0021-972X/9l/7202-0503$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright© 1990 by The Endocrine Society

Vol. 72, No. 2 Printed in U.S.A.

Growth Hormone-Releasing Hormone Reverses Secondary Somatotroph Unresponsiveness T. E. ROMER*, B. RYMKIEWICZ-KLUCZYNSKA, M. OLIVIER, L. SAGNARD, AND M. SZARRAS-CZAPNIK Child Health Center, (T.E.R., B.R.-K, M.S.-C), Warsaw, Poland; and Sanofi Recherche (M.O, L.S.), France

ABSTRACT. Twenty severely GH-deficient prepubertal children aged 10.7 ± 2.1 yr (mean ± SD) and with a height SD of -4.92 ± 1.02 were treated with sc injections of GHRH 1-44 (10 /ig/kg BW) for 6 months either daily (11 patients) or 3 times/ week (nine patients). An acute iv GHRH test (2 Mg/kg BW) was performed before and after 2 and 6 months of treatment. Mean (±SD) peak GH responses to these tests were 2.92 ± 3.01, 4.57 ± 4.91, and 7.56 ± 8.14 jtg/L, respectively (P < 0.05, pretreatment us. 6 months). The mean growth velocity (GV) during treatment was only 2.99 ± 1.67 cm/yr and only two patients increased their GV by

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more than 2 cm/yr. A correlation was found between GV during treatment and the peak serum GH response to GHRH acute test before treatment (r = 0.68, P < 0.005) as well as between GH response to the acute test and patient's bone age (r = —0.46, P < 0.05). The results indicate that in some severely GHD patients with no response to GHRH even after a 2-month priming period, 6 months of treatment with GHRH can evoke pituitary responsiveness. We speculate that the duration of the GHRH deficiency and its severity plays a role in the ability of somatotrophs to respond to this stimulus. (J Clin Endocrinol Metab 72: 503-506, 1991)

C/insulin-like growth factor I (SmC/IGF-1), TSH and PRL before and after iv injection of TRH, and LH and FSH before and after iv injection of LHRH. Urinary 17-OHCS measurements were performed during 2 consecutive days of metyrapone administration (10 mg/kg orally every 4 h). On the basis of these studies, 12 patients were determined to have isolated GHD and 8 to have multiple hormonal deficiencies. Nineteen patients had been treated with pituitary-derived GH (for 0.6 to 3.3 yr) previously, and treatment had been discontinued between 4-5 months before the study began. The pretreatment growth velocity (GV) of these patients (Table 1) was derived from a period longer than 6 months before any GH replacement was started. T4 replacement therapy was prescribed for patients with low serum T4 values and all had normal serum T4 levels for at least 2 months before GHRH was begun.

T IS widely believed that the inability of most patients with so called idiopathic growth hormone deficiency (GHD) to secrete GH is a manifestation of insufficient stimulation of the pituitary by the hypothalamus (1-3). Indeed, several studies confirm that many such patients secrete GH in response to the injection of GHRH (4-7). Some patients however fail to respond to GHRH, raising the question of whether they have a primary pituitary lesion or somatotroph atrophy secondary to long-standing lack of exposure to GHRH. We have addressed this question by measuring the serum GH responses to GHRH after 2 and 6 months of priming with GHRH in a group of severely GHD patients who showed poor initial GH serum responses to GHRH.

