Dosing of growth hormone in growth hormone deficiency

Growth hormone (GH) treatment of GH-deficient (GHD) children is to a certain extent standardized worldwide. Recombinant 22 kDa GH is injected once daily by the subcutaneous route, mostly in the evening. The amount of GH injected (calculated per kg body weight or body surface area, expressed in terms of IU or mg) in prepubertal children mimics the known production rate (approximately 0.02 mg [0. 06 IU]/kg body weight per day). However, there is a wide variation in dosage, the reasons for which are partly unknown and partly due to national traditions and regimes imposed by authorities regulating reimbursement. The situation during puberty is less standardized, with most clinicians still not increasing the dosage according to known production rates. The results of these approaches in terms of adult height outcome are not always satisfactory. In order to achieve optimal height development during childhood, puberty and adulthood, strategies must be developed to individualize GH dosing according to set therapeutical goals taking into account efficacy, safety and cost. The implementation of prediction algorithms will help us to reach these goals. In addition, other response variables will have to be monitored during treatment in order to correct for deficits resulting from GHD.     

Pharmacokinetics of growth hormone secretion in humans induced by growth hormone releasing hormone

This investigation compares the age- and sex-related changes in growth hormone (GH) response to growth hormone releasing hormone (GHRH) in normal subjects using an appropriate pharmacokinetic model. Twenty-five subjects (14 males and 11 females) aged 23-89 yr received a single intravenous bolus dose (1 microgram/kg) of GHRH-40 solution. Plasma GH concentration-time profiles are best characterized by a biexponential equation (or one-compartment model) with first-order release and disappearance rates and an equilibration lag time. The harmonic mean release rate half-life is similar for both sexes (males: 12.6 min vs. females; 11.4 min) but significantly different across age groups (23-35 yr: 7.2 min vs. 50-89 yr: 16.8 min). The mean disappearance rate half-life and GHRH-equilibration time lag for females (33.6 and 20.4 min, respectively) and the higher age group subjects (32.4 and 21.6 min, respectively) are significantly longer than those of males (22.8 and 9 min, respectively) and the lower age-group subjects (21.6 and 8.4 min, respectively). The mean metabolic clearance rate of GH is significantly lower (p less than 0.02) for females than for males (3.1 vs. 4.83 ml/hr.m2). However, the production rate and the amount of GH released by the pituitary for our subjects appear to be very similar for both males (8.7 micrograms/hr.m2 and 4.65 micrograms/m2) and females (9.33 micrograms/hr.m2 and 5.11 micrograms/m2).     

Cognitive function in growth hormone deficiency and growth hormone replacement

There is converging evidence from neuropsychological studies that growth hormone (GH) is associated with cognitive function. The aim of the current study was to review the existing neuropsychological literature for studies in which cognitive assessment had been conducted in patients with GH deficiency (GHD), and where change in cognitive function had been assessed following treatment with GH. Studies that have investigated relationships between GH and cognitive function and those that have developed methodological and statistical approaches that could be useful in future GH studies were identified. In this review, GH levels were found to be associated with cognitive function. Untreated individuals with GHD showed reliable impairment in memory and attentional functions when compared with matched controls. Appropriately designed prospective studies also indicated that cognitive function improved with GH treatment. It was concluded that individuals with GHD do show cognitive impairment and that this is ameliorated to some extent by GH treatment. It is now important to establish the clinical importance of these findings, and further work is required to understand better the nature, magnitude and meaning of GH-related cognitive impairments and improvements.     

