Supraphysiological Doses Of Glucocorticoids Research Articles

SAT275 Generation And Characterization Of A Humanized CYP21A2 Mouse Model For Congenital Adrenal Hyperplasia

Abstract Disclosure: A. Huebner: None. S. Thirumalasetty: None. T. Schubert: None. R. Naumann: None. I. Reichardt: None. M. Rohm: None. D. Landgraf: None. F. Gembardt: None. M.F. Hartmann: None. S.A. Wudy: None. M. Peitzsch: None. N. Reisch: None. K. Koehler, PhD: None. 21-hydroxylase deficiency (21OHD) is the most common form of congenital adrenal hyperplasia (CAH) and is caused by mutations in the CYP21A2 gene. 21OHD causes a wide array of clinical symptoms that result from gluco- and mineralocorticoid deficiency and adrenal androgen excess. Treatment firstly aims to substitute lacking steroid hormones, and secondly to restore negative feedback towards CRH and pituitary ACTH secretion to diminish adrenal androgen overproduction. In most cases supra-physiological glucocorticoid doses are necessary which may cause short stature, obesity, hypertension, and cardiovascular and metabolic co-morbidity with reduced quality of life. Hence, current steroid substitution regimens have significant limitations, so novel therapeutic strategies are required. In recent years new therapeutic approaches have emerged including new non-glucocorticoid substances interfering with the HPA axis to minimize adrenal androgen production and to lower external glucocorticoid substitution to physiological levels. However, valuable in-vivo models for pre-clinical testing of such drugs are lacking. Here we present the first viable and humanized mouse model in which the mouse gene Cyp21a1 is replaced by the human orthologue CYP21A2 in which the human point mutation R484Q is integrated. Twenty-weeks-old homozygous mice show marked adrenal hyperplasia, enhanced expression of the CYP21A2 gene and a weak increase of Cyp11a1 and Cyp11b2 gene expression. Tandem mass spectrometry measurements of the mice plasma at 20 weeks show decreased corticosterone and 11-deoxycorticosterone levels in the presence of increased ACTH levels in both male and female homozygous animals. Progesterone levels in homozygous mice are significantly higher (p<0.01) than in wildtype mice. We also observed increased aldosterone levels in female mutants whereas blood pressure does not differ between wildtype and mutant mice strains. Histologically, mutants exhibit adrenocortical hyperplasia. While mutant male mice are fertile with normal appearing testes, females are infertile, remain in the diestrus phase and present with a reduced number of ovarian follicles. In parallel, a second mouse strain bearing the I173N mutation was developed. This mutation is frequent in human patients causing simple virilizing or rarely salt wasting CAH. Homozygous mice require dexamethasone treatment during pregnancy and until weaning but are viable without treatment afterwards. Preliminary results show adrenal hyperplasia and alteration in steroidogenic gene expression and steroid profiles. In conclusion, we demonstrate that the humanized mutant CYP21A2 mice may represent an excellent animal CAH model to test novel treatment strategies for CAH patients. We believe that this model(s) will facilitate the transition from basic research into clinical application. Presentation: Saturday, June 17, 2023

Glucocorticoid induced adrenal insufficiency in children: Morning cortisol values to avoid LDSST.

Glucocorticoid-induced adrenal insufficiency (GI-AI) is a common side effect of glucocorticoid therapy. However, its diagnosis currently relies on the realization of a Low Dose Short Synacthen Test (LD-SST) that requires an outpatient hospital and several blood samples. Our goal was to evaluate whether morning cortisol values could predict the response to LD-SST, in children, to avoid useless dynamic tests and facilitate diagnosis of glucocorticoid induced adrenal insufficiency. We recorded data of 91 pediatric patients who underwent a LD-SST in our center between 2016 and 2020 in a retrospective observational study. We selected LD-SST realized following administration of supra-physiologic doses of glucocorticoids during more than 3 weeks and performed at least four weeks after treatment was stopped. Adrenal deficiency was defined as a plasma cortisol concentration inferior to 500 nmol/l at LD-SST. Glucocorticoid-induced adrenal insufficiency was diagnosed in 60% of our cohort. Morning cortisol values were predictive of the response to the LD-SST (AUC ROC 0.78). A plasma cortisol concentration of less than 144 nmol/l predicted glucocorticoid induced adrenal insufficiency with a specificity of 94% and a value over 317 nmol/l predicted recovery of the HPA axis with a sensitivity of 95%. We did not find any other predictive factor for glucocorticoid-induced adrenal insufficiency. Morning cortisol values can safely assess recovery of the HPA axis in children treated chronically with glucocorticoids. Using these thresholds, more than 50% of LD-SST could be avoided in children.

