Acquired hypothalamic dysfunction in childhood: 'what do patients need?' - an Endo-ERN survey.

Objective: Hypothalamic dysfunction is a rare condition and can be encountered in patients who have been diagnosed or treated for a suprasellar brain tumor. Due to its rarity, the signs and symptoms of hypothalamic dysfunction may be difficult to recognize, leading to delayed diagnosis of the suprasellar brain tumor or to difficulties in finding the health-care expertise for hypothalamic dysfunction after tumor treatment. To improve the care and outcome of patients with acquired hypothalamic dysfunction, professionals are required to understand the patient's needs. Design: A worldwide online survey was distributed from April 2022 to October 2022 to patients with childhood-onset hypothalamic dysfunction (as reported by the patient) following a brain tumor. Methods: Patients were notified about the survey through patient advocacy groups, the SIOPe craniopharyngioma working group and the Endo-ERN platform. Results: In total, 353 patients with hypothalamic dysfunction following craniopharyngioma (82.2%), low-grade glioma (3.1%) or a pituitary tumor (8.2%) or caregivers responded to the survey. Sixty-two percent had panhypopituitarism. Obesity (50.7%) and fatigue (48.2%) were considered the most important health problems. Unmet needs were reported for help with diet, exercise and psychosocial issues. Patients' suggestions for future research include new treatments for hypothalamic obesity and alternative ways for hormone administration. Conclusions: According to the patient's perspective, care for acquired hypothalamic dysfunction can be improved if delivered by experts with a holistic view of the patient in a multidisciplinary setting with a focus on quality of life. Future care and research on hypothalamic dysfunction must integrate the patients' unmet needs. Significance statement: Patients with hypothalamic dysfunction may experience a variety of symptoms, which are not always adequately recognized or addressed. In previous papers, the perspective of caregivers of children with craniopharyngioma has been reported (Klages et al. 2022, Craven et al. 2022). Now we address the patients' perspective on acquired hypothalamic dysfunction using an Endo-ERN global survey. According to the patients' perspective, care can be improved, with needs for improvement in the domains of obesity, fatigue and lifestyle. Research may focus on ways to improve hypothalamic obesity and alternative ways for hormone administration. Ideally, care should be delivered by doctors who have a holistic view of the patient in a multidisciplinary expert team. The results of this study can be used to formulate best practices for clinical care and to design future research proposals.

Leukocyte Telomere Length in Children With Congenital Adrenal Hyperplasia.

CONTEXT: Exposure to chronic stress and hypercortisolism is associated with decreased leukocyte telomere length (LTL), a marker for biological aging and cardiovascular disease. Children with congenital adrenal hyperplasia (CAH) are treated with glucocorticoids. OBJECTIVE: To investigate LTL in children with CAH. METHODS: In this prospective observational cohort study, conducted at 4 academic pediatric endocrinology outpatient clinics, children with genetically confirmed CAH were assessed at 2 follow-up visits (mean 4.1 ± 0.7 months apart). At each visit, LTL was determined by quantitative real-time PCR. All subjects underwent detailed clinical and endocrinologic evaluation and were classified as undertreated, optimally treated, or overtreated, accordingly. The influence of clinical factors on LTL was investigated using linear mixed models adjusted for age, sex, and BMI-z. RESULTS: We studied 76 patients, of whom 31 (41%) were girls, 63 (83%) had classic CAH, 67 (88%) received hydrocortisone, and 8 (11%) prednisolone. Median age at first visit was 12.0 years (IQR, 6.3-15.1), and median BMI-z was 0.51 (IQR, -0.12 to 1.43). LTL was shorter in patients with classic vs nonclassic CAH (-0.29, P = 0.012), in overtreated than in optimally treated patients (-0.07, P = 0.002), and patients receiving prednisolone compared with hydrocortisone (-0.34, P < 0.001). LTL was not associated with undertreatment or daily hydrocortisone-equivalent dose (P > 0.05). CONCLUSION: LTL is shorter in patients with classic than nonclassic CAH, and in those who are overtreated with hydrocortisone or treated with long-acting glucocorticoids. These findings may be attributed to chronic exposure to supraphysiologic glucocorticoid concentrations and indicate that LTL may be used as a biomarker for monitoring glucocorticoid treatment.