Insulin--a growth hormone

Insulin is a peptide hormone with a high degree of homology with the insulin-like growth factor I (IGF-I). Its biological actions are interlaced with those of GH and IGF-I. The objective of this study is to review the growth promoting actions of insulin. The experimental evidence consists of the use of organ cultures of neonatal mice condilar cartilage insulin which stimulates the cartilage cell differentiation and maturation. Injection of insulin to hypohysectomized rats stimulated tibial growth. Clinical evidence is manifold. Babies with diabetes and hypoinsulinemia are short, whereas babies with hyperinsulinism are big. Children with idiopathic short stature have low insulin whereas obese children with hyperinsulinism are tall. Hypo-insulinized children with diabetes slow their growth until the insulin dose is optimized. It remains to be clarified whether insulin exerts its growth promoting actions via its own receptors, via the IGF-I receptors, or via a hybrid (insulin--IGF-I) receptor.     

Factors influencing the growth hormone response to growth hormone-releasing hormone in children with idiopathic growth hormone deficiency

OBJECTIVE: To evaluate the factors influencing the growth hormone (GH) response to GH-releasing hormone (GHRH) test in idiopathic GH deficiency. METHODS: 28 patients aged 4.9 +/- 0.7 years with certain GH deficiency were given GHRH (2 microg/kg). RESULTS: The GH peak after GHRH was correlated negatively with age at evaluation (r = -0.37, p < 0.05) and body mass index (r = -0.44, p = 0.02), and positively with anterior pituitary height (r = 0.47, p = 0.02), GH peak after non-GHRH stimulation (r = 0.78, p < 0.0001) and spontaneous GH peak (r = 0.82, p = 0.007). It was lower in the patients aged >5 years than in the youngest (p = 0.04), but it was similar in the patients with and without features suggesting a hypothalamic origin. CONCLUSION: The GH response to GHRH test cannot be used to differentiate between hypothalamic and pituitary forms of idiopathic GH deficiency, probably because the GH response decreases after the first 5 years of life, whatever the origin of the deficiency.     

The influence of age on human pancreatic growth hormone releasing hormone stimulated growth hormone secretion

63 non-obese healthy subjects aged 18 to 95 years were investigated for age-dependence of GHRH-stimulated GH-secretion. In addition, priming of GH-secretion with three oral doses of propranolol (3 x 80 mg, the last dose 2 hours prior to the second GHRH-bolus) was carried out in 15 subjects below 40 years and 13 subjects older than 70 years. We found that mean maximal incremental GH-levels were inversely correlated with chronological age (r = -0.44, P = 0.001) of the probands. Propranolol premedication caused a significant rise of both basal and peak GHRH-induced relative increases in all subjects tested, whereas GHRH-induced relative increases of GH remained unchanged. In a well selected group of non-obese healthy subjects stimulated GH-secretion is found to undergo an aging process that is supposed to be of pituitary and suprapituitary origin. Priming GH-secretion with a beta-Blocker is possible both in young and very old healthy subjects and is likely to affect the basal GH secretory tone and not GHRH-stimulated GH-secretion.     

Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance

Growth hormone (GH) secretion is regulated by GH-releasing hormone (GHRH), somatostatin, and possibly ghrelin, but uncertainty remains about the relative contributions of these hypophysiotropic factors to GH pulsatility. Patients with genetic GHRH receptor (GHRH-R) deficiency present an opportunity to examine GH secretory dynamics in the selective absence of GHRH input. We studied circadian GH profiles in four young men homozygous for a null mutation in the GHRH-R gene by use of an ultrasensitive GH assay. Residual GH secretion was pulsatile, with normal pulse frequency, but severely reduced amplitude (<1% normal) and greater than normal process disorder (as assessed by approximate entropy). Nocturnal GH secretion, both basal and pulsatile, was enhanced compared with daytime. We conclude that rhythmic GH secretion persists in an amplitude-miniaturized version in the absence of a GHRH-R signal. The nocturnal enhancement of GH secretion is likely mediated by decreased somatostatin tone. Pulsatility of residual GH secretion may be caused by oscillations in somatostatin and/or ghrelin; it may also reflect intrinsic oscillations in somatotropes.     

Chronic growth hormone administration does not suppress endogenous growth hormone secretion in patients with neurosecretory growth hormone dysfunction.