RF21 | PSAT93 Improvement of Final Height in Congenital Adrenal Hyperplasia Patients Treated With Recombinant Growth Hormone

Abstract Final height (FH) in congenital adrenal hyperplasia (CAH) patients is frequently under -1.5 SDS in relation to the normal population, even in those with good compliance, chronic androgen exposure or supraphysiological glucocorticoid doses could corroborate to this finding. Recombinant human growth hormone (GH) has been used as adjuvant therapy to improve FH in many disorders, but there are scarce data in CAH patients. Objective to analyze the effect of GH therapy on final height of CAH patients with compromised height prediction. Patients and Methods data of 26 patients (7F/19M) were retrospectively evaluated: 10 salt wasting-SW, 11 simple virilizing-SV and 5 with nonclassical form-NC. The SW patients were diagnosed at the neonatal period, SV and NC patients at mean chronological age of 3.6±2 and 7.2±3.8 yrs, respectively. All patients received cortisone acetate, hydrocortisone equivalent dose of 12.6±6.6 mg/m2/day in classical and 8.24±4.7 mg/m2/day in NC form; SW patients also received fludrocortisone 36±9.6mcg/m2/day. Near final height (NFH) was considered as BA of 13yrs for girls and 15yrs for boys; height and target height (TH) were described as SDS. All patients presented hormonal/molecular CAH diagnosis. The t test was used in the statistical analysis. Results Mean chronological and bone age (BA) at the beginning of GH therapy was 9.0±2.4 and 12.3±2yrs, respectively, mean duration of GH therapy was 4.1±1.9yrs and daily dose was 0.15 UI/kg/day. All patients were submitted to pubertal blockage with leuprorelin acetate 11.25 mg each 3 months during 3.9±1.1yrs or cyproterone acetate, mean dose 70±19 mg/m2/d during 4.7±2.5yrs. At the last evaluation, 19 patients (14M/5F) achieved FH: at the beginning of GH therapy mean H/BA in males was -2.1±0.38 and after -0.65±1 SDS (p<0.001). Mean FH in males was 165.7±5.9 cm and mean TH 170.7±8 cm (p>0.05); the TH-FH was -0.6±1.2 SDS. Among females, mean H/BA at the beginning of GH therapy was -2.2±0.7 and after -0.84±0.9 SDS (p=0.01). Mean FH in females was 156±8 cm, mean TH was 160±5.8cm (p>0.05); the TH-FH was -0.6±0.7 SDS. Considering patients with FH and NFH, the FH-TH in males was 0.4±0.2 SDS and -0.15±0.9 SDS in females. An improvement of approximately 12.7cm in males and 12.4cm in females was observed. No patient presented hypertension and 7/26 patients presented insulin resistance, which normalized after GH withdrawal. Conclusion we observed that GH therapy associated with puberty blockers allowed the achievement of final height in the expected range of target height, without significant side effects. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 1:00 p.m. - 1:05 p.m.

