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Luteinizing hormone and cortisol responses to naloxone in normal weight women with bulimia
Psychoneuroendocrinology,Vol. 15, No. 5&6. pp. 463-470, 1990
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LUTEINIZING HORMONE A N D CORTISOL RESPONSES TO NALOXONE IN NORMAL WEIGHT WOMEN WITH BULIMIA V. COrRO, 1 L. D'AMATO,3 C. MARCHESI,2 L. CAI'RET'n,5 R. VOLPI,1 G. ROBERTI,4 L. CERRI,4 and P. CHIODERA1 t Institute of Internal Medicine and 2Institute of Psychiatry, School of Medicine, University of Parma, Parma; 3Endocrine Unit, Division of Pediatrics and Psychiatry, and 4Serviceof Nuclear Medicine, Hospital of Piaeenza, Piacenza; 5Division of Internal Medicine, Hospital of Codogno, Codogno (Milan), Italy (Received 13 March 1990; in final form 5 September 1990) SUMMARY The present study was undertaken in order to establish whether alterations in the endogenous opioid control of luteinizing hormone (LH) and ACTH/cortisol secretion occur in bulimic women with normal body weight and normal menstrual cycles. For this purpose, the capability of the opioid antagonist naloxone (4 mg injected as an intravenous bolus at time 0, plus l0 mg infused over 2 hr) to increase the circulating levels of LH and cortisol was tested in nine bulimic women and in nine age- and weight-matched normal controls. All women were tested on the 22rid day of a normal menstrual cycle. Two days later, a control test with normal saline (NaC1 0.9%) instead of naloxone was performed. The basal levels of LH and cortisol were similar in the bulimic and normal subjects and were not modified by the administration of normal saline. In contrast, the administration of naloxone significantly increased plasma LH and cortisol levels in all subjects, with peak LH responses at 30 rain and peak cortisol responses at 60 rain. The naloxone-induced LH and cortisol increases were significantly higher in the bulimic women than in the normal controls. These data indicate the presence of an increased opioid inhibitory tone in the control of LH and ACTH/cortisol secretion in normal weight bulimic women with normal menstrual cycles.
INTRODUCTION A VARmTY of studies indicate alterations of endogenous opioids in patients affected by major psychiatric disorders, such as endogenous depression (Terenius et al., 1976; Lindstrom et al., 1978; Brambilla et al., 1981; Risch, 1982; Genazzani et al., 1984) and anorexia nervosa (Pickax & Bunney, 1981; Kaye et al., 1982), including changes in the endogenous opioid control of pituitary function (Extein et al., 1980; Judd et al., 1982; Robertson et al., 1984; Zis et al., 1985; Cavagnini et al., 1987; Giusti et al., 1988; Zis, 1988; Zis et al., 1989). Bulimia is a psychiatric disorder which is thought to be related to anorexia nervosa (Russell, 1979; Halmi et al., 1981; Pyle et al., 1981; Hudson et al., 1983). The finding of patients with major depression and with bulimia in the same families suggests a familial linkage between major depression and eating disorders (Hudson et al., 1982; Katz et al., 1984; Strober & Katz, 1988). Bulimia has been described as an alteration in the control o f food intake, characterized by alternating Address correspondence and reprint requests to: Dr. Vittorio Coiro, Cattedra di Clinica Medica Genemle, Universit~ di Parma, Via Gramsci 14,1-43100 Parma, ITALY. 463
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episodes of ingestion of conspicuous amounts of food and periods of starvation, self-induced vomiting, and excessive use of cathartics (Halmi e t al., 1981). Studies of endogenous opioid control of pituitary function in bulimic patients are few. The administration of naloxone in normal w o m e n is unable to modify the basal secretion of FSH, PRL, T S H and G H (Morley, 1983), whereas it stimulates LH and cortisol release (Morley, 1983), suggesting that LH and ACTH/cortisol secretion is tonically inhibited by endogenous opioids. The present study was undertaken in order to establish the possible presence of alterations in the endogenous opioid control of LH and ACTH/cortisol secretion in bulimic women. For this purpose, LH a n d cortisol responses to n a l o x o n e a d m i n i s t r a t i o n were measured in bulimic w o m e n and in normal controls. In order to avoid the possible interference of alterations in b o d y weight or m e n s t r u a l cycles, b u l i m i c w o m e n with n o r m a l b o d y weight and regular menstrual cycles were chosen. SUBJECTS AND METHODS Nine normal women and nine women who met DSM-III criteria (American Psychiatric Association, 1982) for bulimia and had binge eating at least more than once a week participated in this study after giving informed consent. The women were matched for age (bulimic: 28.4 + 1.4 yr (mean + SEM); control: 30.15:1.8 yr) and weight (bulimic: 54.75:1.3 kg (mean + SEM); mean body mass index (BMI): 235: 0.43, bulimic women; 23+ 0.39, controls. There was no clinical or laboratory evidence