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Abnormal serum prolactin responses to luteinizing hormone-releasing hormone (LHRH) in patients with anorexia nervosa and bulimia
Psychoneuroendocrinology. Vol. 12, No. 4, pp. 281-287, 1987. Printedin GreatBritain
©
0306-4530187 $3.00 + 0.00 1987PergamonJournalsLtd.
A B N O R M A L S E R U M P R O L A C T I N R E S P O N S E S TO L U T E I N I Z I N G H O R M O N E - R E L E A S I N G H O R M O N E ( L H R H ) IN P A T I E N T S W I T H ANOREXIA NERVOSA AND BULIMIA HAJIME TAMAI,* CHIE KARIBE, KAYOKO KIYOHARA, KENJI MOPd, KOHICHIRO TAKENO, NOBUYUKI KOBAYASHI, TETSUYA NAKAGAWA a n d LINDY F. KUMAGAI Department of Psychosomatic Medicine, Faculty of Medicine, Kyushu University, Fulmoka, Japan; and Department of Internal Medicine, School of Medicine, University of California, Davis, (LFK), Sacramento, CA 95817, U.S.A.
(Received 22 Apr/l 1986; in final form 2 December 1986) SUMMARY Abnormal responses of serum prolactin (PRL) to luteinizing hormone-releasing hormone (LHRH) stimulation have been observed in anovulatory women and in hypogonadal patients. Various endocrinological abnormalities have been demonstrated in patients with anorexia nervosa (AN). The present study was undertaken to further investigate responses of serum PRL, growth hormone (GH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) to LHRH stimulation in 65 patients with AN and in 12 patients with bulimia before therapy and in the AN patients after several months of treatment, and in comparison to 12 normal women of the same age. Serum PRL responses to LHRH were positive (peak PRL levels >25 ng/ml and A increase in PRL > 10 rig/m1) in 16.9% of AN and 16.6% of bulimic patients; they were negative (absent) in all controls. Following restoration of the AN patients to normal body weight, the PRL responses to LHRH became normalized in those patients whose eating disorder behavior also returned to normal. However, in those patients whose eating disorder patterns continued to be abnormal, abnormal PRL responses persisted. The Imlimic patients were of normal body weight, and yet had abnormal PRL responses. Thus, the responses of PRL conelated more closely with the behavior of the underlying eating disorder rather than with body weight gain or normal body weight. INTRODUCTION
AN INCREASEin growth hormone (GH) in response to thyrotropin-releasing hormone (TRH) and luteinizing hormone-releasing hormone (LHRH) administration can occur in some patients with acromegaly and anorexia nervosa (Rubin et al., 1973; Faglia et al., 1973; Ishibashi et al., 1978; Maeda et al., 1976). A cortisol response to TRH also has been observed in patients with Cushing's syndrome and Nelson's syndrome (Krieger and Lurin, 1977; Pieters et al., 1979). Abnormal responses of serum prolactin (PRL) to LHRH have been demonstrated in anovulatory women with normal resting PRL levels (Giampietro et al., 1979), and injection of LRF or long-acting LRF (LRF-Ag) has resulted in the prompt, simultaneous pulsatile release of both LH and PRL in hypogonadal women (Yen et al., 1980; Casper and Yen, 1981). Endocrine abnormalities have been observed in patients with anorexia nervosa, and abnormal responses to stimulatory tests such as TRH (Maeda et al., 1976), LHRH (Beumont and Abraham, 1981) and oral glucose loading (Alvarez et al., 1972) have been reported. Furthermore, paradoxical PRL responses to LHRH infusions during weight gain in patients with anorexia nervosa have been observed (Beumont et al., 1980). Our study was designed to further investigate the responses of PRL and GH to LHRH stimulation in patients with anorexia nervosa or bulimia. *Address request for reprints to: Dr. Hajime Tamai, Department of Psychosomatic Medicine, Faculty of Medicine, Kyushu University, Fukuoka 812, Japan. 281
282
H.TAMAI et al. METHODS
Subjects The subjects consisted of 77 hospitalized female patients (65 anorexia nervosa and 12 bulimia), ranging in age from 16 to 28 years, who were not taking any medications. Twelve normal women in the follicular phase of their menstrual cycles, ranging in age from 18 to 24 years, were studied as control subjects. All patients with anorexia nervosa and bulimia fulfilled the diagnostic criteria proposed by Feighner et al. (1972) and DSM-m, respectively. Any patient diagnosed as having a concurrent illness was excluded from the study. All investigations were approved by relevant institutional and other human subjects and ethics committees. The Code of Ethics of the World Medical Association was adhered to in this study. The eating behavior pattern of the anorexia nervosa (AN) patients consisted primarily of the abhorrence of food of any type. Daily caloric intake was approximately 500 calories or less. Their body weights were all ___75%ideal body weight. During restoration to normal body weight, their daily caloric intake was gradually increased from 800 calories to approximately 2000 calories per day by the end of treatment. None of the patients were overtly depressed; however, some of the patients continued to avoid eating their meals and did not achieve normal body weight even after several months of hospitalization. The bulimic patients, on the other hand, had normal body weights. Their eating patterns consisted of binge eating and emesis. Their daily caloric intake was about 1600 calories prior to hospitalization, and this daily caloric intake was continued during hospitalization. The LHRH stimulation tests described below were performed in both the AN and the bulimic patients shortly after hospitalization and were repeated in the AN patients following restoration to normal body weight or, if this was not achieved, following prolonged hospitalization and treatment. The tests were not repeated in the bulimic patients.
