Growth hormone, prolactin and thyrotropin responses to gonadotropin-releasing hormone in depressed patients and healthy volunteers

Psychoneuroendocrinology,Vol. 7, No. 2/3, pp. 177-184, 1982.

0306-4530/82/020177 -08 $03.00/0 © 1982PergamonPressLtd.

Printed in Great Britain.

GROWTH HORMONE, PROLACTIN AND THYROTROPIN RESPONSES TO GONADOTROPIN-RELEASING HORMONE DEPRESSED PATIENTS AND HEALTHY VOLUNTEERS

IN

J. D. A M S T E R D A M , * A. W I N O K U R , * I. LUCKI,*'[" P. S N Y D E R , ~ R. I. H A R R I S , ~ S. C A R O F F *

and K.

RICKELS*

*Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A.; t N e u r o p s y c h o p h a r m a c o l o g y Research Unit, Philadelphia Veterans Administration Hospital, Philadelphia, Pennsylvania, U.S.A.; and :~Department of Medicine, Division of Endocrinology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, U.S.A.

(Received 19 February 1982; in final form 18 May 1982)

SUMMARY Growth h o r m o n e (GH), prolactin (PRL) and thyrotropin (TSH) release following gonadotropin-releasing h o r m o n e (GnRH) administration were examined in 56 patients with major affective disorder (37 unipolar, 19 bipolar) and 38 normal healthy subjects. There were no differences in GH, P R L or TSH responses after G n R H infusion between the patients and the normal subjects, in contrast to previously reported abnormalities in depressed patients. Serum GH concentration increased after G n R H in both normal and depressed men; serum TSH increased after G n R H in both normal women and bipolar women, but not in unipolar depressed women. Further studies comparing G n R H to saline infusion will be necessary to determine if the GH and TSH responses seen in this study are due to G n R H or result from the stress of the experimental procedures.

INTRODUCTION

ALTERATIONS in hypothalmic-pituitary responsiveness have been well documented in patients with endogenous depression. Abnormalities in pituitary hormone release have been demonstrated in the hypothalmic- pituitary- thyroid (HPT) axis (Prange et al., 1972; Kastin et al., 1972), hypothalamic-pituitary-gonadal (HPG) axis (Brambilla et al., 1978; Linnoila et al., 1979; Ettigi et al., 1979), hypothalamic- pituitary- adrenal (HPA) axis (Carroll et al., 1981), and the hypothalamic-somatotropic (HPS) axis (Mueller et al., 1969). However, most investigators have employed a single neuroendocrine challenge test and have examined a single hormonal response. Examination of a broad pattern of hormonal responses after a specific challenge may provide a more complete perspective on the nature of neuroendocrine responsiveness in depression. We previously have employed a series of challenge tests (TRH stimulation, GnRH stimulation, insulin tolerance test and dexamethasone suppression test) in patients with major affective disorder, endogenous subtype, and demonstrated multiple hormone Reprint requests to: J. D. A m s t e r d a m , Depression Research Unit - - I Gibson, Hospital of the University of Pennsylvania, 36th and Spruce Streets, Philadelphia, PA 19104. U.S.A. 177

