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Timing of 17β-estradiol (E2) administration in relation to that of GH could influence the "first pass effect" of E2 on hepatic IGF-I secretion. In order to test this hypothesis, a randomized double-blind placebo-controlled crossover study was conducted. Nine Turner girls (12.8-20.0 y) were treated for 2 mo periods with GH 0.1 IU/kg/d sc at bedtime, and oral E2 6-11 µg/kg/d in the morning and placebo in the evening in one 2-mo period and vice versa in the other period. After each period, 24-h blood sampling was performed. IGF-I and mean 24-h integrated GH were comparable. However, the IGF-I/IGFBP-3 ratio was higher (p = 0.05) and insulin levels were lower after evening administration of E2 (24 h: p = 0.03). During an oral glucose tolerance test in the morning, glucagon and insulin were lower following evening E2 administration (ANOVA: glucagon, p = 0.03; insulin, p = 0.04), as well as insulin resistance tended to be lower (p = 0.09). Conclusion: The timing of oral E2 supplementation modulates the IGF-I/IGFBP-3 ratio, insulin and glucagon levels in Turner syndrome during GH treatment. Evening administration of oral estrogen together with evening injections of GH may be preferable. [ABSTRACT FROM AUTHOR]

Objective: Despite seemingly adequate growth hormone (GH) treatment during childhood, children with GH deficiency (GHD) have reduced bone mineral density (BMD) at final height. The aim was to evaluate BMD and bone mineral content (BMC) in adults treated for idiopathic childhood-onset (CO) GHD, 18 years after stopping GH treatment., Subjects and Methods: Twenty-six (11 females) patients with idiopathic CO GHD participated. All patients but two had been treated for isolated GHD in childhood. The childhood diagnosis was established by an insulin tolerance test (ITT) and reassessed in adulthood by an ITT (N = 21) or arginine test (n = 5), revealing that 10 patients had GHD according to adult criteria. Accordingly, the patient group was divided into (1) patients who did not have persistent GHD in adulthood and (2) patients who did have persistent adult GHD. Twenty-six healthy subjects acted as age-, gender- and body mass index (BMI)-matched controls., Results: The patients who did not have persistent GHD had significantly lower IGF-I values and whole-body, femoral neck and lumbar spine BMD compared to controls [0.994 +/- 0.10 vs. 1.114 +/- 0.11 g/cm2 (P = 0.003), 0.842 +/- 0.12 vs. 0.962 +/- 0.11 g/cm2 (P = 0.006) and 1.026 +/- 0.14 vs. 1.127 +/- 0.13 g/cm2 (P = 0.004), respectively]. Femoral neck BMD was significantly reduced in the patients who had persistent GHD, compared to controls (0.842 +/- 0.09 vs. 0.938 +/- 0.11, P = 0.04). Significant correlations were observed between all bone variables and IGF-I in all subjects, whereas no correlations were observed between bone variables and GH peak levels in the 26 patients., Conclusion: In conclusion, we found that (1) patients with idiopathic CO GHD, who at retest in adulthood did not have GHD according to adult criteria, had reduced serum IGF-I and BMD/BMC compared to controls. (2) This observation was also made in the patients who did have persistent GHD in adulthood. The findings may reflect the fact that the present diagnostic criteria for adult GHD (i.e. response to the ITT) do not reflect the clinical consequences of disordered GH-IGF axis in CO GHD young adults who were treated with GH in childhood. Alternatively, despite seemingly adequate GH treatment in childhood an optimal peak bone mass in adolescence may never have been reached in either of the groups. (3) IGF-I levels correlated with clinical signs of the adult GHD syndrome. We believe that further studies on the indications and diagnostic procedures for GH treatment after cessation of linear growth are necessary.

The aim was to reevaluate a group of adults treated for idiopathic childhood onset GH deficiency (GHD) after 18 yr without GH treatment. Twenty-six (11 females) patients participated. All but two had isolated GHD. Childhood diagnosis was established by insulin tolerance test (ITT). The patients were retested with an ITT to evaluate adult GH status. In five patients, an arginine and a synacthen test were performed instead of an ITT. Eleven of 25 patients had a subnormal cortisol response to ITT or synacthen. Ten patients had a GH peak less than 3.0 microg/liter (0.5. +/- 0.5 microg/liter), whereas 16 patients displayed a normal GH response (12.3 +/- 10.6 microg/liter) after ITT. IGF-I values were decreased in the patients with a pathological retest as well as in patients with a normal GH response compared with controls (P < 0.005). In 26 idiopathic childhood onset GHD patients, 44% of the patients had developed adrenal insufficiency; 38.5% had persistent GHD in adulthood, using the same test in both childhood and adulthood. Patients having a normal GH test had decreased IGF-I levels, compared with controls, indicating impaired function of a seemingly normal GH axis. It is imperative that pituitary axes other than the GH axis are tested at regular intervals, even in the absence of GHD in adulthood.

