Pregnancy and acromegaly: clinical outcomes of retrospectively analysed data from the German acromegaly registry.

CONTEXT: Acromegaly is a rare disease caused by excessive growth hormone (GH) secretion, mostly induced by pituitary adenomas. The care of pregnant women with acromegaly is challenging, in part due to existing clinical data being limited and not entirely consistent with regard to potential risks for mother and child. OBJECTIVE: To retrospectively examine data on pregnancy and maternal as well as neonatal outcomes in patients with acromegaly. DESIGN & METHODS: Retrospective data analysis from 47 pregnancies of 31 women treated in centers of the German Acromegaly Registry. RESULTS: 87.1% of the studied women underwent transsphenoidal surgery before pregnancy. In 51.1% a combination of dopamine agonists and somatostatin analogs were used before pregnancy. Three women did not receive any therapy for acromegaly. During pregnancy only 6.4% received either somatostatin analogs or dopamine agonists. In total, 70.2% of all documented pregnancies emerged spontaneously. Gestational diabetes was diagnosed in 10.6% and gravid hypertension in 6.4%. Overall, no preterm birth was detected. Indeed, 87% of acromegalic women experienced a delivery without complications. CONCLUSION: Pregnancies in women with acromegaly are possible and the course of pregnancy is in general safe for mother and child both with and without specific treatment for acromegaly. The prevalence of concomitant metabolic diseases such as gestational diabetes is comparable to the prevalence in healthy pregnant women. Nevertheless, larger studies with more data in pregnant patients with acromegaly are needed to provide safe and effective care for pregnant women with this condition.

Adrenal Crisis - Definition, Prevention and Treatment: Results from a Delphi Survey.

Based on recent data, a total number of about 29 000 patients with adrenal insufficiency can be calculated for Germany, and about 1500 fatalities due to adrenal crises have to be expected within the next decade. Management of adrenal crises is still unsatisfactory. The objectives of this study were to establish consensus for diagnostic criteria, prevention strategies, and treatment recommendations for adrenal crises. The study was conducted from January 2022 to April 2023, using Delphi technique. Four rounds of questionnaires were sent to 45 experts, selected by a coordinating group on behalf of the adrenal section of the German Society of Endocrinology. The survey was implemented online using the REDCap web application. Responses were captured anonymously. During the Delphi process the expert panel developed diagnostic criteria to identify patients likely to have an adrenal crisis. Education about adrenal insufficiency among patients as well as non-endocrine medical personnel were regarded as highly important. It was suggested that recommendations for the management of adrenal insufficiency have to be simplified and made widely available. This study provides pragmatic strategies to identify and treat patients prone to adrenal crisis, thereby highlighting the need for an improved management of patients with adrenal insufficiency.

Morbidity in Patients with Chronic Adrenal Insufficiency - Cardiovascular Risk Factors and Hospitalization Rate Compared to Population Based Controls.

Patients with adrenal insufficiency (AI) have been found to have increased cardiovascular morbidity, partly associated with nonphysiologic glucocorticoid replacement. We included two separate cohorts (cohort 1 n=384 patients, cohort 2 n=180 patients) of patients with chronic primary and secondary AI under standard replacement therapy and compared them to two age- and sex-matched population-based studies (SHIP-TREND/DEGS). Odds ratios with 95% CI for hypertension, hyperlipidemia/HLP, type 2 diabetes/T2DM, obesity, and hospitalization with adjustment for confounders were evaluated by logistic regression. Patient cohort 1 had significantly lower ORs for obesity [0.4 (0.3-0.6), p<0.001] and hypertension [0.5 (0.3-0.6), p<0.001] compared to SHIP-TREND and for obesity [0.7 (0.5-0.9), p=0.01], hypertension [0.4 (0.3-0.5), p<0.001] and HLP [0.4 (0.3-0.6), p<0.001] compared to DEGS. In cohort 2, ORs were significantly lower for HLP compared to both SHIP-TREND [0.4 (0.2-0.7), p=0.001] and DEGS [0.3 (0.2-0.5), p<0.001] and for hypertension [0.7 (0.4-0.9), p=0.04] compared to SHIP-TREND. In patients with SAI from cohort 2, ORs for DM2 [2.5 (1.3-4.9) p=0.009], hypertension [2.5 (1.4-4.5), p=0.002] and obesity [1.9 (1.1-3.1), p=0.02] were significantly higher compared to DEGS, whereas ORs for HLP were significantly lower compared to both SHIP [0.3 (0.1-0.6), p=0.002] and DEGS [0.3 (0.1-0.6), p<0.001]. In most of our AI patients treated with conventional glucocorticoid doses, the risk for T2DM, obesity, hypertension, and HLP was not increased. The number of hospitalizations was significantly higher in AI patients compared to controls, which might reflect increased susceptibility but also a more proactive management of concomitant diseases by physicians and patients.

