Normal spontaneous and stimulated GH levels despite decreased IGF-I concentrations in cystic fibrosis patients.

OBJECTIVE: The aim of the present study was to investigate whether patients with cystic fibrosis (CF) are GH resistant with increased GH release and decreased concentrations of IGF-I as a result of malabsorption, increased catabolism and impaired glucose tolerance. DESIGN: Twenty CF patients were included, ten with normal glucose tolerance (five male, five female, median age 25.5 years (range 20-31)) and ten with diabetes mellitus (five male, five female, median age 25.3 years (range 17-45). Twenty healthy individuals served as controls (ten male, ten female, median age 28.4 years (range 18-36)). METHODS: GH status was evaluated by 12h spontaneous GH release during the night time, arginine-stimulated GH release and the basal concentrations of IGF-I and insulin-like growth factor-binding protein-3 (IGFBP-3). Twelve hour spontaneous GH profiles were estimated using a constant blood withdrawal technique with sampling every 30min and the Pulsar method was used for the analysis of profiles. RESULTS: No significant differences were found in spontaneous and stimulated GH release in CF patients compared with healthy controls, whereas IGF-I and IGFBP-3 were significantly decreased in CF patients compared with healthy controls. The combination of reduced IGF-I and IGFBP-3 with normal GH release points to a relative GH resistance or a disturbance in the pituitary axis in patients with CF. The spontaneous GH release, the stimulated GH release and the basal concentrations of IGF-I and IGFBP-3 were not significantly different in diabetic CF patients compared with CF patients with normal glucose tolerance and the presence of diabetes mellitus was not consistent with increased GH resistance in CF patients. CONCLUSION: CF patients with normal glucose tolerance and diabetic CF patients had normal GH release and decreased concentrations of IGF-I indicating a relative GH resistance.

[Allergy and bronchial reactivity in children and adolescents from Copenhagen]. / Allergi og bronkial reaktivitet hos børn og unge fra København.

The relationship between bronchial responsiveness and the results of a skin prick test was studied in 527 children and adolescents from Copenhagen. All participants completed a questionnaire concerning birth weight, breastfeeding, month of birth, month of examination, allergic symptoms in themselves or their parents. Furthermore, skin prick test reactivity to nine common aero-allergens, lung function, serum IgE, and bronchial responsiveness to histamine and exercise were measured. A total of 158 (30%) subjects showed signs of allergy (defined as a positive reaction to the skin prick test), of whom 53 (10%) subjects had positive skin reactivity and 105 subjects had moderate skin reactivity; 366 (70%) subjects had no signs of allergic disease as measured by the pride test. The most important marker for the degree of bronchial responsiveness was asthma (p < 0.001), month of examination (p < 0.01) and allergy (skin reactivity to one or more allergens) (p < 0.05). Furthermore, the degree of bronchial responsiveness to inhaled histamine was significantly related to a history of asthma in two first degree relatives (p < 0.01) and the skin reactivity to house-dust mites (p < 0.01), whereas the degree of bronchial responsiveness to exercise was significantly associated with the level of serum IgE (p < 0.05), month of birth (p < 0.001) and birth weight (p < 0.05). In conclusion, allergy is an important risk factor for the presence of increased degree of bronchial responsiveness to inhaled histamine and to exercise.

[Reduced concentration of insulin-like growth factor I in patients with cystic fibrosis]. / Nedsatte koncentrationer af insulin-like growth factor I hos patienter med cystisk fibrose.

Cystic fibrosis is frequently accompanied by a catabolic condition with low body mass index caused by a number of disease complications. Insulin-like growth factor I (IGF-I) is an anabolic hormone and an important marker of nutritional status, liver function and linear growth. Using radioimmunoassay we measured IGF-I once in 235 of our 240 patients (114 males, 121 females, median age 16.2 years, range 0.1-44.0 years). IGF-I was significantly reduced compared with a healthy Scandinavian control population: Mean (-2SD to +2SD) IGF-I-SD score -0.97 (-3.7 to 1.7) in males and -0.67 (-3.2 to 1.9) in females, both values were significantly different from zero (p < 0.001). Height SD score was -0.95 (-3.3 to 1.4) in males and -0.81 (-3.2 to 1.6) in females (p < 0.001). The low IGF-I concentrations may reflect the catabolic state of many patients with cystic fibrosis and play a part in their abnormal growth pattern.