of hepatic, renal or other intercurrent diseases in any subject. Normal and bulimic women were not affected by concurrent major affective disorders, as determined by the Schedule of Affective Disorders and Schizophrenia (Endicoa & Spitzer, 1978), nor did they present a history of anorexia nervosa. The duration of the bulimic illness ranged from 2 to 8 yr, with a mean length of 5.2 5:0.7 yr (mean + SEM). All subjects had a history of regular menstrual cycles of normal duration (26 to 30 days). None of them took any drugs for at least 2 wk before the experiment. Basal body temperature and plasma levels of ovarian steroids were evaluated daily and served as criteria to determine the precise period of the cycle. The patterns of basal body temperature and circulating levels of 17-6 estradiol (F_.2)and progesterone (P) were not different between groups at any time during the menstrual cycle, and they had luteal phases of similar duration (range 12-14 days). All women were tested with naloxone (naloxone test) on the 22nd day of a normal menstrual cycle (6-8 days after ovulation), and 2 days later they were tested with normal saline (control test). Naloxone test: At 0900h of the experiment day, two 19-gauge indwelling IV needles were inserted into the antecubital veins of both arms of the subjects, who were lying in the recumbent position and fasting since the previous evening. The needles were kept patent with a slow infusion of normal saline; one of them was used for naloxone administration and the other for blood sampling. Blood samples were withdrawn at 0930h (time 0) just before the IV injection of a bolus of 4 mg naloxone plus the constant infusion over 2 hr of 10 mg in 100 ml of normal saline. Further blood specimens were taken 10, 20, 30, 45, 60, 90 and 120 rain after the beginningof naloxone administration. Control test: This test followed an identical procedure, except for the administration of normal saline (NaCI 0.9%) instead of naloxone. After each experiment, the plasma samples were separated and stored at -20° until assayed. Cortisol (Brock et al., 1978), E2 (De Hertogh et al., 1975) and P (De Villa et al., 1973) concentrations were measured by specific radioimmunoassays (RIA). All samples from the same subject were measured in the same assay in duplicate and in random order. Results were analyzed with the Wilcoxon matched-pair rank sum test and the Kruskall-Wallis analysis of variance (ANOVA), according to a split-plot factorial model (Daniel, 1987), followed by specific mean comparison tests (Tukey's test), as appropriate. Valuesare expressed as mean + SEM. RESULTS Control test
Normal and bulimic w o m e n showed similar basal LH (Fig. 1) and cortisol (Fig. 2) concentrations (Kruskall-Wallis test). The administration of normal saline did not modify the basal
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levels of LH and cortisol. A slight physiological decline in circulating cortisol concentrations was observed during the control test (Fig. 2). Naloxone test Naloxone did not produce side effects in any subject. The blood concentrations of naloxone in normal and bulimic w o m e n during the test could not be measured. This information would have provided a stronger reliability to our r e s u l t s . However, naloxone is metabolized in the liver (Jaffe & Martin, 1980) and all subjects had normal liver function, as judged by clinical and laboratory data. Therefore, a similar metabolic clearance rate of naloxone m a y be hypothesized for the control and bulimic women. The administration of naloxone induced a significant increase of LH concentrations in both subject groups (Fig. 1). LH responses showed a similar pattern in both groups, with a peak mean level at 30 m i n ( p < 0 . 0 1 vs basal value) followed by a slight decline during the next 120
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min. The naloxone-induced LH increase was significantly higher in the bulimic patients than in the controls (p<0.01 at 30, 45, 60, 90 and 120 min; ANOVA according to split-plot factorial model, followed by Tukey's test) (Fig. 1). The mean peak response was 2.27 times higher than baseline in the bulimic women, but only 1.9 times higher than baseline in the normal controls. Naloxone induced a significant cortisol increase in both groups (p < 0.01 vs. basal value), with mean peak responses at 60 min and declining slightly during the next hour. The cortisol response also was significantly higher in the bulimic women than in the normal controls (p < 0.05 at 60 and 90 min.; ANOVA according to split-plot factorial model, followed by Tukey's test) (Fig. 2). The mean peak was 1.8 times higher than baseline in the bulimic patients and only 1.55 times higher than basal value in the normal controls. The mean basal plasma levels of E 2 (bulimic: 85.4 + 3.7 pg/ml; control: 86.8 + 4.0) and P (bulimic: 9.5 + 0.7 ng/ml; control: 10.2+ 0.8) were similar in the two groups (samples collected at time 0 of the naloxone test).
