Glucocorticoid Replacement Regimens Research Articles

12670 CHAMPAIN Study: Initial Results From A Phase II Study Of Efficacy, Safety And Tolerability Of Modified-release Hydrocortisones: Chronocort® (Efmody®) Versus Plenadren®, In Primary Adrenal Insufficiency

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Current glucocorticoid replacement regimens for patients with primary adrenal insufficiency (PAI) mean patients wake with either low or undetectable cortisol levels[1], associated with fatigue and a reduced quality of life (QoL)2. Plenadren® (Takeda, UK) is a once-daily modified-release formulation of hydrocortisone that replaces daytime cortisol levels whereas Chronocort® (modified-release hydrocortisone hard capsules, Diurnal, UK) when taken twice-daily, has been shown to replicate the normal overnight rise in serum cortisol concentration and provide physiological levels throughout the day. We have undertaken a double-blind, double-dummy, two-way cross-over, randomised, phase II study of efficacy, safety and tolerability of modified-release hydrocortisones: Chronocort® Versus Plenadren®. Aim: To test the hypothesis that Chronocort® provides more physiological waking cortisol levels than Plenadren®. Methodology: The study was conducted across 8 sites in the UK and Germany. Male and female patients, aged ≥18 with confirmed PAI (defined as morning pre-dose cortisol <50 nMol/l) on stable therapy over the preceding three months and not currently treated with Chronocort®/Plenadren®. Participants with congenital adrenal hyperplasia (CAH), secondary or tertiary AI were excluded. Each participant was randomised on a 1:1 basis to either; treatment sequence I (Chronocort® first) or treatment sequence II (Plenadren® first) taking a 25mg total daily dose for 4 weeks; either Plenadren® 25mg in the morning or Chronocort® 10mg in the morning and 15mg at night with the associated dummy preparation followed immediately by the other treatment. The pre-dose morning serum cortisol level was assayed at baseline and after each treatment period. A physiological morning cortisol level was defined as a pre-dose level of >140nMol/L. Secondary measures included: morning fatigue measured using the Multidimensional Assessment of Fatigue (MAF) questionnaire and the PROMIS® 7b questionnaire; QoL was assessed using the EuroQol 5-level Standardised Health Questionnaire (EQ-5D-5L™); Health-related Quality of Life in Addison’s disease (AddiQoL) questionnaire and the 36-Item Short Form Health Survey (SF-36®) questionnaire. Results: Of 49 evaluable participants with PAI, 45 achieved a physiological morning cortisol after four weeks of Chronocort® compared with 2 after four weeks of Plenadren® (P<0.0001). The mean (standard deviation) waking cortisol was 422.85 (203.50) vs 36.98 (113.87), respectively. Conclusion: Chronocort® provides more physiological waking cortisol levels than Plenadren®. Further analysis will test the hypothesis that waking with physiological cortisol levels improves fatigue and QoL in patients with PAI. 1.Mah PM, et al. Clin Endocrinol (Oxf). 2004;61(3):367-75.2.Wichers M, et al. Clin Endocrinol (Oxf). 1999;50(6):759-65. Presentation: 6/3/2024

9341 CHAMPAIN Study: Initial Results From A Phase II Study Of Efficacy, Safety And Tolerability Of Modified-release Hydrocortisones: Chronocort® (Efmody®) Versus Plenadren®, In Primary Adrenal Insufficiency