PSAT097 Patient Preference Research: Preferred Adjunctive Medication Attributes of Adult Patients with Classic Congenital Adrenal Hyperplasia

Abstract Background People with classic congenital adrenal hyperplasia (CAH) often require supraphysiologic doses of glucocorticoids (e.g., hydrocortisone, dexamethasone) to treat cortisol deficiency and excess androgen production. Healthcare providers and patients continually try to balance androgen control with side effects from supraphysiologic glucocorticoids. This study aimed to understand the preferences of adults with classic CAH regarding benefits of a potential new adjunctive medication that may provide better androgen control and allow for lower glucocorticoid doses. Methods Discrete choice experiment (DCE) methodology was used to calculate the relative stated preferences for the additional therapy's hypothetical benefits (attributes). Seven attributes were developed for the DCE after review of relevant data and qualitative literature, interviews with eight adults with classic CAH and input from two endocrinologists. The online DCE survey was piloted via interviews with three adults with classic CAH and a soft launch, which confirmed survey content and functioning. Preference data and subgroup differences were analyzed using conditional logit and scale assessment modelling, respectively. Results US adults with classic CAH (N=118, 75% female, age 19–69) valued avoidance of glucocorticoid-induced weight gain by twice the magnitude of other treatment attributes (all coefficients p<0.001 compared to baseline levels of no avoidance/decrease/improvement): complete avoidance of weight gain from glucocorticoids (1.109); moderate decrease in risk of developing health conditions from long-term glucocorticoids: type 2 diabetes (0.540), osteopenia, osteoporosis, fractures (0.521) and cardiovascular disease (0.502); moderate improvement in: fatigue (0.439), fertility (0.437) and excessive body hair (females only) and acne (0.410). Avoidance of glucocorticoid-induced weight gain remained the most preferred attribute across all subgroup analyses. Avoidance of glucocorticoid-induced weight gain was relatively much more important to females (n=89) than males (n=28) and participants with a body mass index ≥30 (n=70) than <30 (n=48). Improvement in fertility was more important to males than females, was valued by participants aged 18–45 (n=82) but was not a significant preference in participants >45 (n=36) and was relatively more important to participants with fertility problems (n=31) than without (n=87). Improvement in hirsutism and acne was highly valued by participants with excessive hair growth (n=38) but had the lowest preference among those without (n=80). Improvement in fatigue was a significant preference for participants with energy problems (n=73) but was not significant for those without (n=45). Conclusions The strong and consistent preference for avoiding glucocorticoid-induced weight gain suggests that patients with classic CAH would most value a novel adjunctive therapy that helps mitigate glucocorticoid-induced weight gain. In relation to other potential adjunctive therapy benefits, reduced risk of glucocorticoid-driven side effects may be valued more than improvement in fatigue or androgen-driven adverse events (fertility and hirsutism/acne). However, subgroup analyses indicated that individuals’ characteristics impact their treatment preferences and priorities, after avoidance of glucocorticoid-induced weight gain. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

EE126 Cost Drivers in Patients with Classic Congenital Adrenal Hyperplasia (CAH)

Classic CAH is a rare condition characterized by cortisol deficiency and androgen excess, typically requiring treatment with supraphysiologic doses of glucocorticoids. This study evaluated the costs and identified key cost drivers for classic CAH in the United States (US).

PCR114 The Adjunctive Therapy Preferences of Adults with Classic Congenital Adrenal Hyperplasia: A Discrete Choice Experiment

Patients with classic congenital adrenal hyperplasia (CAH) often require supraphysiologic doses of glucocorticoids to replace missing cortisol and reduce adrenal androgens. Current treatments aim to control androgen-driven symptoms/impacts but can result in glucocorticoid-related side effects/complications. This study aimed to understand the preferences of adults with classic CAH for the benefits of a potential new adjunctive therapy that could provide better androgen control with lower glucocorticoid doses via an online discrete choice experiment (DCE).

Serum pancreatic lipase immunoreactivity in sick dogs after chronic administration of supraphysiologic doses of glucocorticoids.