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DISCUSSION
A variety of studies provide evidence for a role of endogenous opioid peptides in the regulation of food intake. In various animal species, administration of opioid antagonists inhibits physiological- and stress-induced feeding (Mitchell & Morley, 1987). On the other hand, regulation of feeding behaviour in humans is much more complex. Short term treatments of normal or obese human subjects with naloxone usually produce significant suppressant effects on eating (Mitchell & Morley, 1987). Administration of the long-acting opiate antagonist naltrexone in obese men may decrease appetite (Olson et al., 1989) and change dietary preferences (Sugrue, 1987), but several studies have suggested that naltrexone is unable to modify body weight in obesity (Jonas & Gold, 1987; Mitchell & Morley, 1987). Studies performed in bulimic women provided discrepant results. Naloxone has been found able to reduce food intake in bulimic patients (Mitchell & Morley, 1987), and a significant improvement in the frequency and duration of b.inges and the frequency of purging was found in an open chronic trial of naltrexone (Jonas & Gold, 1987). However, in a double-blind trial. Mitchell et al. (1989) did not find any significant change in binge/vomit frequency in bulirnic women treated with naltrexone. Both elevated (Fullerton et al., 1986 ) and low (Waller et al., 1986) levels of beta endorphin have been found in the blood of bulimic subjects. The results of our present study argue in favour of increased opioid activity in bulimic subjects. Both ACTH/cortisol and LH responses to naloxone were higher in the bulimic patients than in the normal women, suggesting the presence of increased opioid inhibitory tone at the hypothalamo-anterior pituitary level. There are close anatomical and functional interactions between the hypothalamic nuclei controlling adrenal and ovarian function and the hypothalamo-limbic structures regulating food intake (Witkin et al., 1982; Kalra & Kalra, 1983, Filaretov & Filaretova, 1985; Piekut, 1985; Gray et al., 1989). Therefore, our endocrine findings might be part of a more complex opioid alteration in the central nervous system of bulimic patients. Concerning the regulation of the hypothalamo-pituitary-ovarian axis, various ovarian and/or endocrine alterations have been described in bulimic women. In view of the well-known alterations of the menstrual cycle induced by dieting and weight loss (Frisch & Arthur, 1974), amenorrhea, oligomenorrhea and other alterations of the menstrual cycle observed in bulimia have been attributed to intermittent starvation and dieting (Copeland & Herzog, 1987). However, amenorrhea has been described between 20% to 50% of normal-weight bulimic patients (Copeland & Herzog, 1987). Furthermore, longitudinal studies have shown disturbed hormone secretion including an overall decrease of FSH and LH levels and subnormal peaks of both gonadotropins during apparently normal menstrual cycles (Pirke et al., 1988). These findings suggest that other factors such as stress, physical exercise, vomiting and binge eating may influence gonadotropin release through a hypothalamic action on GnRH (Frisch & Arthur, 1974). Endogenous opioids are thought to play an important role in the suppression of GnRH release (Copeland & Herzog, 1987). An excess of opioid influence on the control of GnRH secretion has been shown in a majority of patients with hypothalamie amenorrhea (Khoury et al., 1987). In bulimic patients as well, increased opioid activity may contribute to GnRH suppression. Our data were obtained in normal-weight bulimic women and showed that the naloxone-induced LH increase was higher than normal. These findings agree with the hypothesis of an increased opioid tone in the control of LH release in bulimia. The mechanism underlying the effect of naloxone on LH appears to be sensitive to alterations in body weight; the injection of naloxone is unable to elicit a significant LH increase in
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about haft of underweight patients with anorexia nervosa (Baranowska et al., 1984). Baraban et al. (1986) also showed LH responses to naloxone infusion in some, but not in all patients with eating disorders, indicating that naloxone is more effective in normal-weight bulimic subjects than in underweight anorectic patients. Maintenance of body weight might be an important factor in controlling the ACTH/cortisol response to naloxone as well; naloxone was unable to elicit significant ACTH/cortisol responses in underweight patients with anorexia nervosa, even in the presence of significant LH responses (Baranowska et al., 1984). At present, the regulation of the hypothalamo-pituitary-adrenal axis in bulimia is unclear. Like patients with anorexia nervosa (Walsh et al., 1987b) or endogenous depression (Carroll, 1977), bulimic subjects often show nonsuppressed cortisol responses on the dexamethasone suppression test (Walsh et al., 1987a). The lack of the inhibitory effect of dexamethasone is considered an expression of increased adrenal activity. Studies of 24-hr cortisol profiles have led to discrepant results. Walsh et al. (1987b) did not find any difference between normal and bulimic women, whereas Kennedy et al. (1989) showed elevated cortisol levels in bulimic patients. Mortola et al. (1989) confirmed the results of Kennedy et al. (1989) and showed decreased ACTH/cortisol responses to CRH in bulimic women. Taken together, these findings suggest an abnormal control of ACTH/cortisol secretion in bulimia. Our present results of elevated cortisol responses to naloxone suggest an increased opioid inhibitory tone in bulimic patients. However, this abnormality does not appear to imply altered levels of basal cortisol secretion; basal cortisol concentrations were similar in the bulimic and control subjects during saline infusion. The role played by naloxone-sensitive opioid alterations in the abnormal regulation of ACTH/cortisol secretion in bulimia needs further clarification.
