Plasma growth hormone (GH) response to GH-releasing factor (SM-8144) in children of short stature and patients with GH deficiency

Synthetic human GRF (hGRF (1-44) NH2; SM-8144) was administered as an iv bolus to 141 normal children of short stature (NSC), 73 patients with severe idiopathic GH deficiency (IGD; group A), 30 patients with mild idiopathic GH deficiency (IGD; group B), 29 patients with secondary GH deficiency, 3 patients with primary hypothyroidism, 21 patients with Turner's syndrome and 25 patients with various other disease. Their height was below normal for their age and sex, and they were all below 25 years old without obesity. The maximal GH responses (M+SEM) were 39.5 +/- 2.2, 7.2 +/- 0.9, 27.2 +/- 3.7, 5.2 +/- 0.8, 9.7 +/- 4.4, 25.1 +/- 2.8 and 32.3 +/- 4.8 ng/ml, respectively (significance from the NSC, ; p less than 0.05, ; p less than 0.001). The GH responses to hGRF were greater than those elicited by standard pharmacological tests. There was a negative correlation between bone age and peak plasma GH response to hGRF in patients with idiopathic GH deficiency (IGD) but not in normal children (NSC). In twenty-two percent of the patients with IGD in group A the response was above 10 ng/ml and in 57% of the patients with IGD in group B the response was above 20 ng/ml, suggesting that a large percentage of patients with idiopathic GH deficiency lack hypothalamic GRF. The side effect of flushing was observed in 15.2% of all subjects. These results indicate the potential usefulness of hGRF (1-44) NH2 (SM-8144) in inducing GH release from the pituitary.     

Spontaneous growth hormone secretion and plasma somatomedin-C in children of short stature

We studied 17 short prepubertal children, aged 7.5 to 17.0 years (mean +/- SD: 11.7 +/- 2.4) more than 2.0 SD below the mean height for their age and of delayed bone age (M +/- SD: 8.1 +/- 2.3), to clarify their physiological GH secretory status. The mean concentration of GH (MCGH) was calculated and was compared with the subjects' GH responses to insulin and arginine tolerance tests (IATT) and plasma somatomedin-C (SM-C). The mean 24-h MCGH value was 3.2 +/- 1.3 ng/ml (range 1.6-5.5). The mean peak GH response to the IATT was 13.0 +/- 7.5 ng/ml (range 2.4-33.9). In addition to the two patients with abnormally low GH responses to the IATT, seven with normal responses showed low 24-h MCGH values, a small number of GH pulses and low mean GH amplitude. The mean plasma SM-C in all patients was 0.60 +/- 0.20 U/ml. This was significantly lower than that of age-matched children of normal height (p less than 0.001). The 24-h MCGH was significantly correlated with plasma SM-C levels (r = 0.51, p less than 0.05) and with that of the first three hours of sleep at night (r = 0.84, p less than 0.01). These results indicate that: 1) some short children with normal GH response to pharmacological tests secrete a low amount of GH physiologically and 2) blood sampling during the first three hours of sleep as well as 24-hour sampling is suitable in evaluating the physiological secretion of GH.     

Spontaneous prolactin secretion in growth hormone-deficient children.

OBJECTIVE: To establish the spontaneous nocturnal prolactin (PRL) release in relation to growth hormone (GH)-deficient children and idiopathic short-stature children (ISS). METHODS: A total of 32 prepubertal children (11 girls, 21 boys) aged between 3 and 12 years were studied retrospectively and sorted according to diagnosis: idiopathic GH deficiency (GHD, n = 9), neurosecretory deficiency of GH secretion (NSD, n = 10) and ISS (n = 13). Nocturnal spontaneous hormone secretion was studied by intermittent venous sampling. Secretion profiles and copulsatility were analyzed using Pulsar and AnCoPuls software. RESULTS: (median, range in mug/l): Children with GHD and NSD had significantly lower GH and area-under-the-curve (AUC) levels than normal children (p < 0.001), whereas ISS children showed normal values. In contrast, prolactin levels were significantly higher (p < 0. 05) in children with GHD and NSD (11.1, 4.9 - 13.0 and 10.3, 8. 8 - 19. 6, respectively) compared to the ISS children (8.0, 4.9 - 13.0). In addition, prolactin AUC and peak height were higher (p < 0.05) in GH-deficient patients, whereas all other secretion parameters were the same. Correlation and copulsatility analysis revealed no evidence for a direct relation between PRL and GH secretion. CONCLUSIONS: PRL secretion is significantly higher in children with GHD and NSD compared to ISS children but PRL and GH show no copulsatile secretion pattern.     

