BIOL PSYCHIATRY 1990;27:1227-i230
1227
Paradoxical Growth-Hormone Responses to Thyrotropin-Releasing Hormone in Panic Disorder Manuel E. Tancer, Murray B. Stein, and Thomas W. Uhde
Thyrotropin-releasing hormone (TRtI) has been reported to stimulate growth hormone (GH) release in a variety of pathological conditions, including some studies of major depression. Because of the considerable phenomenological and neuroendocrine overlap between major depr~,ssion and panic disorder, we investigated the rate of positive GH responses to TRH in 38 patients with panic disorder and 23 normal controls. There were no between-group differences in mean GH response to TRH or in the proportion of subjects with positive responses. These findings are discussed in the context of neuroendocrine regulation of GH secretion and the relationship between anxiety and affective disorders.
Introduction In normal individuals, morning infusion of thyrotropin-reieasing hormone (TRH) causes robust secretion of thyroid-stimulating hormone (TSH) and prolactin, but not growth hormone (GH) (Anderson et al. 1971). However, "paradoxical" growth hormone secretion following TRH administration has been reported in anorexia nervosa (Maeda et al. 1976; Gold et al. 1980), bulimia (Levy et al. 1988), and, depending on the criteria, many patients with major depression (see Hsiao et al. 1986 for review). Thus, although the mechanism and factors that influence this response are poorly understood, TRH-induced GH secretion appears to occur in a heterogeneous array of neuropsychiatric conditions characterized by abnormalities in hypothalamic-pituitary regulation (Caroff et al. 1984; Cocchi et al. 1984). Although the relationship between panic and major affective disorders (for review see Stein and Uhde 1988) remains controversial, both syndromes are associated with a wide variety of neuroendocrine abnormalities that suggest possible alterations in hypothalamicpituitary function. The rate of TRH-induced GH responses depends partly on the criteria used. Doubling of baseline GH combined with an absolute GH rise greater than 5 ng/ml is commonly defined as a "positive" GH response to TRH (Brambilla et al. 1978). We have adopted more stringent criteria for a positive GH response to TRH by requiring that the GH response also occur within 45 min of TRH administration, a time frame consistent with
From the Section on Anxiety and Affective Disorders, Biological PsychiaCy Branch, National Institute of Mental Health, Betheuf~, lVlD20892. reprint ~lUeats to Dr. Thomas Uh~, Chief, Sectionon Anxiety and AffcctiveDisorders,BiologicalPsychisl~jBranch, National Institut~ of Mental Health, Building 10, Room 3S239, 9000 R~kville Pike, Bethesda, MD 20892. Received March 7, 1989; nsvisedJune 8, 1989. This mlicle is in the Pubtic Domain.
0006-3223/90/$00.00
1228
BIO' nSYCHIATRY 1992" ~':1227-1230
M.E. Tancer et al.
pituitary responses to specific hypothalamic-releasing factors. These stricter criteria are intended to reduce the frequency of spurious or delayed GH responses (Eastman and Lazarus 1972), which likely do not reflect direct effects of TRH administration. The current study of growth-hormone response to TRH in patients with panic disc~# ;r was undertaken in order to further describe the neuroendocrine responses to TRH in ~,a~c disorder patients. To our knowledge, this is the first study to examine ~ e "paradoxi~" GH response to TRH in patients with panic disorder.
