Joanne Blair

Standard and low‐dose IGF‐I generation tests and spontaneous growth hormone secretion in children with idiopathic short stature

objective  Abnormalities in the GH–IGF‐I axis, consistent with GH insensitivity (GHI), have been reported in some patients with idiopathic short stature (ISS). The standard IGF‐I generation test (IGFGT) has not demonstrated mild GHI in subjects with ISS. The aim of this study was to investigate the GH–IGF‐I axis in ISS by performing standard and novel low‐dose IGFGTs together with determination of spontaneous GH secretion.

Pituitary adenomas in childhood, adolescence and young adulthood: presentation, management, endocrine and metabolic outcomes

OBJECTIVE To elucidate the long-term outcomes of pituitary adenomas diagnosed in childhood and adolescence, knowledge of which remains sparse. DESIGN AND METHODS A retrospective review of patients aged ≤21 years at diagnosis of pituitary adenoma, attending a neuroendocrine service in Liverpool, UK, between 1984-2009. RESULTS There were 41 patients (33 female), mean age at diagnosis 17.3 years (range 11-21) and mean follow-up 9.6 years; 29 patients had prolactinomas (15 macroprolactinomas), 6 non-functioning pituitary adenomas (NFPAs), 5 Cushings disease (CD) and 1 acromegaly. All prolactinoma patients received dopamine agonists (DAs) and three also underwent pituitary surgery. Furthermore, ten patients underwent surgery: five with CD, one with acromegaly and four with NFPA. Four received radiotherapy after surgery. Another ten patients received hormone replacement: nine hydrocortisone, five thyroxine, seven sex steroids and five GH; another seven had severe asymptomatic GH deficiency. Three female patients were treated for infertility (two successfully). Thirteen patients gained significant weight (body mass index (BMI) increase >2 kg/m(2)) since diagnosis and 16 in total are now obese (BMI>30 kg/m(2)). Five were treated with orlistat and one attended a weight management service. Two received antihypertensive medications, two had type 2 diabetes and four were treated for dyslipidaemia. CONCLUSIONS This is one of the largest reviews of patients aged 21 or younger at diagnosis of pituitary adenoma followed up by a single service. Two-thirds had prolactinomas, all were treated with DAs and three underwent surgery. Increased cardiovascular risk factors (obesity and dyslipidaemia) and infertility are important sequelae and active identification and treatment are necessary.

A preliminary trial of the effect of recombinant human growth hormone on short-term linear growth and glucose homeostasis in children with Crohn’s disease

Background  It is unclear whether recombinant human growth hormone (rhGH) improves linear growth in children with Crohn’s disease (CD).

Early morning salivary cortisol and cortisone, and adrenal responses to a simplified low-dose short Synacthen test in children with asthma.

To examine serum cortisol responses to a simplified low‐dose short Synacthen test (LDSST) in children treated with inhaled corticosteroids (ICS) for asthma and to compare these to early morning salivary cortisol (EMSC) and cortisone (EMSCn) levels.

The neuroendocrine sequelae of paediatric craniopharyngioma: a 40-year meta-data analysis of 185 cases from three UK centres

OBJECTIVES The management of paediatric craniopharyngiomas was traditionally complete resection (CR), with better reported tumour control compared to that by partial resection (PR) or limited surgery (LS). The subsequent shift towards hypothalamic sparing, conservative surgery with adjuvant radiotherapy (RT) to any residual tumour aimed at reducing neuroendocrine morbidity, has not been systematically studied. Hence, we reviewed the sequelae of differing management strategies in paediatric craniopharyngioma across three UK tertiary centres over four decades. METHODS Meta-data was retrospectively reviewed over two periods before (1973-2000 (Group A: n = 100)) and after (1998-2011 (Group B: n = 85)) the introduction of the conservative strategy at each centre. RESULTS Patients had CR (A: 34% and B: 19%), PR (A: 48% and B: 46%) or LS (A: 16% and B: 34%), with trends reflecting the change in surgical approach over time. Overall recurrence rates between the two periods did not change (A: 38% vs B: 32%). More patients received RT in B than A, but recurrence rates were similar: for A, 28% patients received RT with 9 recurrences (32%); for B, 62% received RT with 14 recurrences (26%). However, rates of diabetes insipidus (P = 0.04), gonadotrophin deficiency (P < 0.001) and panhypopituitarism (P = 0.001) were lower in B than those in A. In contrast, post-operative obesity (BMI SDS >+2.0) (P = 0.4) and hypothalamic (P = 0.1) and visual (P = 0.3) morbidity rates were unchanged. CONCLUSION The shift towards more conservative surgery has reduced the prevalence of hormone deficiencies, including diabetes insipidus, which can be life threatening. However, it has not been associated with reduced hypothalamic and visual morbidities, which remain a significant challenge. More effective targeted therapies are necessary to improve outcomes.

