9
Psychoneuroendocrinology, Vol.11, N o. 3, pp. 317 - 325, 1986 0306 - 4530/86 $3.00 + 0.00 Printedin GreatBritain. Pergamon Journals Ltd. GROWTH HORMONE AND CORTISOL SECRETION AFTER ORAL CLONIDINE IN HEALTHY ADULTS GLENN E. HUNT, BRENDAN T. O'SULLIVAN, GORDON F. S. JOHNSON and GEORGE A. SMYTHE* Department of Psychiatry, University of Sydney, Sydney, N.S.W., Australia and *Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, N.S,W., Australia (Received 2 November 1984; in final form 12 September 1985) SUMMARY The purpose of this study was to evaluate oral clonidine for testing growth hormone (GH) responsiveness in healthy adults. Oral clonidine (0.15 mg) produced a satisfactory GH response (> 4 ng/ml from basal) in eight out of 10 subjects, which is similar to rates reported after an equivalent intravenous dose. Elevated GH levels at baseline occurred in four out of five female subjects; this did not affect the clonidine-induced GH release. There were no significant differences at any time point in plasma prolactin or cortisol levels following clonidine, compared to placebo controls. Adequate plasma clonidine levels (> 0.4 ng/ml) were achieved in all subjects, with corresponding reductions in mean arterial blood pressure, but with only minimal adverse effects. Results from this study indicate that oral clonidine is a reliable method for testing GH responsiveness in adult subjects. Key Words--Clonidine; growth hormone; cortisol; prolactin; blood pressure; pharmacokinetics; humans. INTRODUCTION CLONIDINE, a specific a-2 adrenoceptor agonist (Starke, 1981), is a potent stimulus of growth hormone (GH) release in man (Lal et al., 1975). Several investigators have reported that depressed patients show a blunted GH response to intravenous (i.v.) administration of clonidine compared to control subjects (Matussek et al., 1980; Checkley et al., 1981; Siever et al., 1982). Such neuroendocrine abnormalities are thought to reflect central neurotransmitter alterations associated with affective disorders, through neurotransmitter-regulated hormone release at the level of the hypothalamus (Johnstone & Ferrier, 1980; Johnson, 1982; Brown et al., 1983). Oral clonidine has been shown to be a safe and reliable test of GH response in children and adolescents (Gil-Ad et al., 1979; Salti et al., 1981; Lanes and Hurtado, 1982, Slover et al., 1984). The purpose of this study was to evaluate this method in normal adult subjects. It was necessary to define the parameters of this procedure prior to testing its usefulness in depressed patients and to establish a criterion level for GH response in control subjects. Measurements of cardiovascular status, side effects, and plasma clonidine, growth hormone, cortisol, prolactin and glucose concentrations were made over a six hour period in a double-blind crossover design. The GH response reported in the literature following i.v. clonidine in healthy adults is summarized in the discussion, and some comparisons are made between oral and i.v. clonidine. Address correspondence to Dr. G. F. S. Johnson, Associate Professor, Department of Psychiatry, University of Sydney, Sydney, N.S.W., Australia, 2006. 317

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Page 1: Growth hormone and cortisol secretion after oral clonidine in healthy adults

Psychoneuroendocrinology, Vol. 11, N o. 3, pp. 317 - 325, 1986 0306 - 4530/86 $3.00 + 0.00 Printed in Great Britain. Pergamon Journals Ltd.