Pubertal development in Danish children: comparison of recent European and US data.

Two recent epidemiological studies (PROS and NHANES III) from the USA noted earlier sexual maturation in girls, leading to increased attention internationally to the age at onset of puberty. We studied the timing of puberty in a large cohort of healthy Danish children in order to evaluate differences between USA and Denmark, as well as to look for possible secular trends in pubertal development. Healthy Caucasian children from public schools in Denmark participated in the study which was carried out in 1991-1993. A total number of 826 boys and 1,100 girls (aged 6.0-19.9 years) were included, and pubertal stages were assessed by clinical examination according to methods of Tanner. In boys testicular volume was determined using an orchidometer. We found that age at breast development 2 (B2) was 10.88 years, and mean menarcheal age was 13.42 years. Girls with body mass index (BMI) above the median had significantly earlier puberty (age at B2 10.42 years) compared with girls with BMI below the median (age at B2 11.24 years, p < 0.0001). Similarly, menarcheal age was significantly lower in girls with BMI above the median compared with girls with BMI below the median (13.12 vs. 13.70 years, p = 0.0012). In Danish boys we found that age at genital stage 2 (G2) was 11.83 years. Both sexes were significantly taller compared with data from 1964, but timing of pubertal maturation seemed unaltered. Finally, puberty occurred much later in Denmark compared with recent data from USA. We could not detect any downwards secular trend in the timing of puberty in Denmark between 1964 and 1991-1993 as seen in the US. Obesity certainly plays a role in the timing of puberty, but the marked differences between Denmark and USA cannot be attributed exclusively to differences in BMI. A possible role of other factors like genetic polymorphisms, nutrition, physical activity or endocrine disrupting chemicals must therefore also be considered. Therefore, we believe it is crucial to monitor the pubertal development closely in Denmark in the coming decades.

Pubertal maturation of the internal genitalia: an ultrasound evaluation of 166 healthy girls.

Pelvic ultrasound is an important tool in the management of children with disturbances of pubertal development; interpretation requires an understanding of the normal relationship between maturation of internal genitalia and the appearance of secondary sex characteristics. We performed pelvic ultrasound examinations in 166 healthy females aged 6.4-25.4 years, and related uterine and ovarian volumes and size of follicles to age and pubertal stage. We demonstrated growth of the uterus and ovaries before the appearance of breast development and pubic hair growth. In prepubertal girls, uterine and ovarian growth was related to height (p = 0.008 and p = 0.010, respectively). From breast stages 1-5, median uterine and ovarian volumes increased from 1.6 ml to 43 ml, and from 1.2 ml to 7.3 ml, respectively (p < 0.0001). Uterine growth continued several years after menarche. Postmenarcheal uterine growth was related to the number of years after menarche (p < 0.001), but not to height, weight or age. Follicles were seen in 86% of prepubertal girls and in 99% of pubertal girls. Follicles up to 8 mm in diameter were observed in prepubertal girls. Maturation of the internal genitalia begins before the onset of clinical puberty, and extends well into the second decade.

Serum ferritin in children and adolescents. Results from population surveys in 1979 and 1986 comprising 1312 individuals.

Iron stores were assessed by measurement of serum ferritin in a population survey comprising 436 randomly selected urban Danish schoolchildren (219 boys, 217 girls) 7 to 17 years old. Median ferritin values were similar in boys and girls 7 to 13 years old, while 14- to 17-year-old boys had significantly higher values than girls of similar age (p < 0.0001). Boys had stable median ferritin values from 7 to 15 years of age, after which a significant rise was found from 16 to 17 years of age (p < 0.01). Girls had unchanged median ferritin values from 7 to 11 years of age, after which a significant decrease was found from 12 to 17 years of age (p < 0.01). The frequencies of low ferritin values < 16 micrograms/l (indicating absent iron stores) were: Children 7 to 11 years, 1.0%. Boys 12 to 15 years, 4.5%; 16 to 17 years, 0%. Girls 12 to 15 years, 7.6%; 16 to 17 years, 16.7%. Ferritin levels in the reported 1986 survey were significantly higher than those obtained in a similar survey in the same area in 1979. The results indicate an overall increase in iron stores in Danish schoolchildren and adolescents during 1979-1986, possibly due to an increase in the consumption of meat, and in the use of vitamin-mineral supplements containing iron.