Serum concentrations of Ltt, FSH, PRL and GH Serum LH, FSH, PRL and GH were determined with RIA kits from Dalnabot Radioisotope Laboratory (Matsudo City, Chiba Prefecture, Japan). Normal ranges for serum levels of LH and FSH (during the tollicular phase), PRL and GH in our laboratory are 5 - 2 0 mlU/ml, 5 - 1 5 mlU/ml, 2 - 2 5 ng/ml and <5 ng/ml, respectively.
LHRH stimulation tests LHRH tests were performed by i.v. injection of a bolus of 100/zg synthetic LHRH (Tanabe Co., Japan) at 0800 hr. Blood samples were obtained 0, 30, 60, 90 and 120 min after LHRH injection. Subjects, who had fasted for 12 hr, were placed at rest with catheterization of an antecubital vein by use of short indwelling catheters. The subjects were fully awake throughout the experiment. Serum PRL responsiveness to LHRH was defined in the present study as being positive when peak PRL values were >25 ng/ml and the incremental increase of PRL values (APRL; peak minus basal value) was > 10 ng/ml. These criteria are similar to those of Ishibashi et al. (1978) and Catania et al. (1976). A positive GH response to LHRH was defined as AGH values were >5 ng/ml (Maeda et al., 1976). Serum LH and FSH responses were considered to be hyporesponsive when peak values of LH and FSH after LHRI-I stimulation were < 30 mlU/ml and < 15 mlU/ml, respectively. RESULTS
Serum PRL concentrations following L H R I t in normal controls A s s h o w n in Fig. 1, s e r u m P R L l e v e l s did n o t i n c r e a s e s i g n i f i c a n t l y a f t e r i.v. i n j e c t i o n o f 1 0 0 / ~ g L H R H i n the 12 c o n t r o l subjects.
Frequency o f positive PRL responders among anorexia nervosa and bulimia patients E l e v e n o f the 65 a n o r e x i a n e r v o s a patients ( 1 6 . 9 % ) a n d t w o o f the 12 b u l i m i a patients ( 1 6 . 6 % ) w e r e p o s i t i v e P R L r e s p o n d e r s to L H R H . T h e r e f o r e , n o a p p a r e n t s i g n i f i c a n t d i f f e r e n c e s in f r e q u e n c y in a b n o r m a l P R L r e s p o n s i v e n e s s b e t w e e n a n o r e x i a n e r v o s a a n d b u l i m i a p a t i e n t s w a s f o u n d , a l t h o u g h t h e l a t t e r w e r e l i m i t e d in n u m b e r .
Hormonal responses to L t t R H before and after weight gain in anorexia nervosa patients T a b l e I s h o w s t w o p a t i e n t s w h o c h a n g e d f r o m b e i n g p o s i t i v e P R L r e s p o n d e r s to n o r m a l r e s p o n d e r s as b o d y w e i g h t r e t u r n e d t o w a r d n o r m a l . I n p a t i e n t A , as the P R L r e s p o n s e b e c a m e normalized, the abnormal GH response disappeared, and the LH response changed from h y p o r e s p o n s i v e to n o r m a l . T h e e a t i n g d i s o r d e r b e h a v i o r also w a s n o r m a l i z e d . In p a t i e n t B, as
P R L RESPONSES TO L H R H IN ANOREXIA NERVOSA AND BULIMIA
283
' LHRH 100~0 ] 40"
g
30.
20'
10
30
60
;0
120
Nlnutes FIG 1. Serum PRL concentrations (mean ± SEM) following LHRH administration in 12 normal control subjects. TABLE I. HORMONAL RESPONSES TO LHRH, AND BEHAVIORAL AND BODY WEIGHT CHANGES IN PATIENTS WITH ANOREXIA NERVOSA BEFORE AND AFTER TREATMENT
Before therapy PRL GH LH FSH (ng/ml) (ng/ml) (mlU/ml) (mlU/ml)
% IBWt
After therapy PRL GH LH FSH (ng/mi) (ng/ml) (mIU/ml) (mlU/ml)
% IBWt
Case A* 28 years
0'
11.0
2.0
8.0
7.5
30' 60' 90' 120'
27.0 32.0 27.0 27.0
8.8 6.2 4.0 3.2
17.0 16.0 15.0 17.0
27.0 29.0 26.0 21.0
Case B* 19 years 0' 16.0 2.1
5.8
8.2
30' 60' 90' 120'
42.0 25.0 20.0 16.0
2.3 5.1 8.2 9.8
7.7 8.3 8.2 6.8
-35 (31.5 kg)
-30 (32.8 kg)
14.0 15.1 16.7 15.6
8.0
1.6
5.6
7.2
12.0 13.0 9.0 11.0
2.0 0.8 2.2 1.9
49.6 36.1 29.4 28.0
26.1 23.9 22.6 20.0
7.2
3.6
12.6
9.6
-1 (47.0 kg)
-8
(43.3 kg) 7.4 10.3 9.4 10.4
2.7 5.2 4.4 3.2
52.2 46.7 38.2 27.6
19.6 19.1 16.4 14.0
*Behavior pattern of the eating disorder improved. fIBW = ideal body weight. the P R L response became normalized, the G H and L H responses (which were abnormal prior to therapy) and the eating disorder behavior also returned to normal, as in patient A. Table II shows two patients whose hormonal responses and clinical courses differed from the two cases in Table I. The P R L response to L H R H in patient C became less positive as her body weight was restored. The G H response was normal before and after therapy. H o w e v e r , even after her weight was restored to normal, the behavior pattern o f her eating disorder continued, i.e. occasional emesis or rejection o f meals. In patiem D, abnormal P R L and G H responses and a normal LH response to L H R H were noted initially. After 7 months, although no significant
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H.TAMAI et al.