Glucocorticoids (GC) are commonly used for a long term to treat a multitude of immune-mediated, inflammatory, and neoplastic diseases in dogs. Conflicting results of published studies on the effects of exogenous and endogenous GCs on serum canine pancreatic lipase immunoreactivity (cPLI) raise the question of whether cPLI concentrations can be reliably interpreted in patients receiving GCs. We sought to determine the effect of long-term GC administration at supraphysiologic doses on serum cPLI concentrations in sick dogs. Serum samples were collected from 35 client-owned dogs. Dogs were administered prednisone at a dose of ≥0.5mg/kg per day for ≥3weeks. Serum cPLI was measured prior to the initiation and after ≥3weeks of GC therapy. There was a significant increase in serum cPLI between baseline (median 101μg/L; range 30-1997μg/L) and following the administration of ≥0.5mg/kg/day of prednisone (median 173μg/L; range 30-2000μg/L) in dogs (P=0.025). However, the median change was small (31μg/L). There was no suspicion of pancreatitis in any of the dogs. Diagnostic interpretation changed in 6/35 dogs, with no apparent dose-response relationship. There was a statistically significant difference from baseline in serum cPLI measurements in sick dogs receiving long-term prednisone. Although the change was small and often clinically insignificant, it could pose a clinical interpretation dilemma in some dogs. It is unknown whether these observations are coincidental due to subclinical pancreatitis or caused by another effect of GCs on pancreatic acinar cells.

MON-175 Structural Instability as an Underlying Pathomechanism in Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting key enzymes of cortisol biosynthesis. In the majority of cases the underlying cause are detrimental mutations in the steroidogenic cytochrome P450 enzyme 21-hydroxylase (CYP21A2). Early diagnosis via newborn screening programs in most Western countries and lifelong oral cortisol replacement therapy enable survival, however quality of life often is reduced and co-morbidities are substantially increased. Treatment is a major challenge as disease control can only be achieved with supraphysiological glucocorticoid doses. In addition, the currently available drugs cannot ideally mimic the circadian rhythm and stress adaption of cortisol secretion. Currently, disease severity is classified by residual enzyme activity. The goal of our research is to better understand the specific biophysico-chemical pathomechanism of 21-hydroxylase deficiency in order to enable causative therapeutic approaches. To this end, we investigated the structural and stability properties of six clinically relevant mutant variants of CYP21A2 (V282G/L, P31L, D323G, R484Q/W). Difficulty in purification of these CYP21A2 variants and various biophysical studies suggest that the proteins were less stable than wild-type (WT). Structural and thermal stability assessment by circular dichroism (CD) spectroscopy of recombinant, purified CYP21A2 mutant variants revealed high α-helical content for the WT (65% α-helix) and the mutants at the position 282 (V282G: 60.6 %, V282L: 57.6%). Other mutations (P31L, D323G, R484Q/W) disrupt the α-helical organization of CYP21A2 in exchange for a slight increase in ß-sheet content but mainly for random coil. Temperature dependent CD spectroscopy showed that all mutant variants have reduced thermal stability (Tm: 41.3 - 45,6°C) compared to the WT (Tm: 47.1°C). Tryptophane fluorescence showed that mutant variants of the protein were more prone to local unfolding at the hydrophobic core compared to WT using urea as denaturant. Furthermore, in UV/Vis spectroscopy at 280 nm and 418 nm we could demonstrate that all mutant variants had a reduced heme incorporation (A418/A280: 0.20 - 0.63) compared to WT (A418/A280: 0.88). Our results show that correct structural folding and stability pose a major problem in specific mutations involved in CAH. Therefore we propose that structural protein instability, play a key role in the pathophysiology of CAH and thus might constitute a novel tailored therapeutic target for the treatment of affected patients.

Late consequences of classic congenital adrenal hyperplasia and its long-term poor control in men (case report and literature review)

