Exaggerated adrenarche in a cohort of Scottish children: clinical features and biochemistry.

OBJECTIVE: To investigate the reported association between exaggerated adrenarche (EA) and reduced foetal growth and to identify possible risk factors for future morbidity in Scottish children with clinical features of EA. DESIGN: Three-year prospective study. MEASUREMENTS: Auxology, blood pressure (BP), biochemical analysis of blood and urine, pelvic ultrasound in girls. RESULTS: Fifty-two patients were recruited of whom one girl had nonclassical congenital adrenal hyperplasia (17-OHP 17 nmol/l) and one had insufficient blood for analysis. The final cohort comprised 42 girls of mean (SD) age 7.7 (0.99) and eight boys of 8.8 (0.67) years. Mean (SD) birth weight was 3.27 (0.49) and 3.10 (0.76) kg in girls and boys respectively. Height/weight SDS were 1.13/1.69 in girls and 1.69/1.88 in boys. Mean systolic/diastolic BP was 107.8/60.4 (50th-75th centile) in girls and 115.5/63.9 (75th-91st centile) in boys. Uterine and ovarian development was prepubertal. Median serum dehydroepiandrosterone sulphate (DHEAS) was 2.1 and 4.1 mumol/l, androstenedione 3.1 and 3.8 nmol/l in girls and boys respectively, with DHEAS within the reference range/undetectable in 18/2 and androstenedione in 12/6 patients. Fasting insulin was 9.0 and 15.0 mU/l in girls and boys respectively, with concomitant low normal SHBG. Anti-Mullerian hormone (AMH) was 15.7 pmol/l in 27 girls, compared with 5.0 pmol/l in normal girls aged 5-8 years. CONCLUSIONS: Our Scottish EA cohort showed female predominance, no evidence of reduced foetal growth, a tendency to overweight with commensurate mild hyperinsulinaemia and modest elevation of serum androgens in some patients. We have found raised AMH levels in the girls, indicating advanced ovarian follicular development.

Effect of high versus low initial doses of L-thyroxine for congenital hypothyroidism on thyroid function and somatic growth.

BACKGROUND AND AIMS: The optimal dose of thyroxine (T4) in congenital hypothyroidism (CH) during infancy is controversial. Higher doses lead to improvement in cognitive scores, but have been linked to later behavioural difficulties. We have examined the effects of initial T4 dosage on somatic growth--a putative surrogate marker of overtreatment. METHODS: 314 CH children (214 girls, 100 boys) were analysed according to initial daily dose of T4: Group 1 (25 mug, n = 152), Group 2 (30-40 mug, n = 63) and Group 3 (50 mug, n = 99). Thyroid function and weight, length and occipito-frontal head circumference (OFC) standard deviation score (SDS) were compared at 3, 6, 12, 18, 24 and 36 months of age. Linear growth SDS was compared between the three groups using a regression adjustment model at 12 and 18 months of age using birth weight and 3-month data as baselines. Thyroid function was also compared at diagnosis (T 0), and 7-21 days after the start of treatment (T1). RESULTS: At T1 median thyroid stimulating hormone (TSH) for Groups 1, 2 and 3 was 58, 29 and 4.1 mU/l, respectively (p<0.001), Group 3 values remaining significantly lower at 3 and 6 months. Median free T4 (fT4) was within or just above the reference range in all groups at T1, but 7.4% of Group 1 had values <9 pmol/l compared with 5.1% and 0% for Groups 2 and 3, respectively. At 3 months weight, length and OFC SDS values were -0.39, -0.35, 0.09; -0.30, -0.47, 0.32; and -0.03, -0.13, 0.18 for Groups 1, 2 and 3, respectively, indicating relatively large OFC in all infants. A regression adjustment model showed no significant difference in growth rate from baseline and 12 or 18 months of age, between the three groups. CONCLUSION: An initial T4 dose of 50 mug daily, normalises thyroid function several months earlier than lower-dose regimes, with no evidence of sustained somatic overgrowth between 3 months and 3 years.

Measured versus reported parental height.