Doppler assessment of flow velocity in the uterine artery during pubertal maturation.

The aim of this study was to investigate the possible changes in uterine artery flow velocity during puberty and young adulthood. In a cross-sectional study, 133 healthy volunteers aged 6.7 to 25.4 years were investigated. Pubertal development according to the Tanner classification was recorded in each subject. Uterine arteries were visualized by transabdominal color-coded ultrasound. Maximum, minimum and time averaged maximum flow velocities were measured and the pulsatility index (PI) was calculated electronically. When flow velocity was compared between patients at different rates of pubertal development, we found that the average velocity increased from Tanner breast stages I and II to V, followed by a slight decrease in adults (p < 0.0001). The PI varied significantly from stage I to adult (p < 0.0001). The PI was similar in breast stage I, stage II and in adults, with median 4.7 (range 2.7-8.5), 6.1 (range 3.0-7.8) and 4.3 (range 1.9-8.1), respectively. The PI decreased in stages III and IV to 2.6 (1.8-8.4) and 2.8 (1.2-7.9), respectively, whereas stage V was intermediate, at 3.7 (1.1-6.3). The variance of PI was independent of age. In summary, we demonstrated a significant increase in the uterine artery flow velocity during puberty. Furthermore, a significant decline in vascular resistance expressed by the PI was observed in the mid-pubertal period, reflecting increasing blood flow to the rapidly growing uterus.

Bone mineral status in 134 patients with cystic fibrosis.

AIM: To investigate bone mineral status in patients with cystic fibrosis (CF). PATIENTS AND METHODS: Whole body bone mineral content (BMC), projected bone area, and bone mineral density (BMD) were determined by dual energy x ray absorptiometry in 134 patients with CF and compared with 396 healthy controls. RESULTS: In patients 19 years of age, BMD and BMC for age were significantly reduced. CONCLUSION: Short and narrow bones were the main reasons for reduced BMC for age in patients

Secular changes in anthropometric data in cystic fibrosis patients.

The aim of this study was to study the secular changes in anthropometric data over calendar time in patients with cystic fibrosis (CF). Growth curves were constructed for 270 patients based on height and weight registrations from the medical files. Height, body mass index (BMI), magnitude of pubertal peak height velocity (PHV) and age at PHV were analysed for possible secular changes from the 1960s to the 1990s. There was a significant change in height over calendar time in only 1 of 12 age groups. BMI showed a significant increase in 10- and 15-y-old boys and girls and in 5-y-old girls. The magnitude of PHV changed significantly over time, whereas age at PHV was constant. No significant changes in height and age at PHV over calendar time were observed; this was probably due to a selection bias since the oldest patients, who survived to be part of the present investigation, represented milder forms of the disease. The increase in BMI and change in magnitude of PHV over calendar time may reflect the improvement in treatment leading to a better survival and clinical status through puberty. The increase in BMI and change in magnitude of PHV were sufficient to overcome the selection bias from older patients with milder disease.

Central precocious puberty in girls: internal genitalia before, during, and after treatment with long-acting gonadotropin-releasing hormone analogues.

