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Insulin resistance (IR) has been proposed as the strongest single predictor for incident type 2 diabetes and is mainly caused by adiposity as a result of chronic excessive energy intake. Loss of body weight and fat mass improve insulin sensitivity. However, independent of energy intake and changes in body weight/composition, dietary content and specific metabolic effects of certain nutrients may play significant additional roles in influencing IR. These effects are mainly relatively modest, with modulation of IR and diabetes risk within the range of 10-30%, but could be of major relevance on a population level. Examples include dietary concepts and patterns such as the traditional Mediterranean diet; the isoenergetic modulation of the composition of types of fatty acids in the diet; low-carbohydrate-high-protein diets; the quality of carbohydrate-rich foods, which includes the concepts of glycaemic index (GI) and glycaemic load; and, not necessarily related to the GI concept, specific metabolic effects of high-fibre diets, with relevant differences between the type of fibre consumed. Effects of further selected foods (e.g. coffee, tea and nuts) and micronutrients (e.g. magnesium, selenium and zinc) on the modulation of IR have been reviewed elsewhere. This study focuses on changes in IR by isoenergetic modulation of the main macronutrients (fat, carbohydrates including dietary fibre, and dietary protein), with discussion of novel concepts and the potential interplay of food components in the current dietary concepts.

Summary Objective Obesity and insulin resistance are key features of the metabolic syndrome. In euthyroidism, the relationships between TSH and insulin resistance or the metabolic syndrome are less clear. We investigated the associations between TSH and the features and prevalence of the metabolic syndrome in euthyroid German subjects. Methods In a cross-sectional study, glucose metabolism was defined by an oral glucose tolerance test (oGTT) (except for those with evident diabetes) in 1333 subjects with TSH values between 0·3 and 4·5 mU/l who did not take any thyroid medication. Lipid parameters were measured, blood pressure and anthromopmetric parameters were taken, and insulin resistance was quantified as HOMA%S. Results TSH was weakly correlated with BMI (R = 0·061, P = 0·025). This association remained significant after adjustment for sex, age, and impaired glucose metabolism (P = 0·002). Subjects with a TSH in the upper normal range (2·5–4·5 mU/l, n = 119) had a significantly higher BMI (30·47 ± 0·57 vs. 28·74 ± 0·18 kg/m2, P = 0·001) and higher fasting triglycerides (1·583 ± 0·082 vs. 1·422 ± 0·024 mmol/l, P = 0·023), and their likeliness for fulfilling the ATP III criteria of the metabolic syndrome was 1·7-fold increased (95% CI: 1·11– 2·60). Conclusion In euthyroidism, subjects with a TSH in the upper normal range (2·5–4·5 mU/l) were more obese, had higher triglycerides, and had an increased likeliness for the metabolic syndrome. Therefore, a TSH below 2·5 mU/l is associated with a favourable metabolic profile. Whether lowering TSH to levels below 2·5 mU/l improves metabolism needs to be investigated in intervention trials.

The growth hormone (GH)-IGF-I axis is essential for normal foetal and childhood growth. Defects at different sites in the axis frequently result in short stature which may compromise adult height. We describe a continuum of clinically relevant abnormalities from GH deficiency through to GH resistance and discuss the implementation and interpretation of investigations. We consider appropriate therapy for patients with abnormal auxology and subnormal adult height prognosis, highlighting new data to clarify therapeutic choices leading to optimal clinical outcome.

Summary Objective Familial glucocorticoid deficiency (FGD) is a rare auto- somal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin-aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification. Design Clinical review of patients with nonsense MC2R mutations. Patients Between 1993 and 2008, 164 patients with FGD were screened for mutations in the MC2R. Totally 42 patients (34 families) were found to have mutations in the MC2R. Of these, 6 patients (4 families) were found to have homozygous nonsense or frameshift mutations. Results Mild disturbances in the renin-angiotensin-aldosterone axis were noted in four out of six patients, ranging from slightly elevated plasma renin levels to low aldosterone levels, although frank mineralocorticoid deficiency or electrolyte disturbance were not found. No patient required fludrocortisone replacement. Conclusion Severe nonsense and frameshift MC2R mutations are not associated with clinically significant mineralocorticoid deficiency and are thus unlikely to require long-term mineralocorticoid replacement.

Summary 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. patients and methods Twenty-one (17 male) prepubertal children with ISS, mean age 8·3 years (4·5–12·2), mean height −3·48 SD (−5·40 to −1·79), mean peak GH to provocation with glucagon/clonidine 32·3 mU/l (14·1–66·0) were studied. Serum IGF-I and IGFBP-3 levels were measured during standard (GH 0·033 mg/kg/day × 4) and low (GH 0·011 mg/kg/day × 4) dose IGFGTs at 0, 12, 36 and 84 h. The low-dose IGFGT was performed in seven naive GH-deficient patients (4 male), mean age 8·5 years (range 4·1–11·1). Determination of spontaneous 24-h GH secretion was performed in the 21 ISS patients. results Basal IGF-I and IGFBP-3 standard deviation scores (SDS) in ISS patients were −1·39 (−2·4–1·16) and −0·45 (−1·13–0·38), respectively, IGF-I being lower than IGFBP-3 (P 2 × coefficient of variation (CV) of assay in the standard test failed to respond in the low-dose test, suggestive of mild GHI. In GH-deficient patients, IGF-I increased at each time point (P

Summary objective To investigate the characteristics of spontaneous GH secretion in four male children with short stature due to partial GH insensitivity. Their molecular defect consists of inclusion of a mutant intronic pseudoexon in the region of the GH receptor involved in homodimerization. subjects The subjects were two pairs of brothers who were first cousins, aged 10·4–14·2 years, heights −3·3 to −5·6 SDS, from a consanguineous Pakistani family. Basal serum IGF-I levels were extremely low (20–29 mg/l; NR > 50), with absent or minimal response to human recombinant GH (hGH) stimulation. Serum IGFBP-3 SDS levels were also low (−2·9 to −8·9). GH binding protein (GHBP) levels were normal (28·1–51·7%). methods Spontaneous GH secretion was studied by intermittent (20 min) venous sampling from 2000 to 0800 h. The secretion profiles were analysed using the Pulsar programme and compared to data from a reference population of 76 prepubertal Swedish children [median age 10·7 years, median height −1·1 SDS (−2·0 to 1·4)] according to Swedish growth standards. results Median (range) Pulsar-derived values in the four patients and controls were, respectively: GHmax (mU/l) 276·6 (178·7–325·8) and 27·2 (13·1–94·9), mean GH (mU/l) 64·5 (41·9–77·8) and 5·8 (3·2–20·6), baseline (mU/l) 12·3 (11·7–20·1) and 1·1 (0·2–6·1), AUCb (mU/l × 24 h) 1210 (684–1555) and 112·5 (60·6–316·4), i.e. all parameters of GH secretion in the four patients were markedly elevated compared with the control population. conclusions Spontaneous GH secretion is elevated in partial GH insensitivity. This investigation could be of diagnostic value in children with short stature.