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response abnormalities (W]nokur et al., 1982). In that study, 58% of the patients, but no control subjects, demonstrated two or more abnormal hormone responses. This suggests that hormonal responses to neuroendocrine challenge tests in depressed patients are most accurately defined in terms of increased variability, compared to responses of normal subjects. The results drew further attention to the broad range of neuroendocrine response abnormalities that can be observed in depressed patients and underscored the importance of multi-hormonal assessment strategies in studies of affective disorders. Our initial studies with the GnRH stimulation test in depressed patients (Amsterdam et al., 1981) concentrated on the responses of the gonadotropic hormones (LH and FSH), and we observed essentially normal HPG axis function in these patients. This finding contrasts with previously reported neuroendocrine response abnormalities in the HPT (Prange et al., 1972; Kastin et al., 1972), H P A (Carroll et al., 1981) and HPS (Mueller et al., 1969) axes, as well as abnormalities in PRL release following TRH (Winokur et al., 1982). In light of one previous report of abnormal GH and PRL responses to GnRH infusion in depressed patients (Brambiila et al., 1978), and the findings of abnormal neuroendocrine responses across several hormonal axes in depressed patients, we decided to examine GH, PRL and TSH responses to GnRH infusion in patients with a major affective disorder and appropriately matched normal, healthy controls. PATIENTS AND METHODS Patients. Twenty-seven male and 29 pre+menopausal female patients with major depressive disorder, endogenous subtype, were studied. Sixteen men had unipolar depression (mean age 36.1 _+ 3.0 years) and 11 had bipolar illness (35.2 _+ 3.7 years); 21 women had unipolar depression ¢33.2 _+ 1.2 years) and eight had bipolar illness (30. 0 -+ 3.0 years). Six were hospitalized and 50 were outpatients at the time of the study. All patients fulfilled the Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) for major depressive disorder, primary, endogenous subtype, and had a Hamilton Depression Rating score (HDR) of /> 18 on the 17-item scale (Hamilton, 1960). The patients were drug-free for at least seven days (one month for neuroleptics) prior to testing; none had ever received slow-release neuroleptics; and none had received electroconvulsive treatment within two years prior to evaluation. The women were studied during the follicular phase of the menstrual cycle. The patients were without physical illness and had no significant laboratory abnormalities. None had a history of endocrinopathy. The women were not taking oral contraceptives, and none of the men had a varicocele, vasectomy or previous testicular surgery. Controls. Twenty male (31.9 _+ 2.6 years) and 18 pre-menopausal female (30.3 _+ 1.5 years) drug-free, healthy volunteers were evaluated under identical conditions. All were given a structured interview and found to be free of psychiatric and medical illness. They had no history of endocrinopathy or steroid use and no family history of psychiatric illness. None of the women were taking oral contraceptives, and all were evaluated during the follicular phase of their menstrual cycles. None of the men had a history of testicular or genitourinary disease. Experimentalprocedure. This study had approval from the Committee for Studies involving Human Subjects of the University of Pennsylvania, which adheres to the Code of Ethics of the World Medical Association. All subjects freely participated after informed consent was obtained. Tests were performed between 0800 and 0900 hr after a 10-hr fast. An indwelling venous catheter with a three-way stopcock was inserted in an antecubital arm vein, and 0.9°70 normal saline was infused slowly. After a 15-rain accommodation period, baseline plasma samples for GH, PRL and TSH were collected at 15 and 0 rain. Synthetic GnRH (Parke-Davis, 250 lag) then was injected as a rapid i.v. infusion, and plasma samples of GH, PRL and TSH were collected at + 10, +20, + 30, + 45, + 60 and + 90 min. All samples were collected in Venoject ® tubes and then were centrifuged for 15 min at 2400 revs/min. Serum was separated and stored at - 20°C until radioimmunoassay (RIA). All samples from each neuroendocrine test always were assayed together, in duplicate. Assays. TSH was measured by a double antibody RIA with ammonium sulphate precipitation. TSH antiserum and TSH reference standard were purchased from Amersham, Arlington Heights, Illinois. The TSH reference

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standard was calibrated against the First International Reference Preparation of H u m a n Thyroid-Stimulating H o r m o n e for l m m u n o a s s a y (68/38). In our laboratory, intra- and interassay coefficients of variation were 6.5 and 7.6% respectively, and the sensitivity was 1.5 p U / m l . The extent of cross-reactivity of LH in the TSH assay was < 0.4°7o at 50°7o TSH binding. It therefore is unlikely that LH increases following G n R H would have been recognized by the anti-TSH antibody. Prolactin was determined by a double antibody RIA, with ':q-prolactin and prolactin standard from BioRIA, Louisville, Kentucky. Intra- and interassay coefficients of variation were 7.1 and 15.2°7o respectively. The sensitivity was 4 ng/ml. GH was determined by a double antibody RIA with a kit from Cambridge Nuclear, Billerica, Massachussetts. The intra- and interassay coefficient of variation were 8.4 and 14.8% respectively, and the lower limit of sensitivity was 1.0 ng/ml.