Pelvic ultrasonography was systematically performed on 33 girls with idiopathic central precocious puberty to investigate the impact of treatment with gonadotropin-releasing hormone analogues on female internal genitalia. All girls were treated with a long-acting gonadotropin-releasing hormone analogue (Decapeptyl Depot; Ferring Co., Copenhagen, Denmark) 75 micrograms/kg every 4 weeks. Before, during, and after treatment, pelvic ultrasonography was performed and ovarian and uterine volumes were calculated. The size of follicles > 5 mm were accurately measured. The results were related to a normative study of healthy Danish schoolgirls. Our data demonstrated that ovaries and uterus are enlarged in a significant number of girls (50%) with the diagnosis of central precocious puberty at the time of diagnosis. Median ovarian volume at time of diagnosis was 1.1 standard deviation scores (range -0.6 to 3.2 SD), median uterine volume was 1.8 standard deviation scores (range 0.0 to 3.5 SD). Within 3 months of treatment, both ovarian and uterine volumes decreased significantly (p < 0.01) to normal values appropriate for age. Median ovarian volume after 3 months of treatment was 0.0 SD (range -2.4 to 1.5 SD); median uterine volume was 0.7 SD (range -0.6 to 4.1 SD). Ovarian and uterine volume remained within normal range (< 2 standard deviation scores) after discontinuation of treatment. Follicles and macrocysts regressed during treatment. None of the girls' ovaries had a polycystic appearance during or after treatment with the gonadotropin-releasing hormone analogue. Our results confirmed pelvic ultrasonography as a reliable tool for investigation of internal genitalia in girls with precocious puberty and as a valid method for evaluation of the efficacy of treatment with gonadotropin-releasing hormone analogues. We suggest that repeated investigations be performed when evaluating treatment because the morphologic changes, including follicular maturation or regression, reflect ovarian stimulation or suppression. We found no evidence that girls with precocious puberty treated with long-acting gonadotropin-releasing hormone analogues have enlarged polycystic ovaries develop.

The distribution of bronchial responsiveness to histamine and exercise in 527 children and adolescents.

The aim of the study was to describe the bronchial responsiveness to inhaled histamine and exercise in a randomly selected group of 527 children and adolescents from Copenhagen, aged between 7 to 16 years. The distribution of the bronchial responsiveness was described as (1) the provoking concentration that causes a 20% reduction in FEV1 (2) the dose-response slope (DRS), that is, the linear slope of the dose-response curve, and (3) reduction in FEV1 after 6 minutes of exercise on a treadmill. The distribution of the concentration that causes a 20% reduction in FEV1 in the responsive range was not significantly different from a unimodal distribution, although the findings were skewed toward the less responsive end of the range (p greater than 0.05). The subjects with asthma represented a subgroup within the responsive distribution tail rather than a separate distribution peak. In asymptomatic individuals, the values of DRS were distributed symmetrically on a logarithmic scale. The deviation from normal was such that the standard deviation only slightly underestimated the "normal" range. The distribution of the bronchial response to exercise was found to be significantly different from a normal distribution. However, a significant relationship was found between the bronchial response to inhaled histamine and exercise (p less than 0.0001). We conclude that there is a log-normal distribution of the bronchial response to inhaled histamine in a random sample of children and adolescents.

Distribution of serum IgE in children and adolescents aged 7 to 16 years in Copenhagen, in relation to factors of importance.

The distribution of total serum-IgE and factors of importance for the level of IgE was studied in a random sample of 508 children and adolescents, aged 7-16 years, from Copenhagen. A detailed history about asthma, rhinitis, dermatitis and urticaria was obtained, and a physical examination, skin prick test with 9 common allergens, lung function test, bronchial challenge with inhaled histamine and exercise, and measurement of IgE (kU/l) were performed. The distribution of IgE among children and adolescents was found to exhibit a log normal distribution and a positive skin prick test, allergic symptoms, a family history of allergic diseases, age and smoking were found to be significantly related to an increased level of IgE. No relationship was found between increased bronchial responsiveness and IgE. The geometric mean of "normal" values of IgE (*1 SD and *2 SD) of the Danish children and adolescents was 18 kU/l (*4.7, *18.2), suggesting that normal IgE values were within 330 kU/l. Measurement of IgE as the only screening for allergic disease is unreliable, as the predictive value of an elevated IgE in population samples was found to be 50%, whereas misclassification (1-specificity) of asymptomatic subjects as allergic because of an increased IgE was low (4%). In conclusion, total IgE is highly influenced by allergen skin reactivity. Further, this study suggests that normal IgE values were within 330 kU/l, although the range was wide.

Diminished concentrations of insulin-like growth factor I in cystic fibrosis.