G R O W T H H O R M O N E A N D C O R T I S O L S E C R E T I O N A F T E R O R A L C L O N I D I N E IN H E A L T H Y A D U L T S

GLENN E. HUNT, BRENDAN T. O'SULLIVAN, GORDON F. S. JOHNSON a n d

GEORGE A . SMYTHE*

Department of Psychiatry, University of Sydney, Sydney, N.S.W., Australia and *Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, N.S,W., Australia

(Received 2 November 1984; in final form 12 September 1985)

SUMMARY

The purpose of this study was to evaluate oral clonidine for testing growth hormone (GH) responsiveness in healthy adults. Oral clonidine (0.15 mg) produced a satisfactory GH response (> 4 ng/ml from basal) in eight out of 10 subjects, which is similar to rates reported after an equivalent intravenous dose. Elevated GH levels at baseline occurred in four out of five female subjects; this did not affect the clonidine-induced GH release. There were no significant differences at any time point in plasma prolactin or cortisol levels following clonidine, compared to placebo controls. Adequate plasma clonidine levels (> 0.4 ng/ml) were achieved in all subjects, with corresponding reductions in mean arterial blood pressure, but with only minimal adverse effects. Results from this study indicate that oral clonidine is a reliable method for testing GH responsiveness in adult subjects.

Key Words--Clonidine; growth hormone; cortisol; prolactin; blood pressure; pharmacokinetics; humans.

INTRODUCTION

CLONIDINE, a specific a-2 adrenoceptor agonist (Starke, 1981), is a potent stimulus of growth hormone (GH) release in man (Lal et al., 1975). Several investigators have reported that depressed patients show a blunted GH response to intravenous (i.v.) administration of clonidine compared to control subjects (Matussek et al., 1980; Checkley et al., 1981; Siever et al., 1982). Such neuroendocrine abnormalities are thought to reflect central neurotransmitter alterations associated with affective disorders, through neurotransmitter-regulated hormone release at the level of the hypothalamus (Johnstone & Ferrier, 1980; Johnson, 1982; Brown et al., 1983).

Oral clonidine has been shown to be a safe and reliable test of GH response in children and adolescents (Gil-Ad et al., 1979; Salti et al., 1981; Lanes and Hurtado, 1982, Slover et al., 1984). The purpose of this study was to evaluate this method in normal adult subjects. It was necessary to define the parameters of this procedure prior to testing its usefulness in depressed patients and to establish a criterion level for GH response in control subjects. Measurements of cardiovascular status, side effects, and plasma clonidine, growth hormone, cortisol, prolactin and glucose concentrations were made over a six hour period in a double-blind crossover design. The GH response reported in the literature following i.v. clonidine in healthy adults is summarized in the discussion, and some comparisons are made between oral and i.v. clonidine.

Address correspondence to Dr. G. F. S. Johnson, Associate Professor, Department of Psychiatry, University of Sydney, Sydney, N.S.W., Australia, 2006.

317

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318 GLENN E. HUNT, BRENDAN T. O'SULLIVAN, GORDON F. S. JOHNSON and GEORGE A. SMYTHE

METHODS

Subjects Ten healthy volunteers (five men and five women) between the ages of 20 and 23

participated in the study. All subjects were of normal weight (mean 67 kg) and height (mean 174 cm) and free of any history of psychiatric illness, endocrinological disorder, or substance abuse. A routine physical examination was carried out to ensure that subjects were healthy and had a normal blood pressure. All subjects gave informed written consent, were not taking any medications for at least four weeks, and were instructed to refrain from any alcohol for 24 hr prior to the test. Five subjects received clonidine only, and the other five subjects (three men and two women) received clonidine and placebo in a crossover design. Neither subject nor investigator knew when clonidine or placebo was to be administered. Subjects receiving both clonidine and placebo were tested one to four weeks apart. All female subjects were intermenstrual during the clonidine test procedure.

Procedure After an overnight fast, the session began at 0830 h. An indwelling i.v. catheter was

inserted into a forearm vein, and a 10 ml baseline blood sample was drawn. At 0900 h another baseline blood sample was collected, and the subjects were given either clonidine hydrochloride (0.15 mg, Catapres, Boehringer-Ingelheim) or an identical placebo tablet. Further blood samples were collected at the following times: 0.5, 1.0, 1.5, 2, 3, 4 and 6 hr. The i.v. catheters were kept patent by regularly flushing with heparinized-saline solution. The blood samples were collected in heparinized tubes and immediately centrifuged. The plasma was separated, placed in encoded containers, and frozen at - 2 0 ° C. Blood pressure and pulse rate were taken at 30 min intervals, temperature was taken hourly, and side effects were self-rated at baseline and throughout the six hr response period. The subjects remained recumbent for the first 2.5 hr of the session. A light meal was served at 1230 h.