Background: Most girls with Turner syndrome (TS) receive growth hormone (GH) treatment during childhood and adolescence, but controlled data on the effects on body composition and glucose metabolism are lacking., Objective: To study the effects of GH treatment on insulin sensitivity, glucose metabolism, bone turnover, and body composition., Methods: A randomized, placebo-controlled, crossover study was conducted with girls with TS. All girls with TS were treated with GH 0.1 IU/kg/d subcutaneously at bedtime or with placebo for 2 months and studied at the end of each period. Control subjects were studied once without treatment. Twelve girls with TS, aged 9.5 to 14.8 years (median: 12.9 years) and 16 age-matched control subjects (10.3-16.0 years; median: 12.1 years) were studied. Twenty-four-hour sampling of blood was performed; GH, insulin-like growth factor I (IGF-I), IGF binding proteins (IGFBPs), insulin, glucose, and lipolytic and gluconeogenic precursors were assayed, followed by an oral glucose tolerance test. Body composition was evaluated by dual-energy x-ray absorptiometry scanning and body mass index (BMI). Fasting bone markers were measured., Results: Height was reduced in TS as compared with control subjects. In the placebo situation, 24-hour integrated GH as well as IGF-I was significantly reduced in girls with TS compared with control subjects. Controlling for differences in lean body mass (LBM; or fat mass [FM]) and sexual development did not explain the difference in 24-hour integrated GH. Differences in sexual development, BMI, FM, insulin sensitivity, and IGFBP-3 could explain the difference in IGF-I between TS and control subjects. Carbohydrate metabolism in TS was comparable with control subjects. GH treatment induced insulin resistance, with increments in fasting glucose and insulin, as well as 24-hour insulin. Circulating levels of lipid and gluconeogenic substrates were comparable in TS and control subjects and unchanged in response to treatment. Bone markers increased in response to GH. Total FM was increased in girls with TS, accounted for by an increased FM in the arms and trunk, whereas LBM was decreased. Especially LBM in the legs was decreased. Overall, bone mineral content was diminished. Treatment with GH reduced FM in TS, especially in the arms and legs, and likewise increased total LBM, primarily in the trunk., Conclusion: This study documented evidence of impaired GH secretion and action, disproportionate body composition, but a normal carbohydrate metabolism in girls with TS. Short-term GH administration was associated with favorable changes in body composition but also with relative impairment of glucose tolerance and insulin sensitivity. We recommend that glucose metabolism be monitored carefully during long-term GH treatment in these patients.

Circulating insulin-like growth factor-I (IGF-I) is predominantly bound in the trimeric complex comprised of IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS). Circulating concentrations of IGF-I, IGFBP-3 and ALS are believed to reflect the GH secretory status, but the clinical use of ALS determination is not known. We therefore, determined the: 1) hepatosplanchnic release of ALS by liver vein catheterization (n=30); 2) 24-h diurnal variation of ALS (n=8); 3) normal age-related ranges of circulating ALS (n=1158); 4) diagnostic value of ALS in 108 patients with childhood-onset GH deficiency (GHD). We found: 1) no significant arteriovenous gradient over the liver ofALS, IGF-I, and IGFBP-3; 2) the diurnal variation of ALS was 12% (mean coefficient of variation percent); 3) ALS levels increased throughout childhood with maximal levels in puberty, with a subsequent decrease with age in adults; and 4) ALS levels were below -2 SD in 57 of 79 GHD patients (sensitivity 72%) and above 2 SD in 22 of 29 patients with normal GH response (specificity 76%), which was similar, compared with the diagnostic utility of IGF-I and IGFBP-3. Finally, our findings indicate that hepatic ALS production is not measurable by this approach or, alternatively, that the liver is not the primary source of circulating ALS, IGF-I, or IGFBP-3 in humans. In conclusion, we have provided extensive normal data for a novel ALS assay and found that circulating ALS levels exhibit minor diurnal variation. We suggest that ALS determination may be used in future classification of adults suspected of GHD.

Seventeen patients (twelve males and five females) with craniopharyngioma were studied by retrospective review (stature, bone age, and hormone therapy) and by follow-up assessment in all seventeen survivors (stature and craniofacial development). Roentgencephalometric films in the lateral and frontal projections were analyzed. Individual and mean facial diagrams were produced based on 221 reference points in the individual patients and compared to normative data. The posterior cranial base was significantly reduced in length and the cranial base angle was significantly increased. In the facial regions great variations in size and prognathy of the jaws were recorded; on average the patients' maxilla and especially the mandible were short and retrognathic in relation to the anterior cranial base when compared to average adults. Average size and shape of the calvaria, cranial base, and facial regions in the adult male craniopharyngioma group corresponded closely to the average male at the stage of maximum growth in body height, i.e., around 14 years of age. It was concluded that size and morphology of the sphenoid and basioccipital bones were severely affected, possibly as a result of the interfering growth of a craniopharyngioma in childhood. The retrusion of the facial regions might be present as a result of the flattening of the posterior cranial base, but the relatively short and retruded mandible could also be caused by growth hormone deficiency before diagnosis/operation and in periods of sub-optimal therapy. The close resemblance of craniofacial morphology between adult males with craniopharyngioma and normal boys at the time of peak height velocity might reflect the fact that imitation of the natural, optimal balance between growth hormone and sex steroid in puberty is difficult to obtain in therapy.