Acknowledgements: This work in part was supported by a grant from the Ministero Pubblica Istruzione and by Bayer Diagnostics s.p.a. (Cavenago Brianza, Italy). REFERENCES American Psychiatric Association (1982) Desk Reference to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Ed. American Psychiatric Association, Washington DC. Baraban JM, Walsh BT, Gladis M (1986) Effects of naloxone on luteinizing hormone secretion in eating disorders: a pilot study, lnt J Eating Disord 5: 149-155. Baranowska B, Rozbicka G, Jeske W, Abdel-Fattah MH (1984) The role of endogenous opiates in the mechanism of inhibited luteinizing hormone (LH) secretion in women with anorexia nervosa: the effect of naloxone on LH, follicle-stimulating hormone, prolactin and beta-endorphin secretion. J Clin Endocrinol Metab 59: 412-416. Brambilla F, Genazzani AR, Facchinetti F, Parrini D, Petraglia F, Sacchetti E, Scarone S, Guastalla A, D'Antona N (1981) Beta-endorphin and beta-lipotropin plasma levels in chronic schizophrenia, primary affective disorders and secondary affective disorders. Psychoneuroendocrinology 6: 321-330. Brock P, Eldred EW, Woiszillo JE, Doran M, Shoemaker MJ (1978) Direct solid phase 125-I radioimmunoassay of serum cortisol. Clin Chem 24: 1595-1598. Carroll B3 (1977) The hypothalamus-pituitary-adrenal axis in depression. In: Burrows GD (Ed) Handbook of Studies on Depression. Elsevier North Holland, New York, pp 325-341. Cavagnini F, Invitti C, Dubini A, Danesi L, Silvestrini G, Passamonti M, Magella A, Morabito F (1987) Endogenous opioids and hypothalamic-pituitary-adrenal function in obesity and anorexia nervosa. In: Nerozzi D, Goodwin FK, Costa E (Eds) Hypothalamic Dysfunction in Neuropsychiatric Disorders. Raven Press, New York, pp 273-281. Copeland PM, Herzog DB (1987) Mensmaal abnormalities. In: Hudson JI, Pope PIG (FAs) The Psychobiology of Bulimia. American Psychiatric Press, Washington DC, pp 31-54. Daniel W (1987) Biostatistics: A Population for Analysis in the Health Sciences. Wiley, New York, pp 298307.
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Mortola JF, Rasmussen DD, Yen SSC (1989) Aherations of the adrenocorticotropin-cortisol axis in normal weight bulimic women: evidence for a central mechanism. J Clin Endocrinol Metab 68: 517-522. Olson GA, Olson RD, Kasfin AB (1989) Endogenous opiates: 1987, Peptides 10: 205-236. Pickar D, Bunney WE (1981) Endogenous opioids and psychiatric illness: CSF studies. Neuroendocrinol Left 2: 80-85. Piekut DT (1985) Relationship of ACTH 1-39 immunostalned fibers and magnocellular neurons in the paraventricular nucleus of rat hypothalamus. Peptides 6: 883-890. Pirke KM, Dogs M, Fichter MM, Tuschl ILl (1988) Gonadotrophins, oestradiol and progesterone during the menstrual cycle in bvlimia nervosa. Clin Endocrino129: 265-270. Pyle RL, Mitchell JE, Eckert ED (1981) Bulimia: a report of 34 cases. J Clin Psychiatry 42: 60-64. Risch SC (1982) Beta-endorphin hypersecretion in depression: possible cholinergic mechanisms. Biol Psychiatry 17: 1071-1079. Robertson AG, Jackman H, Meltzer HY (1984) Prolactin response to morphine in depression. Psychiatry Res 11: 353-364. Russell GFM (1979) Bulimia nervosa: an ominous variant of anorexia nervosa. Psychol Med 9: 939-948. Strober M, Katz JL (1988) Depression in the eating disorders: a review and analysis of descriptive, family, and biological findings. In: Garner DM, Garfink¢l PE (Eds) Diagnostic Issues in Anorexia Nervosa andBulimia Nervosa. Broncr/Maz¢l, New