[The practice guideline 'Diabetes mellitus type 2' (second revision) from the Dutch College of General Practitioners; a response from the perspective of general practice]. / De standaard 'Diabetes mellitus type 2' (tweede herziening) van Het Nederlands Huisartsen Genootschap; reactie vanuit de huisartsgeneeskunde.

The publication of the practice guideline 'Diabetes mellitus' by the Dutch College of General Practitioners in 1989 marked the start of an era of publication of several guidelines that helped general practitioners using evidence-based medicine in clinical practice; the guidelines also helped to teach students. The second revision of this guideline presents many improvements, especially simplifications in the medication-schedules. However, the new recommendation to use thiazolidines is based on only one large study and has some unpractical aspects. The new guidelines do not mention preventive action, nor advice regarding early detection. Clinical practice has changed in recent years with the introduction of nurses specialising in diabetes and, despite published research on this subject, the guidelines do not give any recommendations for this. What is also missing are national clinical guidelines for doctors specialising in internal medicine. When patients do not respond to treatment according to the general practitioners' guidelines and are referred to a specialist in internal medicine, the treatment is diverse and seems to be doctor-dependent. It is important that treatment there be standardised as well so that general practitioners can refer more effectively.

[Post mortem semen acquisition: not without 'informed consent']. / Semenafname post mortem: niet zonder 'informed consent'.

Recently, two requests for post-mortem semen acquisition were evaluated and rejected. The first request was from the wife of a man who died after the wedding night. In the second case, the wife requested that electroejaculation be done on a man who was brain dead because of a gunshot wound in the head. In both cases, the fact that there was no written consent from the men involved before they died was the deciding reason not to grant the requests. Written consent is legally and ethically seen as the final episode of a period in which persons have considered the consequences of the acquisition, storage and use of semen after the death of the husband.

Plasma levels of insulin-like binding protein-2 in prepubertal short children and its diagnostic value in the evaluation of growth hormone deficiency.

AIM: This study was designed to investigate whether determination of plasma insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) levels could be of benefit in the evaluation of childhood growth hormone (GH) deficiency (GHD). METHOD: A retrospective analysis was performed on 91 prepubertal children referred for investigation of short stature. Maximal GH levels in plasma after provocative stimuli were between 1.0 and 93.0 mU/l, 6 subjects exhibiting peak values of <5 mU/l. Initially a GH peak of 20 mU/l was used as a cutoff limit to define GHD and idiopathic short stature (ISS) patients. The results of GH provocative tests were compared to age- and gender-based standard deviation scores (SDS) of plasma IGFBP-2, IGF-I, IGFBP-3 and the molar ratios of the latter two to IGFBP-2. The respective normative range values for these parameters were determined in plasma samples from 353 healthy children (i.e. 171 girls, 182 boys). RESULTS: Circulating IGFBP-2 levels did not correlate with height SDS, height velocity SDS or the peak GH levels after provocative stimuli. A weak negative relationship was found between IGFBP-2 and IGF-I. Plasma levels of IGFBP-2 in GHD patients were higher than those of ISS children, who had normal levels. Although at the optimal cutoff point of -0.71 SDS 91.5% of the GHD patients were identified correctly, a substantial proportion (71.9%) of the ISS subjects also had IGFBP-2 levels above this limit. The use of various combinations of IGFBP-2, IGF-I, IGFBP-3 and the derived ratios only slightly improved the diagnostic efficiency as compared to the results of the individual tests. Neither IGFBP-2 nor the IGFBP-3/IGFBP-2 and IGF-I/IGFBP-2 ratios were found to be related to the short- (1 year) or long-term (3 years) growth response to GH therapy. CONCLUSION: It is concluded that none of the tests investigated, either alone or in various combinations, are reliable in either predicting the peak GH level after provocative stimuli in prepubertal short children or in predicting their growth response to GH.

A nationwide cohort study on Creutzfeldt-Jakob disease among human growth hormone recipients.

