Long-term cardiometabolic morbidity in young adults with classic 21-hydroxylase deficiency congenital adrenal hyperplasia.

PURPOSE: To study the current practice for assessing comorbidity in adults with 21-hydroxylase CAH and to assess the prevalence of comorbidity in these adults. METHODS: A structured questionnaire was sent to 46 expert centres managing adults with CAH. Information collected included current therapy and surveillance practice with a particular focus on osteoporosis/osteopaenia, hyperlipidaemia, type 2 diabetes/hyperinsulinaemia, hypertension, CV disease, obesity. RESULTS: Of the 31 (67%) centres from 15 countries that completed the survey, 30 (97%) screened for hypertension by measuring blood pressure, 30 (97%) screened for obesity, 26 (84%) screened for abnormal glucose homoeostasis mainly by using Hb1Ac (73%), 25 (81%) screened for osteoporosis mainly by DXA (92%), 20 (65%) screened for hyperlipidaemia and 6 (19%) screened for additional CV disease. Of the 31 centres, 13 provided further information on the six co-morbidities in 244 patients with a median age of 33 yrs (range 19, 94). Of these, 126 (52%) were females and 174 (71%) received fludrocortisone in addition to glucocorticoids. Of the 244 adults, 73 (30%) were treated for at least one comorbidity and 15 (21%) for more than 2 co-morbidities. Of 73, the patients who were treated for osteoporosis/osteopaenia, hyperlipidaemia, type 2 diabetes/hyperinsulinaemia, hypertension, CV disease, obesity were 43 (59%), 17 (23%), 16 (22%), 10 (14%), 8 (11), 3 (4%) respectively. CONCLUSION: Cardiometabolic and bone morbidities are not uncommon in adults with CAH. There is a need to standardise the screening for these morbidities from early adulthood and to explore optimal therapy through routine collection of standardised data.

An oral lipidic native testosterone formulation that is absorbed independent of food.

CONTEXT: There is no licensed oral native testosterone (NT) because of challenges in the formulation. Licensed oral formulations of the ester, testosterone undecanoate (TU), require a meal for absorption and generate supraphysiological dihydrotestosterone (DHT) levels. OBJECTIVE: To develop an oral NT formulation. DESIGN AND METHODS: A lipid-based formulation of native testosterone filled into soft-gelatin capsules at 40 mg per capsule was designed with 2 years of stability at ambient temperature. Pharmacokinetic comparison studies of this oral lipidic NT formulation to oral TU were conducted in dogs and hypogonadal men. RESULTS: In dogs, 40 mg NT was well absorbed under fasted conditions whereas 40 mg TU required a high-fat meal: for NT, the mean fed/fasted AUC ratio was 1.63 and for TU 7.05. In hypogonadal men, fed and fasted NT had similar pharmacokinetics: Cmax mean 26.5 vs 30.4 nmol/L (769 vs 882 ng/dL), AUC0-10 h 87 vs 88.6 h nmol/L. NT (fed state) showed a testosterone AUC increase of 45% between 120 and 200 mg, and NT 200 mg gave a similar mean AUC0-10 h to TU 80 mg: 87 vs 64.8 h nmol/L. Serum TU levels were variable and on a molar basis were ~ten-fold higher than serum testosterone levels after TU 80 mg fed. The DHT: testosterone AUC0-10 h ratio was more physiological for NT than TU being 0.19 vs 0.36. There were no emerging safety concerns with NT. CONCLUSION: This novel oral lipidic native testosterone formulation has potential advantages over oral TU of dosing independently of food and a lower risk of supraphysiological DHT levels. Significance statement There is no licensed oral testosterone because of challenges in formulation, and the oral formulations of the ester, testosterone undecanoate, require a fatty meal for absorption and generate supraphysiological dihydrotestosterone levels. We have overcome the design challenges and formulated an oral native testosterone that can be taken with or without food and provides physiological levels of testosterone and dihydrotestosterone in hypogonadal men. This formulation, DITEST, has the potential advantage of being oral for patients who do not tolerate injections and less risk of adverse events that might theoretically be associated with elevated dihydrotestosterone levels. Future studies will need to define the dosing regimen for replacement in hypogonadal men.

International practice of corticosteroid replacement therapy in congenital adrenal hyperplasia: data from the I-CAH registry.