Methods Thirty-eight subjects [23 women, 15 men; mean age 33.5 __. 7.0 (range 23-48)] meeting DSM-III-R (APA 1987) criteria for panic disorder with or without agoraphobia, who were free of concomitant major depression, made up the panic disorder group. Twentythree subjects [12 women, 11 men; mean age 31.8 +_ 9.7 (range 21-57)] with no history of psychiatric disease as determined by a structured interview made up the normal volunteer group. Patients and controls were medically healthy as determined by medical history, physical examination, and routine blood tests (CBC, SMAC-20, urinalysis) and were medication free for at least 2 weeks prior to participation. Written and oral informed consent was obtained from all subjects. Following an overnight fast, 500 ttg TRH was administered intravenously between 9 AM and 10 AM following a 20 min recumbent adaptation period. Subjects were encouraged to relax after intravenous catheter insertion. Blood was drawn at baseline and again at 15, 30, and 45 min after TRH administration. GH was measured by double antibody radioimmunoassay (RIA). The GH assay has a sensitivity of 0.4 ng/ml and an intra- and interassay variability of 4.9% and 7.3%, respectively. The GH response to TRH was initially analyzed by analysis of variance (ANOVA) with repeated measures. The variance differed between groups at all time points (Bartlett's test, p < 0.05) so the Mann-Whitney U-test was used to compare mean GH values at each time point. Yates corrected chi-square was used to compare categorical measures (proportion of subjects with positive GH response to TRH). Relationships between variables were compared using Spearman rank correlation coefficients (rs). All statistical tests were two-tailed. Probabilities >0.05 are reported as not significant (NS).
Results There was no difference in GH response to TRH in patients with panic disorder compared with normal volunteers. Analysis of variance revealed a modest main effect of diagnosis on GH level [F(l,59)ffi 4.03; p ffi 0.05], but no mmn effect of time [F(3,57)ffi 0.69; p = NS] or diagnosis × time interaction [F(3,57) ffi 0.54;p ffi NS]. At each time point, GH levels of the patients with panic disorder demonstrated greater variance than the controls. However, mean GH levels did not differ significantly between groups at any time point (Table 1). Using our criteria for positive GH response to TRH (doubling of baseline GH plus an absolute increase of at least 5 ng/ml within 45 min), 6 of 38 (15.8%) patients with panic disorder and I of 23 (4.3%) controls had a positive GH response to TRH (Yates corrected chi-square = 0.82, df = 1, p ffi NS). One of the 6 patients with a positive GH response
GH Response to TRH in Panic Disorder
BIOL PSYCHIATRY 1990;27:1227-1230
1229
Table 1. GH Response (ng/ml) to TRH in Patients with Panic Disorder and Normal Controls Time
Controls
Patients
Minutes
(n - 23)
(n = 38)
Baseline
0.70 +_ 0.57 (0.4--2.6)
1.22 -4- 1.28 (0.4-4.7)
+ 15
0.67 -4- 0.42 (0.4--2.2) 0.91 .4- I. 14 (0.4--5.4) 0.92 .4- 1.38 (0.4--6.5)
1.73 +_ 2.77 (0.4--12.8) 1.76 _ 2.59 (0.4-12.4) 1.93 .4- 3.42 (0.4--16.9)
+ 30 +45
p - NS for all time points (Mann Whitney U-Test); mean ± so; (range)..
to TRH also had a subnormal & maxTSH response (& maxTSH < 7 ~IU/ml), whereas the other 5 patients with a positive GH response to TRH had normal A maxTSH values. There was a significant positive correlation between baseline GH levels and the GH level 30 min following TRH administration in both patients (rs = 0.39, df = 36, p < 0.02) and controls (rs = 0.59, df = 21, p < 0.005).
Discussion Using two separate analyses, we failed to find evidence for increased GH responses to TRH in patients with panic disorder compared with normal volunteers. Although the GH response to TRH was normal in this study, several lines of evidence suggest that alterations in GH secretion following clonidine (Uhde et al. 1986; Chamey and Heninger 1986) and growth hormone-releasing factor (GRF) (Rapaport et al. I989) may be prevalent in panic disorder patients. Thus, despite our negative findings with this particular neuroendocrine probe, it would be useful from a theoretical perspective to understand those mechanisms that mediate the GH response to TRH. In this regard, there is both preclinical and clinical evidence to suggest that TRH-induced GH release occurs in the presence of elevated GH levels or following GH or growth hormone-releasing factor infusion (Sartorio et al. 1986; Borges et al. 1983). Our finding of a positive significant correlation between baseline GH and + 30 GH levels following TRH is consistent with a permissive role for GH in the TRH stimulation of GH secretion, although circadian alterations in GRF and/or TRH may also influence this response (Caroff et al. 1984). In conclusion, though we failed to find an exaggerated GH response to TRH, these data suggest that circadian patterns and levels of GH secretion may be a relevant factor in the assessment of future investigations using the TRH, clonidine, and GRF challenge paradigms.