Background Selective adenomectomy remains the first-line treatment for Cushing's disease (CD), until recently by microscopic transsphenoidal pituitary surgery. Endonasal transsphenoidal endoscopic surgery (ETES) is emerging as a novel, less invasive treatment for pituitary adenomas and has become the optimal surgical approach. Objective There are no published series for the treatment of paediatric CD by ETES, and we report our centre's preliminary results. Design Retrospective analysis. Patients Six paediatric patients (median age 15·8 years; range 11·7-17·0 years) fulfilled standard diagnostic criteria for CD. Preoperatively, no abnormality was identified on pituitary MR scanning in 3 (50%) patients, one had a macroadenoma. Bilateral petrosal sinus sampling demonstrated central ACTH secretion (IPS/P ACTH ratio ≥3·0, post-CRH) in 3/6 (50%) patients. The same neurosurgeon and endoscopic nasal surgeon undertook all the operations. Outcome measures Therapeutic outcome and rate of complications. Results Clinical recovery and biochemical 'cure' were achieved in 5 (83%) patients, and a corticotroph adenoma was confirmed histologically in all cured cases. One case developed post-operative CSF leak requiring lumbar drain insertion and patching. At a mean interval of 4·7 years (0·1-10·8 years) post-operatively, cured patients have shown no recurrence. One patient, with a large diffuse adenoma requiring more extensive surgery, has panhypopituitarism, and another patient has GH and gonadotrophin deficiencies. Conclusions Our experience shows that ETES for removing corticotroph adenomas in children, in most cases not visualized on MRI, is minimally invasive and gave excellent post-operative recovery/results. In skilled hands, this technique provides an alternative to conventional transsphenoidal microscopic surgery in managing paediatric CD. © 2013 John Wiley and Sons Ltd.

OBJECTIVE Familial glucocorticoid deficiency (FGD) has frequently been associated with tall stature in affected individuals. The clinical, biochemical and genetic features of five such patients were studied with the aim of clarifying the underlying mechanisms of excessive growth in these patients. PATIENTS AND METHODS Five patients with a clinical diagnosis of FGD are described in whom the disorder resulted from a variety of novel or previously described missense or nonsense mutations of the ACTH receptor (MC2-R). All patients demonstrated excessive linear growth over that predicted from parental indices and increased head circumference. RESULTS Growth hormone and IGF-I-values were normal. Growth charts suggest that the excessive growth is reduced to normal following the introduction of glucocorticoid replacement. A characteristic facial appearance including hypertelorism, marked epicanthic folds and prominent frontal bossing was noted. CONCLUSIONS These findings indicate that ACTH resistance resulting from a defective ACTH receptor may be associated with abnormalities of cartilage and/or bone growth independently of the GH–IGF-I axis, but probably dependent on ACTH actions through other melanocortin receptors.

The familial endocrine neoplasia syndromes, multiple endocrine neoplasia (MEN) types 1 and 2 and von Hippel Lindau disease (VHL), are autosomal dominant disorders which most commonly present clinically in early adulthood and onwards. They can, however, cause significant disease in childhood. The discovery of the causative genes for these disorders now allows the identification, by genetic mutation analysis, of most individuals at risk, at least in principle. Subjects found to be carriers of a mutation are at risk of developing the disorder and can be clinically monitored and treated in childhood so that appropriate targeted management may prevent the devastating complications which may develop, e.g. haemorrhage from retinal angiomas, sudden death from phaeochromocytoma and the development of medullary thyroid carcinoma from preexisting C cell hyperplasia. Furthermore, genetic screening allows the children from affected families who have not inherited the mutation to be reassured and avoid regular clinical monitoring. Genetic testing raises many issues over informed consent, counselling and confidentiality; these are reviewed elsewhere (Reilly et al., 1997). Epidemiological and clinical information on the penetrance of familial endocrine neoplasia in childhood is derived mainly from clinical case reports of children presenting with manifestations of these disorders and not from screening data. This paper will review the screening and clinical management strategies for MEN1, MEN2 and VHL. We discuss, using illustrative case reports from our own experience, the role and nature of DNA testing, and review the relevant investigations and their timing in children at risk of endocrine neoplasia syndromes. Multiple endocrine neoplasia type 1

BACKGROUND rhIGF-I has been used effectively to promote growth in growth hormone insensitivity syndrome (GHIS) in doses ranging from 40 μg/kg twice daily to 150–200 μg/kg once daily. It appears that the dose of 80 μg/kg twice daily s.c. may induce an equivalent response to higher doses with less side-effects. OBJECTIVE To study the efficacy and safety of rhIGF-I, 80 μg/kg twice daily s.c., in children with GHIS and to analyse the relationship of growth response to severity of phenotype. PATIENTS AND DESIGN: Eleven prepubertal children (3 females, 8 males) with GHIS; basal GH > 2.5 μg/l, IGF-I

OBJECTIVE To investigate the association of genetic variation of the insulin-like growth factor-I (IGF-I) gene with birth size small for gestational age (SGA). SUBJECTS We have studied a cohort of 120 SGA patients and 147 appropriate for gestational age (AGA) controls from Haguenau, France. METHODS PCR-SSCP analysis was performed to detect sequence variation in the coding region of the IGF-I gene. Microsatellite markers near the IGF-I gene (intronic and D12S78) were selected and amplified to perform further analysis by association studies. RESULTS A novel polymorphism in intron 2 was discovered, but allele-specific PCR analysis in the 120 SGA patients and 147 AGA controls found no association between this polymorphism and birth size SGA. Chi squared (χ2) analysis found no statistically significant association between the allele distribution of the microsatellite markers in the SGA subjects and the AGA controls. Power calculations estimate that the D12S78 marker has an 80% chance of detecting a 10–15% difference. CONCLUSIONS These studies suggest that genetic variation of IGF-I alone does not result in birth size small for gestational age in this population. Thus, if this gene influences fetal size, it plays only a minor role in a multifactorial disorder which involves other genetic and environmental factors.