Short children who respond normally to growth hormone (GH) stimulation, but have a subnormal spontaneous secretion of GH (neurosecretory GH dysfunction, NSD) are treated with exogenous GH which might suppress their endogenous GH secretion. The effect of chronic administration of GH (8-24 months) on plasma GH responses to GHRH, clonidine and spontaneous GH secretion were studied in 17 NSD patients. The diagnosis of NSD was based on a normal GH response to clonidine (greater than 10 micrograms/l) and an integrated concentration of (IC-GH) GH less than 3.2 micrograms/l. The GH dose used in this study was 0.25 IU/kg three times a week in 10 patients and 0.05 IU/kg daily in 7 patients. Insulin-like growth factor I levels (nmol) increased significantly on therapy from 9.3 +/- 3.8 to 24.4 +/- 22.4 (p less than 0.001). The GH response (microgram/l) to GHRH was 20.4 +/- 5.5 before treatment and 22.4 +/- 6.2 on GH. Peak GH after clonidine was 22.4 +/- 8.9 and 22.8 +/- 8.1, respectively. There was no significant decrease in the number of GH spontaneous peaks (1.8 +/- 0.7 vs. 2.0 +/- 0.7, respectively) or in the area under the curve. A subcutaneous GH bolus of 0.25 IU/kg in 4 patients resulted in a GH peak of 55-82 micrograms/l at 3-5 h and a gradual return to basal levels at 15-20 h after GH administration. The first spontaneous GH peak appeared 26-28 h after GH injection, peak amplitude was 10-15 micrograms/l.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased growth hormone responses to growth hormone releasing hormone and thyrotropin releasing hormone in patients with metastatic testicular cancer

In 16 patients with metastatic testicular cancer and 10 age matched male control subjects growth hormone (GH) responses to growth hormone releasing hormone (GHRH; 1 microgram/kg body weight iv.) and thyrotropin releasing hormone (TRH; 200 micrograms iv.) were measured. Basal GH levels and GH levels following stimulation with GHRH or TRH were significantly increased in cancer patients compared to control subjects. 9 patients with testicular cancer were studied both in the stage of metastatic disease and after they had reached a complete remission. In complete remission GH responses to GHRH tended to decrease but the differences did not reach statistical significance. Our data suggest an alteration of hypothalamic and/or pituitary regulation of GH secretion in patients with metastatic testicular cancer.     

Interpretative difficulties with growth hormone provocative retesting in childhood-onset growth hormone deficiency

A review of literature demonstrates that there are many ill-understood factors that determine the results of GH provocative (re)testing, so that these results should be interpreted with extreme caution when used for diagnosis or confirmation of diagnosis of GHD. GH provocation tests are probably of no value at all for what has been called 'partial GHD'. The phenomenon of 'normalization' of test results after long-term treatment with GH needs no 'transient GHD' hypothesis as it can be largely explained by the very low reproducibility of the tests and by a regression to the mean effect. Moreover, it is possible that 'normal values' increase with age. Other determinants of normal peak values may also change from childhood to adulthood and contribute to 'normalization'.     

Radiation-induced growth hormone deficiency

Deficiency of one or more anterior pituitary hormones may follow treatment with external irradiation when the hypothalamic-pituitary axis falls within the fields of irradiation. Hypopituitarism occurs in patients who receive radiation therapy for pituitary tumours, nasopharyngeal cancer and primary brain tumours, as well as in children who undergo prophylactic cranial irradiation for acute lymphoblastic leukaemia, or total body irradiation for a variety of tumours and other diseases. The degree of pituitary hormonal deficit is related to the radiation dose received by the hypothalamic-pituitary axis. Thus, after lower radiation doses isolated growth hormone deficiency ensues, whilst higher doses may produce hypopituitarism. The timing of onset of the radiation-induced pituitary hormone deficit is also dose-dependent. The main site of radiation damage is the hypothalamus rather than the pituitary, although the latter may be affected directly.     