Adherence and long-term outcomes of therapy in paediatric patients in Greece using the easypod™ electromechanical device for growth hormone treatment: The phase IV multicentre easypod™ connect observational study (ECOS).

BACKGROUND: The easypod™ injection device allows automatic recording and transmission of adherence data from patients receiving recombinant human growth hormone (rhGH [Saizen®]) to treat growth disorders. This analysis aimed to evaluate the adherence of Saizen® administered via easypod™ in a cohort of Greek patients from the easypod™ connect observational study (ECOS). METHODS: The phase IV, open-label, multicentre, observational, and longitudinal ECOS study (EMR200104-520, NCT01363674) enrolled patients treated for a minimum of 6 months and up to 3 years. The primary endpoint was to assess the mean rate of adherence to treatment at different time points, where good adherence was defined as ≥85%. Change in height, height standard deviation score (SDS), height velocity and height velocity SDS were evaluated after 1 year of treatment as secondary endpoints, together with the impact of adherence on growth outcomes using the Spearman's product moment. RESULTS: Of the 180 patients enrolled, 86 were included in the analysis. The mean adherence to Saizen®, as recorded via easypod™, was high at each individual time point, and was maintained at 95.5% after 1 year of treatment. Clinically meaningful positive changes were also noted for all of the secondary endpoints (median increase in height = 7.25 cm, height SDS = 0.32, median height velocity = 7.62 cm/year and height velocity SDS = 1.65). However, no significant correlation was noted between adherence and growth outcomes. CONCLUSIONS: rhGH replacement therapy using Saizen® with easypod™ led to full compliance to the treatment in a representative Greek population from ECOS, and provided additional insights on how the easypod™ device can assist physicians in monitoring adherence and help to optimise linear growth in paediatric patients with growth disorders.

Misfolding Ectodomain Mutations of the Lutropin Receptor Increase Efficacy of Hormone Stimulation.

We demonstrate 2 novel mutations of the LHCGR, each homozygous, in a 46,XY patient with severe Leydig cell hypoplasia. One is a mutation in the signal peptide (p.Gln18_Leu19ins9; referred to here as SP) that results in an alteration of the coding sequence of the N terminus of the mature mutant receptor. The other mutation (p.G71R) is also within the ectodomain. Similar to many other inactivating mutations, the cell surface expression of recombinant human LHR(SP,G71R) is greatly reduced due to intracellular retention. However, we made the unusual discovery that the intrinsic efficacy for agonist-stimulated cAMP in the reduced numbers of receptors on the cell surface was greatly increased relative to the same low number of cell surface wild-type receptor. Remarkably, this appears to be a general attribute of misfolding mutations in the ectodomains, but not serpentine domains, of the gonadotropin receptors. These findings suggest that there must be a common, shared mechanism by which disparate mutations in the ectodomain that cause misfolding and therefore reduced cell surface expression concomitantly confer increased agonist efficacy to those receptor mutants on the cell surface. Our data further suggest that, due to their increased agonist efficacy, extremely small changes in cell surface expression of misfolded ectodomain mutants cause larger than expected alterations in the cellular response to agonist. Therefore, for inactivating LHCGR mutations causing ectodomain misfolding, the numbers of cell surface mutant receptors on fetal Leydig cells of 46,XY individuals exert a more exquisite effect on the relative severity of the clinical phenotypes than already appreciated.

Glucocorticoid receptor: implications for rheumatic diseases.