Assays and analysis The plasma samples were analysed under blind conditions for growth hormone (GH),

prolactin, cortisol, glucose and clonidine concentrations. Plasma GH, prolactin and cortisol were measured by specific double antibody radioimmunoassay (RIA). Plasma GH concentrations are expressed in ng/ml of the International Reference preparation. The reference standard for prolactin was MRC75/504. Plasma cortisol was measured using pure cortisol as standard. Glucose was measured by the glucose oxidase method. Plasma clonidine was measured by a modified RIA method described by Jarrott and Spector (1978). Clonidine values are expressed as means of duplicate determinations in ng/ml.

The data were analysed using the SPSS computer package for Student's t-test, linear regression and multivariate analysis of variance (MANOVA) with repeated measures (Hull and Nie, 1981). Mean arterial pressure (MAP) was calculated using the formula: MAP = diastolic + ((systolic - diastolic)/3). The area under the curve (AI.'C) was calculated by the trapezoidal rule. Other kinetic parameters used for analysis were concentration maximum (Cmax) and the time to peak concentration (Tm,~). Results are expressed as mean _+ SEM.

Page 3: Growth hormone and cortisol secretion after oral clonidine in healthy adults

Oral clonidine and growth hormone secretion 319

RESULTS

Growth hormone concentrations rose from a mean 0900 h basal level of 4.3 _+ 1.3 ng/ml to 7.8 _+ 2.0 ng/ml 90 rain after oral clonidine (Fig. 1). The corresponding GH levels after placebo were 3.7 _ 1.3 and 2.7 _+ 0.9 ng/ml. Basal GH levels in female subjects prior to receiving clonidine were higher (7.2 _+ 1.7 ng/ml) compared to the males (1.4 _+ 0.4 ng/ml, p < 0.02) (Fig. 2). However, GH levels 90 min after clonidine were similarly raised in female and male subjects (Fig. 2). Peak GH increments from basal values were similar between males and females (7.2 vs 6.1 ng/ml), and between subjects with basal levels above 3 ng/ml (6.6 ng/ml) or below 3 ng/ml (6.7 ng/ml; five men and one woman) (Fig. 3).

One man had a blunted GH response following clonidine (peak GH = 1.8 ng/ml), and one woman had a peak GH level below 7.5 ng/ml (Fig. 3). The other eight subjects receiving clonidine had peak GH levels above 7.5 ng/ml, which was above the highest value observed after placebo. With a criterion GH increment of 4 ng/ml above baseline, 80% of the clonidine subjects (four men and four women) had GH values above this level, as did one male placebo subject (Fig. 3). Five clonidine subjects had GH increments greater than 8 ng/ml above baseline values.

Whereas clonidine produced a significant increase in GH secretion, no significant differences in prolactin or cortisol levels were observed at any time point in clonidine treated subjects compared to placebo (Fig. 4). Glucose levels were slightly higher after clonidine, but not significantly different from placebo. After lunch (1230 h), glucose levels increased in both clonidine and placebo subjects. During the post-prandial fall in glucose levels, GH levels in both groups increased (See Figs 1 and 4).

Clonidine produced a significant reduction in mean arterial pressure (MAP) from 78 _ 2 mm Hg at 0900 h to 63 _+ 2 mm Hg 3 hr later, whereas no differences were observed following placebo (p <: 0.001). Pulse rate and temperature were similar between subjects receiving clonidine and placebo.