Serum levels of total insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) reflect endogenous GH secretion in healthy children, which makes them good diagnostic markers for screening of GH deficiency (GHD) in short children, although some controversy still exists. Only a minor fraction of the total IGF-I circulates in its free form, which is believed to be the biologically active form. However, our knowledge of the clinical or physiological value of determination of free IGF-I in serum is limited at present. In adults, the diagnostic value of total IGF-I and IGFBP-3 determinations in patients suspected of GHD has only been reported in a few studies, whereas no previous reports on the diagnostic value of free IGF-I levels in adults suspected of GHD exist. Serum levels of free IGF-I were determined in 1430 healthy children, adolescents, and adults by a newly developed, commercially available immunoradiometric assay (Diagnostic Systems Laboratories) to establish valid normative data for this analysis. We studied the diagnostic value of free IGF-I in relation to total IGF-I and IGFBP-3 determinations in adults who were suspected of GHD. A GH provocative test, using oral clonidine, was performed in 108 adult patients who had previously been treated with GH in childhood. In healthy subjects, free IGF-I levels increased during childhood, with the highest mean values during puberty. After puberty, a subsequent decline in serum levels of free IGF-I was apparent. We found, unmeasurable free IGF-I values in 34 of the prepubertal children (3.3%). All individuals over 8 yr of age had measurable free IGF-I levels that amounted to approximately 1% of the total IGF-I concentrations. Free IGF-I levels were below--2 SD in 56 of 79 GHD patients (sensitivity, 71%) and above--2 SD in 24 of 29 patients with a normal GH response (specificity, 83%). Multiple linear regression analysis demonstrated that free IGF-I was significantly dependent on peak GH levels, duration of the disease, and number of other pituitary axes affected. We conclude that free IGF-I serum levels increase during childhood with a peak in puberty, whereafter free IGF-I levels return to prepubertal levels. Three percent of healthy prepubertal children had unmeasurable free IGF-I levels using this assay. We found that determination of the free IGF-I serum concentration may predict the outcome of a GH provocative test in adults suspected of GHD, but that a single determination of free IGF-I offered no significant advantage compared to determination of total IGF-I or IGFBP-3 serum levels.

Serum levels of total insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) reflect the endogenous GH secretion in healthy children and exhibit little diurnal variation, which makes them good diagnostic markers for screening of GH deficiency (GHD) in short children, although some controversy still exists. In adults, the diagnostic value of IGF-I and IGFBP-3 suspected of GHD has been reported in only a few studies. We performed a GH provocative test, using oral clonidine, in 108 patients who had previously been treated with GH during childhood (73 men and 35 women). Basal IGF-I and IGFBP-3 levels were compared to those in 1237 healthy controls (312 controls > 18 yr) as well as to peak GH levels. Seventy-nine patients had peak GH values below a cut-off value of 7.5 micrograms/L (34 with isolated GHD), whereas 29 patients had a normal GH response (28 with previous isolated GHD), i.e. 45% of patients treated with GH during childhood because of isolated GHD had a normal GH response when retested in adulthood. Multiple regression analysis revealed that peak GH levels were dependent on the degree of hypopituitarism, body mass index, and duration of disease. IGF-I levels were below -2 SD in 60 of 79 GHD patients and above -2 SD in 21 of 29 patients with a normal GH response. IGFBP-3 levels were below -2 SD in 54 of 79 GHD patients and above -2 SD in 23 of 29 patients with a normal GH response. Multiple linear regression analysis demonstrated that IGF-I and IGFBP-3 were significantly dependent on peak GH levels and the number of other pituitary axes affected. In this analysis, duration of disease was significantly associated with both IGF-I and IGFBP-3, whereas body mass index was significantly associated with IGFBP-3, but not with IGF-I. We conclude that IGF-I and IGFBP-3 determinations predict the outcome of a GH provocative test in adults suspected of GHD and believe that IGF-I as well as IGFBP-3 serum concentrations are valuable diagnostic parameters in the evaluation of GHD in adults with childhood-onset disease. We suggest that children who have been treated with GH should undergo reassessment of their GH secretory status as young adults by provocative testing as well as by IGF-related peptides before continued adult GH replacement therapy is considered. However, our data suggest that it is not necessary to reconfirm GH deficiency by GH provocative testing in young adults who have two or more pituitary hormone deficiencies in addition to GHD.

