Growth hormone-releasing hormone: studies in normal subjects and patients with disorders of growth hormone secretion

Growth hormone-releasing hormone (GHRH) has been characterised as a 40-44 residue peptide with full biological activity residing in the first 29 residues. In normal subjects GHRH selectively promotes the release of growth hormone (GH) with little change in responsiveness throughout childhood and young adult life. The majority of 'GH-deficient patients' show a GH response to GHRH, suggesting that they have a hypothalamic defect in GH release. GHRH given subcutaneously promotes growth in 50% of GH-deficient children, and it is likely that depot-preparations of GHRH will provide a practical alternative treatment for GH deficiency. GHRH has provided an important method to evaluate pituitary GH reserve and has greatly improved our understanding of both normal and abnormal GH secretion.     

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 children and adolescents with GH deficiency (GHD) than in 20 age-matched controls (15.2+12.7 vs 37.5+28.1 ng/ml, 2P<0.001). Twelve patients exhibited a low GH peak (<5 ng/ml), 27 demonstrated a normal response (>10 ng/ml) and 9 showed an intermediate rise in plasma GH (5–10 ng/ml). Six of the 12 patients with low GH response to the first GHRH stimulation failed to respond to two other tests immediately before and after a 1 week priming with s.c. GHRH. These subjects with subnormal GH increase at repeat testing had total GHD (TGHD) and multiple pituitary hormone deficiency (MPHD) and had suffered from perinatal distress. On the contrary, 26 of 27 patients with normal GH response to the first test had isolated GHD 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 (TGHD and MPHD) of GHD.Presented in part at the 7th Meeting of the Italian Society for Paediatric Endocrinology (Milan, 20–21 October 1989)     

Signal transduction defects in growth hormone insensitivity

Growth hormone (GH) insensitivity is a heterogeneous condition that can result from mutations within the GH receptor (GHR) and that can be inherited as both an autosomal recessive and a dominant trait. However, evidence from a small number of growth hormone binding protein (GHBP)-positive families indicates that their GH insensitivity is independent of GHR mutations. Two of these families appear to have distinct abnormalities in GH signal transduction. Studies suggest that one family (classic Laron syndrome phenotype; designated family H) have a signalling defect close to the GHR, preventing activation of both the STAT and MAPK pathways, whereas the other family (less marked phenotype; family M) have a defect in activating MAPK but not the STAT pathway. The children studied here are specifically insensitive to GH and their defect must be exclusive to this signalling system. Thus, families with GHBP-positive GH insensitivity without GHR mutations are likely to be important models in which to study the specificity of GH signal transduction and the relationship between GH insensitive phenotype and signalling defect.     

Amelogenesis imperfecta with growth hormone deficiency in a 12 year-old boy

Amelogenesis imperfecta (AI) is a diverse group of hereditary disorders that are characterized by a defect in the formation of the tooth enamel and a high degree of clinical diversity. X-linked, autosomal dominant and recessive inheritance have been demonstrated. Growth hormone (GH) has an effect on bone and soft tissue development. Dental and facial abnormalities associated with pituitary dwarfism have been reported, but GH deficiency with AI is very rare. We describe a 12 year-old pre-pubertal boy who was referred to our hospital with teeth deformities and growth retardation. His teeth had brown-yellow pigmented surfaces, and dental examination showed extensive enamel deficiency in his permanent teeth. He also had severe growth retardation; height SDS was -3.6. Laboratory examinations showed reduced GH levels, and he was diagnosed as having idiopathic isolated GH deficiency and AI.     

Growth hormone releasing hormone. Review

Growth hormone-releasing hormone was isolated 1982 from human pancreatic tumours. They were found to consist of three peptides (GHRH1-44, GHRH1-40, GHRH1-37) which in vivo and in vitro were specific stimulators of pituitary growth hormone secretion. These tumor-derived GHRHs were demonstrated to be identical to human hypothalamic GHRHs. Extrahypothalamic GHRH is present in some brain regions and in the gastrointestinal tract. Circulating GHRH is detectable in human plasma, but little is known about its function. Above all binding of GHRH to a specific receptor stimulates growth hormone secretion through formation of cyclic AMP. GHRH secretion is modulated by somatostatin, the somatomedins and growth hormone itself. Following single injection of GHRH1-44 i.v. the equilibration half-time is 1.0 +/- 0.2 min and elimination half-time is 6.8 +/- 1.2 min. Maximal growth hormone response is achieved after injection of 1 microgram/kg GHRH. Using higher GHRH-doses growth hormone can be stimulated via subcutaneous or intranasal application. A single i.v. GHRH-test is not sufficient to prove a pituitary defect since growth hormone can be stimulated following repetitive injections in some cases. About 50% of patients with growth hormone deficiency have a hypothalamic defect of GHRH release. In some of these patients GHRH s.c. can promote linear growth to the same degree as growth hormone treatment.     

