using both peak minus baseline analysis (Z = 1.74,p<0.05 one-tailed) and comparing sampling points post infusion at + 30 min ( Z = 1.99, p<0.05) and at + 60 min (Z = 1.68, p < 0 . 0 5 one-tailed). Area under the curve analysis failed to detect significant between-group differences in prolactin. Because of missing baseline data, only 7 of the 8 controls were analyzed with specific regard to prolactin response. Neither growth hormone nor cortisol secretion was significantly different in BN subjects as reflected by peak minus baseline analyses or area under the curve determinations. However, by comparison of mean hormone levels by group at each postinfusion sampling point, growth hormone levels were significantly lower in BN subjects at times + 60 min ( Z = 2.25, p<0.02) and + 90 min ( Z = 2.41, p <0.01). Although baseline cortisol levels were significantly elevated in BN patients relative to controls at times - 3 0 min ( Z = 1.99, p<0.05) and + 30 min ( Z = 2.10, p<0.05), these differences failed to reach statistical significance at time 0. Cortisol levels were also significantly elevated in BN subjects at time + 9 0 m i n ( Z = 2.5,p<0.01). Reanalysis of the results excluding the two BN subjects with concurrent major depression did not alter any of the significant findings. DISCUSSION This study replicates the findings of Brewerton [6] of a blunted prolactin response to a serotonergic stimulus in BN. In that research, the precursor tryptophan and the postsynaptic receptor agonist m-chlorophenylpiperazine were employed. The current study adds evidence for a blunted growth hormone response. In addition, it provides limited support for previous findings of elevated cortisol levels in BN [45, 46].

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Limitations to this study include the lack of a placebo infusion and the selection of the serotonergic stimulus. The volume of blood to be collected, the requirement of an indwelling venous catheter for several hours and the need for a 3-day hospitalization for both subjects and controls placed ethical and practical constraints against an additional placebo infusion and sampling. However, controlled data indicate that active BN does not exert a significant influence on daytime secretion patterns of prolactin, growth hormone, or cortisol [47]. Controversy regarding the available serotonergic agonists for neuroendocrine testing has been reviewed elsewhere [48, 49]. While L-5HTP is an efficient precursor to 5-HT, it can also enter non-5-HT neurons for decarboxylation and thus act as a false neurotransmitter [50]. Nevertheless, L-5HTP has been a useful tool for investigation of serotonergic function in a neuroendocrine paradigm. An unanticipated finding in this study was the presence of higher plasma 5-HTP levels among BN subjects compared to controls in response to equivalent mean doses of intravenous L-5HTP. What are the implications of this? Both groups received equal doses of carbidopa to block the conversion of L-5HTP to 5-HT in the periphery, and the adequacy of this blockade is suggested by the failure of mean plasma 5-HT levels to rise after the L-5HTP infusion (Table III). One possibility is that transport of L-5HTP across the blood-brain barrier during the study period was less efficient in BN subjects than in controls, resulting in both higher plasma 5-HTP levels and, by implication, lower brain L-5HTP levels. This might then result in a lesser stimulus for brain 5-HT synthesis among BN subjects and translate into the observed blunting of hormonal responses. Support for such an admittedly speculative model comes from a study of positron emission tomography in depressed patients [51]. Using radiolabeled L-5HTP, the study demonstrated a lower brain uptake of L-5HTP among depressed patients compared to healthy controls. A study o f systemic administration of L-5HTP to rats revealed that intraperitoneal injection of this precursor led to an immediate and dose-dependent increase in 5-HT levels in dialysates of the lateral hypothalamus [52]. However, other metabolic and excretory peripheral fates must also be considered, such as the possibility that carbidopa blockade of peripheral conversion of 5-HTP to 5-HT was less complete in controls, leading to greater conversion and lower plasma 5-HTP levels relative to BN subjects. We feel this alternative explanation is unlikely given the consistently lower (but not significantly different) levels of 5-HT in controls over the course of the study. Other more minor peripheral metabolic pathways for 5-HTP may have also been activated, but were not evaluated in this study. The data suggest that the differences found between BN subjects and controls do not reflect differences in current or lifetime weight, acute nutritional intake, or the acute effects of binge eating and purgeing - although it cannot be assured with complete certainty that the BN patients refrained from such behaviors while inpatients in the CIU. While depression scores were elevated in the BN subjects, the mean Hamilton score was below the standard minimum acceptable for entry into depression treatment studies. The two BN subjects with concurrent major depressive episodes did not account for the hormonal differences found. Indeed, their hormonal responses were intermediate between nondepressed BN subjects and controls. However, the high prevalence of lifetime depression and the elevated current depression scores in BN subjects raise the possibility that observed hormonal differences may reflect a diathesis

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f o r d y s p h o r i a w h o s e e x p r e s s i o n is t h e n p s y c h o s o c i a l l y s h a p e d i n t o a v a r i e t y o f d i s c r e t e p s y c h i a t r i c d i s o r d e r s t h a t m a y also b e c l i n i c a l l y r e l a t e d (13, 15-17). W h a t a c c o u n t s f o r t h e o b s e r v e d d i f f e r e n c e s in h o r m o n a l r e s p o n s e to a s e r o t o n e r g i c s t i m u l u s ? A t this p o i n t , all a n s w e r s a r e s p e c u l a t i v e w i t h i n a c o n t e x t o f s e r o t o n e r g i c f u n c t i o n t h a t e x t e n d s f r o m p r e c u r s o r a v a i l a b i l i t y t o p o s t s y n a p t i c r e c e p t o r sensitivity and second messenger systems. However, the advent of positron emission tomography ( P E T ) a n d t h e a v a i l a b i l i t y o f m o r e specific l i g a n d s f o r p r e s y n a p t i c a n d p o s t s y n a p t i c r e c e p t o r s m a y h e l p l o c a l i z e t h e area(s) o f d y s f u n c t i o n . Acknowledgments-Dr. Goldbloom was supported by a Centennial Fellowship of the Medical Research Council of Canada during this study. Our thanks to Lisa K. Hicks and to the Clinical Investigation Unit of The Toronto Hospital for expert administration of the protocol and to Ms. Yvonne Hetherman and Ms. Gwen Duncan for technical preparation of the manuscript.

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