TABLEII. HORMONALRESPONSESTO LHRH, EEHAVIORALANDBODYWEIGHTCHANGESIN PATIENTSWITHANOREXIA NERVOSABEFOREANDAFTERTREATMENT
PRL (ng/ml)
Before therapy GH LH (ng/ml) (mIU/ml)
After therapy GH LH (ng/ml) (mlU/ml)
FSH (mlU/ml)
% IBWt
PRL (ng/ml)
FSH (mlO/ml)
-29 (25.0 kg)
5.0
2.0
13.9
10.8
9.0 17.0 26.0 11.0
1.5 1.0 2.2 1.0
46.6 ~.9 42.1 13.1
19.1 19.1 17.4 14.1
16.0
1.3
8.0
12.8
26.8 36.6 26.0 19.0
1.2 0.8 2.2 2.1
28.1 26.1 21.8 21.8
26.9 36.6 32.8 30.0
% IBWf
Case C* 16 years
0'
8.0
3.0
3.4
9.3
30' ~' ~' 120'
20.0 33.0 26.0 22.0
1.8 2.2 1.4 2.4
33.0 20.0 17.0 13.0
18.6 23.3 22.2 20.0
-2 (33.0 kg)
Case D* 26 years
0'
18.0
2.5
6.5
7.0
30' ~' 90' 120'
32.0 48.0 30.0 22.0
5.7 9.8 6.4 5.4
36.3 28.0 25.3 12.0
10.4 15.3 20.1 18.0
-25 (37.2 kg)
-23 (39.5 kg)
*Behavior pattern of the eating disorder continued, with emesis, rejection of food, etc. tlBW = ideal body weight. TABLEIII. HORMONALRESPONSESTO LHRH IN PATIENTSWITHBULIMIA PRL (ng/ml)
GH (ng/ml)
LH (mlU/ml)
FSH (mlU/ml)
8.4
5.5
5.0
12.1
% IBW*
Case E 22 years
0'
+2
(49.1 ~ ) 30' ~' ~' 120'
11.5 22.6 30.4 18.6
8.6 13.6 7.2 6.0
38.2 25.4 23.3 20.7
24.1 24.3 26.5 28.9
11.0
3.6
9.2
6.1
Case F 19 years
0'
+4
(50.2 kg) 30' 60' 90' 120'
13.0 32.0 26.4 19.0
4.6 4.6 5.0 3.8
23.1 19.8 17.4 15.3
17.2 13.2 11.9 9.9
*IBW = ideal body weight. c h a n g e in b o d y w e i g h t h a d o c c u r r e d , the a b o v e tests w e r e r e p e a t e d . T h e s e r u m P R L r e s p o n s e to L H R H r e m a i n e d positive; h o w e v e r , the G H r e s p o n s e w a s n o r m a l , a n d the L H r e s p o n s e w a s s u b n o r m a l . T h e b e h a v i o r p a t t e r n o f h e r eating d i s o r d e r also c o n t i n u e d w i t h o u t significant i m p r o v e m e n t , i.e. s h e c o n t i n u e d to reject m e a l s o r w o u l d eat o n l y small a m o u n t s , a n d she had occasional emesis.