OBJECTIVE Abnormal linear growth is common in childhood and adolescent Crohn's disease. We have studied the concentrations of the inflammatory marker CRP and of serum IGF-I and IGFBP-3 in patients with active Crohn's disease and have assessed the changes in these parameters during therapeutic intervention with enteral nutrition or intestinal resection. DESIGN Children and adolescents attending the inflammatory bowel disease clinic at our hospital underwent treatment either with enteral nutrition (Study A) or intestinal resection (Study B). These are two separate studies and the results cannot be compared. Serum concentrations of CRP, IGF-I and IGFBP-3 were determined at 0, 2, 8 and 16 weeks after start of enteral nutrition and in addition to height velocity, at 0 and 6 months after intestinal resection. SUBJECTS Study A: 14 patients, 9 male, 5 female, median age 12.5 years (range 7.0-17.2), puberty stage 1 (n = 13), stage 3 (n = 1). All had active Crohn's disease. Study B: 9 patients, 7 male, 2 female, median age 13.5 years (range 7.8-16.5), puberty stage 1 (n = 5), stages 2-4 (n = 4). All had Crohn's disease resistant to medical therapy. METHODS Crohn's disease was confirmed radiologically, endoscopically and histologically. Disease activity was scored using the Lloyd Still index (LSI). Study A: nutritional support was with a polymeric, casein-based formula feed AL 110. Study B: surgical procedures were small bowel resection (n = 2), right hemicolectomy (n = 5), subtotal colectomy (n = 2). MEASUREMENTS Study A: weight SDS, CRP, IGF-1 and IGFBP-3 were measured at 0, 2, 8, 16 weeks after start of enteral feeding. Study B: height velocity, CRP, IGF-I and IGFBP-3 were measured 0, 6 months after intestinal resection. STATISTICAL ANALYSIS Medians and ranges were used. Significance of changes was calculated using the Wilcoxon rank test for the analysis of paired data. RESULTS Study A: median LSI before treatment was 39 and increased after 8 weeks of enteral nutrition to 60 (P < 0.05). Weight SDS increased at 8 and 16 weeks (P < 0.05) compared to pretreatment. CRP was elevated at 0 weeks, falling during treatment. Median (range) values (normal < 5 mg/l) at 0 at 2, 8, 16 weeks were 53 mg/l (15-150), 8 mg/l (5-25), 7 mg/l (5-83) and 14 mg/l (5-39), all P < 0.001 compared with pretreatment. Median IGF-I-values increased during treatment. Median (range) values at 0, 2, 8, 16 weeks (all P < 0.005) compared to pretreatment, median (range) values at 0, 2, 8, 16 weeks were 78 micrograms/l (50-204), 131 micrograms/l (73-251), 119 micrograms/l (77-291) and 133 micrograms/l (67-497), all P < 0.005 compared to pre-treatment. IGFBP-3 levels increased during treatment. Median (range) values at 0, 2, 8, 16 weeks were 2.4 mg/l (1.4-3.1), 2.9 mg/l (1.8-4.6), 3.0 mg/l, 3.2 mg/l (1.8-4.5), all P < 0.01 compared to pretreatment. Study B: height velocity increased during 6 months after surgery. Median (range) values; 3.3 cm/year (0-8.3) before surgery, 8.4 cm/year (2-12.6) 6 months post-surgery, P < 0.01. Median (range) CRP values fell from 45 mg/l (5-150) to 8 mg/l (5-31) and IGF-I-values increased from 163 micrograms/l (64-286) to 226 micrograms/l (71-391). These changes were not statistically significant. IGFBP-3 values did not change. CONCLUSION The IGF system, as shown by serum IGF-I and IGFBP-3, is responsive to therapeutic intervention in active Crohn's disease. It is likely that a combination of decreased inflammatory activity and improved nutrition contributes to these changes.

A boy aged 6 years presented with genital precocity, enlarged testes and advanced linear growth. An ovoid mass 3-4 cm in diameter was identified by MRI scan in the right adrenal gland. Serum concentrations of LH, testosterone, alpha-subnuit, dehydroepiandrosterone sulphate, androstenedione and oestradiol were persistently elevated. LH was unresponsive to bolus i.v. injection of GnRH or to GnRH analogue therapy. Serum FSH was normal. After removal of the adrenal tumour, serum LH, alpha-subunit, testosterone and adrenal androgen levels fell to normal. In incubation medium of cultured disaggregated tumour cells, LH concentrations were greater than twice the mean serum concentration and 4-5-fold higher than in the medium of cultured non-neoplastic adrenal cells. Specific immunostaining of the tumour was positive for LH and alpha-subunit in many areas and these were not found in the adjacent non-neoplastic adrenal. Testicular biopsy showed almost complete spermatogenesis although germinal cell types were numerically lower than in normal men. These findings are consistent with an adrenocortical adenoma secreting LH being the cause of the patient's precocious puberty.