The glucocorticoid receptor (GR), a member of the nuclear receptor superfamily, mediates most of the known biologic effects of glucocorticoids. The human GR gene consists of 9 exons and expresses 2 alternative splicing isoforms, the GRα and GRß. GRα is the classic receptor that binds to glucocorticoids and mediates most of the known actions of glucocorticoids, while GRß does not bind to these hormones and exerts a dominant negative effect upon the GRα-induced transcriptional activity. Each of the two GR splice isoforms has 8 translational variants with specific transcriptional activity and tissue distribution. GRα consists of three subdomains, translocates from the cytoplasm into the nucleus upon binding to glucocorticoids, and regulates the transcriptional activity of numerous glucocorticoid-responsive genes either by binding to its cognate DNA sequences or by interacting with other transcription factors. In addition to these genomic actions, the GR also exerts rapid, non-genomic effects, which are possibly mediated by membrane-localised receptors or by translocation into the mitochondria. All these actions of the GR appear to play an important role in the regulation of the immune system. Specifically, the splicing variant GRß may be involved in the pathogenesis of rheumatic diseases, while the circadian regulation of the GR activity via acetylation by the Clock transcription factor may have therapeutic implications for the preferential timing of glucocorticoid administration in autoimmune inflammatory disorders.

Novel causes of generalized glucocorticoid resistance.

Glucocorticoid resistance is a rare condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. Compensatory elevations in circulating adrenocorticotropic hormone (ACTH) concentrations lead to increased secretion of cortisol and adrenal steroids with mineralocorticoid and/or androgenic activity, but no clinical evidence of hypercortisolism. The clinical spectrum of the condition is broad, ranging from asymptomatic to severe cases of hyperandrogenism, fatigue and/or mineralocorticoid excess. The molecular basis of glucocorticoid resistance has been ascribed to mutations in the human glucocorticoid receptor (hGR) gene, which impair glucocorticoid signal transduction, thereby altering tissue sensitivity to glucocorticoids. The study of functional defects of natural hGR mutants enhances our understanding of the molecular mechanisms of hGR action and highlights the importance of integrated cellular and molecular signaling mechanisms for maintaining homeostasis and preserving normal physiology.

Sexual dimorphism in the synchrony of joint growth hormone and cortisol dynamics in children with classic 21-hydroxylase deficiency.

In humans, growth hormone (GH) and cortisol are secreted in a pulsatile fashion and a mutual bidirectional interaction between the GH/insulin-like growth factor (IGF)-I axis and hypothalamic-pituitary-adrenal (HPA) axis has been established. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in the synthesis of glucocorticoids and often mineralocorticoids, and adrenal hyperandrogenism. In view of the sexually dimorphic pattern in GH secretion, we investigated the GH-cortisol bihormonal secretory dynamics in male and female children with classic CAH. Thirty-eight children with classic 21-hydroxylase deficiency (M: 13, F: 25; age range: 6.1-18.8 yr) were studied prospectively. Serum GH and cortisol concentrations were determined at 20 min intervals for 24 hours. The irregularity of GH and cortisol pattern was assessed using approximate entropy (ApEn), a scale- and model-independent statistic. The synchrony of joint GH-cortisol dynamics was quantified using the cross-ApEn statistic. Cross-correlation analysis of GH and cortisol concentrations was computed at various time lags covering the 24-h period. There was no gender difference in mean 24-hour serum GH (males vs females: 5.25 +/- 4.72 vs 4.44 +/- 2.64 mIU/l) or cortisol (156.2 +/- 44.6 vs 172.0 +/- 58.5 nmol/l) concentrations. For GH, ApEn values were significantly higher in females (0.66 +/- 0.14) than in males (0.53 +/- 0.16) (p = 0.009). No difference in cortisol ApEn values was noted between sexes (0.53 +/- 0.21 vs 0.54 +/- 0.12). Cross-ApEn values of paired GH-cortisol, with cortisol leading GH, were significantly higher in females (0.94 +/- 0.14) than in males (0.83 +/- 0.20) (p = 0.03). These findings suggest that females with classic 21-hydroxylase deficiency have a more irregular pattern of GH secretion and a more asynchronous joint GH and cortisol dynamics than their male counterparts.

Hypothalamo-pituitary-adrenal axis integrity after cranial irradiation for childhood posterior fossa tumours.