BACKGROUND: Parental height data are essential in the assessment of linear growth in children. A number of studies have documented inaccuracy in self-reported adult height. AIMS: To determine whether there is a tendency for men to overestimate and women to underestimate their height. METHODS: Heights of parents of children attending outpatient clinics were measured (MHt) and compared with reported heights (RHt). RESULTS: Two hundred parents (100 males; 100 females), mean (range) age 37.8 (20.8-69.3) years, were measured. Males overestimated height, with mean (SD) RHt-MHt 1.09 (1.96) cm, while females reported height relatively accurately, with RHt-MHt -0.09 (2.37) cm. CONCLUSIONS: The hypothesis that males overestimate height is confirmed. While the hypothesis that women underestimate is not supported, we recommend accurate measurement of both parents, given the considerable degree of individual variation in RHt-MHt for both sexes.

Auxological outcome and time to menarche following long-acting goserelin therapy in girls with central precocious or early puberty.

OBJECTIVE: Following a successful clinical trial in 1996, the long-acting GnRH analogue goserelin (Zoladex LA 10.8 mg; Astra Zeneca) has been our preferred treatment for central early (CEP) or precocious puberty (CPP). However, some female patients have expressed concern about perceived weight gain during therapy and delay in the onset or resumption of menses on completion of therapy. The primary aim of this study was to investigate these concerns by determining the auxological parameters and timing of menarche or re-menarche in all girls with CEP/CPP who have completed a course of Zoladex LA treatment. The secondary aim was to assess auxological outcome in girls who have attained final height. DESIGN AND PATIENTS: Case records of all girls with idiopathic CEP/CPP or CEP/CPP secondary to CNS pathology treated with Zoladex LA since 1996 were reviewed. A total of 46 girls who have completed therapy were identified, of whom 11 had reached final height. measurements Height, weight and bone age (RUS (TW2) method) were measured before treatment, when Zoladex LA was stopped and at final height. Body mass index (BMI) was calculated as a clinical measure of body fatness. Pubertal status was assessed pre- and post-treatment by Tanner staging and pelvic ultrasonography. Timing of menarche or re-menarche following cessation of treatment was recorded. RESULTS: The mean (range) age of starting GnRH analogue therapy was 8.3 (1.8-10.5) years and the duration of treatment was 2.9 (0.7-8.9) years. Pre-treatment height was above average at 0.72 SD but had declined to 0.28 SD by the end of therapy. The 46 girls were heavier than average before treatment (Wt SDS 1.04) with no change in weight status on completion of therapy. Mean BMI SDS increased significantly from 0.93 to 1.2 during treatment, indicating that the girls became relatively fatter. Using recommended BMI cut-off values for defining overweight and obesity in children of the 85th and 95th centiles, 41% of the cohort were overweight and 28% were obese before treatment, rising to 59% and 39%, respectively, at the end of therapy. The average time interval to onset or resumption of menses after stopping treatment was 1.46 years (median 1.5, range 0.8-2.0 years). None of the following variables was found to be predictive of the time interval to menarche after completion of therapy: duration of treatment; chronological age; bone age; Tanner breast stage or uterine maturation at the end of treatment; the frequency of injections required to suppress puberty; or treatment with alternative GnRH analogue prior to Zoladex LA. Mean final height in 11 girls was 159.7 cm (-0.63 SD), close to the mean parental target height of 160.9 cm (-0.48 SD). Nine of the 11 girls (82%) attained final heights within or above their target range. In keeping with the whole cohort this subset of girls became fatter during treatment, although this difference was not statistically significant. However, they returned to their pretreatment size at final height (mean BMI SDS 1.18, 1.41 and 1.16 before, at the end of treatment and at final height, respectively). CONCLUSIONS: Our cohort of 46 girls treated with long-acting goserelin was already considerably overweight at the start of therapy and became fatter during treatment. However, adiposity appeared to return to pretreatment levels in the 11 girls followed up to final height. Most of the girls who have attained final height are within or above their expected target range. The relatively long time interval to menarche of 1.5 years after stopping treatment is unexplained but may reflect a residual suppressive effect on the hypothalamo-pituitary axis of this long-acting GnRH analogue. Anticipation of the timing of menarche has proved to be of value in planning when to stop therapy in girls in whom treatment is mainly for practical and/or psychological reasons.

Improved final height in Turner's syndrome following growth-promoting treatment at a single centre.