References American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders (DSM-IH-R) (ed 3, revised), Washington, DC: American Psychiatric Association Press. Anderson MS, Bowers CY, Kastin AJ, et al (1971): Synthetic thyrotropin-releasing hormone, a potent stimulator of thymtropin secretion in man. N Engl J Med 285:1279-1283. Borges JLC, Uskavitch DR, Kaiser DL, Cronin MJ, Evans WS, Thomer MO (1983): Human
1230
BIOL PSYCHIATRY I990;27:1227-1230
M.E. Tancer et aL
pancreatic growth hormone-releasing factor (hpGRF-40) allows stimulation of GH release by TRH. Endocrinology 113:1519-1521. Brambilla F, Smeraldi E, Sacchetti E, Negri F, Cocchi D, Muller EE (1978): D~ranged anterior pituitary responsiveness to hypothalamic hormones in depressed patients. Arch Gen Psychiatry 35:1231-1238. Caroff S, Winokur A, Snyder PJ, Amsterdam J (1984): Diurnal variation of growth hormone secretion following thyrotropin-releasing hormone infusion in normal men. Psychosom Med 46:59-66. Chamey DS, Heninger GR (1986): Abnormal regulation of noradrenergic function in panic disorder: Effects of clonidine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 43:1042-1054. Cocchi D, Locatelli V, Muller EE (1984): Nonspecific pituitary responses to hypothalamic hormones in basic and clinical research. In Shah D (ed), Psychoneuroendocrine Dysfunction. New York: Plenum Press, pp 173-208. Eastman CJ, Lazarus L (1972): The effect of orally administered synthetic thyrotropin-releasing factor on adenypophyseal function. Horm Metab Res 4:58. Gold MS, Pottash ALC, Martin DM, Finn LB, Davies RK (1980): Thyroid-stimulating hormone and growth hormone responses to thyrotropin-releasing hormone in anorexia nervosa. Int J Psychiatry Med 10:51-57. Hsiao JK, Garbutt JC, Loosen PT, Mason GA, Prange AJ (1986): Is there paradoxical growth hormone response to thyrotropin-releasing hormone in depression? Biol Psychiatry 21:595-600. Levy AB, Dixon KN, Malarkey WB (1988): Pituitary response to ~ in bulimia. Biol Psychiatry 23:476--484. Maeda K, Kato Y, Yamaguchi N, et al (1976): Growth hormone release following thyrotropinreleasing hormone injection in patients with anorexia nervosa. Acta Endocrinol 81:1-8. Rapaport MH, Risch SC, Gillin JC, Golshan S, Janowsky DS (1989): Blunted growth hormone response to peripheral infusions of human growth hormone-releasing factor in patients with panic disorder. Am J Psychiatry 146:92-95. Sartorio A, Spada A, Bochicchio D, Atterrato A, Morabito F, Faglia G (1986): Effect of thyrotropinreleasing hormone on growth hormone release in normal subjects pretreated with human pancreatic growth hormone-releasing factor 1-44 pulsatile administration. Neuroendocrinology 44:470--474. Stein MB, Uhde TW (1988): Panic disorder and major depression" A tale of two syndromes. Psychiatric Clin North Am 11:441-461. Uhde TW, Vittone BJ, Siever I.J, Kaye WH, Post RM (1986): Blunted growth hormone response to clon~dine in panic disorder patients. Biol Psychiatry 21:1077-1081.