Abstract Disclosure: A. Prete: Research Investigator; Self; Diurnal. V. Theiler-Schwetz: Research Investigator; Self; Diurnal. W. Arlt: Research Investigator; Self; Diurnal. I.O. Chifu: Research Investigator; Self; Diurnal. B. Harbeck: Research Investigator; Self; Diurnal. C. Napier: Research Investigator; Self; Diurnal. J.D. Newell-Price: Research Investigator; Self; Diurnal. A. Rees: Research Investigator; Self; Diurnal. N. Reisch: Research Investigator; Self; Diurnal. G.K. Stalla: Research Investigator; Self; Diurnal. N. Aslam: Employee; Self; Diurnal. H. Coope: Employee; Self; Diurnal. K. Maltby: Employee; Self; Diurnal. J. Porter: Employee; Self; Diurnal. J. Quirke: Employee; Self; Diurnal. R.J. Ross: Consulting Fee; Self; Diurnal. Background: Current glucocorticoid replacement regimens for patients with primary adrenal insufficiency (PAI) mean patients wake with either low or undetectable cortisol levels[1], associated with fatigue and a reduced quality of life (QoL)2. Plenadren® (Takeda, UK) is a once-daily modified-release formulation of hydrocortisone that replaces daytime cortisol levels whereas Chronocort® (modified-release hydrocortisone hard capsules, Diurnal, UK) when taken twice-daily, has been shown to replicate the normal overnight rise in serum cortisol concentration and provide physiological levels throughout the day. We have undertaken a double-blind, double-dummy, two-way cross-over, randomised, phase II study of efficacy, safety and tolerability of modified-release hydrocortisones: Chronocort® Versus Plenadren®. Aim: To test the hypothesis that Chronocort® provides more physiological waking cortisol levels than Plenadren®. Methodology: The study was conducted across 8 sites in the UK and Germany. Male and female patients, aged ≥18 with confirmed PAI (defined as morning pre-dose cortisol <50 nMol/l) on stable therapy over the preceding three months and not currently treated with Chronocort®/Plenadren®. Participants with congenital adrenal hyperplasia (CAH), secondary or tertiary AI were excluded. Each participant was randomised on a 1:1 basis to either; treatment sequence I (Chronocort® first) or treatment sequence II (Plenadren® first) taking a 25mg total daily dose for 4 weeks; either Plenadren® 25mg in the morning or Chronocort® 10mg in the morning and 15mg at night with the associated dummy preparation followed immediately by the other treatment. The pre-dose morning serum cortisol level was assayed at baseline and after each treatment period. A physiological morning cortisol level was defined as a pre-dose level of >140nMol/L. Secondary measures included: morning fatigue measured using the Multidimensional Assessment of Fatigue (MAF) questionnaire and the PROMIS® 7b questionnaire; QoL was assessed using the EuroQol 5-level Standardised Health Questionnaire (EQ-5D-5L™); Health-related Quality of Life in Addison’s disease (AddiQoL) questionnaire and the 36-Item Short Form Health Survey (SF-36®) questionnaire. Results: Of 49 evaluable participants with PAI, 45 achieved a physiological morning cortisol after four weeks of Chronocort® compared with 2 after four weeks of Plenadren® (P<0.0001). The mean (standard deviation) waking cortisol was 422.85 (203.50) vs 36.98 (113.87), respectively. Conclusion: Chronocort® provides more physiological waking cortisol levels than Plenadren®. Further analysis will test the hypothesis that waking with physiological cortisol levels improves fatigue and QoL in patients with PAI. 1.Mah PM, et al. Clin Endocrinol (Oxf). 2004;61(3):367-75.2.Wichers M, et al. Clin Endocrinol (Oxf). 1999;50(6):759-65. Presentation: 6/3/2024

Dysregulations in CLOCK genes in immune cells in congenital adrenal hyperplasia depending on the type of glucocorticoid replacement regimens

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Salivary steroid and 11‑oxygenated androgen profiles in patients with congenital adrenal hyperplasia on various glucocorticoid replacement regimens

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The use of prednisolone versus dual-release hydrocortisone in the treatment of hypoadrenalism.