Girls with Turner syndrome are mainly characterized by growth retardation and gonadal insufficiency. In order to evaluate the effect of growth hormone (GH) and/or low dose 17 beta-oestradiol (E2) on growth and pubertal development, 39 Turner girls with a chronological age (CA) of 7.6-18.1 years were divided into three groups depending on pretreatment bone age (BA). They were treated with either GH 0.1 IE/kg per day (n = 13, BA 7.1-10.2), peroral E2 0.01 mg/kg per day (n = 8, BA 8.5-12.7) or both (n = 18, BA 10.5-15.3). In the 2nd year the E2 group also received GH, while the E2 dose was reduced 30%. In the 1st year height velocity (HV) expressed as standard deviation scores (SDS) increased in all groups (mean): from -0.4 to 3.3 (P < 0.01) in the GH group, -0.5 to 2.7 (P < 0.01) in the E2 group, and -0.8 to 4.6 (P < 0.001) in the GH+E2 group. A possible synergistic effect from combination therapy was seen, as HV increase was higher in group 3 than groups 1 and 2 (P < 0.05). In the 2nd year HV was unchanged in groups 1 and 2, while a clear decrease was seen in the GH+E2 group (P < 0.001). In the 1st year BA progression in the E2 group was rapid (1.9 BA/CA year) and higher than in the other groups (P < 0.05). In the 2nd year progression slowed down--particularly in the E2 group (0.7 BA/CA year, P = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Fifteen prepubertal short stature children (10 girls, 5 boys), mean age 9.6 years (range 5.2-12.7 years), with normal response to growth hormone stimulation tests (group A) or partial growth hormone deficiency (GHD) of idiopathic nature (group B) were included in a controlled longitudinal study for evaluation of predictive parameters for the long-term growth response after administration of biosynthetic human growth hormone (B-hGH). The average knee-heel length velocity for the first 3 months was significantly correlated to total body height velocity during the following 9 months (p less than 0.0008). By contrast, this association could not be found for height velocity during the same period. The increase in serum values of alkaline phosphatase and insulin-like growth factor I (IGF-1) during the first month of treatment was not significantly correlated to height velocity during the first year. During one year of treatment with B-hGH the mean height velocity for groups A and B increased from 4.4 cm/year (range 2.5-6.5) to 7.6 cm/year (range 4.7-10.6). Bone age advanced by 1.08 +/- 0.60 per chronological year. The ratio between total height and knee-heel length prior to treatment was 3.34 +/- 0.10 and after one year 3.33 +/- 0.10, suggesting a proportional linear growth. An inverse relationship was observed between the ratio and chronological age. In conclusion, early knee-heel measurement may be a useful non-invasive predictor of long-term linear growth in children during treatment with growth hormone, and the ratio of total height to lower leg length may be of importance in detecting dysproportional growth.

Nation-wide screening for microalbuminuria in Denmark was performed in 22 paediatric departments treating children with Type 1 diabetes. Over a period of 6 months 1020 children (less than or equal to 12 years) and adolescents (greater than 12 to 19 years) were screened (81% of total). Of these, 957 (94%) performed at least two timed overnight urine collections. In 209 non-diabetic subjects the upper 95% limit for normal albumin excretion rate (AER) was 20 micrograms min-1. Mean overnight AER was significantly (p less than 0.001) elevated in diabetic (3.0 x/divided by 2.3 (SD tolerance factor) micrograms min-1) and in non-diabetic (2.5 x/divided by 2.2 micrograms min-1) adolescents compared with diabetic (1.7 x/divided by 2.1 micrograms min-1) and non-diabetic (1.3 x/divided by 2.2 micrograms min-1) children. In the diabetic patients AER was positively correlated with the body surface area and age. Among the patients with Type 1 diabetes, 4.3% (18 males and 23 females) had AER greater than 20 to 150 micrograms min-1 (persistent microalbuminuria). A further 7 adolescents (0.7%) had overt proteinuria (greater than 150 micrograms min-1). Clinical data for the 41 diabetic patients with AER greater than 20 to 150 micrograms min-1 were compared with those for 569 diabetic adolescents with AER less than or equal to 20 micrograms min-1 and duration of diabetes more than 2 years. The group with AER greater than 20 to 150 micrograms min-1 had significantly higher mean age (16.5 years) than the group with AER less than or equal to 20 micrograms min-1 (15.0 years; p less than 0.001). Females with AER greater than 20 to 150 micrograms min-1 had significantly higher mean HbA1c level (10.8 +/- 1.9%) than those with AER less than or equal to 20 micrograms min-1 (9.8 +/- 1.9%, p less than 0.003); they also had impaired linear growth (standard deviation score -0.25 vs + 0.16; p = 0.003). These associations were not found in males. Mean body mass index (BMI) was significantly increased in both females (22.2 +/- 2.9 kg m-2) and males (20.8 +/- 2.7 kg m-2) with AER greater than 20 to 150 micrograms min-1, compared with diabetic patients with AER less than or equal to 20 micrograms min-1 (females 20.8 +/- 3.0 kg m-2, p = 0.02; males 19.7 +/- 2.4 kg m-2, p less than 0.006).(ABSTRACT TRUNCATED AT 400 WORDS)