1227
Paradoxical Growth-Hormone Responses to Thyrotropin-Releasing Hormone in Panic Disorder Manuel E. Tancer, Murray B. Stein, and Thomas W. Uhde
Thyrotropin-releasing hormone (TRtI) has been reported to stimulate growth hormone (GH) release in a variety of pathological conditions, including some studies of major depression. Because of the considerable phenomenological and neuroendocrine overlap between major depr~,ssion and panic disorder, we investigated the rate of positive GH responses to TRH in 38 patients with panic disorder and 23 normal controls. There were no between-group differences in mean GH response to TRH or in the proportion of subjects with positive responses. These findings are discussed in the context of neuroendocrine regulation of GH secretion and the relationship between anxiety and affective disorders.
Introduction In normal individuals, morning infusion of thyrotropin-reieasing hormone (TRH) causes robust secretion of thyroid-stimulating hormone (TSH) and prolactin, but not growth hormone (GH) (Anderson et al. 1971). However, "paradoxical" growth hormone secretion following TRH administration has been reported in anorexia nervosa (Maeda et al. 1976; Gold et al. 1980), bulimia (Levy et al. 1988), and, depending on the criteria, many patients with major depression (see Hsiao et al. 1986 for review). Thus, although the mechanism and factors that influence this response are poorly understood, TRH-induced GH secretion appears to occur in a heterogeneous array of neuropsychiatric conditions characterized by abnormalities in hypothalamic-pituitary regulation (Caroff et al. 1984; Cocchi et al. 1984). Although the relationship between panic and major affective disorders (for review see Stein and Uhde 1988) remains controversial, both syndromes are associated with a wide variety of neuroendocrine abnormalities that suggest possible alterations in hypothalamicpituitary function. The rate of TRH-induced GH responses depends partly on the criteria used. Doubling of baseline GH combined with an absolute GH rise greater than 5 ng/ml is commonly defined as a "positive" GH response to TRH (Brambilla et al. 1978). We have adopted more stringent criteria for a positive GH response to TRH by requiring that the GH response also occur within 45 min of TRH administration, a time frame consistent with
From the Section on Anxiety and Affective Disorders, Biological PsychiaCy Branch, National Institute of Mental Health, Betheuf~, lVlD20892. reprint ~lUeats to Dr. Thomas Uh~, Chief, Sectionon Anxiety and AffcctiveDisorders,BiologicalPsychisl~jBranch, National Institut~ of Mental Health, Building 10, Room 3S239, 9000 R~kville Pike, Bethesda, MD 20892. Received March 7, 1989; nsvisedJune 8, 1989. This mlicle is in the Pubtic Domain.
0006-3223/90/$00.00
1228
BIO' nSYCHIATRY 1992" ~':1227-1230
M.E. Tancer et al.
pituitary responses to specific hypothalamic-releasing factors. These stricter criteria are intended to reduce the frequency of spurious or delayed GH responses (Eastman and Lazarus 1972), which likely do not reflect direct effects of TRH administration. The current study of growth-hormone response to TRH in patients with panic disc~# ;r was undertaken in order to further describe the neuroendocrine responses to TRH in ~,a~c disorder patients. To our knowledge, this is the first study to examine ~ e "paradoxi~" GH response to TRH in patients with panic disorder.