OBJECTIVE The mechanism of adrenarche is controversial, and there have been competing claims that its origin is in the hypothalamo-pituitary axis or in the adrenal gland itself. ACTH is a proposed inducer of adrenarche so patients with ACTH resistance due to the familial glucocorticoid deficiency syndrome provide a model to clarify the degree to which ACTH is involved in the regulation of adrenal androgen secretion during adrenarche. DESIGN Random analysis of plasma adrenal androgens and urinary adrenal androgen output in treated patients with familial glucocorticoid deficiency. PATIENTS Eleven patients (6 males and 5 females, aged 6.5–21.6 years, 4 prepubertal, minimum bone age 9 years) with familial glucocorticoid deficiency were studied. In 6, mutations in the coding region of the ACTH receptor are the cause of their ACTH resistance. In the remaining 5 the receptor was normal. MEASUREMENTS Physical examination, basal serum cortisol, basal plasma ACTH, serum cortisol after stimulation with 250 μg ACTH(1–24), plasma dehydroepiandrosterone-sulphate (DHEAS) and plasma androstenedione (A4), total urinary androgen excretion and single-stranded sequencing of the coding region of the ACTH receptor. RESULTS DHEAS was undetectable in 8, and detectable but below the age-matched reference values in 3 patients. A4 was measured in 10 patients, and in 3 patients (2 in late puberty) was found to be subnormal whereas in the remaining 7 patients A4 was normal for age and pubertal stage consistent with the gonadal contribution to peripheral A4 levels. Significantly diminished output of urinary adrenal androgen metabolites in 3 patients confirmed the results found in serum. The lack of adrenarche was independent of the presence of a mutation within the ACTH receptor and of the severity of glucocorticoid deficiency. Despite adequate glucocorticoid replacement therapy ACTH levels remained elevated in 10 of the 11 patients. CONCLUSIONS Although reduced adrenocortical inner zone cell number may contribute to the lack of adrenarche, in some patients there appears to be a discrepancy between partial glucocorticoid deficiency and significantly diminished adrenal androgen secretion. These data imply a significant contribution of ACTH to the regulation of adrenarche in normal children either by having a priming effect on the adrenal gland or by acting in concert with other adrenal androgen stimulating factors.

OBJECTIVE The recognition of the syndrome of adult GH deficiency suggests that young GH deficient adults, deprived of GH replacement at completion of linear growth, may suffer effects of GH deficiency. We assessed GH reserve in young adults previously diagnosed as having idiopathic GH insufficiency, who were treated with hGH replacement (14 IU/m2/week) in childhood. DESIGN Eight patients (7 males, 1 female) diagnosed as having GH insufficiency by insulin tolerance test (ITT) in childhood (ages 8.5–15.6 years) were retested by ITT at completion of linear growth (ages 15.1–19.6 years), 3 months after discontinuation of hGH therapy. MEASUREMENTS GH reserve was measured during ITT at diagnosis and at retesting. Height velocity (HV) and HV SDS were calculated before and during GH therapy. RESULTS At diagnosis, the mean peak GH response to ITT was 10.5 ± 2.0 mU/l (range 7.7–13.6). At retesting, mean GH was 52.4 ± 33.2 mU/l (range 10.4–100), 7/8 subjects having peak GH levels greater than 15 mU/l. During hGH therapy mean HV increased from 4.0 ± 1.5 cm/year at diagnosis to 7.3 ± 1.9 cm/year during the 1st year (P = 0.004) and 6.9 ± 2.3 cm/year during the 2nd year (P = 0.02). Mean HVSDS increased from −1.6 ± 2.1 at diagnosis to 3.1 ± 2.9 during the 1st year (P = 0.004) and 2.2 ± 4.2 during the 2nd year (P = 0.05, NS) of treatment. CONCLUSIONS Seven out of 8 children diagnosed as having idiopathic GH insufficiency had normal GH secretion at completion of linear growth. Children with GH insufficiency cannot be assumed to become GH deficient adults and should not continue on GH therapy into adult life without reinvestigation. All who were GH insufficient children should be retested at completion of linear growth to identify those who are truly GH insufficient adults and may benefit from replacement therapy.

Summary OBJECTIVE Cushing's syndrome In childhood and adolescence Is rare. We analysed the clinical presentation, Investigation, management and therapeutic outcome In 12 paediatric patients with Cushing's syndrome. DESIGN Retrospective review of case notes. PATIENTS Twelve patients, 7 males and 5 females, aged 7.6-17.8 years with Cushing's syndrome who were admitted to St Bartholomew's Hospital between 1978 and 1993, were studied. Aetiologies of the Cushing's syndrome patients were: Cushing's disease (9), adrenal adenoma (1), nodular adrenocortical dysplasia (1) and ectopic ACTH syndrome (1). One further male patient, aged 17.8 years who presented with Nelson's syndrome after bilateral adrenalectomy for Cushing's disease In 1978, Is described. MEASUREMENTS Presenting symptoms, endocrine tests for hypercortlsolism, Imaging studies, simultaneous bilateral Inferior petrosal sinus sampling and therapeutic strategies are discussed. RESULTS The dominant clinical features were obesity, short stature, virillzation, headaches, fatigue and emotional lability. Investigations confirmed Cushing's syndrome by demonstrating absent Cortisol clrcadlan rhythm and Impaired suppression on low dose dexa-methasone test and differentiated Cushing's disease from other aetiologies by high dose dexamethasone and hCRH tests. In Cushing's disease, pituitary CT scan Identified a microadenoma In 4 out of 9 subjects. In 5 of the 9 patients (3 with a normal pituitary CT, 2 with a suggested microadenoma), a pituitary MRI scan was performed and confirmed the CT findings. Inferior petrosal sinus catheterization for ACTH In 4 patients confirmed excess pituitary ACTH secretion, correctly lateralizing the tumour In all cases. Cushing's disease was treated by transsphenoidal surgery alone In 6 patients and combined with pituitary Irradiation In 3 patients. Of these 9 patients, 7 are cured and 2 are in remission. The patient with Nelson's syndrome Is cured after total hypophysectomy. CONCLUSIONS This series describes the clinical features, aetiologies and management of juvenile Cushing's syndrome. Investigation with low and high-dose dexamethasone suppression tests and hCRH test identified the aetiology In each case. Collaboration between paediatric and adult endocrine units together with an experienced neurosurgeon and a radiotherapist contributed to the successful therapeutic outcome of these patients