AIMS: To examine the final height (FH) outcome of girls with Turner's syndrome (TS) treated at a single Scottish centre (Glasgow group), to compare it with an earlier national analysis (Scottish group) and to suggest reasons for any change. METHODS: Retrospective growth and treatment data for 29 Glasgow patients were compared with those of 26 Scottish patients. RESULTS: Age at GH start (mean +/- SD) was 10.1 +/- 2.6 vs 12.1 +/- 1.7 y (p < 0.01) in the Glasgow versus Scottish groups, with overall duration of treatment 6.2 +/- 2.4 vs 3.7 +/- 1.1 y (p < 0.001) and years of GH treatment before pubertal induction 2.7 +/- 2.8 vs 0.3 +/- 0.8 y (p < 0.001), respectively. Pubertal induction was at a similar age: 12.7 +/- 1.8 vs 12.8 +/- 1.8 y (ns). FH was 151.1 +/- 4.6 cm in the Glasgow group compared with 142.6 +/- 5.6 cm in the Scottish group (p < 0.001), with FH - projected adult height (PAH) 5.7 +/- 4.6 cm vs 0.6 +/- 3.6 cm (p < 0.001), respectively. Univariate analysis of the Glasgow group's FH - PAH with a number of growth and treatment variables identified no statistically significant relationships. CONCLUSION: This group's improved FH and FH - PAH, relative to an earlier sample, are attributed to the introduction of GH treatment from a younger age and for longer, overall and before pubertal induction. In addition, the authors believe that compliance with treatment has been enhanced by this single centre's dedicated Turner clinic and the efforts of its established "growth team". These data demonstrate that a favourable FH can be achieved using a safe and financially viable dose of GH, while inducing puberty at a "normal" age.

Safety of the insulin tolerance test.

Concerns have been raised about the hazards of the insulin tolerance test (ITT), used to measure growth hormone secretion. In Glasgow, we continue to use this test, adhering to a strict protocol. A review of outcome over a 10 year period (1989-99), during which 550 ITTs were performed, was undertaken. No serious adverse events occurred; in particular, no child fitted or required intravenous glucose. Fewer tests were done during the latter five years, with a higher yield of growth hormone (GH) deficiency, reflecting our increasingly conservative approach to paediatric GH therapy during this period. We conclude that the ITT is safe and reliable in a paediatric setting provided that a strict procedure is followed.

The boom that never was: results of a 10 year audit of paediatric growth hormone prescribing in Scotland.

OBJECTIVE: To investigate trends in paediatric growth hormone (GH) prescribing in Scotland. DESIGN: Annual audit of paediatric GH patients, analysed by geographical distribution, diagnosis, age and duration of treatment, dosage, sex ratio and prescribing body. SUBJECTS AND SETTING: Paediatric patients receiving GH who attended the four tertiary referral centres in Scotland: Glasgow, Edinburgh, Dundee and Aberdeen, from 1990-1999. RESULTS: The annual total number of paediatric GH recipients ranged from 296-393. The maximum was recorded in 1994, with a progressive decline thereafter. The latest total (296, 1999) represents a 19% decrease since 1990. There is a marked disparity between these figures and projections published by the Scottish Office Clinical Research and Audit Group (CRAG) in 1990 of 500 patients in 1995 and 600 by 2000. CRAG postulated that GH would prove efficacious in a wider range of conditions, that the number of survivors of childhood cancer would increase and that GH therapy would continue following clinical trials. While there has been a relative increase in oncology survivors during the 10-year period, the overall decline in numbers is largely attributable to familial short stature patients in whom there has been a five fold decrease, following completion of clinical trials of GH. The number of children classified "idiopathic growth hormone deficient" has also decreased, as the overlap between this condition and normal variant short stature is increasingly recognised. CONCLUSION: This expensive drug is being used relatively conservatively in Scotland, in the light of research experience. While a small degree of ad hoc usage is inevitable, we strongly support participation in national trials wherever possible. The adoption of an open approach with the Scottish Office regarding GH usage has proved beneficial in alleviating fear of escalating costs and preventing prescribing problems in a country in which 98% of GH is prescribed by general practitioners.

Efficacy of Zoladex LA (goserelin) in the treatment of girls with central precocious or early puberty.