12.5

7.S x

I,~ 2.5.

e ~ e Clonidine

• ~--* Placebo

I

' i ' i i i i t A M

Hours after Clonidine or Placebo

F,o. 1. The effect of clonidine (0.15 mg) given orally (0900 h) on growth hormone (GH) levels compared to placebo in 10 healthy adults. Peak GH concentrations one to three hr following clonidine were significantly

higher (11.0 _+ 1.6 ng/ml) than after placebo (5.1 _+ 1. l ng/ml).

Page 4: Growth hormone and cortisol secretion after oral clonidine in healthy adults

320 GLENN E. HUNT, BRENDAN T. O'SuLI.IVAN, GORDON F. S. JOHNSON and GEORGE A. SMYTHE

0 ~E

0 "I"

"I" I,-

0 n~ L~

12.5

10

7.5

5

25

• f e m a l e s • m a l e s

~r

-01s 6 ' i ' 2 3 i gAM

H o u r s a f t e r C lon id ine

Fie. 2. Mean growth hormone (GH) levels in male (circles) and female (squares) subjects following oral clonidine (0.15 mg) at 0900 h. Basal GH levels in female subjects were significantly higher compared to males;

however, GH levels were similarly raised 90 min after clonidine.

0 s:

0 "r

T t-

O P~ 0

r-20 ng/rnl

17.5.

15

12.5

10

7.5

-5

2.E

0 Bose Pc,~k Placebo

/

Bose Peak Clonidine 150jug, oral

NORMAL CONTROLS

Fic. 3. Basal and peak growth hormone (GH) concentrations in healthy adults following oral clonidine (0.15 mg) or placebo. Circles indicate men, and squares indicate women. Peak GH concentrations above 7.5 ng /ml discriminated between clonidine and placebo groups. The mean GH increment above baseline was 6.6 ng /ml

following clonidine and 1.4 ng /ml after placebo.

Page 5: Growth hormone and cortisol secretion after oral clonidine in healthy adults

Oral clonidine and growth hormone secretion 321

.o O

7.0 ¸

O

EE 6 . 0

O s.o

4.0

H Clonidine • -- - - - Placebo

i i i i L i

0 I 2 i i 6 Hours after Clonidine or Placebo

FIG. 4. Mean cortisol and glucose concentrations in 10 healthy adults following oral clonidine (0.15 mg) or placebo. Cortisol levels decreased over the test session after both clonidine and placebo. No significant

differences in prolactin levels occurred (data not sho~n).

The mean plasma clonidine maximum (Cmax) was 0.61 ng/mi, and the time to peak concentration (Tmax) was 2.2 hr (Fig. 5). The area under the curve (AUC) was 1.55 ng x hr x ml-' (range 0.88 - 2.31). The 6 hr AUC plasma clonidine values correlated with the fall in arterial pressure (r -- 0.71), but did not correlate with the rise in GH (r = 0.23). The peak plasma clonidine level in the male subject that had a blunted GH response was 0.60 ng/ml. When plasma clonidine levels were at a peak (l - 3 hr after administration), the most common side effects reported were drowsiness, dry mouth and lack of energy (Table I).

D I S S C U S S I O N

Oral clonidine (0.15 mg) produced a satisfactory growth hormone response (peak > 7.5 ng /ml or G H increment />4 ng/ml f rom basal) in eight out of l0 adult subjects. The mean peak G H response to clonidine observed in this study (11 ng/ml) is within the range reported in the literature after an equivalent i.v. dose (8.0 - 16.6 ng/ml) (Table II). The major difference in effect on GH secretion between clonidine given orally and i.v. is that the time to maximum concentration is delayed (90 min vs 45 min after i.v.). In our study, one male subject had a blunted G H response to clonidine (criterion peak GH -- 5 ng/ml), which is similar to the rates reported in previous studies using predominantly young, non- obese males (11/53 = 21%, first six studies in Table II). However, the frequency of blunted G H response in non-depressed controls increases appreciably when older subjects are used, particularly if post-menopausal females are included (30/63 = 48%, studies 7, 9 and 12 in Table II). Matussek et al. (1984) reported raised basal GH levels in a high proport ion of female subjects irrespective of menstrual status, and blunted G H levels following clondine were associated with menses. We observed raised basal GH levels in female subjects, but not the higher frequency of blunted G H levels described by Matussek