Summary OBJECTIVE Growth hormone (GH) secretion Is increased in conditions of GH insensitivity such as Laron syndrome, with elevation of both basal and peak levels. We have studied the effect of recombinant IGF-I therapy on the pattern of GH secretion in two subjects with GH insensitivity. SUBJECTS Two pubertal subjects with GH insensitivity (female, 16.4 years, breast stage 3; male 13.6 years, genital stage 2) were investigated after 6 months of IGF-I therapy (120 μg/kg twice daily s.c. at 0800 and 1900 h). GH profiles taken before the start of IGF-I therapy, when both subjects were prepubertal (aged 14 0 and 11 5 years respectively), were used for comparison. METHODS GH profiles were performed with blood samples taken every 20 minutes between 2000 and 0800 h from an indwelling cannula. MEASUREMENTS Serum samples were assayed for GH by immunoradiometric assay and IGF-I, IGFBP-1 and insulin by radioimmunoassay. RESULTS Before IGF-I therapy, GH profile studies demonstrated pulsatile GH secretion. Basal GH was elevated with no value falling below the limit of detection of the assay and an increase in peak levels (maximum 203 and 206 μ/I at 0000 h and 0020 h respectively). After 6 months IGF-I therapy, the GH profiles were significantly different. With the onset of puberty a further increase in GH secretion would have been expected; nevertheless, following administration of IGF-I at 1900 h, GH secretion decreased with a reduction in mean overnight GH levels from 65 to 33 μ/l and 53 to 11 μ/l respectively. GH pulsatility was also suppressed in the two subjects, for the first 3.5 and 6 hours overnight respectively. Pulsatile GH secretion then returned with peak levels reaching 130 and 63 μ/l respectively. Prior to therapy IGF-I levels were at the lower limit of assay detection. On IGF-I therapy serum IGF-I levels reached a peak within 3 hours (298 and 438 μg/l) coinciding with the suppression of GH secretion. IGF-I levels fell rapidly overnight to 92 and 101 μg/l at 0800 h prior to the next injection. The fall in serum IGF-I coincided with the return of GH secretion. IGFBP-1 levels increased overnight both before and during IGF-I therapy, rising from 24 to 83 and 22 to 110 μg/l before therapy and 13 to 60 and 13 to 71 μg/l during therapy. This rise in IGFBP-1 appeared to be inversely related to the fall in serum insulin levels overnight and appeared not to be affected by IGF-I therapy. CONCLUSION GH secretion is suppressed by exogenous IGF-I therapy in GH insensitive subjects. The failure to maintain high serum IGF-I levels overnight, presumably due to a persisting defect in serum IGFBP-3 levels, was associated with an early return of GH secretion. These findings may have implications for the dose and regimen of IGF-I therapy in subjects with growth hormone insensitivity.

The growth hormone (GH)-IGF-I axis is essential for normal foetal and childhood growth. Defects at different sites in the axis frequently result in short stature which may compromise adult height. We describe a continuum of clinically relevant abnormalities from GH deficiency through to GH resistance and discuss the implementation and interpretation of investigations. We consider appropriate therapy for patients with abnormal auxology and subnormal adult height prognosis, highlighting new data to clarify therapeutic choices leading to optimal clinical outcome.

OBJECTIVE The aim of the study was to investigate whether pyridostigmine, a cholinesterase inhibitor which is thought to act at the hypothalamus to inhibit somatostatin secretion, would augment spontaneous or GHRH-stimulated serum GH levels in patients with GH-insufficiency. DESIGN Oral pyridostigmine 60 mg or placebo was administered at the start of a 9-h subcutaneous infusion of either GHRH (1-29)NH2 10 micrograms/kg/h or saline control. Studies were performed during the daytime (0900-1800 h) in five patients, and the night-time (2100-0600 h) in a further five. PATIENTS Ten short, pre-pubertal children (aged 6-11 years; eight boys) with growth hormone insufficiency were studied. MEASURES Blood for serum GH was sampled every 20 min, and analysed using the PULSAR program. RESULTS The subcutaneous infusion of GHRH 10 micrograms/kg/h increased mean serum GH levels (+/- SEM): by day 17.7(+/- 6.8) vs placebo 2.2(+/- 0.4) mU/l (P less than 0.01), and by night 26.9(+/- 3.3) vs 5.5(+/- 1.3) mU/l (P less than 0.05). There was a significant rise in mean 'baseline' GH concentration: by day 5.5(+/- 1.7) vs 1.0(+/- 0.0) mU/l (P less than 0.05); and night 8.2(+/- 2.7) vs 1.3(+/- 0.3) mU/l (P less than 0.05). Pyridostigmine failed to produce a significant overall increase in either spontaneous or GHRH-stimulated GH secretion by day or night, although there was a significant rise in mean GH levels during the 3 h following pyridostigmine administration in the morning: 4.4(+/- 1.1) vs 2.4(+/- 0.5) mU/l (P less than 0.001). GHRH or pyridostigmine given singly or in combination had no significant effect on the number of pulses. Side-effects attributable to pyridostigmine occurred in seven children. CONCLUSIONS Pyridostigmine, either on its own or as an adjuvant therapy in combination with GHRH, acts for only a brief time and does not offer any potential benefit in the management of children with short stature.

Growth hormone-releasing hormone (GHRH) when given s.c. to GH-insufficient children either as pulses, or once or twice daily, promotes linear growth. These treatment regimens, however, are not ideal as they require frequent drug administration and a significant proportion of patients do not show improved growth. We have now investigated the GH response to a nocturnal s.c. infusion of GHRH (1-29)NH2, at two dosages, 5 and 10 micrograms/kg/h, in a group of five GH-insufficient children. The s.c. infusion of GHRH between 2100 h and 0600 h augmented nocturnal pulsatile GH release in all five children. There was a dose-dependent response for the GH area under the curve (AUC), and mean total GH concentration. The AUC for GH was significantly greater after the 10 than 5 micrograms/kg/h GHRH which in turn was greater than that after placebo; mean (SD) AUC: 14816 (3978), 8125 (1931), 3032 (1582) mU min/l respectively (P less than 0.01 and P less than 0.05). There was no significant change in the number of GH pulses during the 9-h infusions when the subjects were infused with GHRH 10 or 5 micrograms/kg/h compared to placebo, and they occurred at similar times although the number of pulses tended to be greater after GHRH; the mean (SD) numbers of GH pulses were 5.0 (0.7), 3.8 (0.8), 3.2 (0.8), respectively. There was however a significant rise in the mean baseline GH concentration in all patients during the infusion of GHRH 10 micrograms/kg/h compared to placebo, but not with 5 micrograms/kg/h. Thus, GHRH(1-29)NH2 given s.c. augmented nocturnal pulsatile GH release in GH-insufficient children but it also increased baseline GH secretion. These results suggest that a sustained release preparation of GHRH could be a potential treatment for GH-insufficient children, and that a dose of 5 micrograms/kg/h would promote pulsatile GH release, but that at higher dosage it may also raise basal GH secretion.

