Search Results

Puberty is the period during which we attain adult secondary sexual characteristics and reproductive capability. Its onset depends upon reactivation of pulsative GNRH, secretion from its relative quiescence during childhood, on the background of intact potential for pituitary–gonadal function. This review is intended: to highlight those current practices in diagnosis and management that are evidence based and those that are not; to help clinicians deal with areas of uncertainty with reference to physiologic first principles; by sign-posting relevant data arising from other patient groups with shared issues; to illustrate how recent scientific advances are (or should be) altering clinician perceptions of pubertal delay; and finally, to emphasise that the management of men and women presenting in advanced adult life with absent puberty cannot simply be extrapolated from paediatric practice. There is a broad spectrum of pubertal timing that varies among different populations, separated in time and space. Delayed puberty usually represents an extreme of the normal, a developmental pattern referred to as constitutional delay of growth and puberty (CDGP), but organic defects of the hypothalamo–pituitary–gonadal axis predisposing to hypogonadism may not always be initially distinguishable from it. CDGP and organic, or congenital hypogonadotrophic hypogonadism are both significantly more common in boys than girls. Moreover, around 1/3 of adults with organic hypogonadotrophic hypogonadism had evidence of partial puberty at presentation and, confusingly, some 5–10% of these subsequently may exhibit recovery of endogenous gonadotrophin secretion, including men with Kallmann syndrome. However, the distinction is crucial as expectative (‘watch-and-wait’) management is inappropriate in the context of hypogonadism. The probability of pubertal delay being caused by organic hypogonadism rises exponentially both with increasing age at presentation and the presence of associated ‘red flag’ clinical features. These ‘red flags’ comprise findings indicating lack of prior ‘mini-puberty’ (such as cryptorchidism or micropenis), or the presence of non-reproductive congenital defects known to be associated with specific hypogonadal syndromes, e.g. anosmia, deafness, mirror movements, renal agenesis, dental/digital anomalies, clefting or coloboma would be compatible with Kallmann (or perhaps CHARGE) syndrome. In children, interventions (whether in the form or treatment or simple reassurance) have been historically directed at maximising height potential and minimising psychosocial morbidity, though issues of future fertility and bone density potential are now increasingly ‘in the mix’. Apubertal adults almost invariably harbour organic hypogonadism, requiring sensitive acknowledgement of underlying personal issues and the timely introduction of sex hormone replacement therapy at more physiological doses.

Background: Corticotrophin-releasing hormone (CRH) was identified by Vale and co-workers in 1981 and has since been used extensively in the diagnosis of ACTH-dependent Cushing’s syndrome (CS). It was hoped that the CRH test would discriminate between pituitary and ectopic ACTH secretion. In adults, a rise from basal to peak plasma cortisol of ≥20% and ACTH of ≥50% is consistent with Cushing’s disease (CD).

Methods: Twenty-seven paediatric patients, with CD (mean age ± s.d. 13.1 ± 3.2; range 6.4–17.8 years) were investigated in our centre between 1982 and 2005.

Results: During the CRH test, all patients showed an increase in cortisol of >20% (range 106–554%). In one patient with ectopic ACTH syndrome, there was no increase in cortisol after CRH. In six paediatric patients with CS due to primary adrenal hyperplasia, no patient showed an increase in cortisol after CRH of >1%.

Conclusions: A further suggested use of CRH is to increase the sensitivity of the central to peripheral and interpetrosal ratios of ACTH during inferior petrosal sinus catheterisation (IPSS). Bilateral IPSS with human CRH (hCRH) has been performed in our unit in 21 children with CD, as part of the preoperative preparation prior to transsphenoidal surgery (TSS). Its principal role was to identify the site of the microadenoma. Sixteen of 21 patients (76%) who underwent IPSS with hCRH were cured following TSS. In our view, the CRH test is of value during IPSS by clarifying the position of the microadenoma and in this way contributed to the overall outcome of TSS in paediatric patients with CD.

Background/objective: Pituitary radiotherapy (RT) is an effective second-line treatment for paediatric Cushing’s disease (CD). Although the short-term effects of pituitary RT are well documented, there are less data on possible long-term sequelae. We report the long-term anterior pituitary function in a cohort of paediatric CD patients treated with pituitary RT.

Patients and methods: Between 1983 and 2006, 12 paediatric CD patients (10 males and 2 females) of mean age 11.4 years at diagnosis (range 6.4–17.4) underwent second-line pituitary RT (45 Gy in 25 fractions), following unsuccessful transsphenoidal surgery. Out of 12, 11 patients were cured by RT (cure interval 0.13–2.86 years) defined by mean serum cortisol of <150 nmol/l on 5-point day curve and midnight sleeping cortisol of <50 nmol/l. Long-term data are available for six male patients, who received RT at the age of 7.0–17.6 years. The mean follow-up from the completion of RT was 10.5 years (6.6–16.5).