The glycosylated hemoglobin component, hemoglobin A1c, was estimated in 92 children with insulin dependent diabetes mellitus by an iso-electric focusing procedure during an observation period of 18 months. A significant correlation between hemoglobin A1c and the actual metabolic control according to clinical ratings was found. A seasonal variation in the concentration of the hemoglobin A1c was observed with the lowest level in the months of June and July consistent with an improved metabolic control in the diabetic children during the summer period. A direct relationship was found between metabolic control as assessed by hemoglobin A1c and retarded linear growth expressed as standard deviation score for height. Children with poorly controlled diabetes (initial hemoglobin A1c level above 12.5%) improved their carbohydrate tolerance shown by a significantly lower glycohemoglobin level at the end of the observation period. Consequently, hemoglobin A1c is particularly useful in the routine management of insulin dependent diabetic children in poor metabolic control. Frequent determinations are necessary since in these patients the glucose profiles are prone to great variations, which may lead to changes in the hemoglobin A1c concentration of about 1% in a week.

We have conducted a modified double-blind study on the effect of human chorionic gonadotropin (hCG), gonadotropin releasing hormone (GnRH) and placebo on bilateral and unilateral maldescended testes. One hundred and fifty-five boys with bilateral and 88 boys with unilateral cryptorchidism fulfilled the inclusion criteria and completed the treatment protocol. The boys were between 1 and 13 years of age. hCG was administered as intramuscular injections twice weekly for 3 weeks. GnRH and placebo were given intranasally. hCG was superior to GnRH and placebo in the treatment of bilateral maldescended testes (p = 0.0009). Both testes descended in 25% of the boys following treatment with hCG, and improvement in the position of the testes was obtained in a further 25% of the cases. hCG administration resulted in complete testicular descent in 14% of boys with unilateral cryptorchidism compared with 3 and 0% after placebo and GnRH, respectively (p = 0.07). The testis had moved to a more distal position in 46% of the boys treated with hCG. There was no significant difference between the treatment groups with regard to age or initial position of the testes. We conclude that a success rate of 25% justifies the use of hCG in the treatment of maldescended testes, whereas the study did not support a general use of GnRH administered intranasally.

The time course of plasma growth hormone (hGH) levels following sc and im injection of hGH was studied in 12 children with growth hormone deficiency who had received long-term treatment with im injections of highly purified hGH. Also the spontaneous diurnal GH levels in 8 normal children of comparable age were recorded. Blood samples were obtained during 24 h after im and sc injections of 4 IU/m2 hGH and analysed for immunoreactive hGH. While a median peak value of 160 ng/ml (range 135 to 475 ng/ml) was obtained 2 h after im injection, sc injection resulted in a more sustained elevation reaching 41 ng/ml (range 32 to 51 ng/ml) at 6 h subsiding slowly with a median concentration of 15 ng/ml (range 5-24 ng/ml) persisting after 14 h. Gel chromatography demonstrated that the hGH immunoreactivity of blood samples obtained as late as 14 h after sc injection had unaltered molecular size. Seven of the patients were further studied after sc injection of 2 IU/m2 at 20.00 h instead of in the morning. A plasma profile was attained during the night which roughly approximated the average nocturnal plasma pattern of the normal children.

The serum levels of somatomedin A, determined by radioreceptor assay, were significantly higher in 57 adult patients with chronic renal failure (X = 2.57 +/- 0.12 U/ml) than in healthy subjects (n = 131; X = 0.77 +/- 0.02 U/ml). A positive correlation was found between somatomedin A and creatinine levels (r = 0.33), but somatomedin A levels did not decrease after hemodialysis. A reduction was only observed after successful renal allografting. Immunoreactive somatomedin A was also found to be increased in patients with chronic renal failure (X = 2.61 +/- 0.21 U/ml), whereas low levels were obtained by the chick bioassay. However, after separating the inhibitory factors from the stimulatory factors by gel chromatography at neutral pH, uremic serum was shown to contain increased levels of somatomedin activity. Although all somatomedin A, determined by different techniques, was present in high molecular forms, the elution pattern differed from that seen in patients with acromegaly.