OBJECTIVE: Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH. DESIGN: This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry. METHODS: Data were collected from 461 patients aged 0-18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 and 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement were analyzed from 4174 patient visits. RESULTS: The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0-14.5) mg/m2/day at age 1-8 years and the highest dose of 14.0 (11.6-17.4) mg/m2/day at age 12-18 years. Glucocorticoid doses decreased after 2010 in patients 0-8 years (P < 0.001) and remained unchanged in patients aged 8-18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement. CONCLUSIONS: Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.

Hydrocortisone Granules Are Bioequivalent When Sprinkled Onto Food or Given Directly on the Tongue.

BACKGROUND: Immediate-release hydrocortisone granules in capsules for opening in pediatric-appropriate doses have recently been licensed for children with adrenal insufficiency. This study evaluated the bioavailability of hydrocortisone granules administered as sprinkles onto soft food and yogurt compared with direct administration to the back of the tongue. METHODS: Randomized, 3-period crossover study in 18 dexamethasone-suppressed healthy men. In each period, the fasted participants received 5 mg hydrocortisone granules either directly to the back of the tongue or sprinkled onto soft food (applesauce), or yogurt, followed by 240 mL of water. Serum cortisol was measured by liquid chromatography tandem mass spectometry. RESULTS: The cortisol geometric mean maximum concentration (Cmax) and area under the curve (AUC) for direct administration, sprinkles onto yogurt, and sprinkles onto soft food were: Cmax 428, 426, 427 nmol/L and AUC0-inf 859, 886, 844 h × nmol/L, and AUC0-t 853, 882, 838 h × nmol/L respectively. The 90% CI for the ratios of Cmax, AUC0-inf and AUC0-t for administration with soft food or yogurt to direct administration were well within the bioequivalent range, 80% to 125%. Median time to Cmax (Tmax) was similar between methods of administration: 0.63 hours administered directly, 0.75 hours on soft food and 0.75 hours on yogurt. No adverse events occurred during the study. CONCLUSIONS: Hydrocortisone granules administered as sprinkles onto soft food or yogurt but not mixed with these foods are bioequivalent to those administered directly to the back of the tongue. Carers, parents, or patients may choose to administer hydrocortisone granules either directly or sprinkled onto soft food or yogurt.

Accuracy of hydrocortisone dose administration via nasogastric tube.

OBJECTIVE: Hydrocortisone via nasogastric (NG) tube is used in sick children with adrenal insufficiency; however, there is no licensed formulation for NG administration. METHODS: We investigated hydrocortisone recovery after passage through NG tubes in vitro for three formulations: liquid suspension, crushed tablets mixed with water, and hydrocortisone granules designed for oral administration to children. Cortisol was measured by LC-MS/MS. RESULTS: Hydrocortisone content was variable and recovery low after preparation in syringe and prior to passage through NG tubes. For doses, 0.5 and 2.0 mg mean percentage recovery was as follows: liquid suspension 57% and 58%; crushed tablets 46% and 30%; and hydrocortisone granules 78% and 71%. Flushing the administering syringe increased recovery. Hydrocortisone recovery after passage with flushing through 6-12Fr gauge NG tubes was variable: liquid suspension 61%-92%, crushed tablets 40%-174%, hydrocortisone granules 61%-92%. Administration of hydrocortisone granules occluded 6 and 8Fr NG tubes; however, administration using a sampling needle to prevent granules being administered gave a recovery of 74%-98%. CONCLUSIONS: The administration of hydrocortisone through NG tubes is possible; however, current methods deliver a variable dose of hydrocortisone, generally less than that prescribed. Attention should be placed on the technique used to optimize drug delivery such as flushing of the administering syringe. Hydrocortisone granules block small NG tubes but behaved as well as the commonly used liquid suspension when prepared with a filtering needle that filters out granules.

A prospective longitudinal study of Pasireotide in Nelson's syndrome.