Is physiological glucocorticoid replacement important in children

Cortisol has a distinct circadian rhythm with low concentrations at night, rising in the early hours of the morning, peaking on waking and declining over the day to low concentrations in the evening. Loss of this circadian rhythm, as seen in jetlag and shift work, is associated with fatigue in the short term and diabetes and obesity in the medium to long term. Patients with adrenal insufficiency on current glucocorticoid replacement with hydrocortisone have unphysiological cortisol concentrations being low on waking and high after each dose of hydrocortisone. Patients with adrenal insufficiency complain of fatigue, a poor quality of life and there is evidence of poor health outcomes including obesity potentially related to glucocorticoid replacement. New technologies are being developed that deliver more physiological glucocorticoid replacement including hydrocortisone by subcutaneous pump, Plenadren, a once-daily modified-release hydrocortisone and Chronocort, a delayed and sustained absorption hydrocortisone formulation that replicates the overnight profile of cortisol. In this review, we summarise the evidence regarding physiological glucocorticoid replacement with a focus on relevance to paediatrics.

The diagnosis and treatment of adrenal insufficiency during childhood and adolescence

The diagnosis and treatment of adrenal insufficiency in childhood and adolescence poses a number of challenges. Clinical features of chronic adrenal insufficiency are vague and non-specific, and mimic many other causes of chronic ill health. A range of diagnostic tests are available for the assessment of adrenal function, all of which have advantages and disadvantages. Cortisol responses to these tests may vary with age and between genders. Knowledge of normal cortisol levels during health and ill health in childhood is also limited, and the cortisol replacement therapies available in clinical practice enable only crude mimicry of physiological patterns of cortisol secretion. An awareness of the limitations of diagnostic tests and treatments is important, and critical clinical assessment, integrating clinical and biochemical data, is essential for the diagnosis and treatment of children with suspected adrenal insufficiency. The aim of this review is to draw on data from clinical studies to inform a pragmatic approach to the child presenting with symptoms of chronic adrenal insufficiency. Clinical features of primary and secondary adrenal insufficiency, and syndromes associated with these diagnoses are described. Factors to consider when selecting a diagnostic test of adrenal function and interpretation of test results are considered. Finally, the limitations of cortisol replacement therapy are also discussed.

Susceptibility to corticosteroid-induced adrenal suppression: a genome-wide association study

Summary Background A serious adverse effect of corticosteroid therapy is adrenal suppression. Our aim was to identify genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression. Methods We enrolled children with asthma who used inhaled corticosteroids as part of their treatment from 25 sites across the UK (discovery cohort), as part of the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) study. We included two validation cohorts, one comprising children with asthma (PASS study) and the other consisting of adults with chronic obstructive pulmonary disorder (COPD) who were recruited from two UK centres for the Pharmacogenomics of Adrenal Suppression in COPD (PASIC) study. Participants underwent a low-dose short synacthen test. Adrenal suppression was defined as peak cortisol less than 350 nmol/L (in children) and less than 500 nmol/L (in adults). A case-control genome-wide association study was done with the control subset augmented by Wellcome Trust Case Control Consortium 2 (WTCCC2) participants. Single nucleotide polymorphisms (SNPs) that fulfilled criteria to be advanced to replication were tested by a random-effects inverse variance meta-analysis. This report presents the primary analysis. The PASS study is registered in the European Genome-phenome Archive (EGA). The PASS study is complete whereas the PASIC study is ongoing. Findings Between November, 2008, and September, 2011, 499 children were enrolled to the discovery cohort. Between October, 2011, and December, 2012, 81 children were enrolled to the paediatric validation cohort, and from February, 2010, to June, 2015, 78 adults were enrolled to the adult validation cohort. Adrenal suppression was present in 35 (7%) children in the discovery cohort and six (7%) children and 17 (22%) adults in the validation cohorts. In the discovery cohort, 40 SNPs were found to be associated with adrenal suppression (genome-wide significance p<1 × 10−6), including an intronic SNP within the PDGFD gene locus (rs591118; odds ratio [OR] 7·32, 95% CI 3·15–16·99; p=5·8 × 10−8). This finding for rs591118 was validated successfully in both the paediatric asthma (OR 3·86, 95% CI 1·19–12·50; p=0·02) and adult COPD (2·41, 1·10–5·28; p=0·03) cohorts. The proportions of patients with adrenal suppression by rs591118 genotype were six (3%) of 214 patients with the GG genotype, 15 (6%) of 244 with the AG genotype, and 22 (25%) of 87 with the AA genotype. Meta-analysis of the paediatric cohorts (discovery and validation) and all three cohorts showed genome-wide significance of rs591118 (respectively, OR 5·89, 95% CI 2·97–11·68; p=4·3 × 10−9; and 4·05, 2·00–8·21; p=3·5 × 10−10). Interpretation Our findings suggest that genetic variation in the PDGFD gene locus increases the risk of adrenal suppression in children and adults who use corticosteroids to treat asthma and COPD, respectively. Funding Department of Health Chair in Pharmacogenetics.

