Morning versus evening administration of estradiol to girls with turner syndrome receiving growth hormone: impact on growth hormone and metabolism. A randomized placebo-controlled crossover study.

UNLABELLED: Timing of 17beta-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 (12.8-20.0y) were treated for 2 mo periods with GH 0.1 IU/kg/d sc at bedtime, and oral E2 6-11 microg/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.

The acid-labile subunit of human ternary insulin-like growth factor binding protein complex in serum: hepatosplanchnic release, diurnal variation, circulating concentrations in healthy subjects, and diagnostic use in patients with growth hormone deficiency.

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.

Free insulin-like growth factor I serum levels in 1430 healthy children and adults, and its diagnostic value in patients suspected of growth hormone deficiency.

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.

Growth hormone (GH) provocative retesting of 108 young adults with childhood-onset GH deficiency and the diagnostic value of insulin-like growth factor I (IGF-I) and IGF-binding protein-3.

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.

Final height and craniofacial development after surgical resection of craniopharyngioma.

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.

[Adrenogenital syndrome--diagnosis, treatment and therapeutic control]. / Adrenogenitalt syndrom--diagnostik, behandling og behandlingskontrol.

Congenital adrenal hyperplasia is a rare, genetic disorder. In Denmark about 90 cases have been diagnosed over the last 20 years. It is potentially life-threatening in early childhood, and must be intensively controlled in order to achieve a normal growth, pubertal maturation and fertility. This article reviews the pathogenesis and genetic and clinical characteristics underlying congenital adrenal hyperplasia, and outlines pre- and postnatal approaches to the diagnosis and monitoring, with special emphasis on 21-hydroxylase defect.

[Prader-Willi syndrome--clinical picture and genetics]. / Prader-Willi syndrom--kliniske billede og genetik.

Characteristics are hypotonia, problems with feeding and thriving in the neonate and infant, later hyperphagia and severe obesity. Other findings are dysmorphic traits, hypogonadism, short stature, developmental delay, mental retardation and behavioural problems. Diabetes mellitus (NIDDM) is frequent in adults. Treatment is symptomatic. Prognosis is determined by obesity. PWS occurs almost always sporadically and is found in all ethnic groups and in both sexes. The epidemiology of PWS in Denmark is unknown. In 95% of cases with PWS cytogenetic and molecular genetic investigations show either deletion of the paternal chromosome 15q11q13 or uniparental maternal disomy of chromosome 15. Since 1992 150 bloodsamples of patients suspected for PWS have been investigated by cytogenetic and molecular genetic techniques at the John F. Kennedy Institute, DK-2600 Glostrup; deletion of the paternal chromosome 15 was found in 15 and uniparental maternal disomy of chromosome 15 in eight cases.

Growth hormone and 17 beta-oestradiol treatment of Turner girls--2-year results.

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)

[Cryptorchism. Treatment with human chorionic gonadotropin or gonadotropin-releasing hormone?]. / Kryptorkisme. Behandling med human chorion gonadotropin eller gonadotropinfrigørende hormon?

In a modified double-blind study on the effect of human chorionic gonadotrophin (hCG), gonadotrophin releasing hormone (GnRH) and placebo, 163 prepubertal boys (aged 1.8-13.0) with bilateral and 94 (aged 1.5-13.1 years) with unilateral cryptorchidism fulfilled the inclusion criteria and completed the treatment protocol. hCG was administered as intramuscular injections twice weekly for three weeks. GnRH and placebo were given intranasally. hCG was superior to GnRH and placebo in the treatment of both bilateral (p < 0.0016) and unilateral (p < 0.013) cryptorchidism with success rates of respectively 23% and 19%. Linear and logistic regression analysis on the results obtained by treatment of bilateral disease showed that all treatments were more successful the younger the age of the boys. The data indicated that bilateral and unilateral cryptorchidism respond differently to hormonal treatment. We conclude that the success rates obtained in this study justify the use of hCG in prepubertal boys with cryptorchidism.

Hormonal treatment of cryptorchidism--hCG or GnRH--a multicentre study.

In a modified, double-blind controlled study, 163 prepubertal boys (aged 1.8-13.0 years) with bilateral and 94 (aged 1.5-13.1 years) with unilateral cryptorchidism were allocated to treatment with either human chorionic gonadotrophin (im), gonadotrophin releasing hormone (intranasally) or placebo (intranasally). In individuals with the bilateral condition treatment with human chorionic gonadotrophin resulted in complete descent of both testes in 23% of patients. Treatment with human chorionic gonadotrophin in unilateral cryptorchidism resulted in complete descent in 19% of patients; all results were significantly better than those obtained with gonadotrophin releasing hormone or placebo. Linear and logistic regression analysis of the results obtained by treatment of bilateral disease showed that all treatments were more successful the younger the age of the boys. The data indicated that bilateral and unilateral cryptorchidism respond differently to hormonal treatment. We suggest that human chorionic gonadotrophin should be the first choice of treatment for prepubertal boys older than one year.

[Treatment of girls with Turner's syndrome with growth hormone and estrogen--1-year experiences]. / Vaeksthormon- og østrogenbehandling af piger med Turner's syndrom--et års erfaringer.

Girls with Turner's syndrome are characterized by growth retardation and defective pubertal development, among other features. In this investigation, 40 girls with Turner's syndrome were treated with growth hormone in doses of 0.1 IU/kg/day (group 1, n = 14), oral oestradiol in doses of 0.01 mg/kg/day (group 2, n = 8) or a combination of these (group 3, n = 18), depending on the bone age. All three forms of treatment increased the height velocity significantly. The combined treatment increased the height velocity more than the growth hormone of oestradiol alone (p less than 0.05). In group 2, a pronounced progression of bone age leading to a decrease in the prognosis of final height was observed. The serum insulin-like growth factor I was unchanged in group 2 while this rose in groups 1 and 3. Pubertal development was, by and large, satisfactory. No serious side effects were observed. Treatment of girls with Turner's syndrome with growth hormone should not be supplemented with oestrogen prior to the bone age of 11 years. The initial dosage of oestradiol should be less than 0.01 mg/kg/day, but the subsequent increase should be adjusted individually.

Predicting and monitoring of growth in children with short stature during the first year of growth hormone treatment.

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.

A nation-wide cross-sectional study of urinary albumin excretion rate, arterial blood pressure and blood glucose control in Danish children with type 1 diabetes mellitus. Danish Study Group of Diabetes in Childhood.

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)

Age-related reference values for ionized calcium in the first week of life in premature and full-term neonates.

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.

Treatment of cryptorchidism with human chorionic gonadotropin or gonadotropin releasing hormone. A double-blind controlled study of 243 boys.

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.

Oestrogen therapy in Turner's syndrome.

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.