It is now widely recognized that there is a link between certain disorders of sexual differentiation and gonadal neoplasia. This article reviews gonadal neoplasia in such patients and records a personal series of patients with gonadal tumours from St Bartholomew's Hospital. The conditions in which gonadal malignancy may occur are described first and then the histopathological features of clinical importance are outlined. Clinical guidelines for the management of patients at risk of developing gonadal tumours are also given

OBJECTIVE: Although Cushing's disease (CD) rarely occurs in childhood, affected children commonly fail to achieve predicted adult height. Hypercortisolaemia results in reduced GH secretion and GH-deficiency may persist or demonstrate delayed recovery after successful treatment of CD in adults. Whether recovery of spontaneous GH secretion occurs following treatment of childhood CD has yet to be established. DESIGN AND PATIENTS: We performed a retrospective analysis of the GH status of 13 children (10 males; 12.8 +/- 1.0 years, mean +/- SE) who had undergone successful treatment of CD that occurred prior to the completion of linear growth. Each underwent transsphenoidal hypophysectomy, resulting in satisfactory control of glucocorticoid levels in 7/13 (54%). The remaining six patients (46%) received fractionated external beam irradiation (4500 Gy). At the time of GH assessment, circadian dynamics of cortisol were normal in eight patients and five were receiving titrated glucocorticoid replacement. MEASUREMENTS: GH status was assessed using the peak response to a provocative stimulus. Eleven out of 13 underwent testing with insulin-induced hypoglycaemia (nadir plasma glucose 30 mU/l. Intermediate values were taken to represent subnormal GH status. Assessment of GH status was performed 39 +/- 10 months (median +/- SE) following successful treatment (range 9-108 months). RESULTS: Using these criteria 4/13 (31%) patients had severe GH-deficiency. Only 2/13 (15%) had a normal response. 7/13 (54%) achieved peak GH levels in the subnormal range. Those with multiple pituitary hormone deficiencies were most likely to have lower peak GH levels, but there was no clear effect of pituitary irradiation or relationship between duration post cure and peak GH response. CONCLUSION: GH-deficiency is common and may persist for many years following successful treatment of CD prior to completion of linear growth. External radiotherapy does not necessarily result in severe GH-deficiency in the short term. Assessment of GH status and consideration of GH treatment should be considered following treatment of CD in childhood and adolescence in order to maximize the opportunities to achieve a satisfactory final adult height. In those with subnormal GH responses, continued assessment is necessary to determine whether the GH axis subsequently recovers or if these patients develop features of the adult GH-deficiency syndrome.

To investigate the characteristics of spontaneous GH secretion in four male children with short stature due to partial GH insensitivity. Their molecular defect consists of inclusion of a mutant intronic pseudoexon in the region of the GH receptor involved in homodimerization.The subjects were two pairs of brothers who were first cousins, aged 10.4-14.2 years, heights -3.3 to -5.6 SDS, from a consanguineous Pakistani family. Basal serum IGF-I levels were extremely low (20-29 mg/l; NR50), with absent or minimal response to human recombinant GH (hGH) stimulation. Serum IGFBP-3 SDS levels were also low (-2.9 to -8.9). GH binding protein (GHBP) levels were normal (28.1-51.7%).Spontaneous GH secretion was studied by intermittent (20 min) venous sampling from 2000 to 0800 h. The secretion profiles were analysed using the Pulsar programme and compared to data from a reference population of 76 prepubertal Swedish children [median age 10.7 years, median height -1.1 SDS (-2.0 to 1.4)] according to Swedish growth standards.Median (range) Pulsar-derived values in the four patients and controls were, respectively: GHmax (mU/l) 276.6 (178.7-325.8) and 27.2 (13.1-94.9), mean GH (mU/l) 64.5 (41.9-77.8) and 5.8 (3.2-20.6), baseline (mU/l) 12.3 (11.7-20.1) and 1.1 (0.2-6.1), AUCb (mU/l x 24 h) 1210 (684-1555) and 112.5 (60.6-316.4), i.e. all parameters of GH secretion in the four patients were markedly elevated compared with the control population.Spontaneous GH secretion is elevated in partial GH insensitivity. This investigation could be of diagnostic value in children with short stature.

Summary OBJECTIVE To investigate the hypothesis that intracellular, dominant-negative mutations of the growth hormone receptor (GHR) exist in children with idiopathic short stature (ISS) and partial growth hormone insensitivity (GHI). SUBJECTS We studied 31 children aged 4.55–13.14 years with ISS (height ≤-1.8 standard deviation scores, UK standards 1990). GH provocation tests (glucagon 15μg kg−1 i.m.) excluded GH deficiency In all subjects. Serum IGF-I levels were below the 50th centile for age in all subjects and below the 10th centile in 64.5% of cases. GH binding protein levels were normal in the 24 subjects in whom It was measured (mean 25.2%; range 10–42.6%). METHODS Exons 9 and 10 of the GHR were amplified by PCR from leucocyte-derived DNA. Samples were directly sequenced on the ABI 377 DNA analyser using the −21 M13 dye primer cycle sequencing protocol for optimum heterozygote detection. RESULTS No abnormalities were detected in exon 9 which encodes the proline-rich box 1 motif. In exon 10 two sequence variants were found; a heterozygous, single base alteration (TCT to TCC) in codon 325 which does not change the amino acid sequence in one patient, and the L5261 variant in 24 subjects. L5261 is a conservative amino acid change and had an allele frequency of 0.53 in our patients, which is similar to that reported in a control population. CONCLUSIONS The apparent partial growth hormone insensitivity in this group of idiopathic short-stature subjects is not related to heterozygous, dominant-negative variants of the intracellular signalling domain of the GHR. Hence it is likely that other genetic and environmental factors may be involved.