Page 6: Growth hormone and cortisol secretion after oral clonidine in healthy adults

322 GLENN E. HUNT, BRENDAN T. O'SULLIVAN, GORDON F. S. JOHNSON and GEORGE A. SMYTHE

A 0.6"

~ 0.5" Z

,~ 0.4- I.- Z

~ 0.3' 0 u

~ 0.2"

Q

Z I~, 0.1. u

0'.5 i 1'.5 ~ T I M E ( h o u r s )

FIG. 5. Mean plasma clonidine concentrations following a single oral clonidine tablet (0.15 mg) in 10 healthy adults. The time to peak concentrations varied between one and three hr, with a maximum concentration range

of 0.4 to 0.9 ng/ml.

TABLE I. SIDE EFFECTS FOLLOWING ORAL CLONIDINE (0 .15 m g ) ADMINISTRATION IN 10 NORMAL ADULT

SUBJECTS

Rating of severity

Side effect a Nil Mild Moderate Severe

Drowsy-sleepy 1 3 5 1 Dry mouth 3 5 1 1 Lack of energy 6 2 2 0 Headache 6 3 1 0 Dizziness 7 3 0 0

aNo side effects were reported after placebo.

et al. (1984). None o f the female subjects receiving c lonid ine in this s tudy were mens t rua t ing at the t ime o f the c lonid ine test p rocedure . Moreover , subjects with high basal G H levels (> 3 ng /ml ) r e sponded to oral c lonid ine with s imi lar peak G H levels c o m p a r e d to subjects with no rma l ly low basal G H levels. Some inves t igators have excluded subjects with basa l G H levels above 3 n g / m l (Checkley et al., 1981), a l though others have demons t r a t ed tha t their inclusion makes litt le d i f ference to the overal l analysis (Lal et al., 1981; Siever et al., 1982).

Glucose levels increase 15 to 30 min af te r i.v. c lonid ine (0.15 mg) (Lal et al., 1975, 1981; Matussek et al., 1980; Massa r a et al., 1983), but they were not s ignif icant ly raised af ter oral c lonid ine in this s tudy or the s tudy by Lanes et al. (1983). O f interest , G H levels were raised af te r lunch in the male pa t ien t tha t had a b lun ted G H response fo l lowing c lonidine , indica t ing a specific decrement in response to the c lonid ine challenge.

Page 7: Growth hormone and cortisol secretion after oral clonidine in healthy adults

O r a l c lon id ine a n d g r o w t h h o r m o n e secre t ion 323

TAaLE II. CLONIDINE-INDUCED GROWTH HORMONE ( G H ) RELEASE IN NORMAL ADULT SUBJECTS AFTER ORAL OR INTRAVENOUS ADMINISTRATION

Subjects Growth hormone with blunted

No. of Clonidine GH response subjects M F Age (yr) dose Tmax (min) ¢max (ng/ml)(<5 ng/ml) Study

I. C l o n i d i n e a d m i n i s t e r e d i n t r a v e n o u s l y (x- _+ SEM) 6 6 - - 21 - 36 0 .15 m g 45 9.1 + 2 .2 1/6 L a l e t a l . , 1975 7 6 1 19 - 32 0 . 1 5 m g 60 l l _ + 4 0 / 7 L a l e t a l . , 1981 7 7 - - 21 - 23 0 .15 m g 40 10.8 .+ 1.6 2 / 7 Koulu et ak , 1983 6 6 - - 24 - 28 0 .15 m g 40 16.6 .+ 2 .0 0 / 6 M a s s a r a et al., 1983