Growth hormone deficiency of hypothalamic origin in septo-optic dysplasia

Hypothalamic pituitary function and growth hormone releasing hormone (GHRH) loading tests in two children with septo-optic dysplasia (SOD) revealed isolated GH deficiency in one and deficiencies of growth hormone, adrenocorticotropic hormone and antidiuretic hormone in the other. Secretion of GH was elicited in the first patient by single i.v. bolus administration of GHRH and after repetitive i.v. infusions of GHRH in the second. With these results we confirmed that the hypopituitarism in our patients with SOD was of hypothalamic origin. Both patients also had infantile spasms.     

Growth hormone (GH) profiles in response to continuous subcutaneous infusion of GH-releasing hormone(1— 29)-NH2 in children with GH deficiency

Six children presenting with partial growth hormone (GH) deficiency (mean GH peak in two different tests, 8.0 k1.3 μ g/l ) aged 8–10.3 years (mean, 2.7 ± 0.9 years) were treated for 6 months by continuous subcutaneous infusion of GH-releasing hormone(1–29)-NH, (GHRH(1–29)-NH₂); 24-hour GH profiles and height velocity were measured. A biphasic effect of GHRH(1–29)-NH₂ infusion was observed. After an early substantial increase in the 24-hour integrated concentration of GH, from 1.6 ± 0.1 to 3.5 ± 0.7 μg/l/minute, a subsequent consistent decrease occurred by 3 months, which was more pronounced after 6 months (mean 24-hour integrated concentration of GH, 1.9± 0.9 μg/l/minute). This effect reflects modification of both pulse amplitude and frequency of GH secretion. At the end of the study, one child had complete suppression of GH secretion and two others showed only one peak above 5 μg/1 during a 24-hour period. No correlation was found between these changes and height velocity. Three children did not grow significantly; the other three children who had a growth response to GHRH(1–29)-NH₂ were those with the lowest 24-hour integrated GH concentration at the end of the study. The possible mechanisms involved in this biphasic effect, including GHRH antibodies, changes in somatostatin levels and/or desensitization of pituitary GHRH receptors, have been investigated.     

Multiple pituitary hormone deficiencies in eight siblings of one Jewish Moroccan family.

In a Jewish Moroccan inbred family, 8 of 12 siblings were found to have multiple deficiencies of pituitary hormones, including GH, TSH and gonadotrophins. The parents showed no deficiency and are in good health, as are the other 4 siblings. The investigations carried out indicate that in this family the etiology is hereditary in nature, probably being autosomal recessive, with the defect located in the pituitary gland.     

Circulating immunoreactive growth hormone releasing hormone concentrations and growth hormone response to growth hormone releasing hormone in short children

To study the role of peripheral immunoreactive growth hormone releasing hormone (ir-GHRH) concentrations and the GHRH test in the evaluation of growth hormone (GH) secretion in short stature, 46 children with a mean age of 9.4 years (range 1.6–16.3 years) and a mean relative height score of –3.2 SD (range –5.0–2.1 SD) were investigated. The children were divided into prepubertal (n=35) and pubertal (n=11) and the prepubertal children further into three groups based on their maximal GH responses to insulin-induced hypoglycaemia (IIH) and clonidine: (1) GH deficient subjects (maximal GH<10 g/l in both test); (2) discordant responders (maximal GH<10 g/l in one test and 10 g/l in the other); and (3) normal responders (maximal GH10 g/l in both test). Peripheral ir-GHRH concentrations were measured during the IIH test by radioimmunoassay after purification of plasma samples on Sep-pak cartridges. Among the prepubertal children 10 fell into group 1, 16 into group 2 and 9 into group 3. Children in group 1 were older, than those in group 3. There were no significant differences in relative heights and weights or absolute and relative growth velocities between the groups. Subjects in groups 1 and 2 had lower maximal GH responses to GHRH than those in group 3. There were no significant differences in the basal plasma ir-GHRH concentrations between the groups. Nine children (19.6%) had somatotrophs with a poor response to a single dose of exogenous GHRH (maximal GH<10 g/l). These subjects had increased basal plasma ir-GHRH concentrations. All of them had a decreased GH response to IIH and/or clonidine. Pubertal children had higher circulating ir-GHRH levels than the prepubertal subjects. There was an inverse correlation (r=–0.46;P<0.001) between the maximal GH response to GHRH and calendar age in the whole series. These observations suggest that: (1) a substantial proportion of short children have a heterogenous GH response to pharmacological stimuli necessitating complementary evaluation of their spontaneous GH secretion; (2) a poor response to exogenous GHRH is associated with increased ir-GHRH levels in the peripheral circulation; (3) all children with normal GH responses in pharmacological tests respond normally to GHRH and (4) the pituitary sensitivity to GHRH decreases with increasing age. Peripheral ir-GHRH concentrations do not differentiate between short children with growth hormone deficiency (GHD) and those with undefined short stature. The GHRH test is of limited value in the diagnosis of GHD, since a normal GH response does not exclude GHD, although a subnormal response appears to reflect dysfunctional GH secretion.     