BACKGROUND: The evolution of anterior pituitary deficits after treatment for pituitary tumours has been largely attributed to local irradiation, but may be influenced as much by tumour mass or surgery. Other than growth hormone (GH) insufficiency, the late endocrinopathies after survival from non-central brain tumours have been little documented. The aim of this study was to investigate the hypothalamic-pituitary-adrenal (HPA) axis in long-term survivors of cranial irradiation for childhood posterior fossa tumours. PROCEDURE: We studied long-term data in patients treated prepubertally for posterior fossa brain tumours and systematically referred by radiation oncologists for growth and pubertal monitoring to the London Centre for Paediatric Endocrinology over the last 25 years. They must have undergone HPA axis assessment twice, first prepubertally at documentation of growth failure, and second at completion of growth and puberty. Data on sixteen patients (12 males, 4 females; median age: 5.7 years, range: 2.5-8.8 years), who had undergone excision surgery with high dose cranial irradiation and/or chemotherapy for childhood posterior fossa tumours, were examined. Patients were followed for a median of 11.0 (range: 6.8-21.4) years after radiotherapy. HPA axis assessment was undertaken with the insulin-induced hypoglycaemia test (ITT). Basal thyroid, cortisol and gonadal function tests were undertaken annually throughout the follow-up period and any deficits replaced. RESULTS: At each ITT, all patients mounted an inadequate GH response. By the end of the follow-up period all patients remained severely GH deficient, two (12.5%) had partial ACTH insufficiency, one (6.3%) had secondary hypothyroidism but none were gonadotropin deficient or hyperprolactinaemic. CONCLUSIONS: Unlike the severe, evolving multiple pituitary deficits after treatment of pituitary or central tumours in adults, these findings in children with posterior fossa tumours suggest that, with the exception of GH, neurotoxicity due to irradiation per se is associated with a low prevalence of anterior pituitary hormone deficiencies, even at a long follow-up. Since the children in this study were selected for assessment on the basis of growth failure, the high prevalence of GH insufficiency at first testing is to be expected; however, the early onset (within 1-3 years of irradiation) and permanence we have identified supports the view that GH is the most sensitive hormone to radiation injury.

Treatment with flutamide decreases cortisol clearance: implications for therapy in congenital adrenal hyperplasia.

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by a defect in cortisol and often aldosterone secretion, and adrenal hyperandrogenism. Current treatment is to provide adequate glucocorticoid and mineralocorticoid substitution to prevent adrenal crises and to suppress excess adrenocortical androgen secretion. Anti-androgen therapy with flutamide is an option that allows control of hyperandrogenism without recourse to supraphysiological doses of glucocorticoid. METHODS: We examined the pharmacokinetic parameters of hydrocortisone administered i.v. as a bolus at a dose of 15 mg/m2 in a 17.3 year-old female patient with classic CAH before and four weeks after institution of flutamide treatment by determining serum cortisol concentrations at 10 min intervals for 6 h following the i.v. bolus of hydrocortisone. RESULTS: Treatment with flutamide resulted in a decrease in cortisol clearance from 420 ml/l to 305 ml/l (27% reduction), and a decrease in volume of distribution from 51.61 to 451 (12.9% reduction). The half-life of cortisol increased from 85.3 min to 102.1 min. CONCLUSIONS: Flutamide treatment decreases cortisol clearance, thereby prolonging its half-life. These findings indicate that a reduction in the daily dose of glucocorticoid replacement may need to be considered when flutamide is added to the treatment regimen of patients receiving hydrocortisone.

Why is management of patients with classical congenital adrenal hyperplasia more difficult at puberty?

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive condition in which deletions or mutations of the cytochrome P450 21-hydroxylase gene cause glucocorticoid and often mineralocorticoid deficiency. Despite optimal substitution therapy, control of classical CAH is often inadequate at puberty, and the problems encountered relate to hypocortisolism and/or hyperandrogenism. A number of physiological alterations in the endocrine milieu at puberty, which include alterations in the growth hormone/insulin-like growth factor axis, insulin sensitivity, as well as the activity of enzymes participating in cortisol metabolism and adrenal steroidogenesis, may account for the documented hypocortisolism and elevated androgen production, and may explain the difficulty in maintaining adequate adrenocortical suppression in pubertal patients with classical 21-hydroxylase deficiency.

Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase deficiency: is current replacement therapy satisfactory?