The introduction of adrenocortical extract in 1930 improved the life expectancy of hyhpoadrenal patients, with further increases seen after the introduction of cortisone acetate from 1948. Most patients are now treated with synthetic hydrocortisone, and incremental advances have been made with optimisation of daily dosing and the introduction of multidose regimens. There remains a significant mortality gap between individuals with treated hypoadrenalism and the general population. It is unclear whether this gap is a result of glucocorticoid over-replacement, under-replacement or loss of the circadian and ultradian rhythm of cortisol secretion, with the risk of detrimental excess glucocorticoid exposure at later times in the day. The way forwards will involve replacement of the diurnal cortisol rhythm with better glucocorticoid replacement regimens. The steroid profile produced by both prednisolone and dual-release hydrocortisone (Plenadren), provide a smoother glucocorticoid profile of cortisol than standard oral multidose regimens of hydrocortisone and cortisone acetate. The individualisation of prednisolone doses and lower bioavailability of Plenadren offer reductions in total steroid exposure. Although there is emerging evidence of both treatments offering better cardiometabolic outcomes than standard glucocorticoid replacement regimens, there is a paucity of evidence involving very low dose prednisolone (2–4 mg daily) compared to the larger doses (~7.5 mg) historically used. Data from upcoming clinical studies on prednisolone will therefore be of key importance in informing future practice.

Glucocorticoid replacement regimens for treating congenital adrenal hyperplasia.

Glucocorticoid replacement regimens for treating congenital adrenal hyperplasia.

A Cochrane Review of glucocorticoid replacement regimens in the treatment of 21-hydroxylase deficiency congenital adrenal hyperplasia

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Factors impacting on the action of glucocorticoids in patients receiving glucocorticoid therapy.

Glucocorticoids (GCs) are steroid hormones, which are essential for life. They are secreted by the adrenal cortex under the control of the hypothalamic-pituitary-adrenal (HPA) axis. Glucocorticoids are essential for the normal function of most organ systems and, in both, excess and deficiency can lead to significant adverse consequences. Adrenal insufficiency (AI) is a rare, life-threatening disorder characterized by insufficient production of corticosteroid hormones. Primary AI is defined by the inability of the adrenal cortex to produce sufficient amounts of glucocorticoids and/or mineralocorticoids despite normal or increased adrenocorticotropin hormone (ACTH). Secondary AI is adrenal hypofunction due to insufficient amount of ACTH produced by the pituitary gland. Conventional treatment of both primary and secondary adrenal insufficiencies involves lifelong glucocorticoid replacement therapy. The role of cortisol deficiency and the impact of hydrocortisone replacement on morbidity and mortality in this patient group are under increasing scrutiny. Established glucocorticoid replacement regimens do not completely mirror endogenous hormonal production, and their monitoring to ensure optimum therapy is hampered by the lack of reliable biomarkers of hormone sufficiency. A further confounding issue is the tissue-specific regulation of glucocorticoid through the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) with research focusing on the role of this prereceptor regulation in the development of adverse metabolic features in patients. This review defines the factors influencing glucocorticoid action in patients with adrenal insufficiency receiving glucocorticoid therapy.

Glucocorticoids and Bone: Consequences of Endogenous and Exogenous Excess and Replacement Therapy.

Osteoporosis associated with long-term glucocorticoid therapy remains a common and serious bone disease. Additionally, in recent years it has become clear that more subtle states of endogenous glucocorticoid excess may have a major impact on bone health. Adverse effects can be seen with mild systemic glucocorticoid excess, but there is also evidence of tissue-specific regulation of glucocorticoid action within bone as a mechanism of disease. This review article examines (1) the role of endogenous glucocorticoids in normal bone physiology, (2) the skeletal effects of endogenous glucocorticoid excess in the context of endocrine conditions such as Cushing disease/syndrome and autonomous cortisol secretion (subclinical Cushing syndrome), and (3) the actions of therapeutic (exogenous) glucocorticoids on bone. We review the extent to which the effect of glucocorticoids on bone is influenced by variations in tissue metabolizing enzymes and glucocorticoid receptor expression and sensitivity. We consider how the effects of therapeutic glucocorticoids on bone are complicated by the effects of the underlying inflammatory disease being treated. We also examine the impact that glucocorticoid replacement regimens have on bone in the context of primary and secondary adrenal insufficiency. We conclude that even subtle excess of endogenous or moderate doses of therapeutic glucocorticoids are detrimental to bone. However, in patients with inflammatory disorders there is a complex interplay between glucocorticoid treatment and underlying inflammation, with the underlying condition frequently representing the major component underpinning bone damage.