Administration of arginine plus growth hormone releasing hormone to evaluate growth hormone (GH) secretory status in children with GH deficiency

BACKGROUND: Diagnosis of growth hormone deficiency (GHD) in childhood is usually based on growth hormone (GH) response to at least two provocative stimuli. The aim of this study was to determine whether sequential administration of arginine (Arg) plus GH releasing hormone (GHRH) could be a useful tool in evaluating GHD in children. METHODS: Thirty patients with short stature (mean age 9.0 years) with decreased growth rate were tested for GHD with Arg and the insulin tolerance test (ITT). Patients with confirmed GHD (peak GH <8 ng/ml) were subsequently tested with Arg + GHRH. RESULTS: Maximum GH stimulation for Arg and ITT was 6.3 (1.0-7.8) and 6.7 (0.5-7.7) ng/ml, respectively. Peak GH for the Arg + GHRH test was 36.3 (4.3-84.5) ng/ml and significantly different from the other provocative tests. Peak GH values for the three tests were not significantly correlated between tests or with clinical parameters. There were no significant differences in Arg + GHRH results between children with or without abnormal hypothalamic-pituitary MRI scans. CONCLUSION: Arg + GHRH gave higher GH levels than insulin or Arg alone. Because of the different causes of childhood GHD (hypothalamic and/or pituitary dysfunction), the Arg + GHRH test is unsuitable .for evaluating GHD and deciding whether GH replacement therapy is indicated.     

Somatostatin infusion withdrawal in the diagnosis of childhood growth hormone deficiency

OBJECTIVE: An evaluation of growth hormone (GH) testing for GH deficiency (GHD) in childhood is confounded by the lack of a world-wide consensus on the definition of GHD. Although a single GH test remains the most powerful biochemical tool in the evaluation of a child with growth failure, the test remains far from ideal. Withdrawal of somatostatin (SS) infusion is followed by a rebound rise of GH thought to be mediated by endogenous GH-releasing hormone (GHRH) function. This study was designed to compare the GH response to 90 min SS infusion in children with normal GH secretion versus children with GH deficiency. METHODS: Ten children with GHD and 10 healthy controls (NC) have been evaluated for GH response to somatostatin infusion withdrawal (SSIW) and compared with response of two provocative tests, glucagon plus propranolol test and L-Dopa test. All children received constant infusion of somatostatin for 90 min (3 microg/kg per h, Stilamin, Serono, Aubonne, Switzerland). In order to determine GH, blood samples were obtained 90 min before the SS infusion and 0, 15, 30, 45, 60, 75, and 90 min after the cessation of infusion. RESULTS: Growth hormone peak levels with SSIW were significantly lower in GH deficient children than in healthy children (2.5 +/- 1.2 ng/dL, vs 21.9 +/- 5.3 ng/dL, respectively, P < 0.01). No adverse effects were observed during or after somatostatin infusion. CONCLUSION: In the present study, SSIW elicited a significant GH rise in healthy children but not in children with GH deficiency. Although further controlled studies using more data are necessary to expand these findings, the results suggested that children with GH deficiency can be reliably discriminated from healthy children by SSIW.     