OBJECTIVE: In 1991, a Dutch patient who had been treated from 1963 to 1969 with human-derived growth hormone died of Creutzfeldt-Jakob disease (CJD). This study was performed to investigate whether among other Dutch human growth hormone recipients there were clinically suspected cases of iatrogenic CJD. METHODS: In a retrospective cohort study, all patients (n = 564) treated with human-derived growth hormone before May 1985 and recorded in the Dutch National Growth Registry were followed up until January 1995 for a clinical diagnosis of CJD. For this purpose, all human growth hormone recipients were linked to a database of the Foundation for Health Care Information comprising hospital discharges with a clinical diagnosis of iatrogenic CJD. Linkage of the two databases was performed on the basis of date of birth and gender. Subsequently, verification of patient's name and initials of the positively matched pairs took place. RESULTS: Linkage provided 37 positively matched pairs concerning 29 individual patients. After verification, no name from the hospital discharge records corresponded to the names of the human growth hormone recipients. CONCLUSIONS The follow-up of 564 Dutch human growth hormone recipients, who had been treated with human growth hormone until 1985 did not establish any clinically suspected case of iatrogenic CJD. Future cases, however, can still emerge due to the potentially long incubation period of prion diseases.

Repeat noninvasive bladder pressure measurements with an external catheter.

PURPOSE: Previously it has been shown that an objective diagnosis of infravesical obstruction can be made by combining the maximum flow rate and isovolumetric bladder pressure. We evaluate a noninvasive method to measure isovolumetric bladder pressure to help develop a noninvasive modality for diagnosing obstruction. MATERIALS AND METHODS: An external catheter consisting of an incontinence condom, tube and pressure transducer was used. Flow rate through the catheter was remotely interrupted to measure the bladder pressure in the condom. Two series of measurements were done in 11 healthy male volunteers. In the first series we determined whether voiding was affected after flow rate interruption. In the second series we analyzed repeat pressure measurements of 1 voiding to determine whether maximum isovolumetric pressure depended on bladder volume. RESULTS: Flow rate was unaffected after interruption for pressure measurement. Repeat measurements of isovolumetric bladder pressure demonstrated that the pressure depended significantly on bladder volume. Average maximum isovolumetric pressure was 12.2 kPa. at a bladder volume of 251 ml. CONCLUSIONS: As no inhibition of voiding was noted after a single pressure measurement, repeat noninvasive measurements can be made on voiding. With repeat measurements the dependence of isovolumetric bladder pressure on bladder volume can be considered to obtain a reliable estimate of pressure as a basis for a noninvasive diagnosis of obstruction.

Plasma levels of insulin-like growth factor (IGF)-I, IGF-II and IGF-binding protein-3 in the evaluation of childhood growth hormone deficiency.

BACKGROUND: Traditionally, measurement of plasma IGF-I and more recently of IGFBP-3 are used to distinguish GHD from idiopathic short stature in slowly growing children, using a single blood sample. In earlier studies it was claimed that IGFBP-3 was superior to IGF-I, but more recently doubts around this claim have arisen. The role of serum IGF-II has never been studied extensively. On theoretical grounds, it can also be hypothesized that molar ratios of these peptides might be of additional value. DESIGN: Retrospective, multicentre, cohort study. PATIENTS: 96 children evaluated for short stature. METHODS: Serum IGF-I, IGF-II, IGFBP-3 and various molar ratios were, after correction for age and sex using SD scores, compared to the maximum serum GH peak after two standard provocation tests using four different methods (t-test, chi2, likelihood ratios and ROC curves). In addition, the correlations between these parameters and the short-term (1 year) and long-term (3 years) response to GH therapy were calculated. RESULTS: IGF-I performed better than IGFBP-3, but the best results were achieved by the molar ratio IGF-I:IGF-II. However, IGFBP-3 correlated better with the short-term response to GH therapy than IGF-I or the ratios, and none of the parameters investigated was found to be related to the response of long-term GH therapy.

Quality of life in short adults.