York, pp 80-111. Sugrue MF (1987) Neuropharmacology of drugs affecting food intake. Pharmacol Ther 32: 145-182. Tcrenius L, Wahlstrom A, Lindstrom L, Widorl6v E (1976) Increased CSF levels of endorphin in chronic psychosis. Neurosci Left 3: 157-162. Wallcx DA, Kiser RS, Haroy BW, Fuchs I, Feigenbaum LP, Uauy R (1986) Eating behavior and plasma betaendorphin in bulimia. Am J Clin Nutr 44: 20-23. Walsh BT, Roost SP, Katz JL, Dyronfurth I, Wright L, VandeWiele R, Glassman AH (1987a) Hypothalamicpituitary adrenal-cortical activity in anorexia nervosa and bulimia. Psychoneuroendocrinology 12: 131-140. Walsh BT, Roost SP, Lindy DC, Gladis M, Glassman AH (1987b) Hypothalamic-pituitary-adrenal axis in bulimia. In Hudson JI, Pope HG Jr (Eds) The Psychobiology of Bulimia. American Psychiatric Press, Washington DC, pp 3-11. Witkin F¢~, Paden CM, Silverman AJ (1982) The lutcinizing hormone releasing hormone (LHRH) systems in the rat brain. Neuroendocrtnolosy 35: 429-438. Zis AP (1988) Opioidergic regulation of hypothalamo-pituitary-adrenal function in depression and Cushing's disease: an interim report. Psychoneuroendocrinology 13: 419-430. Zis AP, Haskett RF, Albala A, Carroll BJ, Lohr HE (1985) Opioid regulation of hypothalamic-pituitary-adrenal function in depression. Arch Gen Psychiatry 42: 383-386. Zis AP, Remick RA, Clark CM, Goldner E, Grant BEK, Brown GM (1989) Effect of morphine on cortisol and prolactin secretion in anorexia nervosa and depression. Clin Endocrino130: 421-427.
0306--4530/90 $3.00 + 0.00 ©1991 Pergamon Press plc
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LUTEINIZING HORMONE A N D CORTISOL RESPONSES TO NALOXONE IN NORMAL WEIGHT WOMEN WITH BULIMIA V. COrRO, 1 L. D'AMATO,3 C. MARCHESI,2 L. CAI'RET'n,5 R. VOLPI,1 G. ROBERTI,4 L. CERRI,4 and P. CHIODERA1 t Institute of Internal Medicine and 2Institute of Psychiatry, School of Medicine, University of Parma, Parma; 3Endocrine Unit, Division of Pediatrics and Psychiatry, and 4Serviceof Nuclear Medicine, Hospital of Piaeenza, Piacenza; 5Division of Internal Medicine, Hospital of Codogno, Codogno (Milan), Italy (Received 13 March 1990; in final form 5 September 1990) SUMMARY The present study was undertaken in order to establish whether alterations in the endogenous opioid control of luteinizing hormone (LH) and ACTH/cortisol secretion occur in bulimic women with normal body weight and normal menstrual cycles. For this purpose, the capability of the opioid antagonist naloxone (4 mg injected as an intravenous bolus at time 0, plus l0 mg infused over 2 hr) to increase the circulating levels of LH and cortisol was tested in nine bulimic women and in nine age- and weight-matched normal controls. All women were tested on the 22rid day of a normal menstrual cycle. Two days later, a control test with normal saline (NaC1 0.9%) instead of naloxone was performed. The basal levels of LH and cortisol were similar in the bulimic and normal subjects and were not modified by the administration of normal saline. In contrast, the administration of naloxone significantly increased plasma LH and cortisol levels in all subjects, with peak LH responses at 30 rain and peak cortisol responses at 60 rain. The naloxone-induced LH and cortisol increases were significantly higher in the bulimic women than in the normal controls. These data indicate the presence of an increased opioid inhibitory tone in the control of LH and ACTH/cortisol secretion in normal weight bulimic women with normal menstrual cycles.