Efficacy and safety of radiation therapy in advanced adrenocortical carcinoma.

BACKGROUND: International guidelines emphasise the role of radiotherapy (RT) for the management of advanced adrenocortical carcinoma (ACC). However, the evidence for this recommendation is very low. METHODS: We retrospectively analysed all patients who received RT for advanced ACC in five European centres since 2000. PRIMARY ENDPOINT: time to progression of the treated lesion (tTTP). Secondary endpoints: best objective response, progression-free survival (PFS), overall survival (OS), adverse events, and the establishment of predictive factors by Cox analyses. RESULTS: In total, 132 tumoural lesions of 80 patients were treated with conventional RT (cRT) of 50-60 Gy (n = 20) or 20-49 Gy (n = 69), stereotactic body RT of 35-50 Gy (SBRT) (n = 36), or brachytherapy of 12-25 Gy (BT) (n = 7). Best objective lesional response was complete (n = 6), partial (n = 52), stable disease (n = 60), progressive disease (n = 14). Median tTTP was 7.6 months (1.0-148.6). In comparison to cRT20-49Gy, tTTP was significantly longer for cRT50-60Gy (multivariate adjusted HR 0.10; 95% CI 0.03-0.33; p < 0.001) and SBRT (HR 0.31; 95% CI 0.12-0.80; p = 0.016), but not for BT (HR 0.66; 95% CI 0.22-1.99; p = 0.46). Toxicity was generally mild and moderate with three grade 3 events. No convincing predictive factors could be established. CONCLUSIONS: This largest published study on RT in advanced ACC provides clear evidence that RT is effective in ACC.

Mineralocorticoid replacement therapy in salt-wasting congenital adrenal hyperplasia.

Patients with salt-wasting congenital adrenal hyperplasia (SW-CAH) usually show pronounced impairment of aldosterone secretion and, therefore, also require mineralocorticoid replacement. While a lot of research and discussion focusses on the glucocorticoid therapy in SW-CAH to replace the missing cortisol and to control adrenal androgen excess, very little research is dealing with mineralocorticoid replacement. However, recent data demonstrated an increased cardiovascular risk in adult CAH patients urging to reflect also on the current mineralocorticoid replacement therapy. In this review, we explain the role and function of the mineralocorticoid receptor, its ligands and inhibitors and its relevance for the therapy of patients with SW-CAH. We performed an extensive literature search and present data on mineralocorticoid therapy in SW-CAH patients as well as clinical advice how to monitor and optimise mineralocorticoid replacement therapy.

Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study.

BACKGROUND: Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined. OBJECTIVE: To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS. DESIGN: Cross-sectional study. SETTING: 14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016). PARTICIPANTS: 1305 prospectively recruited persons with benign adrenal tumors. MEASUREMENTS: Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor [NFAT]; 50 to 138 nmol/L, possible MACS [MACS-1]; >138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry. RESULTS: Of the 1305 participants, 49.7% had NFAT (n = 649; 64.1% women), 34.6% had MACS-1 (n = 451; 67.2% women), 10.7% had MACS-2 (n = 140; 73.6% women), and 5.0% had CS (n = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased. LIMITATIONS: Cross-sectional design; possible selection bias. CONCLUSION: A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes. PRIMARY FUNDING SOURCE: Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

Clinical Presentation, Treatment, and Outcome of Parathyroid Carcinoma: Results of the NEKAR Retrospective International Multicenter Study.