Change in the growth hormone (GH) response to GH-releasing factor (GRF) caused by exogenous GH in short children

To determine whether exogenous GH induces feedback of GH release in children, growth hormone-releasing factor (GRP) tests were performed before and after 10-day GH administration. Sixteen non-obese short boys, aged 5-14 yr, with normal GH response to pharmacological tests were studied. Mean basal and peak serum GH levels in GRF tests before and after exogenous GH were not significantly different. The subjects were divided into two groups, A and B, according to the percent change in integrated areas under the GH curves in GRF tests (GH AUC) before and after 10-day GH administration. Group A consisted of 6 boys with decreased GH AUC and group B consisted of 10 boys with increased GH AUC. Mean peak GH in GRF tests and mean GH AUC were significantly higher before exogenous GH in group A than in group B. The boys in group A were all prepubertal, while 4 boys in group B had begun their early pubertal change. The mean age in group A (7.8 +/- 1.8 yr) was significantly lower than that of group B (11.9 +/- 2.4 yr). GH AUC before exogenous GH showed a significant correlation with the percent change in AUC (= -0.742, p less than 0.01). These data demonstrated that the exogenous GH suppressed the GH response to GRF in prepubertal children with good response to GRF before exogenous GH, while it exaggerated the GH response to GRF in older children with relatively poor response before GH.     

Plasma growth hormone response to synthetic GH-RH1-44 in 52 children and adults with growth hormone deficiency of various etiologies

52 patients (42 children and 10 adults) with growth hormone deficiency (GHD), grouped into four diagnostic categories, and 6 children with constitutional short stature who served as controls were tested for plasma GH response to synthetic GH-RH1-44 given in an intravenous bolus. The response was classified into three degrees according to the magnitude of the maximal rise: Good, greater than 9 ng/ml; Partial, 3.1-9.0 ng/ml; None, less than or equal to 3 ng/ml. Among the GHD patients the highest response was observed in patients with partial growth hormone deficiency (PGHD), and 60% of the children with isolated GH deficiency (IGHD) showed an increase in plasma GH levels. Nevertheless, the response of the GHD patients was lower than that in the control group. In the children and adolescents with PGHD and IGHD the response was not age related. Among those with multiple pituitary hormone deficiencies-idiopathic (MPHD-ID) there was no response in the adolescents although a hypothalamic disorder had been documented by other tests. Among those with MPHD-organic (MPHD-ORG) the GH-RH stimulated GH secretion in the patients with glioma, who had received only irradiation treatment, and in the youngest of the patients with craniopharyngioma. Of the 10 young adults tested none showed a good response. It is concluded that GH-RH is useful in differentiating between GH deficiency of hypothalamic origin and that of pituitary origin, and in selecting those patients who might benefit from long-term treatment with GH-RH in the future.     

Partial growth hormone deficiency (GHD) in children has more similarities to idiopathic short stature than to severe GHD

INTRODUCTION: Assessment of growth hormone (GH) secretion is based on stimulation tests. Low GH peaks in stimulation tests, together with decreased insulin-like growth factor-I (IGF-I) secretion, confirm a diagnosis of GH deficiency (GHD). However, limitations in interpreting the test results and discrepancies between GH and IGF-I secretion in particular patients have both been reported. GH therapy should improve the prognosis of adult height (PAH). The aim of the study was to compare the deficit of height at diagnosis, IGF-I secretion and PAH in children with either decreased (in varying degrees of severity) or normal GH secretion in stimulation tests. MATERIAL AND METHODS: The analysis comprised 540 short children (373 boys, 167 girls), aged 11.7 +/- 3.2 years. In all the patients two GH stimulation tests were performed, IGF-I serum concentration was measured, bone age was assessed and PAH was calculated. According to the GH peak in the two stimulation tests, the patients were classified into the following groups: severe GHD (sGHD)--GH peak < 5 ng/mL (n = 44), partial GHD (pGHD)--GH peak 5-10 ng/mL (n = 190), idiopathic short stature (ISS)--GH peak at least 10 ng/mL (n = 306). RESULTS: A significantly greater deficit of height, lower IGF-I secretion and worse PAH were observed in sGHD than in both remaining groups, while all the differences between pGHD and ISS in the parameters analysed were insignificant. CONCLUSION: The results obtained indicate the necessity of applying another methods of qualifying short children for GH therapy other than GH stimulation tests with a cut-off value at a level of 10 ng/mL.     