Methods Thirty-eight subjects [23 women, 15 men; mean age 33.5 __. 7.0 (range 23-48)] meeting DSM-III-R (APA 1987) criteria for panic disorder with or without agoraphobia, who were free of concomitant major depression, made up the panic disorder group. Twentythree subjects [12 women, 11 men; mean age 31.8 +_ 9.7 (range 21-57)] with no history of psychiatric disease as determined by a structured interview made up the normal volunteer group. Patients and controls were medically healthy as determined by medical history, physical examination, and routine blood tests (CBC, SMAC-20, urinalysis) and were medication free for at least 2 weeks prior to participation. Written and oral informed consent was obtained from all subjects. Following an overnight fast, 500 ttg TRH was administered intravenously between 9 AM and 10 AM following a 20 min recumbent adaptation period. Subjects were encouraged to relax after intravenous catheter insertion. Blood was drawn at baseline and again at 15, 30, and 45 min after TRH administration. GH was measured by double antibody radioimmunoassay (RIA). The GH assay has a sensitivity of 0.4 ng/ml and an intra- and interassay variability of 4.9% and 7.3%, respectively. The GH response to TRH was initially analyzed by analysis of variance (ANOVA) with repeated measures. The variance differed between groups at all time points (Bartlett's test, p < 0.05) so the Mann-Whitney U-test was used to compare mean GH values at each time point. Yates corrected chi-square was used to compare categorical measures (proportion of subjects with positive GH response to TRH). Relationships between variables were compared using Spearman rank correlation coefficients (rs). All statistical tests were two-tailed. Probabilities >0.05 are reported as not significant (NS).
Results There was no difference in GH response to TRH in patients with panic disorder compared with normal volunteers. Analysis of variance revealed a modest main effect of diagnosis on GH level [F(l,59)ffi 4.03; p ffi 0.05], but no mmn effect of time [F(3,57)ffi 0.69; p = NS] or diagnosis × time interaction [F(3,57) ffi 0.54;p ffi NS]. At each time point, GH levels of the patients with panic disorder demonstrated greater variance than the controls. However, mean GH levels did not differ significantly between groups at any time point (Table 1). Using our criteria for positive GH response to TRH (doubling of baseline GH plus an absolute increase of at least 5 ng/ml within 45 min), 6 of 38 (15.8%) patients with panic disorder and I of 23 (4.3%) controls had a positive GH response to TRH (Yates corrected chi-square = 0.82, df = 1, p ffi NS). One of the 6 patients with a positive GH response
GH Response to TRH in Panic Disorder
BIOL PSYCHIATRY 1990;27:1227-1230
1229
Table 1. GH Response (ng/ml) to TRH in Patients with Panic Disorder and Normal Controls Time
Controls
Patients
Minutes
(n - 23)
(n = 38)
Baseline
0.70 +_ 0.57 (0.4--2.6)
1.22 -4- 1.28 (0.4-4.7)
+ 15
0.67 -4- 0.42 (0.4--2.2) 0.91 .4- I. 14 (0.4--5.4) 0.92 .4- 1.38 (0.4--6.5)
1.73 +_ 2.77 (0.4--12.8) 1.76 _ 2.59 (0.4-12.4) 1.93 .4- 3.42 (0.4--16.9)
+ 30 +45
p - NS for all time points (Mann Whitney U-Test); mean ± so; (range)..
to TRH also had a subnormal & maxTSH response (& maxTSH < 7 ~IU/ml), whereas the other 5 patients with a positive GH response to TRH had normal A maxTSH values. There was a significant positive correlation between baseline GH levels and the GH level 30 min following TRH administration in both patients (rs = 0.39, df = 36, p < 0.02) and controls (rs = 0.59, df = 21, p < 0.005).
Discussion Using two separate analyses, we failed to find evidence for increased GH responses to TRH in patients with panic disorder compared with normal volunteers. Although the GH response to TRH was normal in this study, several lines of evidence suggest that alterations in GH secretion following clonidine (Uhde et al. 1986; Chamey and Heninger 1986) and growth hormone-releasing factor (GRF) (Rapaport et al. I989) may be prevalent in panic disorder patients. Thus, despite our negative findings with this particular neuroendocrine probe, it would be useful from a theoretical perspective to understand those mechanisms that mediate the GH response to TRH. In this regard, there is both preclinical and clinical evidence to suggest that TRH-induced GH release occurs in the presence of elevated GH levels or following GH or growth hormone-releasing factor infusion (Sartorio et al. 1986; Borges et al. 1983). Our finding of a positive significant correlation between baseline GH and + 30 GH levels following TRH is consistent with a permissive role for GH in the TRH stimulation of GH secretion, although circadian alterations in GRF and/or TRH may also influence this response (Caroff et al. 1984). In conclusion, though we failed to find an exaggerated GH response to TRH, these data suggest that circadian patterns and levels of GH secretion may be a relevant factor in the assessment of future investigations using the TRH, clonidine, and GRF challenge paradigms.
