Eur J Pediatr (1992) 151 : 263-265

European Journal of

Pediatrics

9 Springer-Verlag1992

Diagnostic value of growth hormone-releasing hormone test in children and adolescents with idiopathic growth hormone deficiency* T. Arrigo 1, F. Martino 2, F. Lombardo 1, N. Laforgia 3, A. Acqnafredda 3, R. Russo 3, L. Cavallo 3, and F. De Luca 1 Institutes of 1Paediatrics and 2Radiology, University of Messina, 1-98123 Messina, Italy 3Institute of Clinical and Preventive Paediatrics, University of Bari, Italy Received August 16, 1991 / Accepted August 25, 1991

Abstract. Average growth hormone (GH) peaks following an i.v. growth hormone releasing hormone ( G H R H ) 1-29 stimulation test were significantly lower in 48 children and adolescents with G H deficiency ( G H D ) than in 20 age-matched controls (15.2 + 12.7 vs 37.5 + 28.1ng/ ml, 2 P < 0.001). Twelve patients exhibited a low G H peak ( < 5 ng/ml), 27 demonstrated a normal response ( > 10 ng/ml) and 9 showed an intermediate rise in plasma G H (5-10 ng/ml). Six of the 12 patients with low G H response to the first G H R H stimulation failed to respond to two other tests immediately before and after a 1 week priming with s.c. G H R H . These subjects with subnormal G H increase at repeat testing had total G H D ( T G H D ) and multiple pituitary hormone deficiency ( M P H D ) and had suffered from perinatal distress. On the contrary, 26 of 27 patients with normal G H response to the first test had isolated G H D and only a minority (8/27) had signs of perinatal distress. It is concluded that perinatal injuries primarily damage pituitary structures and that a pituitary defect more probably underlies more severe forms ( T G H D and M P H D ) of G H D .

Key words: Growth hormone releasing hormone test -

hormone (GH) secretion [13, 16, 18, 20], its role in the evaluation of children with growth disorders is still to be clarified. The G H R H test is generally considered a helpful tool in the differential diagnosis of hypothalamic and pituitary G H deficiency ( G H D ) and in selecting those patients who might benefit from long-term treatment with G H R H [1, 9, 13, 17, 18]. Nevertheless, in cases with a very low G H response to the first G H R H stimulation a single test may fail to distinguish a pituitary defect from a profound and prolonged G H R H deficiency. Thus a second test, after a repeated priming with G H R H , may be necessary to ascertain the site of lesion by ruling out a hypothalamic defect [2, 6, 7, 9-12, 18]. In the present study we investigated G H response to G H R H in 48 G H D subjects in order to assess the relationship between the releasable G H pool in the pituitary and the features (either mild or severe, isolated or combined with other pituitary hormone deficiency) and aetiology (presence or absence of perinatal distress) of their G H D . In the patients with subnormal G H increase after the first G H R H test, pituitary response was reevaluated after a 1 week priming with s.c. G H R H .

Growth hormone deficiency - Pituitary insufficiency

Patients and methods Introduction Although growth hormone releasing hormone ( G H R H ) is well known to be the most potent stimulator of growth * Presented in part at the 7th Meeting of the Italian Society for Paediatric Endocrinology (Milan, 20-21 October 1989) Offprint requests to: F. De Luca Abbreviations: ACTH = corticotropin; GH = growth hormone;

GHD = growth hormone deficiency; GHRH = growth hormone releasing hormone; IGHD = isolated growth hormone deficiency; MPHD = multiple pituitary hormone deficiency; PD = perinatal distress; PGHD = partial growth hormone deficiency; TGHD = total growth hormone deficiency; TSH = thyrotropin

Our study population comprised 48 children and adolescents (15 females) with idiopathic GHD aged 1.3-19.5 years (mean + SD = 7.2 + 4.2) and 20 healthy prepubertal children (8 females) as controis.

Patients

The diagnosis of GHD had been made on the basis of both auxological (height deficiency exceeding - 3 SD; growth velocity > - 2 SD; delay of at least 2 years in bone age) and biochemical criteria. Total GHD (TGHD) was defined if maximal GH levels during administration of both 0.1 units/kg insulin i.v. and 0.15mg/m2 clonidine p.o. were below 7 ng/ml (n = 38). Partial GHD (PGHD) was defined when plasma GH peaked between 7.0 and 9.9 ng/ml during one of the above tests and below 7 during the other (n = 10) [14].