OBJECTIVE: In this retrospective cohort study, we describe the clinical presentation and workup of parathyroid carcinoma (PC) and determine its clinical prognostic parameters. Primary outcome was recurrence free survival. SUMMARY BACKGROUND DATA: PC is an orphan malignancy for which diagnostic workup and treatment is not established. METHODS: Eighty-three patients were diagnosed with PC between 1986 and 2018. Disease-specific and recurrence-free survivals were estimated with the Kaplan-Meier method. Risk factors for recurrence were identified by binary logistic regression with adjustment for age and sex. Thirty-nine tumors underwent central histopathological review. RESULTS: Renal (39.8%), gastrointestinal (24.1%), bone (22.9%), and psychiatric (19.3%) symptoms were the most common symptoms. Surgical treatment was heterogeneous [parathyroidectomy [PTx)] alone: 22.9%; PTx and hemithyroidectomy: 24.1%; en bloc resection 15.7%; others 37.3%] and complications of surgery were frequent (recurrent laryngeal nerve palsy 25.3%; hypoparathyroidism 6%). Recurrence of PC was observed in 32 of 83 cases. In univariate analysis, rate of recurrence was reduced when extended initial surgery had been performed (P = 0.04). In multivariate analysis low T status [odds ratio (OR) = 2.65, 95% confidence interval (CI) 1.02-6.88, P = 0.045], N0 stage at initial diagnosis (OR = 6.32, 95% CI 1.33-30.01, P = 0.02), Ki-67 <10% (OR = 14.07, 95% CI 2.09-94.9, P = 0.007), and postoperative biochemical remission (OR = 0.023, 95% CI 0.001-0.52, P = 0.018) were beneficial prognostic parameters for recurrence-free survival. CONCLUSION: Despite a favorable overall prognosis, PC shows high rates of recurrence leading to repeated surgery and postoperative recurrent laryngeal nerve palsy and hypoparathyroidism. In view of the reduced recurrence rate in cases of extended surgery, ipsilateral completion surgery may be considered when PC is confirmed.

The Primary Aldosteronism Surgical Outcome Score for the Prediction of Clinical Outcomes After Adrenalectomy for Unilateral Primary Aldosteronism.

OBJECTIVE: To develop a prediction model for clinical outcomes after unilateral adrenalectomy for unilateral primary aldosteronism. SUMMARY BACKGROUND DATA: Unilateral primary aldosteronism is the most common surgically curable form of endocrine hypertension. Surgical resection of the dominant overactive adrenal in unilateral primary aldosteronism results in complete clinical success with resolution of hypertension without antihypertensive medication in less than half of patients with a wide between-center variability. METHODS: A linear discriminant analysis model was built using data of 380 patients treated by adrenalectomy for unilateral primary aldosteronism to classify postsurgical clinical outcomes. The total cohort was then randomly divided into training (280 patients) and test (100 patients) datasets to create and validate a score system to predict clinical outcomes. An online tool (Primary Aldosteronism Surgical Outcome predictor) was developed to facilitate the use of the predictive score. RESULTS: Six presurgical factors associated with complete clinical success (known duration of hypertension, sex, antihypertensive medication dosage, body mass index, target organ damage, and size of largest nodule at imaging) were selected based on classification performance in the linear discriminant analysis model. A 25-point predictive score was built with an optimal cut-off of greater than 16 points (accuracy of prediction = 79.2%; specificity = 84.4%; sensitivity = 71.3%) with an area under the curve of 0.839. CONCLUSIONS: The predictive score and the primary aldosteronism surgical outcome predictor can be used in a clinical setting to differentiate patients who are likely to be clinically cured after surgery from those who will need continuous surveillance after surgery due to persistent hypertension.

Bone mineral density and fractures in congenital adrenal hyperplasia: Findings from the dsd-LIFE study.