P R L RESPONSES TO L H R H IN ANOREXIA NERVOSA AND BULIMIA
285
Positive P R L responses to L H R H in bulimia
Two of 12 patients with bulimia demonstrated a positive PRL response to LHRH. One had an abnormal GH response and normal LH response to LHRH at the same time. In the other patient, serum GH was unresponsive and LH was hyporesponsive to LHRH, as shown in Table hi. DISCUSSION Abnormal PRL responses to LHRI-I have been reported in some anovulatory women (Giampietro et al., 1979). The present study was undertaken in anorexia nervosa and bulimia patients who were also anovulatory to determine whether they, too, had abnormal PRL responses to LHRH and to see if differences existed between the two groups. PRL secretion differs from that of other pituitary hormones because it is regulated in part by a hypothalamic inhibiting factor, prolactin inhibiting factor (PIF), which is thought to be dopamine (Van Loon, 1978). PRL secretion also is influenced by a variety of medications; none of our subjects were taking any type of medication for at least 2 - 4 weeks before being studied. The frequency of abnormal PRL responders to LHRH was similar in both eating disorders and similar to that reported for women with anovulatory amenorrhea, whose ages ranged from 16 to 39 years (Giampietro et al., 1979). Normal subjects do not have a PRL response to LHRH; however, it has been demonstrated that PRL levels increased progressively, with a > 50% rise above basal levels at 3.5 hr, following LHRH infusion and LHRI-I-agonist injection in normal cycling women (Yen et al., 1980). An increase in serum PRL induced by LHRI-I also has been reported to occur in normal men (Van Loon, 1978). Furthermore, Quigley et aL (1981 ) reported a close temporal relationship between food ingestion and release of PRL in normal women. In the present study, however, no increase in serum PRL after LHRH administration was observed in 12 normal women who had previously fasted for 12 hr. The abnormal or positive PRL responses to LHRI-I in our anorexic and bulimic patients did not appear to be due to alterations in other pituitary trophic hormones. No clear relationship was found among PRL, GH, LH or FSH concentrations following LHRI-I administration in the AN and bulirnic patients before therapy, or after treatment in the AN patients. Basal PRL levels and PRL responses to TRH are usually normal in anorexia nervosa (Beumont et al., 1976). Beumont and Abraham (1981) examined whether low levels of LH in patients with anorexia nervosa were associated with a disturbance of PRL secretion. Bromoeriptine enhanced the LH response on one occasion in a patient with anorexia nervosa who had moderately elevated basal plasma PRL levels, hut it failed to produce a similar effect when given to three anorexia nervosa patients with normal PRL levels. It may be inferred that amenorrhea associated with anorexia nervosa is unlikely to be directly related to alterations in the secretion of PRL (Beumont and Abraham, 1981). Beumont et al. (1980) also reported that the paradoxical rise in plasma PRL to LHRH was significantly more marked in patients whose weight gain was rapid (1 or more kg/week). Fichter et aL (1986) demonstrated dramatic changes in function in several endocrine systems (pituitary-adrenal, TSH and GH) following short-term starvation and minimal weight loss in normal healthy women. They concluded that reduced caloric intake, catabolic state and loss in body weight had powerful influences on the hypothalamic-pituitary-adrenal axis and other endocrine functions. However, in our study, abnormal responses of PRL and GH were observed not only in anorexia nervosa patients with marked weight loss, but also in bulimia patients with normal body weight. It appears, therefore, that responses of PRL and GH to LHRH are more
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closely related to the behavior of the eating disorder rather than to changes in body weight. The experimental data of Van Loon (1978) support the hypothesis that PRL release induced by LRF may be mediated by a reduction of hypothalamic dopamine. However, a direct effect of LHRH, similar to that of TRH (Tashjian et al., 1971), on the pituitary lactotrophs cannot be ruled out (Grosvenor and Mena, 1980; Casper and Yen, 1981). In summary, abnormalities in PRL regulation were observed in approximately 16% of patients with anorexia nervosa or bulimia, as manifested by a significant increase in PRL secretion following LHRH administration. Following long-term treatment of the illness, normalization of the PRL responses to LHRH occurred in some of the AN patients. The normalization of the hormonal responses correlated not with any change in body weight, but with improvement in the behavior patterns associated with the eating disorders. The authors would like to express their sincere thanks to Ms April J. Doan and Ms Debra L. Wichner for their excellent secretarial assistance.
REFERENCES Alvarez L C, Dimas C O, Castro A, Rossman L G, Vanderlaan E F, Vanderlaan W P (1972) Growth hormone in malnutrition. J Clin Endocrinol Metab 34: 400-404. Beumout P J V, Abraham S F (1981) Continuous infusion of luteinizing hormone releasing hormone (LHRH) in patients with anorexia nervosa. Psychol Med 11: 477-487. Bcumont P J V, George G C W, Pimstone B L, Vink A I (1976) The pituitary response to hypothalamic releasing hormones in patients with anorexia nervosa. J Clin Endocrinol Metab 43: 487-496. Beumont P J V, Abraham S F, Turtle J (1980) Paradoxical prolacKn responses to gonadotropin releasing hormone during weight gain in patients with anorexia nervosa. J Clin Endocrinol Metab 51:1283 - 1285. Casper R F, Yen S S C (1981) Simultaneous pulsatile release of prolactin and luteinizing hormone induced by luteinizing hormone releasing factor agonist. J Clin Endocrinol Metab 52: 934-936. Catania A, Cantalamessa L, Reschini E (1976) Plasma prolactin response to luteinizing hormone-releasing hormone in acromegalic patients. J Clin Endocrinol Metab 43: 689-691. Faglia G, Beck-Peccoz P, Travaglini P, Paracchi A, Spada A, Lewin A (1973) Elevation in plasma growth hormone concentration after luteinizing hormone-releasing hormone (LHRH) in patients with active acromegaly. J Clin Endocrinol Metab 37: 338-341. Feighner J P, Robins E, Guze S B, Woodruff R A Jr, Winokur G, Munoz R, Louis S (1972) Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 26: 57-63. Fichter M M, Pirke K M, Holsboer F (1986) Weight loss causes neuroendocrine disturbances: experimental study in healthy starving subjects. Psychiatry Res 17: 61-72. Giampietro O, Moggi G, Chisci R, Coluccia A, Luche A D, Simonini N, Brunori I (1979) Unusual prolactin response to luteinizing hormone-releasing hormone in some anovulatory women. J Clin Endocrinol Metab 49: 141-143. Grosvenor C E, Mena F (1980) Evidence that thyrotropin-releasing hormone and hypothalamic prolactin-releasing factor may have function in the release of prolactin in the lactating rat. Endocrinology 107:863 - 866. Ishibashi M, Yamaji T, Kosaka K (1978) Induction of growth hormone and prolactin secretion by luteinizing hormonereleasing hormone and its blockade by bromoergocriptine in acromegalic patients. J Clin Endocrinol Metab 47: 418-421. Krieger D T, Lurin M (1977) Plasma ACTH and cortisol response to TRF, vasopressin and hypoglycemia in Cushing's disease and Nelson's syndrome. J Clin Endocrinol Metab 44:361-368. Maeda K, Kato Y, Yamaguchi N, Chihara K, Ohgo S, Iwasaki Y, Yoshimoto Y, Moridera K, Kuromaru S, Imura H (1976) Growth hormone following thyrotropin-releasing hormone injection into patients with anorexia nervosa. Acta Endocrinol 8 1 : 1 - 6 . Pieters G F F M, Smals A G H, Benraad T J, Kloppenborg P W C (1979) Plasma cortisol response to thyrotropinreleasing hormone and luteinizing hormone-releasing hormone in Cushing's disease. J Clin Endocrinol Metab 48: 874-876. Quigley M E, Ropert J F, Yen S S C (1981) Acute prolactin release triggered by feeding. J Clin Endocrinol Metab 52: 1043-1045. Rubin A L, Levin S R, Bernstein R I, TyrreU J B, Noacco, C, Forsham P H (1973) Stimulation of growth hormone by luteinizing hormone-releasing hormone in active acromegaly. J Clin Endocrinol Metab 37: 160-164.