Results: At a mean of 1.0 year (0.11–2.54) following RT, GH deficiency (peak GH <1–17.9 mU/l) was present in five out of six patients. On retesting at a mean of 9.3 years (7.6–11.3) after RT, three out of four patients were GH sufficient (peak GH 19.2–50.4 mU/l). Other anterior pituitary functions including serum prolactin in five out of six patients were normal on follow-up. All the six patients had testicular volumes of 20–25 ml at the age of 14.5–28.5 years.

Conclusion: This series of patients illustrates the absence of serious long-term pituitary deficiency after RT and emphasises the importance of continued surveillance.

The IGF1 generation test (IGFGT) is often used during the assessment of suspected GH insensitivity (GHI). We report the results of a survey undertaken in 2010 to determine the use of IGFGT amongst members of the European Society for Paediatric Endocrinology to evaluate suspected GHI. The literature surrounding the usefulness and limitations of IGFGT are reviewed, and recommendations provided for its use. Of 112 paediatric endocrinologists from 30 countries who responded to the survey, 91 (81%) reported that they had used the IGFGT in the previous 2 years; >10 IGFGT protocols were used. The IGFGT impacted treatment decisions for 97% of the respondents and was a prerequisite for recombinant human IGF1 treatment for 45% of respondents. From a literature review, sensitivity of the IGFGT was evaluated as 77–91% in molecularly proven cases of GHI; specificity was ≤97%, depending on the protocol. The positive predictive value of the IGFGT is likely to be low, as the frequency of normality is predictably higher than that of abnormality in GH signalling. Given the limitations of the IGFGT in the most severe cases of GHI syndrome (GHIS), the ability of the IGFGT to detect less severe GHIS is doubtful. In a pragmatic approach, the IGFGT may not be useful for the diagnosis of GHIS.

Osteoporosis in children can be primary or secondary due to chronic disease. Awareness among paediatricians is vital to identify patients at risk of developing osteoporosis. Previous fractures and backaches are clinical predictors, and low cortical thickness and low bone density are radiological predictors of fractures. Osteogenesis Imperfecta (OI) is a rare disease and should be managed in tertiary paediatric units with the necessary multidisciplinary expertise. Modern OI management focuses on functional outcomes rather than just improving bone mineral density. While therapy for OI has improved tremendously over the last few decades, this chronic genetic condition has some unpreventable, poorly treatable and disabling complications. In children at risk of secondary osteoporosis, a high degree of suspicion needs to be exercised. In affected children, further weakening of bone should be avoided by minimising exposure to osteotoxic medication and optimising nutrition including calcium and vitamin D. Early intervention is paramount. However, it is important to identify patient groups in whom spontaneous vertebral reshaping and resolution of symptoms occur to avoid unnecessary treatment. Bisphosphonate therapy remains the pharmacological treatment of choice in both primary and secondary osteoporosis in children, despite limited evidence for its use in the latter. The duration and intensity of treatment remain a concern for long-term safety. Various new potent antiresorptive agents are being studied, but more urgently required are studies using anabolic medications that stimulate bone formation. More research is required to bridge the gaps in the evidence for management of paediatric osteoporosis.

Objective: The aim of glucocorticoid replacement therapy in ACTH-deficient patients is to mimic the normal diurnal variation of cortisol. However, current hydrocortisone (HC) replacement results in prolonged episodes of hypocortisolaemia and supraphysiological peaks. Plasma cortisol profiles are an accurate yet labour-intensive method of assessing HC replacement. Salivary and bloodspot cortisol sampling methods are less invasive and may be useful tools for assessing glucocorticoid replacement, particularly in children. Therefore, we aimed to define normal salivary and bloodspot cortisol levels in children and their correlations with the gold standard (plasma cortisol).

Design: Cross-sectional study in a paediatric teaching hospital.

Methods: Plasma, saliva and bloodspot cortisol profiles were performed on 30 ACTH-deficient children and 22 healthy siblings.

Results: In ACTH-deficient patients taking oral HC, the bloodspot–plasma correlation (ρ = 0.90) was stronger than the salivary–plasma correlation (ρ = 0.49). Using target ranges for salivary and bloodspot cortisol levels based on normal data from control subjects, the less invasive sampling methods had low rates of agreement with plasma cortisol target ranges (saliva 65% and bloodspot 75%). Using the plasma–bloodspot correlation regression equation to convert bloodspot to calculated plasma cortisol, there was a high concordance between calculated and actual measured plasma cortisol (88%).

Conclusion: Bloodspot cortisol sampling is a feasible and accurate method for monitoring oral HC replacement in paediatric patients without necessitating hospital admission, but salivary sampling is not useful.

Osteoporosis is being increasingly recognised in paediatric practice as a consequence of several factors. These include the increasing complexity of chronic conditions and the associated treatments managed by paediatricians. In addition, the improved care provided to children with chronic illness has led to many of them living long enough to develop osteoporosis. The availability of methods to assess bone density in children as a surrogate marker of bone strength and the possibility of medical treatment to increase bone density have also resulted in an increased awareness of groups of children who may be at risk of osteoporosis. This article reviews the current definition of osteoporosis in children, aetiological factors and the evidence for effective treatment.

Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that ‘for approved indications, GH is safe’; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.