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of the adrenal cortex characterized by impairment of cortisol biosynthesis (with possible impairment of aldosterone biosynthesis) and excessive pituitary ACTH release, which promotes oversecretion of intact pathways products: 17-hydroxyprogesterone (17OHP), progesterone, and adrenal androgens androstendione and testosterone. 21-hydroxylase deficiency, being the most common cause of congenital adrenal hyperplasia is a chronic disorder, that requires life-long glucocorticoid treatment, that aims both to replace cortisol and prevent ACTH-driven androgen excess. Nevertheless, reaching the optimal glucocorticoid dose is challenging because currently available glucocorticoid formulations cannot replicate the physiological circadian rhythm of cortisol secretion. The difficulties in striking the balance between uneffective normalizing of ACTH-level and excess glucocorticoid exposure leads to different abnormalities, that starts to develop at first months of life and progress, frequently gaining especial clinical meaning in adult age. In the present clinical case we introduce 35 years old male patient with salt-wasting form of 21-hydroxylase deficiency, which had either complications considered to progress due to insufficient glucocorticoid therapy, and some metabolic abnormalities, associated with supraphysiological doses of glucocorticoids.

Cushing Syndrome

Cushing syndrome is a condition with protean manifestations that are caused by chronic exposure to excess glucocorticoids. Treatment with supraphysiologic doses of glucocorticoids is the most common cause. Pathologic hypercortisolism may result from autonomous adrenal production or as a result of the action of excessive adrenocorticotropic hormone (ACTH) production by a tumor, which stimulates adrenal cortisol production. Primary adrenal forms include unilateral adenoma or carcinoma or, rarely, bilateral hyperplasia and/or nodules. This chapter covers the epidemiology, etiology, pathophysiology, and diagnosis of Cushing syndrome. Clinical manifestations, physical examination findings, and laboratory tests, including tests of the blood and other body fluids, imaging studies, and biopsy, are discussed. The differential diagnosis, treatment options, complications, and prognosis are described. Tables outline clinical features and causes of Cushing syndrome, abnormalities associated with primary adrenal causes of Cushing syndrome, diagnostic accuracy of screening tests, endogenous hypercortisolism without Cushing syndrome, and medical therapy for Cushing syndrome. Figures illustrate the causes of Cushing syndrome and a comparison of the hypothalamic-pituitary-adrenal axis in patients with ACTH-dependent Cushing syndrome and those with pseudo–Cushing syndrome. Algorithms show the evaluation of possible Cushing syndrome and evaluation of the causes of Cushing syndrome. Second-line treatments for Cushing syndrome when surgery fails or is not possible are also detailed. This chapter contains 5 figures, 7 tables, 50 references.

Cushing Syndrome

Cushing syndrome is a condition with protean manifestations that are caused by chronic exposure to excess glucocorticoids. Treatment with supraphysiologic doses of glucocorticoids is the most common cause. Pathologic hypercortisolism may result from autonomous adrenal production or as a result of the action of excessive adrenocorticotropic hormone (ACTH) production by a tumor, which stimulates adrenal cortisol production. Primary adrenal forms include unilateral adenoma or carcinoma or, rarely, bilateral hyperplasia and/or nodules. This chapter covers the epidemiology, etiology, pathophysiology, and diagnosis of Cushing syndrome. Clinical manifestations, physical examination findings, and laboratory tests, including tests of the blood and other body fluids, imaging studies, and biopsy, are discussed. The differential diagnosis, treatment options, complications, and prognosis are described. Tables outline clinical features and causes of Cushing syndrome, abnormalities associated with primary adrenal causes of Cushing syndrome, diagnostic accuracy of screening tests, endogenous hypercortisolism without Cushing syndrome, and medical therapy for Cushing syndrome. Figures illustrate the causes of Cushing syndrome and a comparison of the hypothalamic-pituitary-adrenal axis in patients with ACTH-dependent Cushing syndrome and those with pseudo–Cushing syndrome. Algorithms show the evaluation of possible Cushing syndrome and evaluation of the causes of Cushing syndrome. Second-line treatments for Cushing syndrome when surgery fails or is not possible are also detailed. This chapter contains 5 figures, 7 tables, 50 references.