Statistical analysis. The term 'basal' designates the concentration of h o r m o n e at '0 min', immediately before the infusion of G n R H . Mean basal GH, P R L and TSH concentrations were determined separately for unipolar patients, bipolar patients, and for healthy control subjects and compared by Student's t-test. Normal ranges for basal levels of G H , P R L and TSH were then defined as two standard deviations above and below the mean for healthy men and women. The number of depressed patients and control subjects with values falling outside these ranges (abnormal responses) were tabulated and compared by chi-square analysis. Growth hormone, P R L and TSH values were determined at time points 0, + 10, +20, +30, +45, + 6 0 and + 90 min after G n R H administration. These data then were analyzed by two-way analysis of variance (ANOVA) for patients and control subjects. In addition, for each subject group the mean hormone concentration at each interval after G n R H infusion was compared with basal hormone levels using Dunnett's test (Dunnett, 1955). The h o r m o n e responses after G n R H infusion for individual subjects then were analyzed in closer detail. First, peak responses for GH, P R L and TSH were determined for each subject, being defined as the m a x i m u m change from basal hormone concentration following G n R H infusion. Peak hormone responses then were compared with basal h o r m o n e levels using a within-subjects Student's t-test. Second, the number of patients and controls that demonstrated a response to G n R H infusion was determined; any individual whose peak hormone level was above the previously defined normal range was considered to have a response to G n R H . Third, the magnitude of h o r m o n e responsiveness to G n R H was compared between groups. This value was designated by the symbol A and was calculated by subtracting the basal hormone level from the peak h o r m o n e response for each subject. Normal ranges for A G H , A P R L and ATSH then were defined by the two-standard deviation range above the mean for the normal controls; a value falling above this range was designated an 'exaggerated' response. The numbers of exaggerated responses for the patients and the controls were compared by chi-square analysis. RESULTS

Basal hormone values Mean basal GH, PRL and TSH concentrations for the patients and the normal subjects are shown in Table I. Significant differences were found between the patients and the controls; also, bipolar women demonstrated higher PRL levels than unipolar women. TABLE I. MEAN BASAL HORMONE VALUES ± 1

Men Normal Depressed Unipolar Bipolar Women Normal Depressed Unipolar Bipolar

S.D. AND NUMBERS OF SUBJECTS (n) IN EACH GROUP

GH (n) (ng/ml)

P R L (n) (ng/ml)

TSH (n) ~tU/ml)

3.1 __. 2.7 (16)

14.9 __. 2.4 (19)

3.6 ± 2.4 (19)

3 . 0 ± 1.8(12) 3 . 0 ± 1.1 (9)

11.5± 11.1 ±

3.8 (16) 5.4 (8)

2 . 7 ± 1.8(15) 3.3_+2.6 (9)

3.3 -+ 2.9 (18)

14.7 ±

6.5 (18)

2.8 _+ 1.3 (19)

3.1 ± 1.8 (16) 4.2 ± 4.4 (8)

1 1 . 7 ± 3.7 (19)* 20.8 ± 10.6 (8)*

*Female unipolar P R L vs female bipolar PRL: t = 3.36, p < 0.005.

3 . 0 ± 1.7 (21) 3.5 ± 1.4 (8)

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AMSTERDAM

et al.

Individual h o r m o n a l responses to G n R H infusion Growth hormone concentrations for all the male subjects combined (controls and patients) were significantly elevated following GnRH infusion (F = 2.37, p < 0.05) (Fig. 1). Compared to basal levels, GH was significantly higher only at 45 min (p < 0.01, Dunnett's test). However, GH responses to GnRH were variable, and no group, taken separately, showed a significant elevation in GH levels. There was no significant difference in AGH between depressed and healthy men. When individual AGH values were compared to the two-standard deviation normal GH range, four of 16 (25%) normals and three of 21 (14%) patients showed GH responses to GnRH. GH Concentration(ng/ml) after GnRH 20

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FIG. 1. G H responses to administration of G n R H (250 I.tg i.v.) in depressed men and women and sex-matched

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In women, neither the control nor the patient groups showed significant elevations in GH after GnRH infusion compared to their basal GH levels. However, overall GH levels differed significantly between diagnostic groups (F = 5.62, p < 0.01) (Fig. 1); this represented significantly higher GH levels in bipolar w o m e n compared to both control and unipolar depressed w o m e n (p < 0.01, Duncan's multiple-range test). Individually,