Quantitative Brain MRI in Congenital Adrenal Hyperplasia: In Vivo Assessment of the Cognitive and Structural Impact of Steroid Hormones.

ContextBrain white matter hyperintensities are seen on routine clinical imaging in 46% of adults with congenital adrenal hyperplasia (CAH). The extent and functional relevance of these abnormalities have not been studied with quantitative magnetic resonance imaging (MRI) analysis.ObjectiveTo examine white matter microstructure, neural volumes, and central nervous system (CNS) metabolites in CAH due to 21-hydroxylase deficiency (21OHD) and to determine whether identified abnormalities are associated with cognition, glucocorticoid, and androgen exposure.Design, Setting, and ParticipantsA cross-sectional study at a tertiary hospital including 19 women (18 to 50 years) with 21OHD and 19 age-matched healthy women.Main Outcome MeasureRecruits underwent cognitive assessment and brain imaging, including diffusion weighted imaging of white matter, T1-weighted volumetry, and magnetic resonance spectroscopy for neural metabolites. We evaluated white matter microstructure by using tract-based spatial statistics. We compared cognitive scores, neural volumes, and metabolites between groups and relationships between glucocorticoid exposure, MRI, and neurologic outcomes.ResultsPatients with 21OHD had widespread reductions in white matter structural integrity, reduced volumes of right hippocampus, bilateral thalami, cerebellum, and brainstem, and reduced mesial temporal lobe total choline content. Working memory, processing speed, and digit span and matrix reasoning scores were reduced in patients with 21OHD, despite similar education and intelligence to controls. Patients with 21OHD exposed to higher glucocorticoid doses had greater abnormalities in white matter microstructure and cognitive performance.ConclusionWe demonstrate that 21OHD and current glucocorticoid replacement regimens have a profound impact on brain morphology and function. If reversible, these CNS markers are a potential target for treatment.

MANAGEMENT OF ENDOCRINE DISEASE: Risk of overtreatment in patients with adrenal insufficiency: current and emerging aspects.

The effects of long-term replacement therapy of adrenal insufficiency (AI) are still a matter of controversy. In fact, the established glucocorticoid replacement regimens do not completely reproduce the endogenous hormonal production and the monitoring of AI treatment may be a challenge for the lack of reliable clinical and biochemical markers. Consequently, several AI patients are frequently exposed to relative glucocorticoid excess potentially leading to develop chronic complications, such as diabetes mellitus, dyslipidemia, hypertension and fragility fractures with consequent impaired QoL and increased mortality risk. This review deals with the pathophysiological and clinical aspects concerning the over-replacement therapy of primary and secondary AI.

Glucocorticoid replacement regimens in the treatment of 21-hydroxylase deficiency congenital adrenal hyperplasia

Glucocorticoid replacement regimens in the treatment of 21-hydroxylase deficiency congenital adrenal hyperplasia

Glucocorticoid Replacement Regimens in Chronic Adrenal Insufficiency: A Systematic Review and Meta-Analysis

Various glucocorticoid (GC) regimens have been used in the treatment of patients with adrenal insufficiency, yet the differences between such regimens on health outcomes are unclear. We performed a systematic review and meta-analysis to compare the effects of GC regimens on quality of life (QoL), bone density, incidence of adrenal crisis, and death. In pediatric studies, we also searched for final adult height. We searched 6 databases through July 2016. Studies were selected and appraised by independent reviewers. Data were pooled using the profile likelihood random-effects model. We included 34 studies. We found no difference in QoL scores between higher (≥30 mg/day of hydrocortisone [HC] equivalence) vs. lower daily doses (<30 mg/day of HC equivalence) (P = .15) or based on frequency of daily dosing (once, twice or thrice daily). Extended-release (1 study), dual-/modified-release (3 studies), and continuous subcutaneous (3 studies) forms of GCs were associated with higher QoL scores. There was no significant association between dose and type of GC and the incidence of adrenal crises. The effect on bone mineral density was heterogeneous. No data were available on mortality or final adult height in children. The quality of evidence was low due to increased risk of bias, imprecision, and heterogeneity. Extended-/dual-release, and continuous subcutaneous forms of GC may be associated with higher QoL scores. However, this is derived from short-term and imprecise evidence, warranting low confidence. AI = adrenal insufficiency BMD = bone mineral density GC = glucocorticoids HC = hydrocortisone QoL = quality of life RCT = randomized controlled trial.