PURPOSE: Nelson's syndrome is a challenging condition that can develop following bilateral adrenalectomy for Cushing's disease, with high circulating ACTH levels, pigmentation and an invasive pituitary tumor. There is no established medical therapy. The aim of the study was to assess the effects of pasireotide on plasma ACTH and tumor volume in Nelson's syndrome. METHODS: Open labeled multicenter longitudinal trial in three steps: (1) a placebo-controlled acute response test; (2) 1 month pasireotide 300-600 µg s.c. twice-daily; (3) 6 months pasireotide long-acting-release (LAR) 40-60 mg monthly. RESULTS: Seven patients had s.c. treatment and 5 proceeded to LAR treatment. There was a significant reduction in morning plasma ACTH during treatment (mean ± SD; 1823 ± 1286 ng/l vs. 888.0 ± 812.8 ng/l during the s.c. phase vs. 829.0 ± 1171 ng/l during the LAR phase, p < 0.0001). Analysis of ACTH levels using a random intercept linear mixed-random effects longitudinal model showed that ACTH (before the morning dose of glucocorticoids) declined significantly by 26.1 ng/l per week during the 28-week of treatment (95% CI - 45.2 to - 7.1, p < 0.01). An acute response to a test dose predicted outcome in 4/5 patients. Overall, there was no significant change in tumor volumes (1.4 ± 0.9 vs. 1.3 ± 1.0, p = 0.86). Four patients withdrew during the study. Hyperglycemia occurred in 6 patients. CONCLUSIONS: Pasireotide lowers plasma ACTH levels in patients with Nelson's syndrome. A longer period of treatment may be needed to assess the effects of pasireotide on tumor volume. TRIAL REGISTRATION: Clinical Trials.gov ID, NCT01617733.

Recent advances in understanding Cushing disease: resistance to glucocorticoid negative feedback and somatic USP8 mutations.

Cushing's disease is a rare disease with a characteristic phenotype due to significant hypercortisolism driven by over-secretion of adrenocorticotropic hormone and to high morbidity and mortality if untreated. It is caused by a corticotroph adenoma of the pituitary, but the exact mechanisms leading to tumorigenesis are not clear. Recent advances in molecular biology such as the discovery of somatic mutations of the ubiquitin-specific peptidase 8 ( USP8) gene allow new insights into the pathogenesis, which could be translated into exciting and much-needed therapeutic applications.

Androgens correlate with increased erythropoiesis in women with congenital adrenal hyperplasia.

OBJECTIVE: Hyperandrogenism in congenital adrenal hyperplasia (CAH) provides an in vivo model for exploring the effect of androgens on erythropoiesis in women. We investigated the association of androgens with haemoglobin (Hb) and haematocrit (Hct) in women with CAH. DESIGN: Cross-validation study. PATIENTS: Women with CAH from Sheffield Teaching Hospitals, UK (cohort 1, the training set: n = 23) and National Institutes of Health, USA (cohort 2, the validation set: n = 53). MEASUREMENTS: Androgens, full blood count and basic biochemistry, all measured on the same day. Demographic and anthropometric data. RESULTS: Significant age-adjusted correlations (P < 0·001) were observed for Ln testosterone with Hb and Hct in cohorts 1 and 2 (Hb r = 0·712 & 0·524 and Hct r = 0·705 & 0·466), which remained significant after adjustments for CAH status, glucocorticoid treatment dose and serum creatinine. In the combined cohorts, Hb correlated with androstenedione (P = 0·002) and 17-hydroxyprogesterone (P = 0·008). Hb and Hct were significantly higher in cohort 1 than those in cohort 2, while there were no group differences in androgen levels, glucocorticoid treatment dose or body mass index. In both cohorts, women with Hb and Hct in the highest tertile had significantly higher testosterone levels than women with Hb and Hct in the lowest tertile. CONCLUSIONS: In women with CAH, erythropoiesis may be driven by androgens and could be considered a biomarker for disease control.

Rapid-sequence MRI for long-term surveillance for paraganglioma and phaeochromocytoma in patients with succinate dehydrogenase mutations.