The Effect of Dexamethasone on the Αpd-1/L1 and Radiotherapy Stimulated Anti-Tumor Response

Dexamethasone is a potent immunosuppressant. In current practice, if a cancer patient requires dexamethasone, αPD-1/L1 therapy is either stopped or not initiated due to a presumed counteraction of αPD-1/L1’s immune-stimulation. This delay or cessation in αPD-1/L1 treatment likely worsens outcomes. Additionally, many cancer patients require radiotherapy (RT) which can also stimulate an anti-tumor T-cell response. There is a known synergy between αPD-1/L1 and RT leading to improved local and distant tumor control (abscopal effect). Therefore, determining whether dexamethasone impairs the αPD-1/L1 response alone and in combination with RT is an important clinical question. B16F10 tumors were established subcutaneously on the bilateral flanks of wt C57BL/6 mice. Following tumor engraftment, dexamethasone was initiated at a low (0.25-0.5 mg/kg) or high (2.5 mg/kg) dose. Once tumors were palpable, αPD-1 or αPD-L1 was administered with or without tumor RT. Tumor RT (10 Gy in one fraction) was directed at one flank tumor while tumors on both flanks were monitored for growth. Tumor specific T-cells were tracked using a tetramer specific for an LCMV viral glycoprotein inserted into the B16F10 tumor cell line. Neither low (LD) nor high dose (HD) dexamethasone impaired tumor control with αPD-L1 (LD + αPD-L1vs αPD-L1 alone (p=0.40); HD + αPD-L1vs αPD-L1 alone (p=.14); each vs untreated control (p<0.05)). LD led to a mild reduction in intra-tumoral tumor-specific CD8 T-cell numbers. However, concurrent dexamethasone and αPD-L1 treatment showed a robust increase in intra-tumoral tumor-specific CD8 T-cells relative to untreated controls (5.5 fold). Combined RT and αPD-1 improved local tumor control and stimulated an abscopal effect that was not impaired by LD. T-cell analysis did show a reduction in the numbers of tumor specific CD8 T-cells in the RT + αPD-1 mice which received dexamethasone compared to the RT + αPD-1 alone group. Our work suggests that LD should not be an absolute contraindication to checkpoint blockade administration, and a clinical benefit persists for the immune-stimulatory effects of both αPD-1/L1 and RT even in the presence of supra-physiologic doses of glucocorticoids. More study is needed for HD.

Adrenal function following acute discontinuation of glucocorticoids in children with acute lymphocytic leukemia: A prospective study

Background: Children with acute lymphocytic leukemia (ALL) are enrolled in advanced treatment protocols involving high doses of glucocorticoids (GCs). Current protocols do not advocate tapering of GCs doses postinduction phase. Prolonged administration of supra-physiologic doses of GCs can induce transient suppression of the hypothalamic pituitary adrenal axis (HPA). Timely recognition of adrenal insufficiency is important in order to ensure that children at risk receive the necessary treatment and follow-up including stress coverage during illness and surgical procedures.Methods: 21 newly diagnosed patients with ALL aged 3–10 years old were prospectively enrolled in the study over a 2-year period. All enrolled patients received high doses of GCs as part of a chemotherapy treatment protocol. The HPA axis was assessed prior to the induction phase of chemotherapy and 1–2 weeks after un-tapered discontinuation of GCs.Results: All children had normal HPA axis at baseline. Postinduction 1 mcg ACTH stimulation test result was normal (cortisol > 500 nmol/L) in 75% of children and partially responsive in 25% (cortisol 300–500 nmol/L). None of the participants demonstrated clinically significant adrenal insufficiency following abrupt cessation of GCs.Conclusion: All children in our cohort had either normal or subnormal cortisol response during a low dose ACTH stimulation test 1 to 2 weeks following abrupt discontinuation of GCs, suggesting that any inhibition of the HPA axis is of short duration. We suggest that future studies investigate the timing of adrenal function recovery following GC discontinuation as well as whether tapering of the GC should be recommended.