BACKGROUND: In patients with congenital adrenal hyperplasia (CAH) type and doses of glucocorticoids used as well as sex hormone secretion during puberty have important actions on bone mineral density (BMD) in adulthood. AIM: To evaluate BMD in adult CAH patients depending on current glucocorticoid therapy and on androgen levels in adulthood and at age 16 years. METHODS: We included 244 CAH patients from the dsd-LIFE cohort (women n = 147, men n = 97; salt-wasting n = 148, simple-virilizing n = 71, nonclassical n = 25) in which BMD and bloods were available. Clinical and hormonal data at age 16years were retrieved from patients' files. RESULTS: Simple-virilizing women showed lower BMD compared to salt-wasting women at trochanter (0.65 ± 0.12 vs 0.75 ± 0.15 g/cm2 ; P < .050), whole femur T-score (-0.87 ± 1.08 vs -0.16 ± 1.24; P < .05) and lumbar T-score (-0.81 ± 1.34 vs 0.09 ± 1.3; P < .050). Fracture prevalence did not differ significantly between the CAH groups. Prednisolone vs. hydrocortisone only therapy caused worse trochanter Z-score (-1.38 ± 1.46 vs -0.47 ± 1.16; P < .050). In women lumbar spine, BMD correlated negatively with hydrocortisone-equivalent dose per body surface (r2  = 0.695, P < .001). Furthermore, BMI at age 16years correlated positively with lumbar spine T-score (r2  = 0.439, P = .003) and BMD (r2  = 0.420, P = .002) in women. The androstenedione/testosterone ratio at age 16years correlated positively with lumbar spine Z-score in women (r2  = 0.284, P = .024) and trochanter Z-score in men (r2  = 0.600, P = .025). CONCLUSION: Higher glucocorticoid doses seemed to cause lower BMD especially in women. Prednisolone appeared to have more detrimental effects on BMD than hydrocortisone. Higher glucocorticoid doses (lower androstenedione/testosterone ratio) during adolescence may cause lower BMD in adulthood.

Central Diabetes Insipidus Caused by Arginine Vasopressin Gene Mutation: Report of a Novel Mutation and Review of Literature.

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant hereditary disorder characterized by severe polydipsia and polyuria that usually presents in early childhood. In this study, we describe a new arginine vasopressin (AVP) gene mutation in an ethnic German family with FNDI and provide an overview of disease-associated AVP-gene mutations that are already described in literature. Three members of a German family with neurohypophyseal diabetes insipidus were studied. Isolated DNA from peripheral blood samples was used for mutation analysis by sequencing the whole coding region of AVP-NPII gene. Furthermore, we searched the electronic databases MEDLINE (Pubmed) as well as HGMD, LOVD-ClinVar, db-SNP and genomAD in order to compare our cases to that of other patients with FNDI. Genetic analysis of the patients revealed a novel heterozygote missense mutation in exon 2 of the AVP gene (c.274T>G), which has not yet been described in literature. We identified reports of more than 90 disease-associated mutations in the AVP gene in literature. The novel mutation of the AVP gene seems to cause FNDI in the presented German family. Similar to our newly detected mutation, most mutations causing FNDI are found in exon 2 of the AVP gene coding for neurophysin II. Clinically, it is important to think of FNDI in young children presenting with polydipsia and polyuria.

Granulomatous hypophysitis causing compression of the internal carotid arteries reversible with azathioprine and rituximab treatment.

INTRODUCTION: Compression of the internal carotid artery (ICA) in the cavernous sinus area is a rare event and is mostly associated with pituitary adenomas and meningiomas. Other causes of ICA compression are less well known. We present a rare case of granulomatous hypophysitis causing compression of the ICA, which was treated successfully with immune-suppressive agents. METHODS: The electronic database MEDLINE (PubMed) was searched systematically and other cases with ICA compression were identified and analyzed. RESULTS: A female patient with a history of two previous transsphenoidal operations for suspected pituitary adenoma and post-operative complete pituitary insufficiency presented with severe headaches, nausea, fatigue, and diplopia. Pituitary MRI scan suggested relapse of the pituitary lesion with atypical bilateral infiltration of cavernous sinuses and compression of ICAs. After histological reevaluation of her previous pituitary operations, granulomatous hypophysitis was diagnosed. Treatment was started with high doses of prednisolone. With decreasing doses of prednisolone, symptoms recurred, and azathioprine was started, followed by administration of rituximab resulting in clinical recovery and regression of ICA compression. Literature analysis disclosed 36 case reports with ICA compression in the cavernous sinus region (12 pituitary adenoma, 6 meningioma, 7 hypophysitis, 5 other tumors, and 4 other etiologies). Two cases of hypophysitis recovered completely; five cases improved only partly. CONCLUSION: In the case of ICA compression, clinical signs, onset of symptoms, radiological findings and pituitary insufficiencies should be thoroughly evaluated, and hypophysitis should be considered as a possible cause. In our patient, treatment with azathioprine and, finally, rituximab was successful.