References American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders (DSM-IH-R) (ed 3, revised), Washington, DC: American Psychiatric Association Press. Anderson MS, Bowers CY, Kastin AJ, et al (1971): Synthetic thyrotropin-releasing hormone, a potent stimulator of thymtropin secretion in man. N Engl J Med 285:1279-1283. Borges JLC, Uskavitch DR, Kaiser DL, Cronin MJ, Evans WS, Thomer MO (1983): Human
1230
BIOL PSYCHIATRY I990;27:1227-1230
M.E. Tancer et aL
pancreatic growth hormone-releasing factor (hpGRF-40) allows stimulation of GH release by TRH. Endocrinology 113:1519-1521. Brambilla F, Smeraldi E, Sacchetti E, Negri F, Cocchi D, Muller EE (1978): D~ranged anterior pituitary responsiveness to hypothalamic hormones in depressed patients. Arch Gen Psychiatry 35:1231-1238. Caroff S, Winokur A, Snyder PJ, Amsterdam J (1984): Diurnal variation of growth hormone secretion following thyrotropin-releasing hormone infusion in normal men. Psychosom Med 46:59-66. Chamey DS, Heninger GR (1986): Abnormal regulation of noradrenergic function in panic disorder: Effects of clonidine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 43:1042-1054. Cocchi D, Locatelli V, Muller EE (1984): Nonspecific pituitary responses to hypothalamic hormones in basic and clinical research. In Shah D (ed), Psychoneuroendocrine Dysfunction. New York: Plenum Press, pp 173-208. Eastman CJ, Lazarus L (1972): The effect of orally administered synthetic thyrotropin-releasing factor on adenypophyseal function. Horm Metab Res 4:58. Gold MS, Pottash ALC, Martin DM, Finn LB, Davies RK (1980): Thyroid-stimulating hormone and growth hormone responses to thyrotropin-releasing hormone in anorexia nervosa. Int J Psychiatry Med 10:51-57. Hsiao JK, Garbutt JC, Loosen PT, Mason GA, Prange AJ (1986): Is there paradoxical growth hormone response to thyrotropin-releasing hormone in depression? Biol Psychiatry 21:595-600. Levy AB, Dixon KN, Malarkey WB (1988): Pituitary response to ~ in bulimia. Biol Psychiatry 23:476--484. Maeda K, Kato Y, Yamaguchi N, et al (1976): Growth hormone release following thyrotropinreleasing hormone injection in patients with anorexia nervosa. Acta Endocrinol 81:1-8. Rapaport MH, Risch SC, Gillin JC, Golshan S, Janowsky DS (1989): Blunted growth hormone response to peripheral infusions of human growth hormone-releasing factor in patients with panic disorder. Am J Psychiatry 146:92-95. Sartorio A, Spada A, Bochicchio D, Atterrato A, Morabito F, Faglia G (1986): Effect of thyrotropinreleasing hormone on growth hormone release in normal subjects pretreated with human pancreatic growth hormone-releasing factor 1-44 pulsatile administration. Neuroendocrinology 44:470--474. Stein MB, Uhde TW (1988): Panic disorder and major depression" A tale of two syndromes. Psychiatric Clin North Am 11:441-461. Uhde TW, Vittone BJ, Siever I.J, Kaye WH, Post RM (1986): Blunted growth hormone response to clon~dine in panic disorder patients. Biol Psychiatry 21:1077-1081.