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Tashjian A H Jr, Barowsky N J, Jenser D K (1971) Thyrotropin releasing hormone: direct evidence for stimulation of prolactin production by pituitary cells in culture. Biochem Biophys Res Comm 67: 50-55. Van Loon G R (1978) Bromocriptin-inducod inhibition of plasma dopamin¢, noradrenalin¢, and adrenaline responses to LH-RF. Nature 275:331-333. YenS S C, Hoff J D, Lasley B L, Casper R F, Sheehan K (1980) Induction of prolactin release by LRF and LRFagonist. Life Sci 26: 1963-1967.
©
0306-4530187 $3.00 + 0.00 1987PergamonJournalsLtd.
A B N O R M A L S E R U M P R O L A C T I N R E S P O N S E S TO L U T E I N I Z I N G H O R M O N E - R E L E A S I N G H O R M O N E ( L H R H ) IN P A T I E N T S W I T H ANOREXIA NERVOSA AND BULIMIA HAJIME TAMAI,* CHIE KARIBE, KAYOKO KIYOHARA, KENJI MOPd, KOHICHIRO TAKENO, NOBUYUKI KOBAYASHI, TETSUYA NAKAGAWA a n d LINDY F. KUMAGAI Department of Psychosomatic Medicine, Faculty of Medicine, Kyushu University, Fulmoka, Japan; and Department of Internal Medicine, School of Medicine, University of California, Davis, (LFK), Sacramento, CA 95817, U.S.A.
(Received 22 Apr/l 1986; in final form 2 December 1986) SUMMARY Abnormal responses of serum prolactin (PRL) to luteinizing hormone-releasing hormone (LHRH) stimulation have been observed in anovulatory women and in hypogonadal patients. Various endocrinological abnormalities have been demonstrated in patients with anorexia nervosa (AN). The present study was undertaken to further investigate responses of serum PRL, growth hormone (GH), luteinizing hormone (LH) and follicle stimulating hormone (FSH) to LHRH stimulation in 65 patients with AN and in 12 patients with bulimia before therapy and in the AN patients after several months of treatment, and in comparison to 12 normal women of the same age. Serum PRL responses to LHRH were positive (peak PRL levels >25 ng/ml and A increase in PRL > 10 rig/m1) in 16.9% of AN and 16.6% of bulimic patients; they were negative (absent) in all controls. Following restoration of the AN patients to normal body weight, the PRL responses to LHRH became normalized in those patients whose eating disorder behavior also returned to normal. However, in those patients whose eating disorder patterns continued to be abnormal, abnormal PRL responses persisted. The Imlimic patients were of normal body weight, and yet had abnormal PRL responses. Thus, the responses of PRL conelated more closely with the behavior of the underlying eating disorder rather than with body weight gain or normal body weight. INTRODUCTION
AN INCREASEin growth hormone (GH) in response to thyrotropin-releasing hormone (TRH) and luteinizing hormone-releasing hormone (LHRH) administration can occur in some patients with acromegaly and anorexia nervosa (Rubin et al., 1973; Faglia et al., 1973; Ishibashi et al., 1978; Maeda et al., 1976). A cortisol response to TRH also has been observed in patients with Cushing's syndrome and Nelson's syndrome (Krieger and Lurin, 1977; Pieters et al., 1979). Abnormal responses of serum prolactin (PRL) to LHRH have been demonstrated in anovulatory women with normal resting PRL levels (Giampietro et al., 1979), and injection of LRF or long-acting LRF (LRF-Ag) has resulted in the prompt, simultaneous pulsatile release of both LH and PRL in hypogonadal women (Yen et al., 1980; Casper and Yen, 1981). Endocrine abnormalities have been observed in patients with anorexia nervosa, and abnormal responses to stimulatory tests such as TRH (Maeda et al., 1976), LHRH (Beumont and Abraham, 1981) and oral glucose loading (Alvarez et al., 1972) have been reported. Furthermore, paradoxical PRL responses to LHRH infusions during weight gain in patients with anorexia nervosa have been observed (Beumont et al., 1980). Our study was designed to further investigate the responses of PRL and GH to LHRH stimulation in patients with anorexia nervosa or bulimia. *Address request for reprints to: Dr. Hajime Tamai, Department of Psychosomatic Medicine, Faculty of Medicine, Kyushu University, Fukuoka 812, Japan. 281
282
H.TAMAI et al. METHODS