Subcutaneous treatment with growth hormone-releasing hormone for short stature

In the present study we report the effects of therapy with growth hormone-releasing factor (1-29)NH2 (GRF) on growth rate, plasma levels of insulin growth factor I (IGF-I) and growth hormone (GH) secretion in 11 children who were selected solely on the basis of their short stature and normal GH secretion on standard provocative tests. All children received GRF for 6 months (5 micrograms/kg body weight subcutaneously) each evening. The 24-hour GH secretory profile was studied before and after 6 months of treatment. Simultaneously, GH secretory responses to single intravenous bolus GRF (1.5 micrograms/kg body weight) were also studied before, during, and 6 months off therapy with GRF(1-29)NH2. Plasma levels of IGF-I were measured before, during (1, 2 and 6 months), and after 6 months off therapy with GRF. Statural growth was measured at 3-month intervals. The peak plasma GH level in response to GRF was 56.04 +/- (SD) 24.46 ng/ml before treatment, and similar results were found after therapy. The 24-hour GH secretory profile did not show differences before, during, and after treatment. Comparably, no differences were found in GH pulse frequency, pulse amplitude, pulse height, pulse increment, pulse area and total area before, and 6 months off therapy with GRF. The increments in serum IGF-I achieved were not significantly different at all intervals studied. All patients increased growth velocities (mean +/- SD, cm/year) in response to GRF therapy. Our results demonstrate that GRF administration was effective in accelerating growth velocity in 11 children without GH deficiency.     

Oro-maxillofacial development in patients with GH deficiency and in normal short children

Detailed oro-maxillofacial studies using dental cast, pantomogram and cephalogram were performed in 43 patients with GH deficiency aged 7-17 years and compared statistically to the results from 62 short children with normal GH secretion. The dental age was retarded as compared to the chronological age in patients with GH deficiency by a mean of 2.0 +/- 1.3 years. This value did not differ statistically from that observed in normal short children (1.7 +/- 0.8 years). However the bone age was significantly retarded in patients with GH deficiency (3.2 +/- 1.7 yrs vs 1.5 +/- 1.1 yrs, p less than 0.001). There was no difference between tooth size or cephalogram analysis results in the children in the two groups. The coronal arch length, basal arch width and basal arch length were shorter in patients with GH deficiency. These data indicate underdevelopment of the maxilla in patients with GH deficiency.     

Usefulness and limitation of measurement of insulin-like growth factor binding protein-3 (IGFBP-3) for diagnosis of growth hormone deficiency.

To analyze the utility of insulin-like growth factor binding protein-3 (IGFBP-3) radioimmunoassay for diagnosis of growth hormone deficiency (GHD) we measured IGFBP-3 in sera from normal children, short children and patients with GHD. The sensitivity (true positive ratio) of IGFBP-3 for complete GHD (cGHD) was 93%, while the specificity (true negative ratio) for normal short children (NS) was 88%. In contrast, the sensitivity of IGFBP-3 for partial GHD (pGHD) was only 43%. The poor discrimination between patients with pGHD and NS may be the result of their relatively similar GH level, as compared to cGHD, or due to the limitations of GH stimulation tests. The specificity of IGFBP-3 for NS was excellent in children of all ages: less than 10 years old (87%) and older than 10 (88%). However, sensitivity for GHD was good for children less than 10 years old (84%) but poor for children older than 10 (64%). IGFBP-3 may be less sensitive for diagnosing GHD in older children because IGFBP-3 levels may also increase during puberty due to mechanisms independent of the GH-IGF-I axis.     