Autocrine growth hormone: effects on growth hormone receptor trafficking and signaling

GH and GH receptor are expressed in many extrapituitary tissues, permitting autocrine/paracrine activity. Autocrine GH has regulatory functions in embryonic development and cellular differentiation and proliferation and is reported to be involved in the development and metastasis of tumor cells. To understand the principles of transport and signaling of autocrine GH and GH receptor, we used a model system to express both proteins in the same cell. Our experiments show that GH binds the GH receptor immediately after synthesis in the endoplasmic reticulum and facilitates maturation of GH receptor. The hormone-receptor complexes arrive at the cell surface where exogenously added GH is unable to bind these receptors. Autocrine GH activates the GH receptors, but signal transduction occurs only after exiting the endoplasmic reticulum. This model study explains why autocrine GH-producing cells may be insensitive for GH (antagonist) treatment and clarifies autocrine signaling events.     

Enhanced growth hormone responses to growth hormone releasing hormone in male type I diabetic patients.

In a previous paper we have demonstrated that growth hormone (GH) responses to growth hormone releasing hormone (GHRH) are higher in premenopausal normal women than in age matched healthy men. As in type I diabetes mellitus various disturbances of GH secretion have been reported, the aim of our study was to assess the effect of sex on basal and GHRH stimulated GH secretion in type I diabetes mellitus. In 21 female and 23 male type I diabetic patients and 28 female and 30 male control subjects GH levels were measured before and after stimulation with GHRH (1 microgram/kg body weight i.v.) by radioimmunoassay. GH responses to GHRH were significantly higher in female than in male control subjects (p less than 0.02), whereas the GH levels following GHRH stimulation were similar in female and male type I diabetic patients. GH responses to GHRH were significantly higher in the male type I diabetic patients than in the male control subjects (p less than 0.001); in the female type I diabetic patients and the female control subjects, however, GH responses to GHRH were not statistically different. The absence of an effect of sex on GHRH stimulated GH responses in type I diabetes mellitus provides further evidence of an abnormal GH secretion in this disorder.     

New growth hormone secretagogues

Starting from EP 51389, a potent growth hormone secretagogue(GHS), a new series of GHS has been designed, synthesized andtested. This series was built on a gem-diamino moiety and astructure activity relationship study was performed includingN-methylation of the amide bonds. Some analogues exhibited morepowerful activity than Hexarelin, they were active peros on dog and have been selected as candidates for furtherdevelopment.     

Thyroid hormone and growth: relationships with growth hormone effects and regulation

For some years, research in the field of growth endocrinology has been mainly focused on growth hormone (GH). However, it appears that GH does not always control growth rate. For instance, it does not clearly influence intra-uterine growth: moreover, although the results of GRF or GH administration appear convincing in rats, pigs or heifers, this is not the case in chickens and lambs. In addition, GH does not always clearly stimulate somatomedin production, particularly diring food restriction and fetal life, and in hypothyroid animals or sex-linked dwarf chickens. In such situations, this phenomenon is associated with a reduced T3 production, suggesting a significant influence of thyroid function on GH action, and more generally, on body growth. In fact, numerous data demonstrate that thyroid hormone is strongly involved in the regulation of body growth. In species with low maturity at birth, such as the rat. T4 and T3 affect postnatal growth eleven days earlier than the appearance of GH influence. In contrast to GH, thyroid hormone significantly influences fetal growth in sheep. Moreover, the body growth rate is clearly stimulated by T3 in dwarf animals. In addition to its complex metabolic effects involved in the general mechanisms of body growth, thyroid hormone stimulates the production of growth factors, particularly EGF and NGF. Moreover, it affects GH and somatomedin production and also their tissue activity. All these results strongly suggest that it would be difficult to study GH regulation and physiological effects without taking thyroid function into account.