Subjects The subjects consisted of 77 hospitalized female patients (65 anorexia nervosa and 12 bulimia), ranging in age from 16 to 28 years, who were not taking any medications. Twelve normal women in the follicular phase of their menstrual cycles, ranging in age from 18 to 24 years, were studied as control subjects. All patients with anorexia nervosa and bulimia fulfilled the diagnostic criteria proposed by Feighner et al. (1972) and DSM-m, respectively. Any patient diagnosed as having a concurrent illness was excluded from the study. All investigations were approved by relevant institutional and other human subjects and ethics committees. The Code of Ethics of the World Medical Association was adhered to in this study. The eating behavior pattern of the anorexia nervosa (AN) patients consisted primarily of the abhorrence of food of any type. Daily caloric intake was approximately 500 calories or less. Their body weights were all ___75%ideal body weight. During restoration to normal body weight, their daily caloric intake was gradually increased from 800 calories to approximately 2000 calories per day by the end of treatment. None of the patients were overtly depressed; however, some of the patients continued to avoid eating their meals and did not achieve normal body weight even after several months of hospitalization. The bulimic patients, on the other hand, had normal body weights. Their eating patterns consisted of binge eating and emesis. Their daily caloric intake was about 1600 calories prior to hospitalization, and this daily caloric intake was continued during hospitalization. The LHRH stimulation tests described below were performed in both the AN and the bulimic patients shortly after hospitalization and were repeated in the AN patients following restoration to normal body weight or, if this was not achieved, following prolonged hospitalization and treatment. The tests were not repeated in the bulimic patients.
Serum concentrations of Ltt, FSH, PRL and GH Serum LH, FSH, PRL and GH were determined with RIA kits from Dalnabot Radioisotope Laboratory (Matsudo City, Chiba Prefecture, Japan). Normal ranges for serum levels of LH and FSH (during the tollicular phase), PRL and GH in our laboratory are 5 - 2 0 mlU/ml, 5 - 1 5 mlU/ml, 2 - 2 5 ng/ml and <5 ng/ml, respectively.
LHRH stimulation tests LHRH tests were performed by i.v. injection of a bolus of 100/zg synthetic LHRH (Tanabe Co., Japan) at 0800 hr. Blood samples were obtained 0, 30, 60, 90 and 120 min after LHRH injection. Subjects, who had fasted for 12 hr, were placed at rest with catheterization of an antecubital vein by use of short indwelling catheters. The subjects were fully awake throughout the experiment. Serum PRL responsiveness to LHRH was defined in the present study as being positive when peak PRL values were >25 ng/ml and the incremental increase of PRL values (APRL; peak minus basal value) was > 10 ng/ml. These criteria are similar to those of Ishibashi et al. (1978) and Catania et al. (1976). A positive GH response to LHRH was defined as AGH values were >5 ng/ml (Maeda et al., 1976). Serum LH and FSH responses were considered to be hyporesponsive when peak values of LH and FSH after LHRI-I stimulation were < 30 mlU/ml and < 15 mlU/ml, respectively. RESULTS
Serum PRL concentrations following L H R I t in normal controls A s s h o w n in Fig. 1, s e r u m P R L l e v e l s did n o t i n c r e a s e s i g n i f i c a n t l y a f t e r i.v. i n j e c t i o n o f 1 0 0 / ~ g L H R H i n the 12 c o n t r o l subjects.
Frequency o f positive PRL responders among anorexia nervosa and bulimia patients E l e v e n o f the 65 a n o r e x i a n e r v o s a patients ( 1 6 . 9 % ) a n d t w o o f the 12 b u l i m i a patients ( 1 6 . 6 % ) w e r e p o s i t i v e P R L r e s p o n d e r s to L H R H . T h e r e f o r e , n o a p p a r e n t s i g n i f i c a n t d i f f e r e n c e s in f r e q u e n c y in a b n o r m a l P R L r e s p o n s i v e n e s s b e t w e e n a n o r e x i a n e r v o s a a n d b u l i m i a p a t i e n t s w a s f o u n d , a l t h o u g h t h e l a t t e r w e r e l i m i t e d in n u m b e r .
Hormonal responses to L t t R H before and after weight gain in anorexia nervosa patients T a b l e I s h o w s t w o p a t i e n t s w h o c h a n g e d f r o m b e i n g p o s i t i v e P R L r e s p o n d e r s to n o r m a l r e s p o n d e r s as b o d y w e i g h t r e t u r n e d t o w a r d n o r m a l . I n p a t i e n t A , as the P R L r e s p o n s e b e c a m e normalized, the abnormal GH response disappeared, and the LH response changed from h y p o r e s p o n s i v e to n o r m a l . T h e e a t i n g d i s o r d e r b e h a v i o r also w a s n o r m a l i z e d . In p a t i e n t B, as
P R L RESPONSES TO L H R H IN ANOREXIA NERVOSA AND BULIMIA
283
' LHRH 100~0 ] 40"
g
30.