18 18 - - 31 .+ 2 0 .15 m g 60 11.9 .+ 2 .0 6 / 1 8 " * Lal et al., 1983 9 9 - - 25 - 36 0 .15 m g 45 8 .0 .+ * 2 / 9 C a t a l a n o et al., 1984

32 14 18 41 _+ 3 0 .15 m g 45 6.5 .+ 2 .0 15/32 a'b Matussek et al., 1980 10 6 4 41 .+ 5 2 .0 p .g /kg 60 9 .0 .+ * * ,a Checkley et al., 1981 20 * * 19 - 61 2 .0 p .g /kg * 6 .2 .+ 1.1 10 /20 a Siever et al., 1982

II. C I o n i d i n e a d m i n i s t e r e d o r a l l y l 0 10 - - 20 - 25 0 .15 m g 180 ¢ 6 .6 _+ 2 .6 6 / 1 0 c L a n c r a n j i a n & M a r b a c h , 10 10 - - 20 - 25 0 .30 m g 180 c 6 .6 .+ 4.3 1 /10 ¢ 1977 11 6 5 42 _+ 4 5 .0 ~tg/kg * 2 .9 _+ 0 .8 5/11 a C h a r n e y et al., 1982 12 7 5 28 - 43 0 .15 m g / m 2 90 33 .4 _+ 9 .9 0 / 1 2 Lanes et al., 1983 10 5 5 20 - 23 0 .15 m g 90 11.0 .+ 6 .6 1 /10 This s tudy

* N o t s t a t ed in m a n u s c r i p t . **Based on increment of GH above basal level. alncludes post-menopausal females. blncludes subjects with high alcohol intake. ¢Sampling started three hr after clonidine; probably missed GH peak.

Whereas GH levels increased after clonidine, this effect was hormone-specific, because prolactin and cortisol levels did not differ at any time compared to levels in subjects after receiving placebo. There is a general consensus that low doses of clonidine do not produce raised cortisol levels during the GH surge (Matussek et al., 1980; Lanes et al., 1983; Siever et al., 1984) angi do not affect prolactin secretion in humans (Lal et al., 1975; Lanes et al., 1983; Siever and Uhde, 1984). Both Matussek et al. (1980) and Lanes et al. (1983) reported that clonidine may actually reduce cortisol secretion, which is in contrast to the results of this study. Since Matussek et al. (1980) did not compare the cortisol decrease with levels in placebo controls, the normal circadian fall in cortisol may have confounded their results (Sachar et al., 1973; Sherman et al., 1984). Likewise, Lanes et al. (1983) reported a significant decrease in cortisol after clonidine, but these levels were not significantly different from placebo values (69 _+ 11 vs. 85 _+ 7 ng/ml at 120 min). Siever et al. (1984), using placebo-corrected values, did not observe decreased cortisol levels in normal controls after clonidine (1 hr after 2 ~tg/kg, i.v.), but they did report a significant fall in depressed patients.

Adequate plasma clonidine levels (above 0.4 ng/ml) were achieved in all 10 of our • ubjects following oral clonidine; these were similar to previously reported levels (Arndts et al., 1983; Louis et al., 1983). The peak plasma clonidine concentrations were correlated with the fall in mean arterial pressure, but not with the GH response. Following oral clonidine, the peak clonidine levels reported here (range 0 . 4 - 0.9 ng/ml) are much lower

Page 8: Growth hormone and cortisol secretion after oral clonidine in healthy adults