Study protocol

Materials and Methods Patients and prestudy evaluation Twenty prepubertal children with idiopathic GHD (10 boys, 10 girls) aged from 5.8 to 16.4 yr (10.7 ± 2.7 mean ± SD) are included in the study. Organic hypopituitarism had been excluded in each patient by neurological and ophthalmological examinations and by CT scanning. Obstetrical complications had occurred in 7 patients: 6 cases of breech delivery, one cervical rupture, and 2 premature births. Serum GH responses to clonidine (50 Mg/m2, orally) had been measured in all subjects; responses to one other stimulus, either L-dopa (300 mg/ m2; 15 subjects), bromocriptine (1.5 mg/m2; 4 subjects) or insulin hypoglycemia (1 subject) were also measured. Additional hormonal measurements included T4, T3, somatomedin-

Serum GH responses to the iv injection of 2 Mg/kg GHRH 1-44 NH2 (Sanofi, Toulouse, France) were measured after an overnight fast, 15 days before GHRH therapy was begun. Blood samples were collected at —15, 0, 15, 30, 60, and 120 min and the serum was stored at -20 C until assay. This GHRH test was repeated after 2 and 6 months of GHRH therapy, 36 h after the last sc GHRH injection. Eleven patients (1-11, Table 1) were treated with 10 Mg/kg GHRH given daily at bedtime, and nine received the same dosage of GHRH three times per week. Because comparison of these two treatment groups revealed no differences in serum GH or growth responses, their data are considered together. The protocol was approved by the ethics committee of the Child Health Center, Warsaw and written informed consent was obtained from parents and from

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JCE&M-1991 Vol 72 • No 2

ROMER ET AL.

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patients older than 12 yr. All height measurements were obtained by the same observer between 0900 and 1100 h using a Harpenden stadiometer. Serum GH was determined by double antibody precipitation RIA using a kit (ORIPI; Swierk, Poland); all of the samples collected during one test were measured in the same assay. The intra and interassay coefficient of variations at 7.8 /xg/L were 9.2 and 11.0%, respectively. SmC/IGF-1 was measured by RIA in unextracted serum samples (Nichols, San Juan Caspistrano, CA). Other hormones were measured by standard RIAs. The study was analyzed using Stratgraf Software Analysis of variance and Student's t test were used to assess differences between means. The results are given as the mean ± SD.

0.5-30.5 Mg/L (mean 7.56 ± 8.1 jug/L, P < 0.05, compared to pretreatment responses) and 11 patients now had responses greater than 5 fig/L (Fig. 1). During the 6 months oi' GHRH therapy, the mean growth rate was 2.99 ± 1.7 om/yr (range, 1.2-8.3 cm/yr). There was a significant correlation (r = 0.68, P < 0.005) between GV during GHRH therapy and peak serum GH response to GHRH before treatment. Children with less advanced bone age responded better to the GHRH acute test (r = —0.46, P < 0.05) administered before the treatment. Correlation between response to GHRH before the treatment and duration of the GH treatment was not found (r = -0.12).

Results The higher peak serum GH responses to each of the two standard provocative tests was below 4.5 Mg/L in all patients (Table 1). The peak GH responses to GHRH

during the pretreatment test ranged between 0.1 and 10.8 ixg/L (mean 2.92 ± 3.01 ixg/L), and there was no significant difference between the higher of the two standard provocative test responses and the response to GHRH. Only two patients had GH responses to GHRH of >5 /xg/L (Fig. 1). After 2 months of GHRH therapy, the peak GH response varied between 0.1 and 18.1 jug/L (mean 4.57 ± 4.9 yug/L, NS for pretreatment us. 2 month responses), with 6 patients having values greater than 5 . After 6 months, the range of GH after GHRH was TABLE

Discussion The results of this studj' indicate that prolonged administration of GHRH exerts a priming effect on the somatotrophs of some patients with severe idiopathic GH deficiency, and that their improvement in responsiveness to GHRH occurs over a prolonged period of time. Of the seven patients who experienced an increase of 5 fig/L or more in their GH response between pretreatment and 6 months of treatment, the responses at 6 months invariably exceeded the responses to GHRH at 2 months. In other studies; this priming effect was not found in groups of GHD patients after 3 days (8), 5 or 7 days (9,10,11), 4 weeks (12), or 3 months (13) of GHRH

1. Clinical data GV (cm/year)

No. 1° 2 3 4 5 6 ?6

8° 9° 10* 11* 12° 13* 14 15 16 17 18 19 20"