The use of (costly) growth hormone (GH) treatment in short children is often justified by the assumption that short stature considerably reduces quality of life in adults. We tested this assumption in 5 groups of short adults: 25 patients with isolated GH deficiency; 17 male patients with childhood onset renal failure; 25 women with Turner syndrome and 26 patients who were presented as a child to a paediatrician for idiopathic short stature. A group of 44 short individuals with presumably idiopathic short stature, who had not been presented to a paediatrician for short stature, was sampled from the general population ('normal shorts'). We measured quality of life in terms of socio-economic variables, the Nottingham Health Profile and time trade-off. The mean height of most groups was close to the 3rd percentile. The chance of having a partner was low for all groups, except for the normal shorts. Problems with job application were only reported in Turner syndrome. The scores on the Nottingham Health Profile were all within the normal range, but GH-deficient adults had a higher score on the domain energy than normal shorts. Women with Turner syndrome, individuals with renal failure, and those with idiopathic short stature had a wish to be taller, with an estimated reduction in quality of life of 2-4% (time trade-off). As the normal shorts did not show any sign of a reduced quality of life, we falsify the assumption of a direct relation between short stature and quality of life. The complaints of patients with idiopathic short stature around the 3rd percentile seem to be the result of unsuccessful coping strategies.

Final height in central precocious puberty after long term treatment with a slow release GnRH agonist.

OBJECTIVE: To study the resumption of puberty and the final height achieved in children with central precocious puberty (CPP) treated with the GnRH agonist triptorelin. PATIENTS: 31 girls and five boys with CPP who were treated with triptorelin 3.75 mg intramuscularly every four weeks. Girls were treated for a mean (SD) of 3.4 (1.0) years and were followed up for 4.0 (1.2) years after the treatment was stopped. RESULTS: The rate of bone maturation decreased during treatment and the predicted adult height increased from 158.2 (7.4) cm to 163.9 (7.5) cm at the end of treatment (p < 0.001). When treatment was stopped bone maturation accelerated, resulting in a final height of 161.6 (7.0) cm, which was higher than the predicted adult height at the start of treatment (p < 0.001). Height at the start of treatment was the most important factor positively influencing final height (r = 0.75, p < 0.001). Bone age at cessation of treatment negatively influenced final height (r = -0.52, p = 0.03). A negative correlation between bone age and height increment after discontinuation of treatment was observed (r = -0.85, p = 0.001). Residual growth capacity was optimal when bone age on cessation of treatment was 12 to 12.5 years. Body mass index increased during treatment and remained high on cessation. At final height, the ratio of sitting height to subischial leg length was normal. Menarche occurred at 12.3 (1.1) years, and at a median (range) of 1.1 (0.4 to 2.6) years after treatment was stopped. The ovaries were normal on pelvic ultrasonography. CONCLUSIONS: Treatment of CPP with triptorelin increases final height, with normal body proportions, and seems to increase body mass index. The best results were achieved in girls who were taller at the start of treatment. Puberty was resumed after treatment, without the occurrence of polycystic ovaries.

Spontaneous growth and response to growth hormone treatment in children with growth hormone deficiency and idiopathic short stature.

Isolated idiopathic growth hormone deficiency (GHD) and idiopathic short stature (ISS) can be difficult to distinguish, but the therapeutical consequences are different. In this report the data on final height of untreated and treated children with GHD and ISS are reviewed. Untreated GH-deficient individuals who underwent spontaneous puberty (22 male, 14 female patients) reached a mean final height of 4.7 SD (range 3.9 to 6.0) below the population's mean. If puberty was induced (19 male patients), mean final height SD score (SDS) was -3.1. Traditional regimens of GH administration (2-4 injections/wk) in 236 children (184 boys, 52 girls) with GHD and spontaneous puberty resulted in a final height SDS of -2.8 (range -1.5 to -4.7). In 190 children in whom puberty was induced (139 boys, 51 girls) mean final height was -1.6 (range - -1.1 to -2.4). The mean gain in final height SDS is therefore estimated at 1.5-2.0 in average cases, and 3.5 in extreme cases. Preliminary data suggest that on present regimens mean final height may approach target height. In untreated boys with ISS the mean final height was 2-5 cm lower than that predicted before puberty, whereas in girls it was almost equal to the prediction. After GH treatment the mean final height was 0.4-3.0 cm higher than the predicted adult height, which results in an average net gain in final height SDS of approximately 0.5-0.8 (3-5 cm).