INTRODUCTION A VARmTY of studies indicate alterations of endogenous opioids in patients affected by major psychiatric disorders, such as endogenous depression (Terenius et al., 1976; Lindstrom et al., 1978; Brambilla et al., 1981; Risch, 1982; Genazzani et al., 1984) and anorexia nervosa (Pickax & Bunney, 1981; Kaye et al., 1982), including changes in the endogenous opioid control of pituitary function (Extein et al., 1980; Judd et al., 1982; Robertson et al., 1984; Zis et al., 1985; Cavagnini et al., 1987; Giusti et al., 1988; Zis, 1988; Zis et al., 1989). Bulimia is a psychiatric disorder which is thought to be related to anorexia nervosa (Russell, 1979; Halmi et al., 1981; Pyle et al., 1981; Hudson et al., 1983). The finding of patients with major depression and with bulimia in the same families suggests a familial linkage between major depression and eating disorders (Hudson et al., 1982; Katz et al., 1984; Strober & Katz, 1988). Bulimia has been described as an alteration in the control o f food intake, characterized by alternating Address correspondence and reprint requests to: Dr. Vittorio Coiro, Cattedra di Clinica Medica Genemle, Universit~ di Parma, Via Gramsci 14,1-43100 Parma, ITALY. 463
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episodes of ingestion of conspicuous amounts of food and periods of starvation, self-induced vomiting, and excessive use of cathartics (Halmi e t al., 1981). Studies of endogenous opioid control of pituitary function in bulimic patients are few. The administration of naloxone in normal w o m e n is unable to modify the basal secretion of FSH, PRL, T S H and G H (Morley, 1983), whereas it stimulates LH and cortisol release (Morley, 1983), suggesting that LH and ACTH/cortisol secretion is tonically inhibited by endogenous opioids. The present study was undertaken in order to establish the possible presence of alterations in the endogenous opioid control of LH and ACTH/cortisol secretion in bulimic women. For this purpose, LH a n d cortisol responses to n a l o x o n e a d m i n i s t r a t i o n were measured in bulimic w o m e n and in normal controls. In order to avoid the possible interference of alterations in b o d y weight or m e n s t r u a l cycles, b u l i m i c w o m e n with n o r m a l b o d y weight and regular menstrual cycles were chosen. SUBJECTS AND METHODS Nine normal women and nine women who met DSM-III criteria (American Psychiatric Association, 1982) for bulimia and had binge eating at least more than once a week participated in this study after giving informed consent. The women were matched for age (bulimic: 28.4 + 1.4 yr (mean + SEM); control: 30.15:1.8 yr) and weight (bulimic: 54.75:1.3 kg (mean + SEM); mean body mass index (BMI): 235: 0.43, bulimic women; 23+ 0.39, controls. There was no clinical or laboratory evidence of hepatic, renal or other intercurrent diseases in any subject. Normal and bulimic women were not affected by concurrent major affective disorders, as determined by the Schedule of Affective Disorders and Schizophrenia (Endicoa & Spitzer, 1978), nor did they present a history of anorexia nervosa. The duration of the bulimic illness ranged from 2 to 8 yr, with a mean length of 5.2 5:0.7 yr (mean + SEM). All subjects had a history of regular menstrual cycles of normal duration (26 to 30 days). None of them took any drugs for at least 2 wk before the experiment. Basal body temperature and plasma levels of ovarian steroids were evaluated daily and served as criteria to determine the precise period of the cycle. The patterns of basal body temperature and circulating levels of 17-6 estradiol (F_.2)and progesterone (P) were not different between groups at any time during the menstrual cycle, and they had luteal phases of similar duration (range 12-14 days). All women were tested with naloxone (naloxone test) on the 22nd day of a normal menstrual cycle (6-8 days after ovulation), and 2 days later they were tested with normal saline (control test). Naloxone test: At 0900h of the experiment day, two 19-gauge indwelling IV needles were inserted into the antecubital veins of both arms of the subjects, who were lying in the recumbent position and fasting since the previous evening. The needles were kept patent with a slow infusion of normal saline; one of them was used for naloxone administration and the other for blood sampling. Blood samples were withdrawn at 0930h (time 0) just before the IV injection of a bolus of 4 mg naloxone plus the constant infusion over 2 hr of 10 mg in 100 ml of normal saline. Further blood specimens were taken 10, 20, 30, 45, 60, 90 and 120 rain after the beginningof naloxone administration. Control test: This test followed an identical procedure, except for the administration of normal saline (NaCI 0.9%) instead of naloxone. After each experiment, the plasma samples were separated and stored at -20° until assayed. Cortisol (Brock et al., 1978), E2 (De Hertogh et al., 1975) and P (De Villa et al., 1973) concentrations were measured by specific radioimmunoassays (RIA). All samples from the same subject were measured in the same assay in duplicate and in random order. Results were analyzed with the Wilcoxon matched-pair rank sum test and the Kruskall-Wallis analysis of variance (ANOVA), according to a split-plot factorial model (Daniel, 1987), followed by specific mean comparison tests (Tukey's test), as appropriate. Valuesare expressed as mean + SEM. RESULTS Control test