Genotype and phenotype heterogeneity in patients with GH insensitivity syndrome suggests that partial defects exist in the GH receptor. Children with partial GH resistance would be expected to have short stature, elevated GH levels and relatively low levels of IGF-I and IGFBP-3. Provocation tests of the GH-IGF-I axis may help to identify such children. The IGF-I generation test in particular may demonstrate impaired secretion of IGF-I and IGFBP-3. This prospective study assesses the usefulness of the IGF-I generation test in the identification of short children with possible GH insensitivity.Prepubertal children referred for assessment of short stature underwent a standard GH provocation test followed by an IGF-I generation test.Thirty-seven prepubertal children (14 girls, 23 boys) with short stature (height2nd centile UK standards 1990) aged 4.5-12.6 years were investigated prospectively.Assessment included history, physical examination, auxological observations (height, weight, bone age). GH provocation tests (glucagon 15 micrograms/kg i.m. or insulin 0.15 U/kg/i.v.) was followed by an IGF-I generation test (hGH 0.1 iu/kg/s.c. daily for 4 days).GH was assayed during the provocation test. IGF-I and IGFBP-3 were measured at 0900 h on day 0 and 4 of the IGF-I generation test. GH and IGF-I were measured by radioimmunoassay, IGFBP-3 by IRMA and basal GHBP by HPLC.Height SDS was calculated according to the UK Height Standards 1990. The absolute and percentage changes of IGF-I and IGFBP-3 during the IGF-I generation test were calculated.The 37 children were divided into three groups according to the peak GH level (mean +/- SEM) during the provocation test: Group 1 (peak GH20 mU/l) n = 11, five girls, six boys age 7.1 +/- 0.7 years, height SDS -2.5 +/- 0.1, peak GH 14.5 +/- 1.6 mU/l, IGF-I 92.0 +/- 10.4 micrograms/l, IGFBP-3 2.6 +/- 0.4 mg/l. Group 2 (peak GH 20-40 mU/l) n = 12, six girls, six boys age 8.6 +/- 0.7 years, height SDS -2.6 +/- 0.1, peak GH 28.4 +/- 1.6 mU/l, IGF-I 121-5 +/- 13.4 micrograms/l, IGFBP-3 2.9 +/- 0.2 mg/l. Group 3 (peak GH40 mU/l) n = 14, three girls, 11 boys, aged 8.5 +/- 0.6 years, height SDS -2.3 +/- 0.1, peak GH 60.7 +/- 4.1 mU/l, IGF-I 112.4 +/- 10.9 micrograms/l, IGFBP-3 3.1 +/- 0.3 mg/l. There were no significant differences in the absolute increases of IGF-I or IGFBP-3 (mean +/- SEM) during the IGF-I generation test, IGF-I; Group 1, 48.8 +/- 9.5 micrograms/l, Group 2, 42.7 +/- 4.8 micrograms/l. Group 3, 45.5 +/- 5.1 micrograms/l, IGFBP-3; Group 1, 1.1 +/- 1.2 mg/l. Group 2, 1.2 +/- 0.2 mg/l, Group 3, 0.85 +/- 0.1 mg/l. There were no significant differences in the percentage increases (mean +/- SEM) of IGF-I; Group 1, 55 +/- 9%, Group 2, 35 +/- 5%, Group 3, 42 +/- 8%, or IGFBP-3; Group 1, 64 +/- 17%, Group 2, 44 +/- 8%, Group 3.32 +/- 6%. GHBP values were normal in all three groups. In Group 3 (peak GH40 mU/l) four individual patients had either low basal IGF-I levels (n = 2) (5th centile of normal range for age) or low basal IGFBP-3 levels (n = 1) (5th centile of normal range for age) or low IGF-I responses in the IGF-I generation test (2 x CV of IGF-I assay) (n = 1). No single subject had all the characteristics of GH insensitivity syndrome.The responses during an IGF-I generation test did not identify a clear group of children with GH insensitivity. Individual patients had low basal IGF-I or IGFBP-3 values and a poor response in the generation test, features which, in the presence of high GH levels on provocation, are consistent with partial GH insensitivity.

UNLABELLED In children with hypothalamic causes for GH deficiency there are theoretical reasons why a GHRH analogue might be better than conventional GH therapy in promoting growth. OBJECTIVE We have aimed to determine the efficacy and safety of growth hormone-releasing hormone (GHRH) (1-29)-NH2 given as a twice daily subcutaneous injection in the treatment of growth failure in children with radiation-induced GH deficiency. DESIGN A multicentre study comparing growth before and after 1 year of treatment with GHRH (1-29)-NH2, 15 micrograms/kg twice daily, by subcutaneous injection in children with radiation-induced GH deficiency. On completion of the study year all children were treated with GH (0.5 U/kg/week) and growth parameters were documented over the next year. PATIENTS Nine children (six boys) with radiation-induced GH deficiency following cranial (n = 4) or craniospinal (n = 5) irradiation for a brain tumour distant from the hypothalamic-pituitary axis (n = 8) or prophylaxis against central nervous system leukaemia (n = 1) were studied. All were prepubertal when the study commenced, which was at least 2 years from radiotherapy. MEASUREMENTS Anthropometry and pubertal staging were carried out at 3-monthly intervals and bone age estimations at 6-monthly intervals (TW2 method). Pretreatment standing height velocities were compared with values during the year of GHRH treatment and then after the first year of GH therapy. In those that had received craniospinal irradiation, a change in leg-length Standard deviation score (SDS) was noted before and after GHRH therapy. Changes in skin-fold thickness and bone age during the GHRH study year were documented. Adverse events and 3-monthly measurements of clinical chemistry, haematology, lipid profile and thyroid function were recorded. RESULTS There was a significant increase in height velocity from 3.3 (SD 1.1) cm/year before treatment, to 6.0 (SDS 1.5) cm/year after 1 year of GHRH treatment (P = 0.004). GHRH maintained or improved the leg length SDS in children who had received craniospinal irradiation. Bone age increased by a mean of 1.1 years/chronological year during treatment with GHRH. Subsequent height velocity during 1 year of GH therapy was 7.5 (SD 1.5)cm/year. No adverse changes in biochemical or hormonal analyses were noted or adverse events that could be attributed to GHRH therapy. One child went into puberty during the GHRH study year and three were pubertal during the first year of GH therapy. CONCLUSION In cranially irradiated children, GHRH was effective in increasing growth velocity but this was less than that seen in response to GH therapy, although it matched that in children with isolated idiopathic GH deficiency treated with the same dose and schedule of GHRH administration.