Impaired social status of growth hormone deficient adults as compared to controls with short or normal stature. Dutch Growth Hormone Working Group.

OBJECTIVES: In adults with growth hormone deficiency (GHD) social problems have been reported, but so far the relative contributions of GHD, additional pituitary deficiencies and short stature have not been distinguished. We therefore compared social data from GHD patients with social data from controls with short or normal stature. Furthermore we investigated whether social problems are caused solely by the deficiency of GH or also by the associated absence of other pituitary hormones. DESIGN: A questionnaire was sent to patients and controls with items on education, profession, income, partner and living situation. PATIENTS: Two hundred and ten GHD patients treated in childhood but not in adulthood with GH (93 isolated GHD (IGHD), 111 patients with multiple pituitary deficiency (MPD)) were compared with 53 short controls (height in childhood < third percentile for population) and 39 normal stature controls. RESULTS: There were no differences between short and normal controls. There were also no differences between IGHD and MPD patients in any of the investigated items. GHD patients did not differ from controls on education level, but scored lower on the profession scale, had a lower income and had a partner less often; if they had a partner they less often had children; also, more of them lived with their parents. CONCLUSION: Since patients with multiple pituitary deficiency did not differ from patients with isolated growth hormone deficiency, this suggests that the lower scores on the social parameters are the result of the growth hormone deficiency itself. Since short stature controls had higher scores than patients with growth hormone deficiency and did not differ from normal stature controls in any of the aspects investigated, it seems unlikely that the problems of the patients with growth hormone deficiency can be attributed to short stature.

Catch-up growth in early treated patients with growth hormone deficiency. Dutch Growth Hormone Working Group.

Catch-up growth of 26 children with growth hormone deficiency during four years of growth hormone treatment, which was started young (< 3 years), was compared with that of 16 children with coeliac disease on a gluten free diet. In children with growth hormone deficiency mean (SD) height SD score increased from -4.3 (1.8) to -1.9 (1.4) and in patients with coeliac disease from -1.8 (0.9) to -0.1 (0.8). Height SD score after four years correlated positively with injection frequency and height SD score at start of treatment in children with growth hormone deficiency. All patients with coeliac disease reached a height above -2 SD scores after four years, while the height of 26% of children with growth hormone deficiency on daily injections and of 86% of children on 2 or 4 injections/week was still below -2 SD scores. In patients with growth hormone deficiency on daily injections with an initial height SD score between -2 and -4 catch-up was similar to that of patients with coeliac disease with a comparable initial height deficit. Growth hormone deficient children with an initial height SD score < -4 did not reach full catch-up growth within four years. In conclusion, catch-up growth in early treated children with growth hormone deficiency over four years is adequate provided that daily injections are given and the initial height SD score is not less than -4.

Long-term results of growth hormone therapy in children with short stature, subnormal growth rate and normal growth hormone response to secretagogues. Dutch Growth Hormone Working Group.