Normal and bulimic w o m e n showed similar basal LH (Fig. 1) and cortisol (Fig. 2) concentrations (Kruskall-Wallis test). The administration of normal saline did not modify the basal
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levels of LH and cortisol. A slight physiological decline in circulating cortisol concentrations was observed during the control test (Fig. 2). Naloxone test Naloxone did not produce side effects in any subject. The blood concentrations of naloxone in normal and bulimic w o m e n during the test could not be measured. This information would have provided a stronger reliability to our r e s u l t s . However, naloxone is metabolized in the liver (Jaffe & Martin, 1980) and all subjects had normal liver function, as judged by clinical and laboratory data. Therefore, a similar metabolic clearance rate of naloxone m a y be hypothesized for the control and bulimic women. The administration of naloxone induced a significant increase of LH concentrations in both subject groups (Fig. 1). LH responses showed a similar pattern in both groups, with a peak mean level at 30 m i n ( p < 0 . 0 1 vs basal value) followed by a slight decline during the next 120
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min. The naloxone-induced LH increase was significantly higher in the bulimic patients than in the controls (p<0.01 at 30, 45, 60, 90 and 120 min; ANOVA according to split-plot factorial model, followed by Tukey's test) (Fig. 1). The mean peak response was 2.27 times higher than baseline in the bulimic women, but only 1.9 times higher than baseline in the normal controls. Naloxone induced a significant cortisol increase in both groups (p < 0.01 vs. basal value), with mean peak responses at 60 min and declining slightly during the next hour. The cortisol response also was significantly higher in the bulimic women than in the normal controls (p < 0.05 at 60 and 90 min.; ANOVA according to split-plot factorial model, followed by Tukey's test) (Fig. 2). The mean peak was 1.8 times higher than baseline in the bulimic patients and only 1.55 times higher than basal value in the normal controls. The mean basal plasma levels of E 2 (bulimic: 85.4 + 3.7 pg/ml; control: 86.8 + 4.0) and P (bulimic: 9.5 + 0.7 ng/ml; control: 10.2+ 0.8) were similar in the two groups (samples collected at time 0 of the naloxone test).
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DISCUSSION
A variety of studies provide evidence for a role of endogenous opioid peptides in the regulation of food intake. In various animal species, administration of opioid antagonists inhibits physiological- and stress-induced feeding (Mitchell & Morley, 1987). On the other hand, regulation of feeding behaviour in humans is much more complex. Short term treatments of normal or obese human subjects with naloxone usually produce significant suppressant effects on eating (Mitchell & Morley, 1987). Administration of the long-acting opiate antagonist naltrexone in obese men may decrease appetite (Olson et al., 1989) and change dietary preferences (Sugrue, 1987), but several studies have suggested that naltrexone is unable to modify body weight in obesity (Jonas & Gold, 1987; Mitchell & Morley, 1987). Studies performed in bulimic women provided discrepant results. Naloxone has been found able to reduce food intake in bulimic patients (Mitchell & Morley, 1987), and a significant improvement in the frequency and duration of b.inges and the frequency of purging was found in an open chronic trial of naltrexone (Jonas & Gold, 1987). However, in a double-blind trial. Mitchell et al. (1989) did not find any significant change in binge/vomit frequency in bulirnic women treated with naltrexone. Both elevated (Fullerton et al., 1986 ) and low (Waller et al., 1986) levels of beta endorphin have been found in the blood of bulimic subjects. The results of our present study argue in favour of increased opioid activity in bulimic subjects. Both ACTH/cortisol and LH responses to naloxone were higher in the bulimic patients than in the normal women, suggesting the presence of increased opioid inhibitory tone at the hypothalamo-anterior pituitary level. There are close anatomical and functional interactions between the hypothalamic nuclei controlling adrenal and ovarian function and the hypothalamo-limbic structures regulating food intake (Witkin et al., 1982; Kalra & Kalra, 1983, Filaretov & Filaretova, 1985; Piekut, 1985; Gray et al., 1989). Therefore, our endocrine findings might be part of a more complex opioid alteration in the central nervous system of bulimic patients. Concerning the regulation of the hypothalamo-pituitary-ovarian axis, various ovarian and/or endocrine alterations have been described in bulimic women. In view of the well-known alterations of the menstrual cycle induced by dieting and weight loss (Frisch & Arthur, 1974), amenorrhea, oligomenorrhea and other alterations of the menstrual cycle observed in bulimia have been attributed to intermittent starvation and dieting (Copeland & Herzog, 1987). However, amenorrhea has been described between 20% to 50% of normal-weight bulimic patients (Copeland & Herzog, 1987). Furthermore, longitudinal