324 GLENN E. HUNT, BRENDAN T. O'SULLIVAN, GORDON F. S. JOHNSON and GEORGE A. SMYTHE

than those after equivalent i.v. administration (1 .5 -3 .6 ng/ml; Matussek et al . , 1980). Davies et al. (1977) compared oral to i.v. clonidine (0.30 mg) and observed equivalent changes in diastolic blood pressure, sedation, and salivary flow, though i.v. administration produced a more rapid onset of effects. The most significant difference between the two routes of clonidine administration was the higher peak plasma clonidine levels (1.4 vs 5 ng/ml after i.v.). Since good dose- response relationships were observed for blood pressure, sedation, and salivary flow when clonidine levels were below 2 ng/ml (Davies et al. , 1977), the higher peak levels produced by i.v. clonidine administration probably should be avoided. Oral clonidine administration avoids the higher peak levels observed in the first 30 min after i.v. administration and thus is a safe, reliable model for testing the GH response in adults.

We thank Boehringer-lngelheim for their generous support and for supplying clonidine and placebo tablets; Dr. Bevan Jarrott, Department of Clinical Pharmacology, University of Melbourne, for the clonidine determinations; and the staff members at the Garvan Institute of Medical Research for GH, prolactin, cortisol, and glucose determinations.

REFERENCES

Anavekar S N, J arrott B, Toscano M, Louis W J (1982) Pharmacokinetic and pharmacodynamic studies of oral clonidine in normotensive subjects. Eur J Clin Pharmacol 23:1 - 5.

Arndts D, Doevendans J, Kirsten R, Heintz B (1983) New aspects of the pharmacokinetics and pharmacodynamics of clonidine in man. Eur J Clin Pharmacol 24:21 - 30.

Brown G M, Garfinkel P E, Grof E, Grof P, Cleghorn J M, Brown P (1983) A critical appraisal of neuroendocrine approaches to psychiatric disorders. In: Mtiller E E, MacLeod R M (Eds) Neuroendocrine Perspectives (Vol 2). Elsevier Science, Amsterdam, pp 3 2 9 - 364.

Catalano M, Bellodi L, Lucca A, Brambilla F (1984) Lithium and alpha,-adrenergic receptors: effects of lithium ion on clonidine-induced growth hormone release. Neuroendocrinol Lett 6:61 - 6 6 .

Charney D S, Heninger G R, Sternberg D E, Hafstad K M, Giddings S, Landis H (1982) Adrenergic receptor sensitivity in depression: effects of clonidine in depressed patients and healthy subjects. Arch Gen Psychiatry 39:290 294.

Checkley S A, Slade A P, Shur E (1981) Growth hormone and other responses to clonidine in patients with endogenous depression. Br J Pochia t 138:51 - 55.

Davies D S, Wing L M H, Reid D M, Neill E, Tippett P, Dollery M B(1977) Pharmacokinetics and concentration effect relationships of intravenous and oral clonidine. Clin Pharmacol Ther 21: 5 9 3 - 601.

Gil-Ad 1, Topper E, Laron Z (1979) Oral clonidine as a growth hormone stimulation test. Lancet ii: 278 - 280. Hull C H, Nie N H (1981) SPSS Update 7 - 9. McGraw-Hill, New York. Jarrott B, Spector S (1978) Disposition of clonidine in rats as determined by rad io immunoassay . . I Pharmacol

Exp Ther 207 :195-202 . Johnson G F S (1982) Endocrine dysfunction in depression. In: Beumont P J V, Burrows G (Eds) Handbook oJ'

Psychiatry and Endocrinology. Elsevier Biomedical Press, Amsterdam, pp 2 3 9 - 266. Johnstone E C, Ferrier I N (1980) Neuroendocrine markers of CNS drug effects. Br J Clin Pharmacol 10:5 - 21. Koulu M, Pihlajamaki K, Huupponen R (1983) Effect of the benzodiazepine derivative, diazepam, on the

clonidine-stim ulated growth hormone secretion. J Clin Endocrinol Metab 56:1316-1318. kal S, Tolis G, Martin J B, Brown G M, Guyda H (1975) Effect of clonidine on growth hormone, prolactin,

luteinizing hormone, follicle-stimulating hormone and thyroid-stimulating in the serum of normal men. J Clin Endocrinol Metab 41: 8 2 7 - 832.