Deletion of exon 3 in the growth hormone receptor gene in adults with growth hormone deficiency: comparison of symptomatic and asymptomatic patients

There is some evidence that GH deficient (GHD) children with a common polymorphism in the GH receptor (GHR) gene, resulting in deletion of exon 3 (d3GHR) on one (d3/fl) or both alleles (d3/ d3), have a better growth response to rhGH than those without, although this remains controversial. We speculated that adult patients with this polymorphism may also be more sensitive to GH and less likely to be symptomatic from GH Deficiency than those without. To investigate this hypothesis, we studied the relationship between Quality of life (QoL), the need for rhGH therapy and exon 3 deletion polymorphism in the GHR gene. A total of 173 white Caucasian patients (57% males) with hypothalamic–pituitary disorders (mean age 50 years, range 16–75 years) were studied. Seventy-nine per cent had structural hypothalamic–pituitary disorders, 15% had other intracranial disorders and 44% had received hypothalamic irradiation. All patients had severe GH Deficiency, peak GH <9 mU/l following 1 mg subcutaneous glucagon. Ethical approval was obtained from the Local Research Ethics Committee. Waist-hip ratio and waist circumference were measured by a single observer. Height standard deviation scores (SDS) were derived from normative data from the British white Caucasian population. Percentage body fat was measured using a bioimpedance meter (Tanita Bodyfat Analyzer model TBF-305). Quality of Life was measured using 4 validated questionnaires: Adult Growth Hormone Deficiency Assessment (AGHDA) questionnaire, Hospital Anxiety and Depression (HADS) questionnaire, Life Fulfilment Scale and Disease Impact Scale adapted for GHD patients. Energy levels were determined using a 10-cm Visual Analogue Scale, VAS (0 cm – no energy, 10 cm – full of energy). The questionnaires were answered in a single session and completed in the same order. Higher scores indicated worse QoL in AGHDA questionnaires, HADS and Satisfaction Scale. Lower scores indicated worse QoL in Disease Impact Scale and VAS. Hormone replacement in patients with multiple pituitary hormone deficiencies was optimized before assessment for rhGH replacement. According to National Institute for Clinical Excellence (NICE) guidelines, a score ‡11/25 on the AGHDA questionnaire qualifies for rhGH replacement. Asymptomatic patients were defined as having an AGHDA score <11/25, despite biochemical evidence of severe GH Deficiency and were not on rhGH. Genomic DNA was extracted from 10 ml whole blood using magnetic bead technology and Chemagic Magnetic Separation Module I. DNA was amplified using a multiplex strategy. The G1, G2 and G3 primers are described in GenBank accession no. AF155912. The fl allele (GHRfl) is represented by a 935-bp fragment and the d3 allele (d3-GHR) by a 532-bp fragment. Quality control assessment used both positive and negative controls in each batch of samples. Serum GH and IGF-1 levels were analysed in the hospital laboratory using chemiluminescent immunometric assays. The results show no difference in the frequency of the different genotypes: 55% fl/fl, 39% d3/fl and 6% d3/d3 in the treated population and 55%, 33% and 12% in the asymptomatic patients, respectively (v = 0Æ43). The asymptomatic GHD patients had significantly better AGHDA QoL scores (mean 5/25) than the GHD patients on treatment (mean 12/25) (P < 0Æ001). Body composition and QoL were compared between genotype groups for patients treated with rhGH and the asymptomatic patients (Table 1). The asymptomatic GHD patients with the d3 isoform had significantly lower HADS depression scores (mean 2) than those with the fl/fl isoform (mean 5) (P = 0Æ02). However, no other difference in QoL scores or body composition was found in the d3 isoform patients compared with the fl/fl patients in the treated and untreated populations. We speculated that adult GHD patients with exon 3 deletion are less likely to be symptomatic from GH Deficiency than those without. The prevalence of the three GHR-d3 genotypes in this population was comparable with previous studies in which up to half of the population was homozygous for the fl allele. As previous studies in childhood suggest that patients with exon 3 deletion on one or both alleles (d3/fl and d3/d3) have a similar growth response to rhGH, data from these patients were analysed together and separately. The results of this study do not support the hypothesis that adult patients with the fl/d3 or d3/d3 genotype are less likely to need rhGH therapy to improve QoL than those with the fl/fl genotype (shown in Table 1). Also, this study shows no difference in baseline serum IGF-1 levels between the symptomatic and asymptomatic patients, which suggest that a GHR genotype-mediated modulation of QoL is unlikely. The small difference in mean depression scores between the two genotype groups in the asymptomatic patients is probably of little clinical significance because scores of 0 to 7 are classed as normal. Data from this study also suggest that the GHR-d3 polymorphism does not influence body composition. This study suggests that in the adult population with GH Deficiency, factors other than the GHR-d3 polymorphism influence QoL. There are many causes of hypopituitarism in GHD adults, and patients receive multiple and prolonged treatments, with follow-up MRI/CT scanning which generate anxiety. As a result, determinants of QoL in adults are probably multifactorial and it may in fact be difficult to relate to a single cause, such as the GHRd3 polymorphism. Coexisting medical conditions can also have an impact on QoL. In childhood, response to GH replacement is easily measured by growth velocity. However, QoL measures remain the best way of monitoring response to treatment in adults with GH Deficiency, although QoL is difficult to measure and interpret. The data show that despite adequate hormone replacement, patients on Clinical Endocrinology (2010) 72, 422–426