Effects of standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, crossover study in patients with secondary adrenal insufficiency

For secondary adrenal insufficiency (SAI), established biochemical parameters for dosage control are lacking and no optimal substitution dosage and daily distribution have been determined yet. Therefore, in clinical practice, the individual total dose is often adjusted based on patients' subjective well-being. Effects of three standard glucocorticoid replacement regimens on psychological variables were assessed in patients with SAI based on a randomized double-blind study design. SAI patients (n=18) were treated with three different established glucocorticoid replacement regimens in a randomized, double-blind, crossover study (treatment A, hydrocortisone 10 mg-placebo-5 mg-placebo; treatment B, hydrocortisone 10 mg-5 mg-placebo-5 mg; and treatment C, prednisone 5 mg-placebo-placebo-placebo). Following each 4-week replacement regimen, quality of life (SF-36) and emotional distress (brief symptom inventory (BSI)) were assessed along with diurnal changes in current well-being (Bf-S) and alertness (Stanford Sleepiness Scale (SSS)) using validated questionnaires, and additionally compared with patient (patients with pituitary disease and adrenal sufficiency) and healthy control groups. SAI patients showed improvements in physical quality of life (i.e. SF-36 physical function, P<0.05; physical role function, P<0.05) and current well-being (at 1800 h, P<0.05) under treatment A (hydrocortisone 10-0-5-0 mg) compared with the other replacement regimens. Quality of life and current well-being were significantly impaired compared with healthy controls but did not differ from patient controls. Although the observed improvements in psychological parameters were comparatively small, our results indicate beneficial effects of a 10-0-5-0 mg hydrocortisone replacement regimen. Nevertheless, treatment effects were insufficient to restore subjective health compared with healthy controls, indicating the need for improved replacement regimens and supportive psychosocial interventions in SAI patients.

Glucocorticoid replacement therapy and fibrinolysis in patients with hypopituitarism

Hypopituitarism is associated with increased cardiovascular mortality, and it has been suggested that unphysiological glucocorticoid replacement regimens might contribute to this risk. Traditional glucocorticoid replacement regimens have often led to excessive serum cortisol levels. The hypercortisolaemia of Cushing's syndrome is associated with an increased risk of thromboembolism. To examine whether short-term higher-dose hydrocortisone replacement regimens adversely affect the fibrinolytic system. Crossover study comparing tailored low-dose (LD) glucocorticoid regimen (mean, 17·5 mg hydrocortisone daily), with a traditional high-dose (HD, 30-mg hydrocortisone daily) regimen for 2 weeks. Ten patients with hypopituitarism and ACTH deficiency - median (range) age, 59 (41-75) years - and 10 age- and sex-matched controls. Nine patients had growth hormone deficiency (five replaced), nine patients had TSH deficiency (nine replaced), eight had gonadotrophin deficiency (five replaced). During the study, other pituitary hormone replacement therapy remained unchanged. Patients with acromegaly and Cushing's syndrome were excluded. Hourly serum cortisol for 11 h, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and fibrinogen levels after 2 weeks of treatment with both LD and HD regimens. No overall significant differences were found between the three groups using the Kruskal-Wallis test: PAI-1: [median (range)] HD, 25 (5-53) ng/ml; LD, 21 (4-56) ng/ml; controls, 27 (8-51); P = 0·3; tPA: HD, 10 (5-15) ng/ml; LD, 10 (4-13) ng/ml; controls 10 (3-13); P = 0·46; and fibrinogen: HD, 2·5 (1·8-3·5) g/l; LD, 3·0 (2·3-4·4) g/l; controls, 2·6 (1·6-3·2): P = 0·97 In addition, no significant differences between HD and LD using Wilcoxon's paired test; PAI-1 (P = 0·91), tPAag (P = 0·47) and fibrinogen (P = 0·09). An increased dose of hydrocortisone for 2 weeks creates excessive glucocorticoid exposure, but does not significantly affect fibrinolytic-coagulation parameters.