Bone age progression during the first year of growth hormone therapy in pre-pubertal children with idiopathic growth hormone deficiency, Turner syndrome or idiopathic short stature, and in short children born small for gestational age: analysis of data from KIGS (Pfizer International Growth Database)

BACKGROUND/AIMS: The beneficial effects of growth hormone (GH) therapy on statural growth in children are well established, but the effects on skeletal maturation are less clear. The progression of bone age (BA) was therefore studied during the first year of GH treatment in pre-pubertal children with idiopathic GH deficiency (GHD), Turner syndrome (TS) or idiopathic short stature (ISS), and in short pre-pubertal children born small for gestational age (SGA). METHODS: Cross-sectional data on 2,209 short children with idiopathic GHD, 694 with TS, 569 with ISS and 153 with SGA were analysed. Longitudinal data were also analysed from 308 children with idiopathic GHD, 99 with TS, 57 with ISS and 29 with SGA. All patients included in the study were enrolled in KIGS (Pfizer International Growth Database) and were being treated with recombinant human GH (Genotropin). BA was assessed using the Greulich and Pyle method at baseline and after 1 year of GH therapy. RESULTS: In all groups of patients the mean progression of BA was 1 year during the year of GH therapy, although there was considerable individual variation. Progression of BA was not correlated with chronological age, BA, height SD score (SDS) or body mass index SDS at the onset of GH therapy. There was also no consistent effect of the GH dose on BA progression. CONCLUSION: Progression of BA appears to be normal in patients receiving GH in these diagnostic groups, at least over the first year of treatment in pre-puberty.     

Response to long-term growth hormone therapy in short children with reduced GH bioactivity

BACKGROUND/AIMS: The aim of the present study was to investigate whether short children with normal growth hormone (GH) immunoreactivity, but reduced bioactivity (bioinactive GH) could benefit from rhGH treatment as GH deficient (GHD) patients. Methods: We evaluated 12 pre-pubertal children (8 M, 4 F), with GH deficiency-like phenotype showing normal serum GH peak levels (>10 ng/ml), measured by immunofluorimetric assay (IFMA-GH), in contrast with a reduced GH bioactivity (bio-GH), evaluated using the Nb(2) cells. We also evaluated 15 age-matched GHD pre-pubertal children (11 M, 4 F) with serum GH peak <5 ng/ml. Both groups were treated with rhGH therapy at the dose of 0.23 mg/kg/week s.c. RESULTS: Serum bio-GH/IFMA-GH ratio at peak time for each patient during the provocative test was significantly lower in bioinactive GH than in GHD children (0.29 vs. 2.05, p = 0.00001). Recombinant human GH therapy induced a significant (p < 0.001) increase in growth rate in both groups during the first 2 years. In the third year of treatment, while growth rate in GHD children is maintained, in bioinactive GH patients it decreases remaining, however higher compared to the pre-treatment one. CONCLUSIONS: Short rhGH therapy given to selected bioinactive GH children improve growth rate and might result in greater final adult height.     

Impact of growth hormone status on body composition and the skeleton

Severe growth hormone (GH) deficiency (GHD) induces a well-defined clinical entity encompassing, amongst the most reported features, abnormalities of body composition, in particular increased fat mass, especially truncal, and reduced lean body mass. The results from virtually all treatment studies are in agreement that GH replacement improves the body composition profile of GHD patients by increasing lean body mass and reducing fat mass. More recently, the observations have been extended to adults with partial GHD, defined by a peak GH response to insulin-induced hypoglycaemia of 3-7 microg/l. These patients exhibit abnormalities of body composition similar in nature to those described in adults with severe GHD; these include an increase in total fat mass of around 3.5 kg and a reduction of lean body mass of around 5.5 kg. The increase in fat mass is predominantly distributed within the trunk. The degree of abnormality of body composition is intermediate between that of healthy subjects and that of adults with GHD. The impact of GH replacement on body composition in adults with GH insufficiency, although predictable, has not been formally documented. The skeleton is another biological endpoint affected by GH status: in adults with severe GHD, low bone mass has been reported using dual energy x-ray absorptiometry (DEXA) and other quantitative methodologies. The importance of low bone mass, in any clinical setting, is as a surrogate marker for the future risk of fracture. Several retrospective studies have documented an increased prevalence of fractures in untreated GHD adults. Hypopituitary adults with severe GHD have reduced markers of bone turnover which normalize with GH replacement, indicating that GH, directly or via induction of insulin-like growth factor-I, is intimately involved in skeletal modelling. Whilst the evidence that GH plays an important role in the acquisition of bone mass during adolescence and early adult life is impressive, the impact of GHD acquired later in adulthood is less clear. Recently we examined the relationship between bone mineral density (BMD) and age in 125 untreated adults with severe GHD using DEXA. A significant positive correlation was observed between BMD (z-scores) and age at all skeletal sites studied. Overall, few patients, except those aged less than 30 years, had significantly reduced bone mass (i.e. a BMD z-score of less than -2); correction of BMD to provide a pseudo-volumetric measure of BMD suggested that reduced stature of the younger patients may explain, at least in part, this higher frequency of subnormal BMD z-scores. Despite normal BMD, however, an increase in fracture prevalence may still be observed in elderly GHD adults as a consequence of increased falls related to muscle weakness and visual field defects.     