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three of 18 (17070) control women and three of 24 03070) depressed women showed GH responses above the normal control range. PRL concentrations were not increased by GnRH infusion in the male subjects (not shown), nor did PRL response to GnRH differ significantly between the groups of men. Only three of 43 (7°7o) male subjects, both normal and depressed, demonstrated a PRL level above the two-standard deviation range from normal. For all the women, both normal and depressed, PRL did not rise significantly after G n R H infusion (data not shown). An apparent PRL increase after GnRH seen in the normal and unipolar depressed women was accompanied by a large variance and therefore was not statistically significant. However, PRL did appear to be released after GnRH in some women; six of 18 (3307o) normal and six of 26 (2307o) depressed women had a PRL response above normal basal PRL levels. Mean A P R L values were similar for female patients and controls. G n R H infusion did not alter TSH levels in men (Fig. 2). Individually, only four of 44 (9%) male subjects, both normal and depressed, had a TSH value greater than two standard deviations above normal basal TSH levels. TSH Concentration (,uU/ml) after GnRH I0

MALES

'=Controls AUnipolors x Bipolars

N = 19 N =16 N =8

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FIG. 2. T S H r e s p o n s e s t o a d m i n i s t r a t i o n o f G n R H ( 2 5 0 I.tg i . v . ) in d e p r e s s e d m e n a n d w o m e n a n d s e x - m a t c h e d c o n t r o l s . A t e a c h t i m e p o i n t t h e g r o u p m e a n _ S . E . M . f o r G H in u n i p o l a r p a t i e n t s ( - - A - - ), b i p o l a r p a t i e n t s ( - - X - - ) and normal subjects ( - - o - - ) are shown.

Interestingly, the women demonstrated a small but consistent TSH response to GnRH infusion (F -- 4.02, p < 0.001) (Fig. 2). In the normal women, significant elevations in TSH above baseline occurred at 20 min (p < 0.05) and all later time intervals (p < 0.01, Dunnett's test). Similarly, in bipolar women TSH was increased above basal levels at 10, 20 and 30 min following G n R H infusion (p < 0.05, Dunnett's test). In contrast, no

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significant alterations of TSH levels occurred in the unipolar women. Peak TSH levels also were significantly elevated above basal values for the normal controls (t = 3.84, p < 0.01) and for the bipolar women (t = 3.87, p < 0.01), but not for the unipolar women. Individual TSH responses to GnRH infusion were seen in seven of 19 (37°7o) normal women, three of eight (37%) bipolar women, and five of 21 (24°7o) unipolar women. No significant differences in ATSH values were observed between any patient or control group after GnRH infusion. DISCUSSION Reports of altered pituitary hormone response to GnRH in depressed patients have been limited. In most studies only a small number of patients have been evaluated, and appropriate normal subjects have not been studied concomitantly, leading to contradictory results (Brambilla et al., 1978; Ettigi et al., 1979; Linnoila et al., 1979). While some studies describe either blunted or exaggerated LH and FSH responses to GnRH infusion, we have reported the HPG axis to be normal in endogenous depression (Amsterdam et al., 1981). Prior studies using GnRH in normal subjects have reliably demonstrated that it provokes release of LH and FSH in a dose-dependent manner (Haug & Torjensen, 1973; Rebar et al., 1973; Snyder et al., 1975). However, the possibility of GH, prolactin and TSH release after GnRH has received little attention (Haug & Torjensen, 1973; Yen et al., 1980). In the only attempt to measure multiple hormonal responses to GnRH in depressed patients, Brambilla et al. (1978) administered GnRH (100 I~g i.v.) to 10 patients with primary affective disorder and reported an exaggerated GH response in one patient (10%0) and an exaggerated PRL response in three (30%). TSH was not measured. Only five normal subjects were evaluated and the values for men and women were pooled, making interpretation difficult. In the present study, we generated normative data as a basis for evaluating hormone responses in depressed patients. Prior studies of GnRH doses demonstrated maximum gonadotropin response after 250 ~tg (Snyder el al., 1975), and we therefore chose this GnRH dose. In contrast to the findings of Brambilla et al. (1978), we observed that many normal subjects, as well as patients, showed a substantial elevation of one or more pituitary hormones after GnRH administration. Thus, our findings do not support the contention that non-gonadotropic pituitary hormone responses are limited to depressed patients, and they agree with the findings of Yen et al. (1980), who demonstrated PRL responses after GnRH infusion in healthy women. We observed significantly higher basal PRL levels in bipolar women than in unipolar women. Prior studies of basal PRL concentrations in depressed patients have been contradictory (Coppen et al., 1980; Linkowski et al., 1980; Asnis et al., 1980; Mendlewicz et al., 1980); one possible explanation might be methodologic differences between the studies, with PRL samples having been taken at slightly different times under different experimental conditions. Additionally, PRL has been found to be a stress-related hormone. It is possible that the stress of venipuncture elevated basal PRL levels for a longer period in the bipolar women, which had not returned to a stable baseline by the