One of the main aims in the management of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency is to achieve adequate suppression of the adrenal cortex with the smallest possible dose of glucocorticoid substitution. To evaluate the administration schedule of current replacement therapy regimens, we investigated the cortisol-17-hydroxyprogesterone interrelation in 36 patients (13 males and 23 females; median age, 12.3 yr; range, 6.1-18.8 yr) with salt-wasting congenital adrenal hyperplasia. As sufficient variation in 17-hydroxyprogesterone concentrations was required to allow analysis of the cortisol-17-hydroxyprogesterone interrelation, patients were divided into 2 groups depending on the adequacy of hypothalamic-pituitary-adrenal axis suppression. The first group consisted of 17 patients with suppressed 17-hydroxyprogesterone concentrations (group 1), and the second group consisted of 19 patients with nonsuppressed 17-hydroxyprogesterone concentrations (group 2). We determined serum cortisol and 17-hydroxyprogesterone concentrations at 20-min intervals for a total of 24 h while patients were receiving their usual replacement treatment with hydrocortisone and 9alpha-fludrocortisone. We also determined the lowest dose of dexamethasone required to suppress the 0800 h serum ACTH concentrations when administered as a single dose (0.3 or 0.5 mg/m(2)) the night before. Mean 24-h cortisol and 17-hydroxyprogesterone concentrations were 3.9 microg/dl (SD = 2.1) and 66.2 ng/dl (SD = 92.7), respectively, in group 1 and 4.1 microg/dl (SD = 2.5) and 4865.7 ng/dl (SD = 6951) in group 2. The 24-h 17-hydroxyprogesterone concentrations demonstrated circadian variation, with peak values observed between 0400-0900 h. In group 2, 17-hydroxyprogesterone concentrations decreased gradually in response to the rise in cortisol concentrations during the day, but remained low during the night despite the almost undetectable cortisol concentrations between 1600-2000 h. Mean 0800 h androstenedione concentrations correlated strongly with integrated 17-hydroxyprogesterone concentrations (r = 0.81; P < 0.0001), but not with integrated cortisol concentrations. There was a significant negative correlation between cortisol and 17-hydroxyprogesterone at lag time 0 min (r = -0.187; P < 0.0001), peaking at lag time 60 min (r = -0.302; P < 0.0001), with cortisol leading 17-hydroxyprogesterone by these time intervals. Finally, 0800 h serum ACTH concentrations were sufficiently suppressed after a dexamethasone dose of 0.3 mg/m(2) in all but three patients. These findings indicate that in classic 21-hydroxylase deficiency, hydrocortisone should be administered during the period of increased hypothalamic-pituitary-adrenal axis activity, between 0400-1600 h, with the biggest dose given in the morning. Blood investigations performed as part of monitoring of congenital adrenal hyperplasia patients should include androstenedione and 17-hydroxyprogesterone concentrations determined in the morning before the administration of hydrocortisone. It should also be emphasized that blood investigations are only complementary to the overall assessment of these patients, which is primarily based on the evaluation of growth and pubertal progress.

Joint growth hormone and cortisol spontaneous secretion is more asynchronous in older females than in their male counterparts.