BACKGROUND: Patients with SDHx mutations need long-term radiological surveillance for the development of paragangliomas and phaeochromocytomas, but no longitudinal data exist. The aim of the study was to assess the performance of rapid-sequence non-contrast magnetic resonance imaging (MRI) in the long-term monitoring of patients with SDHx mutations. METHODS: Retrospective study between 2005 and 2015 at a University Hospital and regional endocrine genetics referral centre. Clinical and imaging data of 47 patients with SDHx mutations (SDHB (36), SDHC (6) and SDHD (5)) who had surveillance for detection of paragangliomas by rapid-sequence non-contrast MRI (base of skull to pubic symphysis) were collected. RESULTS: Twelve index cases (nine SDHB, one SDHC and two SDHD) and 35 mutation-positive relatives were monitored for a mean of 6.4 years (range 3.1-10.0 years). Mean age at the end of the study: SDHB 46.9 ± 17.6 years; SDHC 42.3 ± 24.4 years; SDHD 54.9 ± 10.6 years. On excluding imaging at initial diagnosis of index cases, 42 patients underwent 116 rapid-sequence MRI scans: 83 scans were negative and 31 scans were positive for sPGL/HNPGL in 13 patients. Most patients had multiple scans (n = number of patients (number of rapid-sequence MRI scans during screening)): n = 9 (2), n = 20 (3), n = 6 (4), n = 1 (6). Nine patients (three index) were diagnosed with new paragangliomas during surveillance and non-operated tumour size was monitored in nine patients. There were two false-positive scans (1.6%). Scans were repeated every 27 ± 9 months. CONCLUSIONS: Biannual rapid-sequence non-contrast MRI is effective to monitor patients with SDHx mutations for detection of new tumours and monitoring of known tumours.

Effectiveness of Metyrapone in Treating Cushing's Syndrome: A Retrospective Multicenter Study in 195 Patients.

BACKGROUND: Cushing's syndrome (CS) is a severe condition with excess mortality and significant morbidity necessitating control of hypercortisolemia. There are few data documenting use of the steroidogenesis inhibitor metyrapone for this purpose. OBJECTIVE: The objective was to assess the effectiveness of metyrapone in controlling cortisol excess in a contemporary series of patients with CS. DESIGN: This was designed as a retrospective, multicenter study. SETTING: Thirteen University hospitals were studied. PATIENTS: We studied a total of 195 patients with proven CS: 115 Cushing's disease, 37 ectopic ACTH syndrome, 43 ACTH-independent disease (adrenocortical carcinoma 10, adrenal adenoma 30, and ACTH-independent adrenal hyperplasia 3). MEASUREMENTS: Measurements included biochemical parameters of activity of CS: mean serum cortisol "day-curve" (CDC) (target 150-300 nmol/L); 9 am serum cortisol; 24-hour urinary free cortisol (UFC). RESULTS: A total of 164/195 received metyrapone monotherapy. Mean age was 49.6 ± 15.7 years; mean duration of therapy 8 months (median 3 mo, range 3 d to 11.6 y). There were significant improvements on metyrapone, first evaluation to last review: CDC (91 patients, 722.9 nmol/L [26.2 µg/dL] vs 348.6 nmol/L [12.6 µg/dL]; P < .0001); 9 am cortisol (123 patients, 882.9 nmol/L [32.0 µg/dL] vs 491.1 nmol/L [17.8 µg/dL]; P < .0001); and UFC (37 patients, 1483 nmol/24 h [537 µg/24 h] vs 452.6 nmol/24 h [164 µg/24 h]; P = .003). Overall, control at last review: 55%, 43%, 46%, and 76% of patients who had CDCs, UFCs, 9 am cortisol less than 331 nmol/L (12.0 µg/dL), and 9 am cortisol less than upper limit of normal/600 nmol/L (21.7 µg/dL). Median final dose: Cushing's disease 1375 mg; ectopic ACTH syndrome 1500 mg; benign adrenal disease 750 mg; and adrenocortical carcinoma 1250 mg. Adverse events occurred in 25% of patients, mostly mild gastrointestinal upset and dizziness, usually within 2 weeks of initiation or dose increase, all reversible. CONCLUSIONS: Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS.

Diagnosis of Cushing's disease.

Diagnosis of Cushing's disease frequently remains a challenge. In this review we critically appraise the clinical features, biochemical tests, and imaging modalities used for this purpose. We outline recommendations for approaches to clinical investigation, with a particular focus on developments made within the last two years.

Therapy of endocrine disease: steroidogenesis enzyme inhibitors in Cushing's syndrome.

Steroidogenesis enzyme inhibitors are the mainstay of medical therapy in Cushing's syndrome (CS). Ketoconazole (KTZ) and metyrapone are the most commonly used agents. Although there is considerable experience of their use in individual specialist centres, these drugs have not been rigorously tested in prospective clinical trials. Clinicians face uncertainties and concerns with respect to the safety profile of these agents, and best means to monitor effect. We review steroidogenesis inhibitors in the management of CS, including older agents (KTZ, metyrapone, etomidate and mitotane) and those currently under development (LCI699, non-racemic KTZ), and offer a practical approach for their use in clinical practice.