Severe growth retardation is found in patients with high levels of growth hormone and low sulphation factor activity or somatomedin. Also non-suppressible insulin-like activity (NSILA-s) has been found to be very low in a patient with this condition as measured by bioassay, protein binding assay and radioimmunoassay and to be below activities found in hypopituitary patients. Partially purified NSILA-s restored the ability of serum to increase sulphation activity although full restitution may still depend on other factors. These findings support the hypothesis that NSILA-s belongs to the family of somatomedin and thus is involved in promoting growth, and that low activity of these growth factors is a primary cause of the growth retardation found in these patients.

In 23 growth retarded children two consecutive insulin tolerance tests (ITT) were performed to establish a diagnosis of growth hormone (GH) deficiency. Nine children did not respond (GH peak value less than 8 mU/1), whereas 14 were classified as having partial GH deficiency (GH peak value less than 20 mU/1). All were treated for an average period of 40 months with human growth hormone (HGH). In a combined stimulation test at the end of the treatment period 9 children demonstrated a persistent GH deficiency, whereas a normal response was found in 14 of the previous partial GH deficient children. During treatment the monthly growth rate rose from 0.21 cm 0.58 cm in the GH deficient children and from 0.31 cm to 0.70 cm in the partial deficient children, in most of whom spontaneous pubertal development occurred during treatment. Somatomedin (SM) values were decreased in the GH deficient children before and after treatment but increased to normal levels during treatment. Growth velocity in these children during treatment was correlated to SM values before treatment. In the partial GH deficient children SM values were subnormal before but normal after treatment. This supports the assumption that in some children with constitutional delay in puberty a reversible functional hypopituitarism exists, which is normalized after the onset of puberty, due to androgens sensitizing growth hormone releasing mechanisms. Treatment with HGH may induce increased growth velocity in some of these patients.

Circulating autoantibodies to thyroid hormones are occasionally detected and may cause confusion, because symptoms and signs are inconsistent with the measured thyroid hormone values. We present a 5 1/2 year old girl with Hashimoto's thyroiditis and false high concentrations of free thyroxine and total triiodothyronine.

Growth hormone release inhibiting hormone (GH-RIH) was infused at a rate of 1.3 mug/min for 28 hours into four patients with acromegaly, two of whom also had clinical diabetes mellitus. Growth hormone and glucagon were suppressed throughout the infusion though delayed secretion of insulin occurred in association with both meals and an oral glucose load. Glucose tolerance was improved in one diabetic patient who was taking chlorpropamide while the other required much less insulin than usual. Secretion of endogenous thyroid-stimulating hormone was lowered in one euthyroid patient on carbimazole. Luteinizing hormone, follicle-stimulating hormone, ACTH, and prolactin were not affected. Serum somatomedin levels were reduced in one patient. There was a rapid rebound of all the suppressed hormones when the infusions stopped. Longer-acting analogues of GH-RIH will be needed before long-term therapy of acromegaly or diabetes mellitus becomes possible, but such preparations should be available soon for clinical trial.

Early therapy with a low dose of estrogen (estradiol-17 beta) was given to 33 girls with Turner's syndrome (T.s.) for a period of 4 years. The dose (0.25-2 mg/day) was adjusted every 3 months to maintain plasma estradiol in the normal concentration range for bone age. Growth velocity was compared with that of untreated girls with T.s. All girls were above age 10 years. Bone age was below 10 years in 11 girls (group I) and above 10 years in 22 girls (group II). Growth velocity in the first year of treatment in group I 7.5 +/- 1.3 cm (SD) with mean SD score (SDS) of +4.3 and in group II 4.9 +/- 1.3 with mean SDS of +3.5. Growth velocity decreased in the following years to 1.6 +/- 1.0 cm, SDS -1.44 in group I and 0.9 +/- 0.6 cm, SDS -2.34 in group II during the fourth year. Withdrawal bleeding occurred in 16 girls of group II after the mean of 23 (range 15-33) months and in 3 girls of group I after 15 to 51 months of treatment. The treatment did not cause an inappropriate acceleration of pubertal development. Breast development appeared in most girls by 3 months of treatment. Pubic hair appeared by 12 months of treatment in group I; it was present in most girls in group II at start of treatment. Final height is known for 12 girls of group II; it was 144.2 +/- 4.5 cm. The final height as predicted at the start of therapy was 142.2 +/- 5.3 cm.(ABSTRACT TRUNCATED AT 250 WORDS)

A total number of 23 patients treated with human growth hormone were retested by use of a combined pituitary stimulation test. Plasma concentrations of GH, FSH, LH, TSH, T4, T3, prolactin (PRL), ACTH and cortisol were measured before and after stimulation with hypoglycemia, TRH and LHRH. The test was performed in patients with persistent GH deficiency (group A) and patients with transitory GH deficiency (group B). In group A a normal pubertal development was found in three patients, whereas in prepubertal subjects the FSH/LH responses were smaller than those of prepubertal patients in group B. Also plasma ACTH increase was less pronounced in group A patients than in group B. In contrast, the plasma TSH and PRL responses were more sustained in group A than in group B. The secretory pattern of TSH and PRL was comparable in the two groups of patients. Thus, in patients with persistent GH deficiency additional multiple disturbances of the hypothalamic-pituitary function often appeared whereas in most patients with transitory GH deficiency the combined pituitary test was normal at the reinvestigation.