Total pubertal growth and markers of puberty onset in adolescents with GHD: comparison between mathematical growth analysis and pubertal staging methods

Two methods of determining puberty onset (Preece- Baines model 1 (PB1) and Tanner staging) were used to calculate total pubertal growth (TPG) in adolescents with growth hormone deficiency (GHD). PATIENTS AND METHODS: 34 patients (11 girls) met the following inclusion criteria: isolated GHD, >2 years growth hormone therapy prior to puberty onset, regular weight-adjusted GH dosage, known final height (age >21 years or height velocity <0.5 cm/year), no induction of puberty. PB1 was used to define age and height at onset of the pubertal growth spurt ("take-off"). RESULTS: The results (mean +/- SD) were as follows: in girls, mean age at take-off was 9.8 years; 2.0 +/- 1.1 years before breast stage B2. In boys, mean age at take-off was 11.3 years; 1.4 +/- 0.8 years before testes volume >3 ml. Height at take-off was lower than at Tanner stage 2 by 12.4 +/- 7.6 cm in girls and 7.7 +/- 5.3 cm in boys. TPG was thus markedly greater (p < 0.001) using the PB1 method, as compared with Tanner stage2. Peak height velocity was normal. Final height was -0.5 +/- 0.7 SDS in females and -0.4 +/- 0.9 SDS in males. CONCLUSIONS: The method of measuring TPG from take-off is more objective, and has potentially greater implications for GH therapeutics than the Tanner stage method. In our study, 40% of TPG occurred before "breast stage B2" was attained in GHD girls; whereas 23% of TPG occurred before "testes >3 ml" in GHD boys.     

Long-term evolution of endocrine disorders and effect of GH therapy in 35 patients with pituitary stalk interruption syndrome

We report long-term evolution of endocrine functions and the results of GH treatment in 35 patients (26 male and 9 female) with pituitary stalk interruption. At diagnosis, mean chronological age was 4.8 +/- 2.7 years, mean SDS for height -3.1 +/- 0.8 with a bone age retardation of 2.3 +/- 1.3 years and a mean SDS for growth velocity of -0.5 +/- 1.1; 80% presented complete GH deficiency (GHD) and 20% partial GHD; thyroid deficiency was present in 47.1% of children with complete GHD but absent in all partial GHD. Diagnosis was made during the first months of life in only 2 patients while 23% presented with severe neonatal distress; neonatal signs were only observed in the group with pituitary height below 2 mm (45.7% of patients). GHD was isolated in 40.6% of patients below 10 years while multiple hormone deficiencies was consistent at completion of growth in all patients. Height gain was significantly higher in patients who started GH treatment before 4 years (p = 0.002). GH treatment is very effective: in 13 patients, final height was -0.4 +/- 1.0, total height gain 3.2 +/- 1.2 and distance to target height -0.3 +/- 1.6 SDS.     