Vertebral fractures assessed with dual-energy X-ray absorptiometry in patients with Addison's disease on glucocorticoid and mineralocorticoid replacement therapy.

to assess bone damage and metabolic abnormalities in patients with Addison's disease given replacement doses of glucocorticoids and mineralocorticoids. A total of 87 patients and 81 age-matched and sex-matched healthy controls were studied. The following parameters were measured: urinary cortisol, serum calcium, phosphorus, creatinine, 24-h urinary calcium excretion, bone alkaline phosphatase, parathyroid hormone, serum CrossLaps, 25 hydroxyvitamin D, and 1,25 dihydroxyvitamin D. Clear vertebral images were obtained with dual-energy X-ray absorptiometry in 61 Addison's disease patients and 47 controls and assessed using Genant's classification. Nineteen Addison's disease patients (31.1%) had at least one morphometric vertebral fracture, as opposed to six controls (12.8%, odds ratio 3.09, 95% confidence interval 1.12-8.52). There were no significant differences in bone mineral density parameters at any site between patients and controls. In Addison's disease patients, there was a positive correlation between urinary cortisol and urinary calcium excretion. Patients with fractures had a longer history of disease than those without fractures. Patients taking fludrocortisone had a higher bone mineral density than untreated patients at all sites except the lumbar spine. Addison's disease patients have more fragile bones irrespective of any decrease in bone mineral density. Supra-physiological doses of glucocorticoids and longer-standing disease (with a consequently higher glucocorticoid intake) might be the main causes behind patients' increased bone fragility. Associated mineralocorticoid treatment seems to have a protective effect on bone mineral density.

Acromegaly and bone disease.

To provide an update on current understanding of osteoporosis associated with acromegaly. Patients with acromegaly have an increased risk of morphometric vertebral fractures. This seems to correlate with acromegaly activity and its duration, but it persists after biochemical control is achieved. Coexistent hypogonadism, diabetes mellitus and over-replacement with glucocorticoids have additional detrimental effects. Bone mineral density can be normal, increased or decreased, and is usually discordant with occurrence of fractures. However, a decrease in the hip bone mineral density during follow-up has been associated with development of new vertebral fractures. Bone turnover markers are increased and tend to normalize after biochemical control of acromegaly. Hypercalcemia rarely occurs in acromegaly and may be parathyroid hormone-dependent or 1,25 dihydroxy-vitamin D dependent. The latter improves with biochemical control of acromegaly. Screening with thoracic and lumbar vertebral radiographs is indicated in patients with acromegaly. We recommend biochemical control of acromegaly, treatment of hypogonadism and other risk factors of osteoporosis and avoiding supraphysiologic doses of glucocorticoids. Further studies are needed to understand mechanisms of skeletal fragility in acromegaly and clinical impact of vertebral fractures. Further studies of tailored therapy for patients with acromegaly and osteoporosis are also needed.

Congenital Adrenal Hyperplasia: Issues in Diagnosis and Treatment in Children

Congenital adrenal hyperplasia (CAH) is a common disorder of impaired adrenal cortisol biosynthesis with associated androgen excess. The clinical presentation of 21-hydroxylase deficiency, the commonest cause of CAH, forms a spectrum and can be divided into classic and non-classic types. The former consists of life threatening salt wasting and non-life threatening simple virilizing phenotypes. Patients with the non-classic form are asymptomatic or have mild features of androgen excess. Most developed countries have newborn screening facilities for CAH. In the absence of newborn screening, the diagnosis of CAH may be missed or delayed. This can result in neonatal mortality in salt wasting forms and incorrect sex of rearing in females with simple virilizing form. The diagnosis is reached by demonstrating high serum 17-hydroxyprogesterone (17OHP) levels. Preterm birth and neonatal illness can cause physiological elevation of 17OHP, thus complicating the diagnosis of CAH in the newborn period. Prenatal diagnosis and treatment with dexamethasone to prevent virilization of affected female fetuses is another area of controversy. The management of CAH is complicated by the need to use supraphysiologic doses of glucocorticoids to suppress adrenal androgen synthesis. In this review, the authors address pertinent issues related to the diagnosis and management of CAH in children.