OBJECTIVE: To assess the efficacy of a longer acting preparation of the gonadotrophin releasing hormone (GnRH) analogue goserelin (Zoladex LA, 10.8 mg) in 12 girls with central precocious or early puberty. METHODS: Two girls started treatment de novo; the remainder had been on suppressive treatment for a median duration of 1.5 (range, 0.2-5.6) years. Assessment comprising auxology, pubertal staging, and pelvic ultrasound examination was carried out at weeks 0, 4, 8, 10, and 12 (first cycle) and weeks 8, 10, and 12 (second cycle) to evaluate the required injection frequency. Thereafter, assessment was performed on the day of injection. Zoladex LA was given every 12 weeks unless pubertal progression occurred. RESULTS: Satisfactory control was achieved in eight patients using this regimen, and three patients required more frequent injections. One girl was removed from the study because of clinical progression and extreme mood swings. No serious adverse effects occurred. Mean height velocity during the study period was 4.5 cm/year (range, 3.1-6.6) compared with 6.5 cm/year (range, 3.8-9.6) before treatment in nine patients for whom data were available. CONCLUSIONS: Zoladex LA was effective in controlling precocious puberty in girls when given at intervals of 9-12 weeks and it is recommended that an initial assessment is made eight weeks after beginning treatment.

Variable effect of growth hormone on growth and final adult height in Scottish patients with Turner's syndrome.

The aim of this work was to assess the outcome of recombinant growth hormone (rGH) therapy in a large unselected group (72) of patients with Turner's syndrome (TS), 26 of whom have reached final height. Growth data were collected from Scottish patients with TS and outcome was assessed in three ways: response to therapy in the first year, response in subsequent years and final height. Phenotypic, auxological, genetic and biochemical factors, all of which may have affected the first-year response, were investigated. Fifty-one percent of the cohort had a clinically "good" first-year response to therapy and 49% had a "poor" response, a "good" response was defined as a change in the TS standard deviation score (SDS) of +0.5 or more and a "poor" response as a change in the TS SDS of less than +0.5. The percentage of children showing a positive change in TS SDS after 2, 3 and 4 years of therapy declined (88%, 78%, 41%). Mean (range) final height was 142.6 (133.4-153.6) cm, mean (range) pretreatment TS SDS was -0.27 (-2.1 to +1.09) and mean (range) final TS SDS was -0.05 (-1.4 to +1.59). Thirteen (50%) patients attained a final height that was greater than projected, eleven did not attain their projected final height and two achieved their exact projected final height. Short girls with TS appear to benefit more from rGH supplementation than tall girls, but otherwise there was no significant correlation between any of the parameters studied and the response to treatment. It is concluded that large-scale prospective studies are still required to assess the impact of rGH on final height in TS and to identify factors responsible for the variability in response.

Possible role of imprinting in the Turner phenotype.

We have attempted to investigate the role of imprinting in the phenotype of Turner's syndrome. Sixty-three patients were investigated for parental origin of the retained normal X chromosome; 43 were found to retain the maternal X (XM) and 20 the paternal (XP). The relationship between a child's pretreatment height centile and parental height centiles was examined in 36 patients. No significant correlation was found between child and parental height centiles for XP or child and paternal height centiles for XM (p > 0.05) but a strong correlation was found between child's height centile and maternal height centile (p < 0.01) for XM. Using pooled data from this and other studies there was no significant correlation with renal anomalies but a strong correlation between cardiovascular abnormalities and XM (0.01 > p > 0.001) and neck webbing and XM (p < 0.05). We conclude that imprinting may play a part in the Turner's syndrome phenotype, especially with respect to pretreatment height, cardiovascular anomalies, and neck webbing.

Localization of alpha-uterine protein in human endometrium.

Immunoperoxidase staining was used to investigate the origin of human alpha-uterine protein (AUP). Specific staining was observed in the glandular epithelium of the endometrium during the secretory phase of the menstrual cycle and during pregnancy, and in a patient on an oestrogen-progestagen contraceptive pill. The pattern of staining strongly suggests that AUP is secreted into the uterine lumen. The location and concentration of AUP in the uterus may explain the relative concentrations of AUP in amniotic fluid and maternal serum.

Serological identity between human alpha uterine protein and human progestagen-dependent endometrial protein.

Alpha uterine protein and progestagen-dependent endometrial protein were previously described in human endometrium by two independent groups of workers. Serological evidence is presented in this paper that these two proteins are the same.