studies have shown disturbed hormone secretion including an overall decrease of FSH and LH levels and subnormal peaks of both gonadotropins during apparently normal menstrual cycles (Pirke et al., 1988). These findings suggest that other factors such as stress, physical exercise, vomiting and binge eating may influence gonadotropin release through a hypothalamic action on GnRH (Frisch & Arthur, 1974). Endogenous opioids are thought to play an important role in the suppression of GnRH release (Copeland & Herzog, 1987). An excess of opioid influence on the control of GnRH secretion has been shown in a majority of patients with hypothalamie amenorrhea (Khoury et al., 1987). In bulimic patients as well, increased opioid activity may contribute to GnRH suppression. Our data were obtained in normal-weight bulimic women and showed that the naloxone-induced LH increase was higher than normal. These findings agree with the hypothesis of an increased opioid tone in the control of LH release in bulimia. The mechanism underlying the effect of naloxone on LH appears to be sensitive to alterations in body weight; the injection of naloxone is unable to elicit a significant LH increase in
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about haft of underweight patients with anorexia nervosa (Baranowska et al., 1984). Baraban et al. (1986) also showed LH responses to naloxone infusion in some, but not in all patients with eating disorders, indicating that naloxone is more effective in normal-weight bulimic subjects than in underweight anorectic patients. Maintenance of body weight might be an important factor in controlling the ACTH/cortisol response to naloxone as well; naloxone was unable to elicit significant ACTH/cortisol responses in underweight patients with anorexia nervosa, even in the presence of significant LH responses (Baranowska et al., 1984). At present, the regulation of the hypothalamo-pituitary-adrenal axis in bulimia is unclear. Like patients with anorexia nervosa (Walsh et al., 1987b) or endogenous depression (Carroll, 1977), bulimic subjects often show nonsuppressed cortisol responses on the dexamethasone suppression test (Walsh et al., 1987a). The lack of the inhibitory effect of dexamethasone is considered an expression of increased adrenal activity. Studies of 24-hr cortisol profiles have led to discrepant results. Walsh et al. (1987b) did not find any difference between normal and bulimic women, whereas Kennedy et al. (1989) showed elevated cortisol levels in bulimic patients. Mortola et al. (1989) confirmed the results of Kennedy et al. (1989) and showed decreased ACTH/cortisol responses to CRH in bulimic women. Taken together, these findings suggest an abnormal control of ACTH/cortisol secretion in bulimia. Our present results of elevated cortisol responses to naloxone suggest an increased opioid inhibitory tone in bulimic patients. However, this abnormality does not appear to imply altered levels of basal cortisol secretion; basal cortisol concentrations were similar in the bulimic and control subjects during saline infusion. The role played by naloxone-sensitive opioid alterations in the abnormal regulation of ACTH/cortisol secretion in bulimia needs further clarification.
Acknowledgements: This work in part was supported by a grant from the Ministero Pubblica Istruzione and by Bayer Diagnostics s.p.a. (Cavenago Brianza, Italy). REFERENCES American Psychiatric Association (1982) Desk Reference to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Ed. American Psychiatric Association, Washington DC. Baraban JM, Walsh BT, Gladis M (1986) Effects of naloxone on luteinizing hormone secretion in eating disorders: a pilot study, lnt J Eating Disord 5: 149-155. Baranowska B, Rozbicka G, Jeske W, Abdel-Fattah MH (1984) The role of endogenous opiates in the mechanism of inhibited luteinizing hormone (LH) secretion in women with anorexia nervosa: the effect of naloxone on LH, follicle-stimulating hormone, prolactin and beta-endorphin secretion. J Clin Endocrinol Metab 59: 412-416. Brambilla F, Genazzani AR, Facchinetti F, Parrini D, Petraglia F, Sacchetti E, Scarone S, Guastalla A, D'Antona N (1981) Beta-endorphin and beta-lipotropin plasma levels in chronic schizophrenia, primary affective disorders and secondary affective disorders. Psychoneuroendocrinology 6: 321-330. Brock P, Eldred EW, Woiszillo JE, Doran M, Shoemaker MJ (1978) Direct solid phase 125-I radioimmunoassay of serum cortisol. Clin Chem 24: 1595-1598. Carroll B3 (1977) The hypothalamus-pituitary-adrenal axis in depression. In: Burrows GD (Ed) Handbook of Studies on Depression. Elsevier North Holland, New York, pp 325-341. Cavagnini F, Invitti C, Dubini A, Danesi L, Silvestrini G, Passamonti M, Magella A, Morabito F (1987) Endogenous opioids and hypothalamic-pituitary-adrenal function in obesity and anorexia nervosa. In: Nerozzi D, Goodwin FK, Costa E (Eds) Hypothalamic Dysfunction in Neuropsychiatric Disorders. Raven Press, New York, pp 273-281. Copeland PM, Herzog DB (1987) Mensmaal abnormalities. In: Hudson JI, Pope PIG (FAs) The Psychobiology of Bulimia. American Psychiatric Press, Washington DC, pp 31-54. Daniel W (1987) Biostatistics: A Population for Analysis in the Health Sciences. Wiley, New York, pp 298307.
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