264 The 48 patients were further divided according to diagnosis into the following subgroups: (1) isolated GHD (IGHD): 34 subjects in whom physical examination and extensive laboratory investigation revealed no abnormality except for GHD; (2) multiple pituitary hormone deficiency (MPHD): 14 subjects in whom GHD was recognized by clinical and biochemical criteria to be associated with the deficiency of one or more additional pituitary hormones, i.e. thyrotropin (TSH) (n = 4), T S H + corticotropin (ACTH) (n = 2), TSH +gonadotropins LH/FSH (n = 2), LI-I/FSH (n = 2), TSH + LH/FSH + A C T H (n = 4). Thyrotrophic function was considered insufficient when serum free thyroxine was subnormal [3]. A C T H insufficiency was diagnosed when basal serum cortisol concentrations were subnormal and increased by less than 100ng/ml during insulin-induced hypoglycaemia [10]. Diagnosis of hypogonad 9 hypogonadism was assessed in the cases with absent secondary sexual characteristics and subnormal (for bone age) testosterone or oestradiol serum levels and gonadotropin responses to LH releasing hormone test [8]. At the time of this study each patient was euthyroid and no hydrocortisone substitutive therapy exceeded 10 mg/m 2 per day. All patients had received G H replacement treatment for several years previously and had show a good response. Prior to G H R H testing GH substitution was withdrawn for at least 30 days. In 19 patients there was a positive history, reconstructed from obstetric records, of pathology at birth or in the early neonatal period: breech delivery and/or prolonged asphyxia, indicated by an Apgar score persisting below 8, 5 min after birth. Perinatal distress (PD) was absent in the remaining 29 cases.

Results

Average GH peaks following G H R H stimulation were significantly lower (2 P < 0.001) in patients (15.2 + 12.7 ng/ml; range 1.3 -59.9) than in controls 37.5 + 28.1 ng/ ml, range 9.6 +103.5). In G H D subjects a positive relationship was found between maximal G H levels in response to G H R H and those elicited by conventional stimuli (r = 0.38, P < 0.01) (Fig. 1). Figure 2 demonstrates individual and average values of GH peaks after G H R H in controls and in the patients divided into four subgroups. Twelve patients (and none of controls; X = 6.1, P < 0.025) exhibited a low G H response, as defined above; 27 (and 18 controls) demonstrated a normal increase, 9 (and 2 controls) showed an intermediate rise in plasma GH. All the patients with low GH response had

12 9

10

,,

.c ~3

Controls Their ages ranged from 4.1 to 11.5 years (mean + SD = 7.0 + 1.8) and bone age did not substantially differ from chronological age. All of them had height deficiency exceeding - 3 SD but normal (> 10 ng/ml) G H peaks in response to both insulin and clonidine.

oe 6 -d

4 .'I, 000 e,

2 go

q-

0 ~"

Methods Patients' and controls' height and growth velocity were evaluated according to Sempe et al. [19]. Bone age was estimated from wrist and hand X-ray films using the atlas of Greulich and Pyle [4]. Both patients and controls underwent an i.v. GH-RH 1-29 (Serono, Italy) stimulation test at a dose of 1 gg/kg after an overnight fast. Blood samples were collected in heparinized syringes at - 15, 0, 5, 15, 30, 45, 60, 90 and 120min, centrifuged and stored frozen at - 2 0 ~ until processed in duplicate in two different runs. G H was determined by radioimmunoassay using a second polyclonal antibody system to separate free and bound label (Biodata kits, Milan, Italy; sensitivity 0.25 ng/ml; intraassay and interassay coefficients of variation 3% and 6%, respectively). Results are expressed as ng/ml of the MRC International Standard 66/217. The response of plasma GH to G H R H was classified into 3 degrees according to the maximal level reached at any time during the test: (1) normal: plasma GH peak > 10ng/ml (2) low: plasma G H peak < 5 ng/ml; (3) intermediate: plasma G H peak of 5-10 ng/ ml [2]. Six patients with low GH response to the first G H R H stimulation (Table 1) underwent two other provocation tests immediately before and after they had received twice daily s.c. injections of 1 gg/kg G H R H for 7 days [2]. Plasma samples from these two tests were assayed for GH in the same run. Student's t-unpaired (two-tailed) test, chi-square test and correlation analysis were employed for statistical evaluation as appropriate. Due to their non-Gaussian distribution, G H maximal levels were log-transformed for statistical purpose. Data are given as mean + SD. Informed consent was obtained from all subjects or their parents and approval was also given by the Hospital Ethical Committee.

I

1

I

i

e

,

10

20

30

40

50

60

GH (ng/ml) after GH-RH

Fig. 1. Relationship between GH peaks following i.v. G H R H and those elicited by conventional stimuli in 48 G H D patients (r = 0.38, P < 0.01 on log-transformed values)

120-

.~ 100-

8oO

E x::

o9

609o

40 i oooo 9

o

~176

o9

9

0J

9 9

I

9

o~

~o~..~

II

OoOoo

o

III

9

IV

9

oao 0{3 9 o o~

9

: o 4 4 >. V

Fig. 2. Individual and average (horizontal bars) G H peaks following i.v. G H R H in controls and in four subgroups of G I l D patients; open circles characterize patients with antecedents of perinatal distress.

I, Controls ( n = 2 0 ) ; II, Isolated GHD ( n = 3 4 ) ; III, Multiple pituitary hormone deficiency (n = 14); IV, Partial GHD (n = 10); V, Total GHD (n = 38)

265 T G H D and 11/12 had M P H D . On the contrary, 26 of 27 subjects with maximal G H levels > 10 ng/ml had I G H D (~2=30.2, P

Diagnostic value of growth hormone-releasing hormone test in children and adolescents with idiopathic growth hormone deficiency.

Average growth hormone (GH) peaks following an i.v. growth hormone releasing hormone (GHRH) 1-29 stimulation test were significantly lower in 48 child...
355KB Sizes 0 Downloads 0 Views