Early growth hormone treatment start in childhood growth hormone deficiency improves near adult height: analysis from NordiNet® International Outcome Study

Objective To investigate the effect of age at growth hormone (GH) treatment start on near adult height (NAH) in children with isolated GH deficiency (GHD). Design NordiNet® International Outcome Study (IOS) (Nbib960128), a non-interventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (somatropin) (Novo Nordisk A/S) in the real-life clinical setting. Methods Patients (n = 172) treated to NAH (height at ≥18 years, or height velocity <2 cm/year at ≥16 (boys) or ≥15 (girls) years) were grouped by age (years) at treatment start (early (girls, <8; boys, <9), intermediate (girls, 8–10; boys, 9–11) or late (girls, >10; boys, >11)) and GHD severity (<3 ng/mL or 3 to ≤10 ng/mL). Multiple regression analysis was used to evaluate the effect of age at treatment start (as a categorical and continuous variable) on NAH standard deviation score (SDS). Results Age at treatment start had a marked effect on NAH SDS; NAH SDS achieved by patients starting treatment early (n = 40 (boys, 70.0%); least squares mean (standard error) −0.76 (0.14)) exceeded that achieved by those starting later (intermediate, n = 42 (boys, 57.1%); −1.14 (0.15); late, n = 90 (boys, 68.9%); −1.21 (0.10)). Multiple regression analysis showed a significant association between NAH SDS and age at treatment start (P < 0.0242), baseline height SDS (HSDS) (P < 0.0001), target HSDS (P < 0.0001), and GHD severity (P = 0.0012). Most (78.5%) patients achieved a normal NAH irrespective of age at treatment start. Conclusions Early initiation of GH treatment in children with isolated GHD improves their chance of achieving their genetic height potential.