CA (yr)

BA (yr)

Height (SDS)

14.8 12.5 8.3 9.6 11.5 9.9 8.8 12.5 8.8 12.2 10.8 8.8 13.6 8.3 11.1 16.4 5.8 9.5 13.8 7.2

10.0 6.0 4.5 9.0 9.0 8.0 3.5 4.0 5.0 7.0 6.0 3.5 8.0 3.0 6.5 10.0 2.5 3.5 9.0 3.5

-4.4 -7.2 -4.4 -3.1 -5.1 -4.5 -4.5 -5.3 -4.3 -5.4 -5.1 -4.6 -7.1 -3.8 -4.8 -6.5 -4.7 -4.7 -4.8 -4.0

Peak GH responses (iig/L)

Before GH

On GHRH

Standard stimuli

Before GHRH

GHRH (2 m)

GHRH (6 m)

5.1 2.1 2.8 4.0 3.2 2.8 1.6 3.8 3.6 2.4 4.4 3.7 3.0 3.5 1.4 1.6 4.4 2.6 5.2 2.8

3.5 3.1 3.2 1.7 1.8 1.5 2.7 2.1 4.5 2.4 2.3 2.2 2.8 5.8 1.2 1.3 8.4 3.2 2.7 3.5

0.5 1.2 1.2 1.7 1.0 3.1 1.2 0.5 1.3 1.2 4.4 2.3 1.6 3.4 0.7 0.7 2.3 1.3 3.8 3.0

5.0 1.8 1.9 0.2 0.2 0.2 3.0 1.9 4.8 0.8 3.8 3.5 1.4 2.2 0.1 0.4 10.8 9.9 4.3 1.5

7.3 4.6 7.4 0.5 0.1 0.1 3.8 1.9 3.9 2.1 5.3 0.6 1.4 3.6 3.2 9.9 15.0 18.1 0.3 2.6

12.2 7.0 14.4 0.5 0.4 0.5 5.5 3.3 7.4 3.1 5.2 6.6 1.7 2.5 4.5 10.3 30.5 26.8 5.2 3.4

Period of GH (weeks) 85 65 90 114 78 78 108 53 79 84 143 149 170 23 117 46 54 55 30

Standard provocative stimuli included clonidine, L dopa, bromocriptine, or insulin-hypoglycemia. m, months; BA, bone age; CA, chronological age; SDS . 0 With TSH deficiency. * With TSH and gonadotropin deficiency.

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ROLE OF GHRH IN SOMATOTROPHS 2O, < 5 ng/ml 5.1-10 15.

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E 3 2

5J

OJ Before 2 months 6 months treatment treatment treatment Peak GH response to GHRH acute test FIG. 1. Peak serum GH responses to iv injection of GHRH (2 before and after 2 and 6 months of treatment. The responses are divided into three groups at each time period: those of 5 /xg/L or less, 5.1-10 /xg/L, and those greater than

treatment. The failure to observe a priming effect over these intervals is in keeping with our results. In contrast, P. Rochiccioli et al. (14) observed an improved GH response to GHRH injected iv in a group of severely GHD children after 6 months of GHRH administration. Unlike our patients, these children had good serum GH responses (34.5 ± 14.2 /ug/L) to GHRH initially. In a similar group of patients (15) the GH response to the acute test did not increase after 6 months of treatment. As a group, our patients are unusual because of the uniformly poor GH response to provocative stimuli and to the initial test injection of GHRH. These poor responses differ from those observed on other groups of patients (9, 13, 15-17) and by us in a different study of other GHD patients. We believe that, in the current study, there was bias toward selecting patients that were severely GHD, because recruitment took place after the discovery that GH-treated patients had developed Creutzfeldt-Jakob disease, and the patients selected for this GHRH therapeutic trial were those most in need, being relatively old (mean age, 10.7 yr) and severely growth retarded (mean height SD, 4.92 ± 1.02). The long period needed for priming of some of the patients and the failure of others to exhibit priming raise questions about underlying mechanisms. One conclusion that could be drawn from the failure of many of our patients to improve their GH responses to GHRH after prolonged GHRH therapy is that they may have primary pituitary lesions. Alternatively, in view of the prolonged