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time of the first blood sample (Adler et al., 1975). One other possibility is that the bipolar women represent a neuroendocrine subgroup of depressed patients with higher basal PRL levels, conceivably reflecting differences in underlying neurotransmitter sensitivity (either a decrease in dopaminergic or increase in serotonergic function in this subgroup). Only one prior study has examined TSH release after G n R H infusion (Haug & Torjensen, 1973). We found no difference in TSH release between patients and controls, but we did demonstrate a small, but significant, increase in TSH concentration after G n R H in both normal women and bipolar depressed women. In fact, 33°7o of all women demonstrated TSH values in excess of two standard deviations from the mean basal TSH value in normal women. In contrast to Haug & Torjensen (1973), we did not demonstrate TSH release after G n R H in men. One possible explanation for TSH release after G n R H infusion might be that G n R H and T R H contain identical C-terminal dipeptide sequences (pyro - glu - his). The concept of cross-talk between hypothalamic-releasing hormones (Warner & Santen, 1981) suggests that these neuropeptides may not be as specific at the pituitary level as is conventionally believed. For example, T R H has been reported to produce small but significant increases in LH concentration in normal healthy men (Snyder et al., 1980). The modest TSH response to G n R H administration observed in our subjects may represent another example of h y p o t h a l a m i c - pituitary cross-talk. The failure to produce a larger response of G H , P R L or T S H might have resulted from the dose of G n R H chosen for the study, which, as mentioned, is optimal for the release of LH and FSH. A higher dose of G n R H , or perhaps a prolonged infusion, might have resulted in larger G H , P R L or T S H responses. Our findings of GnRH-stimulated G H release in men, T S H release in normal and bipolar depressed women, and a non-significant elevation of P R L in normal women are intriguing, but they should be viewed as preliminary. Placebo-controlled trials, performed in an identical fashion to the G n R H infusions, will be necessary to determine if G H , P R L and TSH actually are released by G n R H , or if their increases simply result from the conditions of the experimental procedure. This research was supported by NIMH Research Scientist Development Award MH-0044 to Dr. Winokur; Training Program in Neuropsychopharmacology (MH-14655) awards to Drs. Amsterdam and Caroff; NIMH Grants MH-33823 and MH-32702; USPHS Grant HD 13869 to Dr. Snyder; Clinical Research Center Grant NIH 5-MO1-RR00040; research funds from the Veterans Administration; and the Michael R. Babitts Fund for Psychoneuroendocrinology. We thank Cordelia Shute, R.N., and Clinical Research Center staff who provided nursing care, and Larry Potter and Joyce Larkin for their valuable technical assistance. REFERENCES ADtER, R. A., NOEL, G. L., WARVOESKV,L. & FRANTZ, A. G. (1975) Failure of oral water loading and intravenous hypotonic saline to suppress plasma prolactin in man. J. din. Endocr. Metab. 4 1 , 3 8 3 - 389. AMSTERDAM, J. D., WINOKUR, A., CAROFF, S. & SNYDER, P. (1981) Gonadotropin release after administration of GnRH in depressed patients and healthy volunteers. J. Affect. Dis. 3, 367 - 380. ASN~S, G. M., NAY.AN, R. S., HALBREJCH, U., HALPERN, F. S. & SACHAR, E. J. (1980) Prolactin changes in major depressive disorders. A m . J. Psychiat. 13"/, 1117 - 1118, BRAMBILLA, F., SMERALDI, E., SACCHETTI, E., NEGRI, F., COCCHt, D. & MULLER, E. E. (1978) Deranged anterior pituitary responsiveness to hypothalamic hormones in depressed patients. Archs. gem Psychiat. 35, 1231 - 1238.

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