Evaluation of cutaneous modifications in seventy-seven growth hormone-deficient children

Cutaneous parameters such as dermal thickness, stiffness, elasticity, skin surface lipid and hydration were evaluated using noninvasive methods in 77 growth hormone-deficient (GHD) children before replacement therapy and in 70 non-GHD children. We showed that in GHD children, dermis was thinner (0.70 +/- 0.10 vs. 0.80 +/- 0.10 mm, p < 0.0001 for prepubertal children and 0.81 +/- 0.10 vs. 0.94 +/- 0.11 mm, p < 0.0001 for pubertal children), stiffer (178.5 +/- 57.3 vs. 113.09 +/- 37 kPa, p < 0.0001 for prepubertal children and 172.5 +/- 61.7 vs. 117.3 +/- 42.5 kPa for pubertal children, p < 0.001) and less elastic (0.44 +/- 0.09 vs. 0.39 +/- 0.06 (nonelasticity index), p < 0.01 for prepubertal children and 0.39 +/- 0.05 vs. 0.33 +/- 0.04, p < 0.001 for pubertal children) compared to controls. Fourteen GHD children were re-evaluated after 1 year of GH treatment: dermal thickness and skin stiffness were significantly improved (p < 0.001 and p < 0.05 respectively) while elasticity was not modified. During the same period, 11 controls did not show any significant cutaneous modification. IGF-1 values, but not IGFBP-3 values, correlated positively with dermal thickness in GHD children, before and after 1 year of GH treatment. To conclude, GHD children exhibited specific cutaneous modifications. In a subset of GHD children, we showed that these modifications were influenced by GH treatment. More extensive studies are needed to see if these changes correlated with other GH effects.     

Spontaneous growth hormone secretion in healthy prepubertal children of normal stature.

To evaluate the dynamics of growth hormone (GH) secretion in healthy prepubertal children of normal stature, we determined spontaneous GH secretion by measuring GH every 30 min in 21 Japanese subjects, age: 5.4 +/- 2.3 (1.6-10.6) years; height: -1.4 +/- 1.1 (-1.98-1.77) SD. The 24-h mean GH concentration was 4.8 +/- 1.5 ng/ml. The 24-h mean GH was similar in boys and girls (mean +/- SD: 4.8 +/- 1.7 vs 4.7 +/- 1.1 ng/ml). No correlation was found between chronological age and the 24-h mean GH. The 24-h mean GH was closely correlated with GH pulse amplitude (r = 0.94; P less than 0.001), but not with the number of GH pulses. The 24-h mean GH was also highly correlated with 3-h mean GH after sleep and 3-h peak GH after sleep (r = 0.86; P less than 0.001 and r = 0.72; P less than 0.001, respectively). Our data suggest that in healthy prepubertal children of normal stature, (1) spontaneous GH secretion is independent of sex and age, (2) the amount of spontaneous GH secretion is controlled by pulse amplitude, not by number of pulses. (3) 3-h mean GH and 3-h peak GH after sleep might represent 24-h total spontaneous GH secretion.     

Final height in children with idiopathic growth hormone deficiency treated with a fixed dose of recombinant growth hormone

There is no consensus regarding the optimal dosing of recombinant human growth hormone (rhGH) for children with growth hormone deficiency (GHD). Our objective was to evaluate the final adult height (FAH) in children with idiopathic GHD treated with a fixed rhGH dose of 0.18 mg/kg/week. We reviewed all charts of patients with idiopathic GHD treated with rhGH since 1985 who reached FAH. Ninety-six patients were treated for an average of 5.4 years. The mean age was 11.9 years, the mean height -2.87 standard deviation score (SDS) and the mean FAH was -1.04 SDS. Females had a lower predicted adult height than males at the initiation of therapy (-2.0 vs. -1.01 SDS; p = 0.0087) but a higher FAH - predicted adult height (1.08 vs. 0.04 SDS; p = 0.0026). In multiple regression analysis, the FAH SDS was positively related to the midparental height SDS, the height SDS at GH initiation and growth velocity during the first year of therapy, and negatively correlated with peak GH and bone age at initiation (r(2) = 0.51; p < 0.005). Treatment of children with idiopathic GHD with a fixed dose of 0.18 mg/kg/week rhGH is sufficient to reach FAH within 2 SDS of the normal population range (84%) with an average FAH within -0.5 SDS of midparental height.     