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interval required for priming, it seems possible that some may have a severe primary deficiency of hypothalamic GHRH with secondary somatotroph atrophy (18, 19). Data from several studies indicate that long-standing GHRH deficiency may lead to somatotroph unresponsiveness (8, 17, 20). A longer period of GHRH administration would have provided further confirmation of possible reversion of secondary somatotroph unresponsiveness. But GH became available again after the 6-month period of GHRH therapy and was judged to be a better form of treatment. The negative relationship observed between bone age and GH response to GHRH (r = -0.46, P < 0.05) raises the questions of whether prolonged deficiency of GHRH might lead to permanent somatotroph atrophy and whether atrophy could be reversed by GHRH treatment of younger children. The negative correlation between chronological age and GH response to GHRH is less pronounced in our series (r = -0.35 not significant). Although not entirely comparable, the idea that revival of atrophic somatotrophs is time limited is opposed by the observation that excessive proliferation of somatotrophs continues throughout the lifespan of GHRH transgenic mice (21). Poor growth response observed during GHRH treatment cannot be compared with the pretreatment growth velocity (before previous GH therapy) in somewhat younger children. It could be explained by inappropriate mode of GHRH treatment, including duration and by low GH response to GHRH. The correlation we observed between the acute GH response to iv GHRH and growth response to chronic GHRH treatment was not reported by others (12, 14-21). This may be in part the result of the unusual selection of this group of patients. We have not observed such a correlation in another group of patients with better acute GH responses. Our study confirms that poor serum GH responses to GHRH are a predictor of poor growth responses (13) and suggests that patients with very low serum GH responses to iv GHRH test are probably not good candidates for GHRH therapeutic trials. Acknowledgment The authors are indebted to L. E. Underwood for his valuable remarks and help in preparing this manuscript. References 1. Goodman HG, Grumbach MM, Kaplan SL. Growth and growth hormone. A comparison of isolated growth-hormone deficiencies in 35 patients with idiopathic hypopituitary dwarfism. N Engl J Med. 1968;278:57-68. 2. Grossman A, Savage MO, Blackley A et al. The use of growth hormone-releasing hormone in the diagnosis and treatment of short stature. Hormone Res. 1985;22:52-57. 3. Kaplan SL. Endocrine and Genetic Diseases of Childhood and

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ROMER ET AL. Adolescence. Hypopituitarism, Gardner LI, ed. WB Saunders, Philadelphia, 1975. Hizuka N, Takano K, Shizume K, Hirose N, Ling NC. Plasma growth hormone responses to repetitive administration of growth hormone releasing factor in patients with pituitary dwarfism. Endocrinol Jpn. 1984;3l:697-704. Pertzelan A, Keret R, Bauman B et al. Plasma growth hormone response to synthetic GHRH 1-44 in 52 children and adults with growth hormone deficiency of various etiologies. Hormone Res. 1985;22;24-31. GHRH European Multicenter Study Group. Growth hormone (GH) response to a single intravenous injection of synthetic GH releasing hormone in prepubertal children with growth failure. J Clin Endocrinol Metab. 1987;65:387-394. Van Vliet G, Bosson D, Robyon C, Craen M, Malvaux P, Vanderschueren-Lodweyckx WR. Effect of growth hormone-releasing factor on plasma growth hormone, prolactin and somatomedin C in hypopituitary and short normal children. Hormone Res. 1985;22:32-45. Chihara K, Kashio Y, Abe et al. Idiopathic growth hormone (GH) deficiency, and GH deficiency secondary to hypothalamic germinoma: effect of single and repeated administration of human GHreleasing factor (hGRF) on plasma GH level and endogenous hGRF-like immunoreactivity level in cerebrospinal fluid. J Clin Endocrinol Metab. 1985;60:269-278. Takano K, Hizuka N, Shizume K, Honda N, Ling NC. Plasma growth hormone (GH) responses to single and repetitive subcutaneous administration of GH releasing factor (hpGRF-44) in normal and GH deficient children. Acta Endocrinol (Copenh). 1985;108:ll-19. Borges JLC, Blizzard RM, Evans WS et al. Stimulation of growth hormone (GH) and somatomedin C in idiopathic GH-deficient subjects by intermittent pulsatile administration of synthetic human pancreatic tumor GH-releasing factor. J Clin Endocrinol Metab. 1984;59:l-6. Gelato MC, Ross JL, Malozowski S et al. Effects of pulsatile administration of growth hormone (GH)-releasing hormone on short term linear growth in children with GH deficiency. J Clin Endocrinol Metab. 1985;61:444-450. Low LCK, Wang C, Cheung PT et al. Long term pulsatile growth