A Search for Variables Predicting Cortisol Response to Low-Dose Corticotropin Stimulation Following Supraphysiological Doses of Glucocorticoids

To determine which biological or clinical variables may predict cortisol response to low-dose adrenocorticotropic hormone (ACTH) stimulation following supraphysiological doses of glucocorticoids in children. This retrospective study included all patients who underwent ACTH testing (1 μg) between October 2008 and June 2010 at the Sainte-Justine University Hospital Center, Montreal, after supraphysiological doses of glucocorticoids. Data from 103 patients (median age, 8.0 years; range, 0.6-18.5 years; 57 girls) were analyzed, revealing growth deceleration in 37% and excessive weight gain in 33%. Reasons for glucocorticoid treatment included asthma (n = 30) and hematologic (n = 22), dermatologic (n = 19), rheumatologic (n = 16), and miscellaneous (n = 16) disorders. The following information was recorded: duration of glucocorticoid treatment (median, 374 days; range, 5-4226 days); duration of physiological hydrocortisone replacement (median, 118 days; range, 0-1089 days); maximum daily (median, 200 mg/m(2)/day; range, 12-3750 mg/m(2)/day) and cumulative (median, 16 728 mg/m(2); range, 82-178 209 mg/m(2)) doses, in hydrocortisone equivalents; and interval since the last dose (median, 43 days; range, 1-1584 days). Sixty-two patients (58%) exhibited a normal response (ie, peak cortisol >500 nmol/L) to ACTH stimulation. Peak cortisol level was not related to sex, prior morning cortisol level, duration of treatment, or cumulative glucocorticoid dose; 28% of the patients with normal baseline cortisol levels nevertheless demonstrated a subnormal response to ACTH. Given the absence of clinical or biological predictors of the cortisol response to ACTH after suppressive doses of glucocorticoids, physicians have only 2 options: (1) empirically advocate glucocorticoid stress coverage during 18 months after cessation of high-dose glucocorticoid treatment; or (2) perform serial ACTH testing in all such patients until a normal peak cortisol level is attained.

Glucocorticoid induced hyperglycaemia

Modern medicine has discovered numerous benefits of supra-physiological doses of glucocorticoids, both as immunosuppressive as well as anti inflammatory agents. Hyperglycaemia is one important side effect of steroids, with a number of unresolved issues on its diagnosis and management. This article describes important points regarding the pathophysiology and diagnosis of steroid induced hyperglycaemia. It also discusses a practical approach to its management. DOI: http://dx.doi.org/10.4038/sjdem.v2i1.4330 Sri Lanka Journal of Diabetes, Endocrinology and Metabolism 2012; 2 : 25-27

Can Recovery From Hypothalamic-Pituitary-Adrenal (Hpa) Axis Suppression Following Supraphysiological Doses of Glucocorticoids Be Predicted?

Can Recovery From Hypothalamic-Pituitary-Adrenal (Hpa) Axis Suppression Following Supraphysiological Doses of Glucocorticoids Be Predicted?

Bone Health Should Be an Important Concern in the Care of Patients Affected by 21 Hydroxylase Deficiency

Osteoporosis has been an understandable concern for children and adult patients with congenital adrenal hyperplasia (CAH) who may receive or have received supraphysiological doses of glucocorticoids. Some previous reports on bone mineral density (BMD) in adult CAH patients showed no significant differences in BMD between patients with CAH and controls, but others have found lower BMD in CAH patients. In reports documenting the BMD reduction, this outcome has been attributed to an accumulated effect of prolonged exposure to excess glucocorticoids during infancy and childhood. We recently conducted a trial to establish the role of the total cumulative glucocorticoid dose on BMD. We established for the first time that there was a negative relationship between total cumulative glucocorticoid dose and lumbar and femoral BMD. Women might benefit from the preserving effect of estrogens compared to men. BMI (Body Mass Index) also appeared to protect patients from bone loss. In light of this, physicians should bear in mind the potential consequences of glucocorticoids on bone and therefore adjust the treatment and improve clinical and biological surveillance from infancy. Furthermore, preventive measures against corticosteroid-induced osteoporosis should be discussed right from the beginning of glucocorticoid therapy.