Cystic fibrosis is frequently accompanied by a catabolic condition with low body mass index caused by a number of disease complications. Insulin-like growth factor-I (IGF-I) is an anabolic hormone and an important marker of nutritional status, liver function, and linear growth. Available data on IGF-I in cystic fibrosis are sparse and conflicting. From 1990-3, 235 of our 240 patients (114 males, 121 females, median age 16.2 years, ranged 0.1-44.0 years) had IGF-I measured once by radioimmunoassay. IGF-I was significantly reduced compared with a healthy Scandinavian control population: mean (-2 SD to +2 SD) IGF-I SD score was -0.97 (-3.7 to 1.7) in males and -0.67 (-3.2 to 1.9) in females. Height SD score was -0.95 (-3.3 to 1.4) in males and -0.81 (-3.2 to 1.6) in females. In patients who were still in the growth period a significant correlation of IGF-I SD score to height SD score (r = 0.28, p < 0.001) was found. The low IGF-I concentrations may reflect the catabolic state of many patients with cystic fibrosis and play a part in their abnormal growth pattern.

Atopy and bronchial responsiveness in random population sample of 527 children and adolescents.

The relationship between bronchial responsiveness, lung function, and results of skin prick testing was studied in 527 children and adolescents from Copenhagen. All participants completed a questionnaire concerning allergic symptoms (asthma, rhinitis, atopic dermatitis, and urticaria). Furthermore, skin prick test reactivity to nine common aeroallergens, lung function, serum IgE and bronchial responsiveness to histamine and exercise were measured. A total of 53 subjects were atopic, (skin prick 3+), 105 subjects had moderate skin reactivity (1-2+), and 366 subjects had no signs of atopic disease (prick test negative); 58% of the subjects with skin test reactivity (1-3+) were asymptomatic. Increasing degree of atopy was correlated significantly with symptoms such as asthma, rhinitis, dermatitis, and urticaria (P less than .001); increasing level of IgE (P less than .001); month of birth (P = .001); and family history of allergic diseases (P less than .05). The most important markers for the degree of bronchial responsiveness to inhaled histamine were the presence of respiratory symptoms (P less than .001), the degree of atopy (P = .001), a history of asthma in at least two first degree relatives (P less than .01), and the skin reactivity to house dust mites (P = .001), horse epithelium (P = .01), Alternaria iridis, and dog epithelium (P less than .05). In contrast, the degree of bronchial responsiveness to exercise was significantly correlated with asthma (P less than .001), the level of IgE (P less than .05), month of birth (P less than .001), and birth weight (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Sensitivity and specificity of the histamine challenge test for the diagnosis of asthma in an unselected sample of children and adolescents.

The purpose of this investigation was to study factors of importance for the degree of bronchial responsiveness and, furthermore, to evaluate the sensitivity, specificity and predictive value of a bronchial challenge test with histamine for the diagnosis of asthma in 495 randomly selected children and adolescents, aged 7-16 yrs, from Copenhagen, Rigshospitalet. Detailed history about allergic symptoms, physical examination and bronchial histamine challenge tests were performed at the out-patient clinic. Asthma, atopic disease and height were found to be of great importance for the degree of bronchial responsiveness, whereas the age, sex and smoking habits were of no significance. The percentage of asthmatics with bronchial hyperresponsiveness, i.e. sensitivity to the test, increased towards 100% on inhaling increasing concentrations of histamine, but this was accompanied by a decrease in specificity and predictive values of positive test in regard to the diagnosis of asthma. However, lower concentrations of histamine may be preferable in order to distinguish between asthma and non-asthma in population samples, as inhalation of 2.4 mg.ml-1 and provocative concentration producing a 20% fall in forced expiratory volume in one second (FEV1) (PC20) provided an acceptable sensitivity (57%), specificity (98%), and predictive value of a positive test (60%). We conclude that as regards the diagnosis of asthma, a low predictive value confirms that the bronchial challenge test plays only a supplementary, but valuable, role in detecting the disease in population samples.

Bronchial responsiveness in children and adolescents: a comparison between previously asthmatic, currently asthmatic, and normal subjects.