In humans, cortisol and GH are secreted in a pulsatile manner, and an interaction between GH and the hypothalamic-pituitary-adrenal axis has been established. In view of the sexually dimorphic pattern in GH secretion, we investigated the GH-cortisol bihormonal secretory dynamics in male and female healthy older individuals. We studied the GH and cortisol secretory patterns in 83 healthy subjects (45 men and 38 women; age range, 59.4-73.0 yr) by determining serum GH and cortisol concentrations at 20-min intervals for 24 h. The irregularity of GH and cortisol secretion was assessed using approximate entropy (ApEn), a scale- and model-independent statistic. The synchrony of joint GH-cortisol spontaneous secretion was quantified using the cross-ApEn statistic. Cross-correlation analysis of GH and cortisol patterns was computed at various time lags covering the 24-h period. Mean 24-h serum GH concentrations were significantly higher in females (mean, 1.31 mU/L; SD, 0.87) than in males (mean, 0.88 mU/L; SD, 0.42; P = 0.009), whereas mean 24-h serum total cortisol concentrations were higher in males (mean, 9.0 microg/dL; SD, 1.4) than in females (mean, 7.3 microg/dL; SD, 1.4; P = 0.0001). GH secretion was more irregular in females (mean ApEn, 0.81; SD, 0.23) than in males (mean ApEn, 0.60; SD, 0.20; P < 0.001). No significant difference in the regularity of cortisol secretion was noted between sexes. Cross-ApEn values of paired GH-cortisol were higher in females (mean, 1.15; SD, 0.18) than in males (mean, 1.01; SD, 0.16; P = 0.0003). Stepwise multiple linear regression analysis indicated that estradiol and insulin-like growth factor-binding protein-3 concentrations were independently related to GH ApEn values (r(2) = 0.14; P = 0.01), whereas cross-ApEn values of paired GH-cortisol were best predicted by FSH concentrations (r(2) = 0.37; P = 0.003). Cross-correlation analysis revealed a significant positive correlation between GH and cortisol, peaking at lag time of 4.7 h in males (r = 0.30; P < 0.0001) and 4.3 h in females (r = 0.14; P < 0.0001), with GH leading cortisol by these time intervals. In addition, a significant negative correlation between the two hormones was noted over time, peaking at 4.7 h in males (r = -0.21; P < 0.0001) and 6.3 h in females (r = -0.25; P < 0.0001), with cortisol leading GH by these time intervals. The above results indicate that in the elderly, females have a more disordered GH secretory pattern and a more asynchronous joint GH-cortisol secretion than their male counterparts. These observations most likely reflect bidirectional interactions between the GH and hypothalamic-pituitary-adrenal axis in humans as well as diminution of subsystem integrity and synchronous control of interconnected hormonal systems with advancing age.

Plasma nitrate concentrations in children with infectious and noninfectious diarrhea.

BACKGROUND: In patients with intact renal function and low dietary nitrate intake, plasma nitrate concentrations reflect endogenous nitric oxide production and are shown to be increased during inflammatory processes. The aim of this study was to compare plasma nitrate concentrations and hence endogenous nitric oxide production in children with infectious and noninfectious diarrhea and to determine whether plasma nitrate concentrations could serve as a discriminant test between acute and chronic diarrhea in children. METHODS: Three groups of patients were identified: 14 patients with acute gastroenteritis, 13 patients with chronic noninfectious diarrhea, and 14 patients with no evidence of gastrointestinal pathology and no underlying infectious process, who served as control subjects. Plasma nitrate concentrations were determined spectrophotometrically using the Greiss reaction before reduction to nitrite with a copper-coated cadmium column. RESULTS: Mean plasma nitrate concentrations were 405.3 micromol/L +/- 281.6 micromol/L (standard deviation) in patients with infectious diarrhea, 134.7 micromol/L +/- 77.0 micromol/L in patients with chronic diarrhea, and 54.1 micromol/L +/- 20.1 micromol/L in control subjects (F = 42.6, P < 0.0001; analysis of variance). Plasma nitrate concentrations were significantly higher in the infectious diarrhea group compared with the noninfectious diarrhea and control groups (Student-Newman-Keuls test, P < 0.5). CONCLUSIONS: Although an optimal cutoff concentration cannot be defined, plasma nitrate concentrations in excess of 300 micromol/L are suggestive of an infectious process whereas values less than 100 micromol/L are indicative of noninfectious diarrhea.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: alterations in cortisol pharmacokinetics at puberty.