13. 14.

15.

16. 17.

18. 19. 20.

21.

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hormone (GH)-releasing hormone therapy in children with GH deficiency. J Clin Endocrinol Metab. 1988;66:611-617. Ross RJM, Rodda C, Tsagarakis S et al. Treatment of growth hormone deficiency with growth hormone releasing hormone. Lancet. 1987;l:5-8. Rochiccioli PE, Tauber MT, Coude FX et al. Results of 1-year growth hormone (GH)-releasing hormone-(l-44) treatment on growth, somatomedin-C, and 24-hour GH secretion in six children with partial GH deficiency. J Clin Endocrinol Metab. 1987;65:268274. Thorner MO, Rogol AD, Blizzard RM et al. Acceleration of growth rate in growth hormone-deficient children treated with human growth hormone-releasing hormone. Pediatric Res. 1988;24:145150. Smith PJ, Brook CGD. Tho place of intravenous GHRH 1-40 studies in the therapy of growth hormone-deficient children with GHRH. Clin Endocrinol. 1987;27:97-105. Schriock EA, Hulse JA, Harris DA, Kaplan SL, Grumbach MM. Evaluation of hypothalamic dysfunction in growth hormone (GH)deficient patients using singh; versus multiple doses of GH-releasing hormone (GHRH-44) and evidence for diurnal variation in somatotroph responsiveness to GHRH in GH-deficient patients. J Clin Endocrinol Metab. 1987 65:1177-1182. Cheng TC, Beamer WG, Phillips III JA, Bartke A, Mallonee RL, Dowling C. Etiology of growth deficiency in Little, Ames and Snell dwarf mice. Endocrinology. 1983; 113:1669-1678. Clark RG, Robinson ICAF. Effects of a fragment of human growth hormone-releasing factor in normal and "Little" mice. J Endocrinol. 1985;106:l-5. Schriock EA, Lustig RH, Rcsenthal SM, Kaplan SL, Grumbach MM. Effect of growth hormone (GH)-releasing hormone (GRH) on plasma GH in relation to magnitude and duration of GH deficiency in 26 children anc. adults with isolated GH deficiency, or multiple pituitary hormone deficiencies: evidence for hypothalamic GRH deficiency. J Cl.n Endocrinol Metab. 1984;58:10431049. Mayo KE, Hammer RE, Swanson LW, Brinster RL, Rosenfeld MO, Evans RM. Dramatic piluitary hyperplasia in transgenic mice expressing a human growth hormone-releasing factor gene. Mol Endocrinol. 1988;2:606-612.

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Growth hormone-releasing hormone reverses secondary somatotroph unresponsiveness.

Twenty severely GH-deficient prepubertal children aged 10.7 +/- 2.1 yr (mean +/- SD) and with a height SD of -4.92 +/- 1.02 were treated with sc injec...
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