Altered insulin requirement in patients with type 1 diabetes and primary adrenal insufficiency receiving standard glucocorticoid replacement therapy

Current glucocorticoid replacement regimens fail to fully mimic physiologic cortisol secretion in patients with primary adrenal insufficiency. This may lead to changes in insulin requirement in patients with primary adrenal insufficiency and type 1 diabetes. Therefore, we assessed insulin requirement in patients with autoimmune polyendocrine syndrome type 2 (APS-2). Ten females with primary adrenal insufficiency and type 1 diabetes (mean duration of type 1 diabetes 13+/-11 years and of primary adrenal insufficiency 11+/-9 years) were retrospectively assessed regarding insulin regimen and insulin dose adjustment. Data were compared with control patients matched for age, sex and duration of diabetes drawn from all patients with type 1 diabetes attending the diabetes outpatient clinics at the University Hospital Wuerzburg for a scheduled consultation. Glycaemia was well controlled in both groups (mean HbA1c 6.99+/-0.81% in APS-2 patients versus 6.69+/-1.03% in control patients). The mean weight-adjusted daily dose of insulin was non-significantly higher in patients with APS-2 compared with control patients (0.69+/-0.35 IU/kg body weight versus 0.51+/-0.17 respectively). The mean insulin (IU)/carbohydrate-ratio for 10 g of carbohydrate in the morning was 1.9+/-1.0 and 1.4+/-0.5 respectively. However, the insulin/carbohydrate-ratios were significantly higher in the APS-2 patients both at noon (mean ratio 2.0+/-0.9 vs 1.1+/-0.5 in control patients) and in the evening (mean ratio 2.1+/-1.1 vs 1.3+/-0.5 respectively; P<0.05). Glucocorticoid replacement therapy in patients with primary adrenal insufficiency and type 1 diabetes leads to significant changes in insulin requirement compared with patients with type 1 diabetes only.

Impaired subjective health status in chronic adrenal insufficiency: impact of different glucocorticoid replacement regimens

Recent studies have suggested that current glucocorticoid replacement therapies fail to fully restore well-being in patients with adrenal insufficiency (AI). To investigate the effect of different glucocorticoid preparations used for replacement therapy on subjective health status (SHS) in AI. In a cross-sectional study, primary and secondary AI patients were contacted by mail. Individual glucocorticoid replacement regimens, underlying diagnoses and comorbidities were verified by questionnaires and review of medical records. Patients were asked to complete three validated self-assessment questionnaires (Short Form 36 (SF-36), Giessen Complaint List (GBB-24), and Hospital Anxiety and Depression Scale). Results were compared with sex- and age-matched controls drawn from the questionnaire-specific reference cohort. Of the 883 patients identified, 526 agreed to participate in the study. Completed questionnaire sets were available from 427 patients (primary AI n=232; secondary AI n=195). AI patients showed significantly impaired SHS compared with controls irrespective of the glucocorticoid used for replacement. The only difference in SHS between patients on prednisolone (PR) and hydrocortisone (all patients and sub-analysis for primary AI) was significant higher bodily pain (lower Z-score in SF-36) in patients on PR (P<0.05, P<0.01 respectively). In patients with secondary AI, the PR group showed significantly (P<0.05) less heart complaints (lower Z-score) in the GBB questionnaire compared with the cortisone acetate group. Glucocorticoid replacement therapy with PR seems to be equivalent to hydrocortisone regarding SHS in patients with AI. However, SHS remains impaired in all patient groups suggesting a need for further improved glucocorticoid replacement strategies.