In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, treatment with glucocorticoid and mineralocorticoid substitution is not always satisfactory. Suboptimal control is often observed in pubertal patients, despite adequate replacement doses and adherence to treatment. We investigated whether the pubertal process is associated with alterations in cortisol pharmacokinetics resulting in a loss of control of the hypothalamic-pituitary-adrenal axis. We determined the pharmacokinetics of hydrocortisone administered iv as a bolus. A dose of 15 mg/m(2) body surface area was given to 14 prepubertal (median age, 9.4 yr; range, 6.1--10.8 yr), 20 pubertal (median, 13.5 yr; range, 10.6--16.8 yr), and 6 postpubertal (median, 18.2 yr; range, 17.2--20.3 yr) patients with salt-wasting CAH. All patients were on standard replacement therapy with hydrocortisone and 9 alpha-fludrocortisone. Serum total cortisol concentrations were measured at 10-min intervals for 6 h following iv hydrocortisone bolus and analyzed using a solid-phase RIA. The serum total cortisol clearance curve was monoexponential. Mean clearance was significantly higher in the pubertal group (mean, 427.0 mL/min; SD, 133.4) compared with the prepubertal (mean, 248.7 mL/min; SD, 100.6) and postpubertal (mean, 292.4 mL/min; SD, 106.3) (one-way ANOVA, F = 9.8, P < 0.001) groups. This effect persisted after adjustment for body mass index. The mean volume of distribution was also significantly higher in the pubertal (mean, 49.5 L; SD, 12.2) than the prepubertal (mean, 27.1 L; SD, 8.4) patients but not in the postpubertal (mean, 40.8 L; SD, 16) (ANOVA, F = 15.2, P < 0.001) patients. The significance remained after correction for body mass index. There was no significant difference in mean half-life of total cortisol in prepubertal (mean, 80.2 min; SD, 19.4), pubertal (mean, 84.4 min; SD, 24.9), and postpubertal (mean, 96.7 min; SD, 9.9) patients. Similar differences between groups were observed when the pharmacokinetic parameters of free cortisol were examined. In addition, the half-life of free cortisol was significantly shorter in females compared with males (P = 0.04). These data suggest that puberty is associated with alterations in cortisol pharmacokinetics resulting in increased clearance and volume of distribution with no change in half-life. These alterations probably reflect changes in the endocrine milieu at puberty and may have implications for therapy of CAH and other conditions requiring cortisol substitution in the adolescent years.

Congenital adrenal hyperplasia: management during critical illness.

BACKGROUND: Little is known of the optimal dose and administration schedule of hydrocortisone in critically ill patients with congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency. AIM: To determine plasma cortisol concentrations after intravenous administration of hydrocortisone in children with CAH and to relate these to plasma cortisol concentrations achieved by endogenous secretion in the stress of critical illness in previously healthy children. METHODS: Plasma cortisol concentrations were measured in 20 patients with classical CAH (median age 11.2 years, range 6.1-16.4) following intravenous administration of hydrocortisone 15 mg/m(2); and in 60 critically ill mechanically ventilated children (median age 2.5 years, range 0.25-16.3) on admission to the paediatric intensive care unit and for 24 hours thereafter. RESULTS: In the CAH patients, plasma cortisol reached a mean peak of 1648.3 nmol/l (SD 511.9) within 10 minutes of the intravenous bolus, and fell rapidly thereafter; levels remained greater than 450 nmol/l for 2.5 hours only. In critically ill children, mean plasma cortisol on admission to the intensive care unit was 727 nmol/l (SD 426.1). Cortisol concentrations remained raised during the first 24 hours. CONCLUSIONS: Critically ill patients with classical CAH may be best managed with a single intravenous hydrocortisone bolus followed by a constant rate infusion of hydrocortisone.

Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

The management of congenital adrenal hyperplasia due to 21-hydroxylase (CYP21) deficiency requires glucocorticoid substitution with oral hydrocortisone given twice or thrice daily. In paediatric practice little is known of the bioavailability of oral hydrocortisone tablets used in these patients. The aim of this study was to assess the bioavailability of oral hydrocortisone and to evaluate current replacement therapy in the light of cortisol pharmacokinetic properties. We determined the bioavailability of hydrocortisone following oral and intravenous administration in sixteen (median age: 10.9 years, range: 6.0-18.4 years) adequately controlled CYP21 deficient patients. Serum total cortisol concentrations were measured at 20-min intervals for 24 h while patients were on oral substitution therapy, and at 10-min intervals for 6 h following an intravenous bolus of hydrocortisone in a dose of 15 mg/m(2) body surface area. The area under the serum total cortisol concentration versus time curve (AUC) following oral and intravenous administration of hydrocortisone was calculated using the trapezoid method. The bioavailability was estimated by dividing the corrected for dose AUC after oral hydrocortisone administration by the corrected for dose AUC after the intravenous hydrocortisone administration and was exemplified as a percentage. After oral administration of hydrocortisone in the morning, median serum total cortisol concentrations reached a peak of 729.5 nmol/l (range: 492-2520 nmol/l) at 1.2 h (range: 0.3-3.3 h) and declined monoexponentially thereafter to reach undetectable concentrations 7 h (range: 5-12 h) after administration. Following administration of the evening hydrocortisone dose, median peak cortisol concentration of 499 nmol/l (range: 333-736 nmol/l) was attained also at 1.2 h (range: 0.3-3.0 h) and subsequently declined gradually, reaching undetectable concentrations at 9 h (5-12 h) after administration of the oral dose. After the intravenous hydrocortisone bolus a median peak serum total cortisol concentration of 1930 nmol/l (range: 1124-2700 nmol/l) was observed at 10 min (range: 10-20 min). Serum cortisol concentrations fell rapidly and reached undetectable levels 6 h after the hydrocortisone bolus. The absolute bioavailability of oral hydrocortisone in the morning was 94.2% (90% confidence interval (CI): 82.8-105.5%) whereas the apparent bioavailability in the evening was estimated to be 128.0% (90% CI: 119.0-138.0%). We conclude that the bioavailability of oral hydrocortisone is high and may result in supraphysiological cortisol concentrations within 1-2 h after administration of high doses. The even higher bioavailability in the evening, estimated using as reference the data derived from the intravenous administration of hydrocortisone bolus in the morning, is likely to reflect a decrease in the hydrocortisone clearance in the evening. Decisions on the schedule and frequency of administration in patients with congenital adrenal hyperplasia should be based on the knowledge of the bioavailability and other pharmacokinetic parameters of the hydrocortisone formulations currently available.

Kinetics and effect of percutaneous administration of dihydrotestosterone in children.

BACKGROUND: Percutaneous administration of dihydrotestosterone (DHT) has been successful in promoting phallic growth in infants and children with 5 alpha-reductase deficiency raised as males. We investigated whether percutaneous administration of DHT is similarly effective in patients with micropenis due to alternative diagnoses. METHODS: Six patients (age range 1.9-8.3 years) with micropenis of variable etiology were studied prospectively. 2.5% DHT gel was applied to the phallus once daily at a dose of 0.15-0.33 mg/kg body weight. Serum DHT concentrations were measured at 0, 2, 4, 8, 12 and 24 h following application of DHT gel. RESULTS: Peak DHT concentrations were attained within 2-8 h after application of the gel and subsequently remained within the normal adult range in all but 1 patient, who had received the lowest dose of 0.15 mg/kg. An increase in phallic growth, ranging from 0.5-2.0 cm, was achieved after 3-4 months of treatment in all patients whose DHT concentrations were maintained within adult range. CONCLUSION: Percutaneous administration of DHT in a dose of 0.2-0.3 mg/kg once daily for a period of 3-4 months may be useful in the management of patients with testosterone biosynthetic defects, who have sufficient masculinization to warrant male sex assignment, or in patients with micropenis prior to reconstructive surgery.

Frasier syndrome, part of the Denys Drash continuum or simply a WT1 gene associated disorder of intersex and nephropathy?

Dysfunction of the Wilms' Tumour gene (WT1), a transcription factor critical for normal development and function of the urogenital tract, can result in both tumourigenesis [corrected] and urogenital abnormalities. The association of WT1 gene mutations with most cases of Denys-Drash syndrome is well described. More recently WT1 mutations have also been described in a related condition, Frasier syndrome. We report a case where genetic analysis showed a WT1 mutation typically associated with Frasier syndrome: a 1228 + 5 guanine to adenine substitution at the 3' alternative splice donor site in intron 9. The case provides a focus for the discussion of recent evidence that Denys Drash and Frasier syndrome form two ends of a spectrum of disorders. In addition, it illustrates the increasing significance of genetic investigation within clinical practice for diagnostic, prognostic and therapeutic purposes and the importance of karyotype analysis in phenotypically normal girls with renal disease.