Lal S, Tolis G, McDonald T J, Cervantes P, Dupre J (1981) Effect of clonidine on growth hormone and glucagon secretion. Horm Metab Res 13: 6 4 8 - 649.

Lal S, Nair P V, Thavundayil J X, Monks R C, Guyda H (1983) Clonidine-induced growth hormone secretion in chronic schizophrenia. Acta Psvchiat Scand 68: 8 2 - 88.

Lancranjian 1, Marbach P (1977) New evidence for growth hormone modulat ion by the c~-adrenergic system in man. Metabolism 26:1225 - 1230.

Lanes R, Hurtado E (1982) Oral c l o n i d i n e - a n effective growth hormone releasing agent in prepubertal subjects..1 Pedlar 100: 7 1 0 - 714.

Lanes R, H~--rera A, Palacios A, Moncada G (1983) Decreased secretion of cortisol and ACTH after oral clonidine ~.dministration in normal adults. Metabolism 32:568 - 570.

Page 9: Growth hormone and cortisol secretion after oral clonidine in healthy adults

Oral clonidine and growth hormone secretion 325

Louis W J, Anavekar S N, Conway E L, Jarrott B (1983) Relationship of immunoassayable clonidine plasma levels to its pharmacologic action in clinical and experimental hypertension. Chest (Suppl) 83:352 - 354.

Massara F, Limone P, Cagliero E, Tagliabue M, lsaia G C, Molinatti G M (1983) Effects of naloxone on the insulin and GH responses to a-adrenergic stimulation with clonidine. Acta Endocr 103:371 -375.

Matussek N, Ackenheil M, Hippius H, Muller F, Schroder H-Th, Schultes H, Wasilewski B (1980) Effect of clonidine on growth hormone release in psychiatric patients and controls Psychiatry Res 2:25 - 36.

Matussek N, Ackenheil M, Herz M (1984) The dependence of the clonidine growth hormone test on alcohol drinking habits and the menstrual cycle. Psychoneuroendocrinology 9:173 - 177.

Sachar E J, Hellman L, Roffwarg H P, Halpern F S, Fukushima D K, Gallagher T F (1973) Disrupted 24-hour patterns of cortisol secretion in psychotic depression. Arch Gen Psychiatry 28: 19-24.

Salti R, Galluzzi F, Becherucci P, Seminara S, Calzolari C, lnnocenti S, LaCauza C (1981) Oral clonidine: an effective provocative test of growth hormone release. Helv Paediat Acta 36: 527-531.

Sherman B, Pfohl B, Winokur G (1984) Circadian analysis of plasma cortisol levels before and after dexamethasone administration in depressed patients. Arch Gen Psychiatry 41:271 -275.

Siever S J, Uhde T W (1984) New studies and perspectives on the noradrenergic receptor system in depression: effects of the ct2-adrenergic agonist clonidine. Biol Psychiat 19:131 - 156.

Siever L J, Uhde T W, Silberman E K, Jimerson D C, Aloi J A, Post R M, Murphy D L (1982) Growth hormone response to clonidine as a probe of noradrenergic receptor responsiveness in affective disorder patients and controls. Psychiatry Res 6:171 - 183.

Siever L J, Uhde T W, Jimerson D C, Post R M, Lake R, Murphy D L (1984) Plasma cortisol responses to clonidine in depressed patients and controls. Arch Gen Psychiatry 41: 63 - 68.

Slover R H, Klingensmith G J, Gotlin R W, Radcliffe J (1984) A comparison of clonidine and standard provocative agents of growth hormone. Am J Dis Child 138: 314-317.

Starke K (1981) a-Adrenoceptor subclassification. Rev Physiol Biochem Pharmacol 88: 199-236.