Growth hormone response to growth hormone-releasing hormone (hp GHRH1-44) as an index of growth hormone secretory dysfunction after prophylactic cranial irradiation for acute lymphoblastic leukemia (24 grays)

The growth hormone response to growth hormone releasing hormone hp GHRH1-44 (2 micrograms/kg i.v.) was studied in 19 prepubertal children who had been irradiated with 24 Gy for acute lymphoblastic leukemia (ALL) or lymphosarcoma (LS) at a mean chronological age of 4 10/12 years (limits 10/12 to 9 years). They were evaluated after a mean time interval of 4 8/12 +/- 3/12 years and compared to 14 prepubertal children with constitutional short stature (CSS). The individual responses to GHRH were decreased in all but three of the irradiated children. The mean GH response was 16.7 +/- 2.5 ng/ml as compared to 52.6 +/- 8.5 ng/ml in the control group (p less than 0.001). The GH response to GHRH was not correlated with the GH response to arginine-insulin tolerance test (AITT). A decreased response to GHRH with values between 12.5 and 19.4 ng/ml was observed in four cases with normal growth rates and normal GH responses to AITT. These results suggest that an impaired GH response to GHRH is a frequent finding after cranial irradiation for ALL or LS and may be the only sign of GH secretory dysfunction. It is probably indicative of early hypothalamic impairment of GH secretion.     

Correlation between pituitary growth hormone reserve and degree of growth failure in children with short stature

The correlation between a releasable pituitary growth hormone (GH) pool and degree of growth failure was examined in 30 children with GH deficiency (group I) and 19 children with normal short stature (group II). Based on the responsiveness of GH to GH-releasing hormone (GHRH), group I, with low GH responses (below 7 ng/ml) to both insulin and arginine, was classified into three subgroups; I_a (peak value less than 10 ng/ml, n=19), I_b (10–20 ng/ml, n=5) and I_c (above 20 ng/ml, n=6). Group II, with a GH response above 10 ng/ml to either insulin or arginine, was also divided into II_a (below 20 ng/ml, n=5) and II_b (above 20 ng/ml, n=14). Body length and growth velocity in I_a and I_b were significantly reduced vs I_c; bone age in I_a was retarded vs I_c; plasma somatomedin C (Sm-C) levels in I_a and I_b were decreased vs I_c, who had almost normal levels (0.90±0.55 U/ml). The incidence of other combined pituitary hormone deficiencies and previous perinatal distress was definitely high in I_a and I_b, but zero in I_c. In group II also, body length and growth velocity were significantly decreased in II_a vs II_b (P<0.01). These results indicate that [1] the pituitary reserve of GH estimated by GHRH is a good reflection of the degree of growth failure in GH-deficient children as well as in those of normal short stature, [2] hypothalamic GHRH deficiency tends to have a milder effect on growth retardation than pituitary GH deficiency, and [3] normal short children with a diminished GH reserve may be potential candidates for the GH treatment.Abbreviations ACTH adrenocorticotropin - LH luteinizing hormone - LH-RH luteinizing hormone-releasing hormone - GH growth hormone - GHRH growth hormone-releasing hormone - Sm-C somatomedin C - TRH thyrotropin-releasing hormone - TSH thyrotropin     

The catecholamine response to hypoglycemia in children with isolated growth hormone deficiency syndromes and multiple pituitary hormone defects

We examined the catecholamine response to insulin-induced hypoglycemia in 46 short children evaluated for growth hormone (GH) deficiency by both pharmacologic stimulation and integrated concentration of GH. Twelve patients had quantitatively normal GH secretion by both pharmacologic stimulation and integrated concentration of GH (GHNORM). Twenty-two patients had normal GH to pharmacologic stimulation but subnormal integrated concentration of GH (GHND). Twelve patients had GH deficiency by both tests (GHD): six had isolated GH deficiency (GHD type 1) and six had multiple hormone deficiencies (GHD type 2). There was no significant difference between the peak epinephrine, norepinephrine, and cortisol responses of GH-NORM, GHND, and GHD type 1 patients. The mean peak epinephrine response of GHD type 2 patients was significantly lower (564 +/- 561 pg/ml, p less than 0.03) compared to the other patient groups. There was no significant difference between the peak norepinephrine levels between GHD type 2 patients and the remaining groups. There was no correlation between decrease in blood glucose and either increase in growth hormone, catecholamine, or cortisol concentrations. There was a significant correlation between log peak epinephrine and peak cortisol response (r = 0.53, p less than 0.0002) of the 46 subjects. Neither the basal nor stimulated catecholamine levels correlated with the integrated concentration of cortisol. We conclude that isolated GH deficiency is not associated with impairment of the catecholamine response to hypoglycemia; impairment of the epinephrine response to hypoglycemia is only associated with multiple pituitary hormone deficiencies; in children, the degree of glucose lowering is not correlated with the magnitude of peak GH, catecholamine, or cortisol responses.     