In a boy 4 years old with clinical hypopituitary dwarfism, high plasma and urinary levels of immunoreactive growth hormone were found. Somatomedin A levels in serum were low and failed to respond after short-term treatment with human growth hormone. The parents were first cousins. In the arginine and insulin tolerance tests the initially high immunoreactive growth hormone levels were later followed by a decrease to high normal values. Insulinopenic response was present during the arginine and glucose tolerance tests. As a growth hormone molecule defect is not found in these patients and no growth or other metabolic response to exogenous HGH can be demonstrated, it is concluded that a defective somatomedin generation may be present, probably in conjunction with a generalized receptor defect and deficient feedback system with abnormal release of HGH. The lack of somatomedin A is responsible for the severe growth retardation and the disturbance in carbohydrate metabolism is probably caused by sustained high growth hormone levels.

Urinary excretion of adrenalin has been reported to be reduced during insulin-induced hypoglycemia in a significant proportion of children having ketotic hypoglycemia. By employing a sensitive double-isotope derivative technique, plasma adrenalin and plasma noradrenalin were determined in a boy 6 years 9 months old who had had ketotic hypoglycemia with intermittent hypoglycemic symptoms from the age of 10 months. Bilateral calcifications of the suprarenal glands were present. The adrenocortical function was normal. The plasma adrenalin response to hypoglycemia were practically absent, being only 4% of the value obtained in healthy children. The results were related to previous findings of a low plasma adrenalin response in patients with ketotic hypoglycemia without adrenal calcifications and support the assumption that ketotic hypoglycemia is associated with hypoadrenalinemia.

In a short-term cross-over study the effect of daily sc human growth hormone was compared with that of thrice weekly im treatment. At the end of each 6-week treatment period the 10 growth hormone deficient children were admitted to hospital for evaluation of diurnal plasma levels of hormones and intermediary metabolites. Somatomedin A as well as C levels were higher in 9 of 10 children after sc than after im growth hormone therapy. This may be the basis for previous observations of improved growth after change to sc treatment.

Serum lipids and lipoproteins were measured in 157 insulin dependent diabetic children and adolescents (IDDM) and in 350 healthy reference individuals. Serum triglyceride values were lower and total cholesterol and high density lipoprotein cholesterol higher in IDDM. Metabolic regulation reflected by glucosuria, postprandial blood glucose, number of hypoglycemic episodes and hemoglobin A1c all correlated strongly with serum triglyceride and very low density lipoprotein cholesterol. Serum lipids and lipoproteins did not correlate with obesity. Three children had genetic hyperlipoproteinemia. In IDDM measurement of serum lipids and lipoproteins can thus be used to further assess metabolic regulation. Measurement of serum lipids and lipoproteins seems warranted for future evaluation of the risk of cardiovascular disease in IDDM.

In a follow-up study of 40 tall girls treated with intramuscular estradiol and progesterone, the final height, bone age maturation, side effects and acceptance of treatment were evaluated. The mean duration of treatment was 18 months. During treatment, mean height increase was 6.5 cm (height velocity 3.7 cm/year), which is nearly 50% reduction of normal growth rate. The mean increase in bone age was 2.7 years (bone age velocity 1.8 years/year), which approximates twice the normal maturation rate. The mean reduction in final height was 5.0 cm as evaluated by the method of Bayley. Pinneau (BP), 2.9 cm by the method of Tanner et al. (TW) and 3.0 cm by the method of Roche et al. (RWT). The reduction was greatest when treatment was started before menarche, according to all three prediction methods. When treatment was started after menarch the calculated height reduction was greatest according to the BP method. There was good agreement between the three prediction methods in girls with a bone age below 12 years before treatment. In girls with a bone age above 12 years the height reduction by the BP method was much greater than when measured by the other methods. Side effects evaluated at follow-up were minimal and first menstruation occurred within 3 months (mean) after cessation of treatment. The number of pregnancies was estimated to be normal for age. All but three accepted the treatment. It is concluded that this type of treatment must be restricted to girls with severe psychological problems due to excessive height prognosis and selection for treatment must be based on an individualized evaluation.