Effects of corticotropin releasing factor and growth hormone releasing factor on pituitary hormone secretion in patients with congenital thyrotropin deficiency. Abnormal response of growth hormone to corticotropin releasing factor

Blood concentrations of anterior pituitary hormones, ACTH, GH, TSH, PRL, LH, and FSH were determined in corticotropin releasing factor (CRF) test (synthetic ovine CRF 1.0 microgram per kg body weight) and growth hormone releasing factor (GRF) test (synthetic human pancreatic GRF-44 100 micrograms) in 2 female sibling patients with congenital isolated TSH deficiency, in their mother, in 2 patients with congenital primary hypothyroidism and in 8 normal controls. The patients with isolated TSH deficiency showed normally increased plasma ACTH and serum GH after CRF and GRF, respectively, and also showed an abnormal GH response to CRF. The serum GH showed a rapid increase to maximum levels (12.9 ng/ml) within 30 to 60 min followed by decrease. The possibility of secretion of abnormal GH could be excluded by the fact that on serum dilution, GH value gave a linear plot passing through zero. In addition, serum PRL, LH and FSH levels after CRF administration in case 1 and PRL after GRF in case 2 were also slightly increased but these responses were marginal. The mother of the patients, patients with congenital primary hypothyroidism, and normal healthy controls showed normal responses of pituitary hormones throughout the experiment. Data from the present study and a previous report show that abnormal GH response to the hypothalamic hormones (CRF, TRH and LHRH) may be observed in patients with congenital isolated TSH deficiency.     

Plasma growth hormone secretion during constant growth hormone-releasing factor infusion

Synthetic human pancreatic growth hormone-releasing factor (hpGRF-44) was infused intravenously at a constant rate of 2.5 micrograms/min for 180 minutes in 3 normal boys of short stature. Plasma GH levels reached a peak at 60-120 min with a mean value (+/- SEM) of 69.1 +/- 14.3 ng/ml, and then, declined gradually in spite of continuous hpGRF-44 infusion up to 180 minutes. Similarly, constant infusion of hpGRF-44 at a rate of 2.5 micrograms/min in 5 normal but short boys for 90 minutes, together with an iv bolus injection of hpGRF-44 (2 micrograms/kg) administered at 0 and 90 minutes, elicited a prompt rise in plasma GH 15-30 minutes after the first bolus but no significant elevation of GH was observed after the second bolus. In contrast, when two iv bolus injections of hpGRF-44 (2 micrograms/kg) were given in 4 normal boys with short stature at 0 and 90 minutes, respectively, significant elevation of plasma GH was found after each bolus. These results suggest that under constant infusion of GRF the pituitary experiences a down-regulation after the initial peak of GH response, possibly due to desensitization to GRF.     

Paradoxical growth hormone response following thyroid-stimulating hormone administration in the polycystic ovary syndrome

Growth hormone (GH) and prolactin (PRL) responses after TRH administration were studied in 31 women presenting with the clinical, biochemical and ultrasonographic characteristics of the polycystic ovarian (PCO) syndrome; their results were compared with those of 20 normally menstruating women investigated during the early follicular phase of the cycle. Based on the GH responses two PCO subgroups were observed: (a) nonresponders (n = 16) who showed delta max GH responses (0.7 +/- 0.27 ng/ml, x +/- SE) similar to those of the normals (0.97 +/- 0.20 ng/ml), and (b) responders (n = 15), 48.4% of the PCO patients who showed a paradoxical increase in GH levels (delta max GH, 18.0 +/- 1.96 ng/ml) following thyrotropin-releasing hormone (TRH) administration significantly higher than those observed either in nonresponder PCO patients or in normals. Furthermore, basal GH levels were found to be significantly higher in the responder PCO subgroup (5.65 +/- 0.75 ng/ml) compared to either nonresponders (1.58 +/- 0.21 ng/ml) or normals (1.8 +/- 0.18 ng/ml). However, no correlation was found between basal GH levels and delta max GH responses observed. Additionally, basal PRL and delta max PRL levels following TRH administration did not differ either between the two PCO subgroups or those observed in normal controls. delta 4A, T and E2 levels were similar between the two PCO subgroups. No correlation was found between the delta max GH responses to delta max PRL or the post-luteinizing hormone-releasing hormone stimulation test delta max luteinizing hormone:follicle-stimulating hormone ratio observed or to steroid levels.(ABSTRACT TRUNCATED AT 250 WORDS)