Clinical value of the gonadotropic hormone releasing hormone (GHRH) test in the diagnosis of growth deficiency

Many stimulation tests are available for the assessment of growth hormone release from the pituitary in clinical practice. Three of the most common tests are insulin-hypoglycaemia, arginine stimulation and spontaneous hGH nocturnal peaks and profiles. In this study we compared the Growth hormone releasing-hormone (GHRH)-test in a dose of 1 microgram/kg b.w. with these three other tests for evaluation of the somatotropic function of the pituitary. Each of these four tests was performed in 29 children with short stature due to growth failure of various etiologies and height-deficits (-SDS) of -3.0 +/- 0.5 SE. The peak plasma hGH levels of all patients after GHRH stimulation did not correlate with the respective peak values during insulin (r = 0.02) and arginine (r = 0.28) stimulation and with peak levels during the spontaneous nocturnal hGH profile (r = 0.18). The diagnostic value of the GHRH test alone is thus still questionable in establishing the diagnosis of a hypothalamic GHRH/GH defect, because some of these patients do not react to the first GHRH dose as one might expect, but only after a few days of repeated injections of GHRH (priming). The tolerance of intravenous injections of GHRH was excellent. The mean plasma GH response to GHRH was higher (p less than 0.05) in the group of children with constitutional short stature than in GH deficient patients, but there were overlaps in this group with normal volunteers and other groups of patients with growth failure.     

Growth hormone deficiency, brain development, and intelligence.

Twenty-nine patients with growth hormone (GH) deficiency were selected according to the following criteria: no evidence of reversible GH deficiency, onset of growth retardation in early childhood, and no evidence of pituitary tumors or other direct pituitary trauma. Fourteen patients had evidence of multiple hormone deficiencies, 14 had isolated GH deficiency, and one patient questionable isolated GH deficiency. Psychometric testing showed a normal IQ distribution. The GH deficiency was not associated with deficiencies in specific mental abilities. Likewise, GH treatment in later childhood and adolescence did not seem to influence intelligence. Patients with multiple hormone deficiencies had somewhat lower IQs than patients with isolated GH deficiency when socioeconomic status was controlled. We conclude that GH deficiency itself does not seem to affect human brain development and intelligence.     

Comparison of growth hormone releasing hormone therapy and growth hormone therapy in growth hormone deficiency

Seven children with growth hormone deficiency of hypothalamic origin responded to an i.v. bolus of growth hormone releasing hormone (GHRH) (1–29)-NH2 with a mean serum increase of 10.7 ng/ml growth hormone (GH) (range 2.5–29.3 ng/ml). Continuous s.c. administration of GHRH of 4–6 g/kg twice daily for at least 6 months did not improve the growth rate in five of the patients. One patient increased his growth rate from 1.9 to 3.8 cm/year and another from 3.5 to 8.2 cm/year; however, the growth rate of the latter patient then decreased to 5.4 cm/year. When treatment was changed to recombinant human growth hormone (rhGH) in a dose of 2 U/m² daily, given s.c. at bedtime, the growth rate improved in all patients to a mean of 8.5 cm/year (range: 6.2 to 14.6). Presently GHRH cannot be recommended for the routine therapy of children with growth hormone deficiency since a single daily dose of rhGH produced catch-up growth which GHRH therapy did not.Abbreviations GH growth hormone - GHD growth hormone deficiency - GHRH growth hormone releasing hormone - hGH human growth hormone - rhGH recombinant human growth hormone - SM C/IGF I somatomedin C/insulin-like growth factor I On the occasion of the 85th birthday of Prof. Dr.Dr.h.c. mult. Adolf Butenandt     

Wilms tumour in a patient with growth hormone replacement therapy

Wilms tumour was found in a Japanese boy aged 5 years 9 months with isolated growth hormone (GH) deficiency and some congenital anomalies. He had received pituitary GH replacement therapy from the age of 2 years 1 month to 4 years 7 months and after a 1 year interval he received biosynthetic GH for 2 months until the tumour became clinically apparent. This was the sixth known patient with GH deficiency to develop a malignant neoplasm during or after GH replacement therapy and the first with a solid tumour in Japan since 1975, when treatment with pituitary GH for patients with GH deficiency was introduced.