The aim of this study was to examine the degree of bronchial responsiveness in previously asthmatic subjects. Of 253 patients, born within 1964-1974, followed in the pediatric department at the University hospital in Copenhagen, 224 subjects (89%) were successfully contacted by telephone; of these 195 complained of persistent asthma and 29 (13%) had had no asthmatic symptoms for at least 2 years. On the basis of the degree of respiratory symptoms, 58 individuals were examined at the outpatient clinic. Of these, (1) 19 were previously asthmatics, (2) 20 had current mild asthma, and (3) 19 had current severe asthma. Furthermore, 19 healthy individuals, age-matched with the preceding asthmatic subjects, were selected as controls. In all subjects, skin prick tests, lung function tests, and bronchial challenge tests with inhaled histamine and bronchodilator were performed. Furthermore, the subjects measured their peak expiratory flow (PEF) twice daily during a period of 4 weeks. Of the 39 current asthmatic subjects, 82% had a PC20 < or = 8 mg/ml, whereas all previously asthmatic subjects and the controls had a PC20 > 8 mg/ml. The degree of bronchial responsiveness as indicated by the dose-response slope (DRS), the percentage change in forced expiratory volume in 1 sec (FEV1) per inhaled mumol of histamine, was found to be significantly higher in previously asthmatic patients (median logDRS 0.1 delta %FEV1/mumol) than in controls (median logDRS-0.4 delta %FEV1/mumol) (p < 0.001). Furthermore previously asthmatic subjects had significantly increased change in FEV1 after inhalation of bronchodilator and peak expiratory flow variability compared to controls. These findings suggest that apparently asymptomatic previously asthmatic subjects have increased airway variability.

The effect of astemizole on bronchial hyperresponsiveness and exercise-induced asthma in children.

The ability of the new generation H1-receptor antagonist, astemizole, to prevent histamine-induced airway obstruction and exercise-induced asthma (EIA) was studied in 20 children with asthma. The study was a randomised clinically controlled trial of oral astemizole versus placebo in a cross-over study. In each of the two treatment periods the children were tested at days 0, 6, 15 and 22 of therapy. The two treatment periods were separated by a washout period of 50 days, and at each visit a bronchial challenge with increasing concentrations of histamine followed by an exercise test was performed, and peak flow and asthmatic symptom score were recorded daily. The children tolerated significantly higher mean concentrations of histamine when treated with astemizole compared with placebo (P less than 0.001). Astemizole postponed the response to exercise, but no change in the maximal response was found. No differences between the treatment periods were found regarding frequency of asthmatic symptoms or the daily recording of peak flow.

Controlled trial of inhaled budesonide in patients with cystic fibrosis and chronic bronchopulmonary Psuedomonas aeruginosa infection.

The efficacy and safety of anti-inflammatory treatment with inhaled glucocorticosteroids in patients with cystic fibrosis (CF) and complicating chronic Pseudomonas aeruginosa (P.a.) lung infection was studied in a placebo-controlled, parallel, double-blind single center trial. Active treatment consisted of budesonide dry powder, 800 microg twice daily, delivered from a Turbuhaler. The study period covered two successive 3-mo intervals between elective courses of intravenous anti-Pseudomonas antibiotics. Fifty-five patients entered the study, with a mean age of 20 yr and a mean FEV1 of 63% of predicted. Analysis of all patients entered, irrespective of trial adherence ("intention to treat"), showed a decrease in FEV1 in the first period of -0.032 L in patients on budesonide versus -0.187 L in patients on placebo (p = 0.08). The corresponding figures for the patients adhering to the protocol during the first period were -0.017 L versus -0.198 L (p < 0.05, confidence interval of the difference: -0.035 to +0.327 L). For all patients entered, as well as for patients adhering to the trial, there was always a trend in favor of budesonide, as judged by changes in FEV1 and FVC in both 3-mo periods. None of the patients had asthma, but the patients on budesonide had a mean improvement in histamine reactivity of +1.15 dose steps over the entire 6-mo period, as opposed to +0.017 dose steps in patients on placebo (p < 0.05). There was also a significant (p = 0.01) correlation between pre-trial histamine reactivity and the change in FEV1 in the first period in patients on budesonide. We conclude that inhaled glucocorticosteroids can be of short-term benefit in patients with CF and chronic P.a. infection and that those patients most likely to benefit from this treatment are patients with hyperreactive airways. Prolonged studies in larger number of patients are necessary to determine the long-term efficacy of this treatment.