Bioelectrical impedance analysis of body fatness in childhood congenital adrenal hyperplasia and its metabolic correlates

There is a tendency to adiposity in patients with congenital adrenal hyperplasia (CAH) despite physiological corticosteroid doses. This study investigated body fatness in children with CAH under corticosteroid replacement therapy. Seventeen children with CAH (female:male, 9:8; age range 1.6-10.5 years) and 18 controls (female:male, 9:9; age range 1.4-10.2 years) were studied. Serum lipids, leptin, insulin, anthropometry, body circumferences, skinfold thickness, and body fat ratio as measured with bioelectrical impedance analysis (BIA) were the study parameters. Weight standard deviation scores (SDS), body mass index (BMI), BMI-SDS, body circumferences, skinfold thickness, and body fat ratio were higher and leptin was positively correlated with all of the body circumference and skinfold thickness parameters as well as body fat ratio in the study group. Waist/hip ratio was lower in the study group. Body fatness is a serious problem starting in early childhood in CAH patients and further refinement of the glucocorticoid replacement regimens as well as lifestyle measures are needed.

The Impact of Glucocorticoid Replacement Regimens on Metabolic Outcome and Comorbidity in Hypopituitary Patients

Hypopituitary patients with untreated GH deficiency and patients on inappropriately high doses of glucocorticoid (GC) share certain clinical features. The aim of the study was to examine the influence of GC substitution on clinical characteristics in hypopituitary patients before and after GH replacement therapy. A total of 2424 hypopituitary patients within the KIMS (Pfizer International Metabolic Database) were grouped according to ACTH status. Comparisons were performed between subjects on hydrocortisone (HC) (n = 1186), cortisone acetate (CA) (n = 487), and prednisolone/dexamethasone (n = 52), and ACTH-sufficient patients (AS) (n = 717) before and after 1 yr of GH treatment in terms of body mass index, waist and hip circumference, blood pressure, glucose, glycosylated hemoglobin (HbA1c), serum lipids, IGF-I, and comorbidity. Hydrocortisone equivalent (HCeq) doses were calculated, and measurements were adjusted for sex and age. At baseline, the HC group had increased total cholesterol, triglycerides, waist circumference, and HbA1c, and the prednisolone/dexamethasone group had increased waist/hip ratio as compared with AS. After HCeq dose adjustment, the HC group retained higher HbA1c than the CA group. GC-treated patients showed a dose-related increase in serum IGF-I, body mass index, triglycerides, low-density lipoprotein cholesterol and total cholesterol levels. Subjects with HCeq doses less than 20 mg/d (n = 328) at baseline did not differ from AS in metabolic endpoints. The 1-yr metabolic response to GH was similar in all GC groups and dose categories. All new cases of diabetes (n = 12), stroke (n = 8), and myocardial infarction (n = 3) during GH treatment occurred in GC-treated subjects. HCeq doses of at least 20 mg/d in adults with hypopituitarism are associated with an unfavorable metabolic profile. CA replacement may have metabolic advantages compared with other GCs.

Cardiovascular disease and risk factors in adults with hypopituitarism.

In 1992, Cuneo et al. (1992) reviewed, in this journal, the consequences of growth (GH) deficiency during adult life and coined the term ‘Growth hormone deficiency (GHD) syndrome in adults’. Limited information was available then on cardiovascular disease and risk factors in adults with hypopituitarism. More data have been published since on cardiovascular morbidity in symptom-free hypopituitary adults. Several groups have also published results on the effects of GH therapy on cardiac structure and function and on the cardiovascular risk factors. We shall review here the epidemiological and experimental data on cardiovascular morbidity and mortality in adult hypopituitarism. We shall also examine the prevalence of cardiovascular risk factors in this group of patients and their potential causes focusing on the possible role of GH deficiency and the effects of GH replacement.