20'
10
30
60
;0
120
Nlnutes FIG 1. Serum PRL concentrations (mean ± SEM) following LHRH administration in 12 normal control subjects. TABLE I. HORMONAL RESPONSES TO LHRH, AND BEHAVIORAL AND BODY WEIGHT CHANGES IN PATIENTS WITH ANOREXIA NERVOSA BEFORE AND AFTER TREATMENT
Before therapy PRL GH LH FSH (ng/ml) (ng/ml) (mlU/ml) (mlU/ml)
% IBWt
After therapy PRL GH LH FSH (ng/mi) (ng/ml) (mIU/ml) (mlU/ml)
% IBWt
Case A* 28 years
0'
11.0
2.0
8.0
7.5
30' 60' 90' 120'
27.0 32.0 27.0 27.0
8.8 6.2 4.0 3.2
17.0 16.0 15.0 17.0
27.0 29.0 26.0 21.0
Case B* 19 years 0' 16.0 2.1
5.8
8.2
30' 60' 90' 120'
42.0 25.0 20.0 16.0
2.3 5.1 8.2 9.8
7.7 8.3 8.2 6.8
-35 (31.5 kg)
-30 (32.8 kg)
14.0 15.1 16.7 15.6
8.0
1.6
5.6
7.2
12.0 13.0 9.0 11.0
2.0 0.8 2.2 1.9
49.6 36.1 29.4 28.0
26.1 23.9 22.6 20.0
7.2
3.6
12.6
9.6
-1 (47.0 kg)
-8
(43.3 kg) 7.4 10.3 9.4 10.4
2.7 5.2 4.4 3.2
52.2 46.7 38.2 27.6
19.6 19.1 16.4 14.0
*Behavior pattern of the eating disorder improved. fIBW = ideal body weight. the P R L response became normalized, the G H and L H responses (which were abnormal prior to therapy) and the eating disorder behavior also returned to normal, as in patient A. Table II shows two patients whose hormonal responses and clinical courses differed from the two cases in Table I. The P R L response to L H R H in patient C became less positive as her body weight was restored. The G H response was normal before and after therapy. H o w e v e r , even after her weight was restored to normal, the behavior pattern o f her eating disorder continued, i.e. occasional emesis or rejection o f meals. In patiem D, abnormal P R L and G H responses and a normal LH response to L H R H were noted initially. After 7 months, although no significant
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TABLEII. HORMONALRESPONSESTO LHRH, EEHAVIORALANDBODYWEIGHTCHANGESIN PATIENTSWITHANOREXIA NERVOSABEFOREANDAFTERTREATMENT
PRL (ng/ml)
Before therapy GH LH (ng/ml) (mIU/ml)
After therapy GH LH (ng/ml) (mlU/ml)
FSH (mlU/ml)
% IBWt
PRL (ng/ml)
FSH (mlO/ml)
-29 (25.0 kg)
5.0
2.0
13.9
10.8
9.0 17.0 26.0 11.0
1.5 1.0 2.2 1.0
46.6 ~.9 42.1 13.1
19.1 19.1 17.4 14.1
16.0
1.3
8.0
12.8
26.8 36.6 26.0 19.0
1.2 0.8 2.2 2.1
28.1 26.1 21.8 21.8
26.9 36.6 32.8 30.0
% IBWf
Case C* 16 years
0'
8.0
3.0
3.4
9.3
30' ~' ~' 120'
20.0 33.0 26.0 22.0
1.8 2.2 1.4 2.4
33.0 20.0 17.0 13.0
18.6 23.3 22.2 20.0
-2 (33.0 kg)
Case D* 26 years
0'
18.0
2.5
6.5
7.0
30' ~' 90' 120'
32.0 48.0 30.0 22.0
5.7 9.8 6.4 5.4
36.3 28.0 25.3 12.0
10.4 15.3 20.1 18.0
-25 (37.2 kg)
-23 (39.5 kg)
*Behavior pattern of the eating disorder continued, with emesis, rejection of food, etc. tlBW = ideal body weight. TABLEIII. HORMONALRESPONSESTO LHRH IN PATIENTSWITHBULIMIA PRL (ng/ml)
GH (ng/ml)
LH (mlU/ml)
FSH (mlU/ml)
8.4
5.5
5.0
12.1
% IBW*
Case E 22 years
0'
+2
(49.1 ~ ) 30' ~' ~' 120'
11.5 22.6 30.4 18.6
8.6 13.6 7.2 6.0
38.2 25.4 23.3 20.7
24.1 24.3 26.5 28.9
11.0
3.6
9.2
6.1
Case F 19 years
0'
+4
(50.2 kg) 30' 60' 90' 120'
13.0 32.0 26.4 19.0
4.6 4.6 5.0 3.8
23.1 19.8 17.4 15.3
17.2 13.2 11.9 9.9
*IBW = ideal body weight. c h a n g e in b o d y w e i g h t h a d o c c u r r e d , the a b o v e tests w e r e r e p e a t e d . T h e s e r u m P R L r e s p o n s e to L H R H r e m a i n e d positive; h o w e v e r , the G H r e s p o n s e w a s n o r m a l , a n d the L H r e s p o n s e w a s s u b n o r m a l . T h e b e h a v i o r p a t t e r n o f h e r eating d i s o r d e r also c o n t i n u e d w i t h o u t significant i m p r o v e m e n t , i.e. s h e c o n t i n u e d to reject m e a l s o r w o u l d eat o n l y small a m o u n t s , a n d she had occasional emesis.