Summary OBJECTIVE Insulin resistance increases during adolescence, and is exaggerated in patients with insulin dependent diabetes mellitus (IDDM). A relative deficiency of insulin-like growth factor-I (IGF-I) may contribute to this increased insulin requirement. Two mechanisms have been proposed: (a) increased GH secretion, caused by failure of IGF feedback control, leading to increased insulin resistance and (b) lack of Insulin-like action of the IGFs which is reinforced by high plasma levels of IGFBP-1, an inhibitor of IGF action. The contribution of these two mechanisms to the ‘dawn phenomenon’ is assessed. DESIGN The two possible mechanisms were studied during the dawn rise of glucose in pubertal adolescent patients with IDDM. Two overnight studies were performed in each subject. Patients remained on the same insulin regimen throughout. SUBJECTS Twenty-two diabetic adolescent subjects, aged (mean ± SEM) 14.0 ± 0.4 years, duration of IDDM 7.9 ± 0.8 years, were recruited. Pubertal status was: group 1 (breast stage 1–2; testicular volume < 4–8ml) 3 male and 4 female, group 2 (breast stage 3; testicular volume 10–12 ml) 0 male 4 female, group 3 (breast stage 4–5; testicular volume 15–25 ml) 4 male and 7 female. Height standard deviation score (mean ± SD) (-0.02 ± 099) and dally insulin dose (50.4 ± 3.1 U/day) did not change between studies. There were no differences in HbA1 (study A 11.26 ± 0.45%, study B 11.09 ± 0.42%). METHODS The subjects were admitted for the two studies 0.3 ± 0.03 years apart. Blood samples were taken via an indwelling cannula every 20 minutes between 1900 and 0700 h. MEASUREMENTS GH was assayed every 20 minutes, IGFBP-1, glucose and free Insulin every hour and lGF-I at 0700h. GH, IGFBP-1, IGF-I and free insulin were measured by radioimmunoassay. IGFBPs were also analysed by Western ligand blotting techniques. GH profiles were analysed by Pulsar and results compared by paired Student's t-test. The relations between the dawn rise In glucose and the changes in IGFBP-1, GH and free insulin were examined by multiple linear regression analysis. RESULTS Serum IGFBP-1 levels rose overnight In the two studies (study A, from 9·1 at 2200 to 59 ± 9μg/l at 0700 h; study B, from 10±1 at 2100 to 64 ± 14μg/l at 0700h) whilst insulin levels fell from 47 ± 5 at 2200 to 16 ± 2mU/l at 0700 h (study A) and from 45·5 at 2000 to 14 ± 2mU/l at 0700 h (study B). Glucose levels fell from 16.0 ± 1.0 to 9.3 ± 0.9 mmol/l at 0400h, and then rose to 11.9 ± 1.1 mmol/l at 0700 h during study A, and from 13.4 ± 1.3 to 10.1 ± 1.1 mmol/l at 0400 h and then rose to 13.5 ± 1.0 mmol/l at 0700 h during study B. There were no differences in GH secretion between studies (mean GH levels (mean ± SD) (study A, 15.7 ± 6.6 mU/I; study B, 16.2 ± 7.1 mU/l; correlation within subjects between studies r= 0.77, P < 0.001), sum of GH peaks (study A, 189.9 ± 903 mU/l; study B, 185.8 ±100.2 mU/l; r= 0.57, P= 0.006)). Mean GH levels varied with pubertal stage (group 1,12.1 ± 1.5 mU/l; group 2, 23.3 ± 2.1 mU/I; group 3, 15.3 ± 1.2mU/I). Serum IGF-l levels were not different (study A, 203 ± 12 μg/l; study B, 218 ± 13 μg/l). REGRESSION ANALYSIS The change In plasma glucose between 0200 and 0700 h In both studies related to free insulin, IGFBP-1 and the sum of the GH levels over the preceding hour (log glucose =7.87 + 5.32 log IGFBP-1 (P= 0.0001) −5.05 log free insulin (P= 0.0001)-1.44 log GH (P= 0.004); R2= 72%). Mean overnight GH levels did not predict the morning rise In plasma glucose. CONCLUSION The morning rise of IGFBP-1 and plasma glucose appear to be related in this group of subjects with IDDM and this was a consistent finding In the two studies. This relation was additive to the effect of Insulin deficiency. No positive relation was noted between GH secretion and glucose levels. These findings support the hypothesis that the increased GH secretion In IDDM Is a marker of IGF-I deficiency rather than a direct causal factor in the increase In insulin resistance. The IGFs may therefore have a direct role In glucose homeostasis via the ‘free’ fraction of circulating IGFs, the availability of which may be modulated by changes in IGFBP-1 levels.

Summary OBJECTIVE The aim of the study was to test the hypothesis that clinically unaffected female carriers of X-linked Kallmann's syndrome have an olfactory defect. DESIGN Assessment of the olfactory threshold to seven standard odorants, each at a concentration of 1-10-8mol/1. PATIENTS Five families with X-linked Kallmann's syndrome (KS) were tested, containing 19 males with KS, and 9 female carriers. Related but unaffected males (n= 8) were used as a control group, and in addition seven patients with Turner's syndrome (XO) were assessed. MEASUREMENTS The olfactory threshold was taken as the lowest concentration at which each odorant was clearly distinguished from control (liquid paraffin). The threshold for each odorant was compared between the subject groups using the non-parametric Mann-Whitney test. RESULTS All patients with KS were anosmic to all odorants. The female carriers had hyposmla, with a significant reduction in the olfactory threshold to putrid, peppermint, floral and pungent odorants compared to control subjects, and to peppermint, floral and pungent odorants compared to subjects with Turner's syndrome. The latter had olfactory thresholds which were statistically identical with the control group. CONCLUSIONS Obligate female carriers of X-linked Kallmann's syndrome are hyposmic compared to control subjects. The overlap between the two groups, however, makes olfactory testing unreliable as a diagnostic test.