BACKGROUND AND OBJECTIVE: Growth hormone treatment in children with idiopathic short stature (ISS) leads to growth acceleration in the first years, but the effect on final height is still poorly documented. We therefore studied the long-term effect of GH therapy in children with idiopathic short stature. DESIGN: We have treated 27 prepubertal children with ISS with recombinant human GH (rhGH) in an initial dosage of 2 IU/m2 body surface/day subcutaneously, which was doubled either after the first year if the height velocity increment was less than 2 cm/year, or thereafter if height velocity fell below the P50 for bone age. Growth and bone maturation of the treatment group (ISS group, n = 21) were compared to those of an untreated control group with ISS (ISS controls, n = 27) and of a group of rhGH treated children with isolated GH deficiency (GHD group, n = 7). RESULTS: In 9 patients of the ISS group still on treatment, height standard deviation score (HSDS) for chronological age increased from -3.8 +/- 0.7 to -2.3 +/- 0.9 (mean +/- standard deviation) over 6 years, while in matched ISS controls HSDS for age did not change. HSDS for age in the GHD group increased from -3.9 +/- 0.6 to -1.8 +/- 0.7 after 4 years, significantly more than the ISS group. Bone maturation was accelerated in the ISS and GHD groups. HSDS for bone age and predicted adult height did not change in either group. Final height in 12 children of the ISS group was -2.6 +/- 1.0 SDS. In the untreated controls final height was similar. A low integrated GH concentration over 24 hours, a low GH peak to provocative stimuli, and minimal initial BA delay predicted a favourable outcome. CONCLUSION: rhGH treatment in this group of children with idiopathic short stature did not increase average final height. Part of the heterogeneity of the response can be attributed to the variation in endogenous GH secretion and initial bone age delay.

Final height in a large cohort of Dutch patients with growth hormone deficiency treated with growth hormone. Dutch Growth Hormone Working Group.

Final height was evaluated in 203 patients with growth hormone (GH) deficiency, who had been treated with GH in childhood, and was related to other factors. Mean final height was 168.1 cm (men) and 154.7 cm (women), -2.07 and -2.20 SD of the population mean, respectively. Patients with GH deficiency due to cerebral tumour were taller than those with idiopathic GH deficiency, and patients with induced puberty were taller than those with spontaneous puberty. Target height (r = +0.37), birth length (r = 0.36), height SDS at the start of therapy (r = +0.51) and at the start of puberty (r = +0.58) were significantly correlated with final height. Multiple linear regression analysis revealed that after correction for height at the start of puberty, age at the start of puberty was also positively correlated with final height. Patients who were treated after 1983 (when treatment regimens were changed) were taller than patients who finished treatment before 1983. The results suggest the importance of preventing a large initial height deficit and attaining optimal height at the start of puberty.

Comparative effect of two doses of growth hormone for growth hormone deficiency. The Dutch Growth Hormone Working Group.

The comparative effect and safety of 2 IU compared with 4 IU/m2/day of recombinant human growth hormone (rhGH) was studied in 38 growth hormone deficient children regarding the impact of several factors on short term (one year) and long term (three year) growth response. In 21 newly diagnosed patients, three years of rhGH treatment resulted in a significant increase of height velocity SD score, height SD score, and predicted adult height SD score, irrespective of rhGH dose. In 17 transfer patients (previously treated with 12 IU rhGH/m2/week) 4 IU/m2/day resulted in a significantly higher height velocity SD score and height SD score for chronological age than 2 IU/m2/day, while more of them reached their target range or showed a substantial height SD score increment. Height SD score for bone age and predicted adult height SD score only increased significantly with 4 IU rhGH. After one year of rhGH treatment, new patients showed significant negative correlation between delta height SD score with age and baseline insulin-like growth factor I (IGF-I) SD score, and positive correlation with rhGH dose. After three years of treatment, delta height SD score for chronological age was significantly, negatively correlated with age and baseline 'corrected' height SD score (height SD score for chronological age minus target height SD score). There was no significant correlation with rhGH dose. Prolonged treatment with either dose had no adverse effect on IGF-I concentrations, carbohydrate or lipid metabolism. As early age and divergence between height SD score and target height SD score seem more important for growth response than rhGH dose, it is recommended that treatment starts early with 2 IU rhGH/m(2)/day and the dose is doubled if growth is insufficient after several years of treatment.

Body proportions in individuals with Turner syndrome. The Dutch Growth Hormone Working Group.