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Positive P R L responses to L H R H in bulimia
Two of 12 patients with bulimia demonstrated a positive PRL response to LHRH. One had an abnormal GH response and normal LH response to LHRH at the same time. In the other patient, serum GH was unresponsive and LH was hyporesponsive to LHRH, as shown in Table hi. DISCUSSION Abnormal PRL responses to LHRI-I have been reported in some anovulatory women (Giampietro et al., 1979). The present study was undertaken in anorexia nervosa and bulimia patients who were also anovulatory to determine whether they, too, had abnormal PRL responses to LHRH and to see if differences existed between the two groups. PRL secretion differs from that of other pituitary hormones because it is regulated in part by a hypothalamic inhibiting factor, prolactin inhibiting factor (PIF), which is thought to be dopamine (Van Loon, 1978). PRL secretion also is influenced by a variety of medications; none of our subjects were taking any type of medication for at least 2 - 4 weeks before being studied. The frequency of abnormal PRL responders to LHRH was similar in both eating disorders and similar to that reported for women with anovulatory amenorrhea, whose ages ranged from 16 to 39 years (Giampietro et al., 1979). Normal subjects do not have a PRL response to LHRH; however, it has been demonstrated that PRL levels increased progressively, with a > 50% rise above basal levels at 3.5 hr, following LHRH infusion and LHRI-I-agonist injection in normal cycling women (Yen et al., 1980). An increase in serum PRL induced by LHRI-I also has been reported to occur in normal men (Van Loon, 1978). Furthermore, Quigley et aL (1981 ) reported a close temporal relationship between food ingestion and release of PRL in normal women. In the present study, however, no increase in serum PRL after LHRH administration was observed in 12 normal women who had previously fasted for 12 hr. The abnormal or positive PRL responses to LHRI-I in our anorexic and bulimic patients did not appear to be due to alterations in other pituitary trophic hormones. No clear relationship was found among PRL, GH, LH or FSH concentrations following LHRI-I administration in the AN and bulirnic patients before therapy, or after treatment in the AN patients. Basal PRL levels and PRL responses to TRH are usually normal in anorexia nervosa (Beumont et al., 1976). Beumont and Abraham (1981) examined whether low levels of LH in patients with anorexia nervosa were associated with a disturbance of PRL secretion. Bromoeriptine enhanced the LH response on one occasion in a patient with anorexia nervosa who had moderately elevated basal plasma PRL levels, hut it failed to produce a similar effect when given to three anorexia nervosa patients with normal PRL levels. It may be inferred that amenorrhea associated with anorexia nervosa is unlikely to be directly related to alterations in the secretion of PRL (Beumont and Abraham, 1981). Beumont et al. (1980) also reported that the paradoxical rise in plasma PRL to LHRH was significantly more marked in patients whose weight gain was rapid (1 or more kg/week). Fichter et aL (1986) demonstrated dramatic changes in function in several endocrine systems (pituitary-adrenal, TSH and GH) following short-term starvation and minimal weight loss in normal healthy women. They concluded that reduced caloric intake, catabolic state and loss in body weight had powerful influences on the hypothalamic-pituitary-adrenal axis and other endocrine functions. However, in our study, abnormal responses of PRL and GH were observed not only in anorexia nervosa patients with marked weight loss, but also in bulimia patients with normal body weight. It appears, therefore, that responses of PRL and GH to LHRH are more
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closely related to the behavior of the eating disorder rather than to changes in body weight. The experimental data of Van Loon (1978) support the hypothesis that PRL release induced by LRF may be mediated by a reduction of hypothalamic dopamine. However, a direct effect of LHRH, similar to that of TRH (Tashjian et al., 1971), on the pituitary lactotrophs cannot be ruled out (Grosvenor and Mena, 1980; Casper and Yen, 1981). In summary, abnormalities in PRL regulation were observed in approximately 16% of patients with anorexia nervosa or bulimia, as manifested by a significant increase in PRL secretion following LHRH administration. Following long-term treatment of the illness, normalization of the PRL responses to LHRH occurred in some of the AN patients. The normalization of the hormonal responses correlated not with any change in body weight, but with improvement in the behavior patterns associated with the eating disorders. The authors would like to express their sincere thanks to Ms April J. Doan and Ms Debra L. Wichner for their excellent secretarial assistance.
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Tashjian A H Jr, Barowsky N J, Jenser D K (1971) Thyrotropin releasing hormone: direct evidence for stimulation of prolactin production by pituitary cells in culture. Biochem Biophys Res Comm 67: 50-55. Van Loon G R (1978) Bromocriptin-inducod inhibition of plasma dopamin¢, noradrenalin¢, and adrenaline responses to LH-RF. Nature 275:331-333. YenS S C, Hoff J D, Lasley B L, Casper R F, Sheehan K (1980) Induction of prolactin release by LRF and LRFagonist. Life Sci 26: 1963-1967.