Reference values for ionized calcium were measured in anaerobic samples of capillary blood from 22 healthy premature neonates, gestational age 33-36 weeks, birth weight 1660-2480 g. Reference values (mean +/- 2SE) for premature neonates aged 5-12, 13-19, 25-48, 51-72, 77-99, 108-140, 150-185 h were: 1.21 +/- 0.16, 1.17 +/- 0.12, 1.21 +/- 0.16, 1.28 +/- 0.18, 1.34 +/- 0.14, 1.38 +/- 0.13, 1.40 +/- 0.16 mmol/l, respectively. Ionized calcium in 59 full-term neonates with mild pathological hyperbilirubinaemia (no phototherapy needed) and 28 neonates born by section (no neonatal complications) showed no statistical difference (unpaired t-test) in age-related values compared with matching healthy neonates with no clinical remarks. Data for full-term neonates were pooled and age-related reference values (mean +/- 2SE) for ionized calcium in capillary whole blood for 168 full-term neonates, gestational age 38-41 weeks, birth weight 2550-4700 g, aged 1-12, 13-24, 25-48, 49-72, 73-99, 99-120, 121-144, 146-168, 178-264 h were: 1.24 +/- 0.11, 1.19 +/- 0.12, 1.21 +/- 0.13, 1.22 +/- 0.14, 1.29 +/- 0.17, 1.35 +/- 0.12, 1.37 +/- 0.12, 1.38 +/- 0.16, 1.40 +/- 0.10 mmol/l, respectively.

Oestradiol stimulates growth and development in Turner's syndrome. Previous results with low-dose oestradiol on growth rate are reviewed. The effect of oestradiol in low concentrations on somatomedin generation, GH secretion and directly on osseous tissue, may explain the growth response. The observations presented here of 35 girls treated with 17-beta-oestradiol demonstrated a definite increase in growth rate in the first year of therapy. Bone maturation was accelerated, but a reduction in final height was not found.

The significance of somatomedin A (SM) and human chorionic somatomammotropin (HCS) in fetal growth was examined. SM, determined by chick embryo assay, was studied during the last trimester of pregnancy, in maternal serum and cord blood at term and in a group of normal newborns in the first week of life. Furthermore a group newborns of diabetic mothers was studied in the first or second day of life. HCS was measured in maternal serum and in cord blood at term. In amniotic fluid inhibitory factors caused a low SM activity as measured by the bioassay. The following results were obtained: 1) Normal values of SM in the last trimester with a decline at term were found in 3 normal primigravidae. 2) The mean levels of SM in 22 mothers and their offspring were decreased. The difference between the two values was significant, but a positive correlation was found between the maternally related pairs of SM values. Moreover, a positive correlation was found between maternal SM, birth weight and length. HCS was not correlated to above-mentioned parameters, but there was positive correlation between placental weight and birth weight. 3) In 6 newborns during the first 5 days SM rose from very low values to normal values found in infants in their first year. 4) The mean value of SM in ten newborns of diabetic mothers was not significantly different from the mean value of control group. The results do not exclude the possibility of a transplacental transport of SM and the positive correlation between SM levels and birth weight found in this investigation supports the concept that SM plays an important role in fetal growth.

Bioassayable somatomedin-A (SM-A) and serum concentrations of testosterone (T) and dehydroepiandrosterone (DHEA) were determined longitudinally in 26 normal boys during puberty. The mean trend of SM-A increased in relation to age, pubic hair development and peak height velocity (PHV) and significant correlations were observed with testicular volume, height velocity and T (all P less than 0.001) but not with DHEA. In relation to growth SM-A increased mainly during 12 to 6 months prior to PHV but no further increase was seen in the 6 months thereafter. Thus pubertal growth and development have to be taken into account in the evaluation of changes in bioassayable SM-A concentrations in boys.

The effect of more frequent (daily) injections of human growth hormone (hGH) on growth rate was studied in 16 growth hormone deficient children (12 boys, 4 girls) during 2 years. All had previously been treated with im injection of hGH 2-3 times weekly and in the majority of the patients a waning growth response was observed. For a total weekly dose of 12 IU hGH a daily dose of 2 IU was injected sc at night before sleep. This dosage has been shown by us to imitate the average nocturnal hGH profile in plasma. Growth response on the im treatment was 5.2 +/- 1.2 cm/year (SD) in boys and 5.4 +/- 0.9 cm/year in girls. A significant increase was seen during the first year of sc treatment to 7.9 +/- 2.7 cm in boys and 6.3 +/- 2 cm in girls. During the second year the growth response was still significantly increased in boys (7.2 +/- 1.9 cm). Bone age was more advanced and the period of previous im treatment was longer in girls (6.7 vs 3.6 years) which may be the main cause of the waning second year response (4.7 +/- 1.3 cm/year). Pubertal development occurred in 9 children during treatment. However, the highest growth rates were not found in these children. Absence of antibodies against hGH and local reactions at the injection site is evidence of the safety of the treatment, which was very well accepted by the children. Daily sc injections thus represent an effective alternative to conventional im injections ensuring high acceptance in children with growth hormone deficiency.