The body proportions in 191 individuals with Turner syndrome (TS) were investigated. At 3 years of age the mean sitting height in TS was normal, thereafter trunk growth was impaired, resulting in a standard deviation score (SDS) of -2.4 in the adult. From 3 to 12 years of age the mean SDS of leg length increased from -2.7 to -3.6; and then fell to -2.5. At 3 years of age the ratio of sitting height to leg length was 3.2 standard deviations (SD) above the normal mean. Thereafter the ratio slowly approached the normal percentiles. It was +0.6 SD in 15- to 18-year-old women. Thereafter it increased to 1.7 for adults with TS. Knemometric measurements in 32 individuals with TS and 32 controls revealed that in TS the upper legs were relatively shorter than the lower legs. We conclude that children with TS, and to a lesser extent adults, have a disproportionately short stature with relatively short legs whereas body proportions are almost normal in adolescents.

Shape of the craniofacial complex in children with Turner syndrome.

The shape of the craniofacial complex was established in 69 children with Turner syndrome aged between 3.5 and 16.6 years. The children had not been treated with growth hormone (GH) or anabolic steroids. On a standardized lateral roentgenencephalogram 13 linear and 7 angular variables were measured. Data of all variables were available from normal Dutch children for comparison. The main abnormalities were located in the cranial base and in the mandible and consisted of a short posterior cranial base, all increased cranial base angle and a short, retrognathic and posteriorly rotated mandible. The maxilla was smaller than normal and also slightly posteriorly rotated. The abnormalities were already present in young children with Turner syndrome. Indications were found that in Turner syndrome interstitially as well as appositionally growing cartilage is affected. The changes in the maxilla can be explained in various ways. They may be due to defective growth of the nasal cartilage or to a disorder in the intramembranous ossification of the maxilla or they may be adaptive to the changes in the cranial base and the mandible. From this study it can be concluded that patients with Turner syndrome exhibit several craniofacial abnormalities, probably due to a cartilage disorder.

[Growth hormone deficiency: diagnosis and treatment]. / Groeihormoondeficiëntie: diagnostiek en behandeling.

Growth hormone (GH) and thyroxine are the major growth promoting hormones in postnatal life. The pulsatile pattern of GH-release by the anterior pituitary is regulated by the interaction of stimulating and inhibiting hormones and influenced by physiological and pharmacological factors. GH promotes longitudinal bone growth mainly through activation of insulin-like growth factor I (IGF-I), but there may also be a direct effect. The most important clinical feature of growth hormone deficiency (GHD) is a low growth velocity resulting in short stature. In addition to retardation of bone maturation many GH-deficient children exhibit a number of typical, clinical characteristics. The diagnosis GHD can be confirmed by performing GH-stimulation tests and IGF-I measurements. However, the maximal GH-response to provocative stimuli is a poor indicator of the spontaneous GH-secretion. Classifications and etiology of GHD are given. Since 1958 GH-deficient children are treated with human GH with initially disappointing results regarding attained final height. Early diagnosis and treatment and optimization of GH-dose, mode of administration and injection frequency might improve final height. In The Netherlands the currently used GH-dose is 12-14 IU/m2/week in 6 or 7 daily doses administered subcutaneously. Ongoing retrospective and prospective studies serve to determine optimal treatment schedules. Up to now, important adverse effect of GH-therapy with the current GH-doses in GH-deficient children are not known. The beneficial effects of long-term GH-treatment of GHD adults is at present subject to ongoing investigation.(ABSTRACT TRUNCATED AT 250 WORDS)

Prepubertal height velocity references over a wide age range.

In order to correct height velocities for the confounders age and sex, SD scores can be calculated using the mean and the SD of the height velocity in the normal population. However, current methods are inappropriate for prepubertal children in the age range in which puberty occurs, because reference groups then consist of a mixed prepubertal/pubertal population. The mathematical infancy-childhood-puberty (ICP) model opens up the possibility of dissecting the puberty component from the total growth curve. New references for height velocity for prepubertal children calculated over a 12 month interval up to the ages of 15.5 years (boys) and 13.5 years (girls) have been constructed on the basis of adaptations of the ICP model and the Swedish longitudinal growth study.