Daily adjustment of glucocorticoids by patients with adrenal insufficiency.

BACKGROUND: Patients with adrenal insufficiency (AI) require lifelong glucocorticoid (GC) replacement. AI patients need to adjust GC dosage in response to stressful events and illness in order to prevent life-threatening adrenal crisis (AC). AIM: To evaluate self-management of patients with AI. METHODS: Four German centres, which are using patient's diary as part of their routine clinical practice, instructed AI patients to prospectively document any discomfort, intercurrent illness or stressful events as well as changes in GC therapy on a daily basis. Diaries of 80 patients (44 females, 52.9 ± 15.9 years, 34 primary AI) were collected and analysed. A symptom score sheet was used to evaluate severity of discomfort. RESULTS: In total, 34 074 patient days (93.4 years) were recorded. 4622 days with discomfort were documented. On 35% of those days (n = 1621), patients increased their GC dose (4.8% of all days). Patients who recorded discomfort had a median of four episodes of discomfort, which lasted a median of 2 days. Women documented significantly more episodes of discomfort than men (P = 0.014). Low-to-median symptom scores resulted in GC increase by 50%-60%, whereas high symptom scores and/or fever resulted in doubling GC daily dose. However, dose increase was only 55% in situations indicating gastrointestinal (GI) infection. CONCLUSION: Severe discomfort did not always result in dose increase, especially in GI infection. However, low symptom scores resulted in an inappropriate GC increase in some patients. This underscores an urgent need for improved training methods. Keeping daily records might be a useful tool for continued and individualized patient education.

Management of adrenal emergencies in educated patients with adrenal insufficiency-A prospective study.

OBJECTIVE: To evaluate the management of adrenal emergencies (AE) requiring parenteral glucocorticoid (GC) treatment in patients with chronic adrenal insufficiency (AI). DESIGN: Prospective, multicentre, questionnaire-based study. PATIENTS AND MEASUREMENTS: Participating patients (n = 150) with chronic AI were provided with a questionnaire on the management of emergency situations, which had to be completed and sent back in case of an AE. In addition, patients were contacted by phone on a regular basis. RESULTS: Fifty-nine AE in 39 patients were documented. The time interval from contact to arrival of a medical professional was 20 minutes (1-240). In total, in 43 AE, patients received parenteral GC by a medical professional. The time interval between showing the emergency card and GC injection by a medical professional was 60 minutes (5-360). A total of 26 patients administered GC by self-injection. The time from the beginning of symptoms to GC injection was significantly shorter in case of self-injection (self-injection vs injection by medical professional; 85 minutes [20-280] vs 232.5 minutes [1-3135]; P < .001). After self-injection, 62% of the patients were treated outpatient, compared to 27% of the patients after exclusive injection by a medical professional (P = .008). To improve the emergency management, most of the patients (84%) indicated a need for an easier way of self-injection. CONCLUSION: While management of AE by both patients and medical professionals still shows high variability, patients profit from the option of self-injection. Patient care, including education of patients and health-professionals, as well as the way of GC administration, needs further optimization.

Mortality data from the European Adrenal Insufficiency Registry-Patient characterization and associations.

OBJECTIVE: Mortality from primary and secondary adrenal insufficiency (AI; PAI and SAI, respectively) is 2-3-fold higher than in the general population. Mortality relates to cardiovascular disease, acute adrenal crisis (AC), cancer and infections; however, there has been little further characterization of patients who have died. DESIGN/METHODS: We analysed real-world data from 2034 patients (801 PAI, 1233 SAI) in the European Adrenal Insufficiency Registry (EU-AIR; NCT01661387). Baseline clinical and biochemical data of patients who subsequently died were compared with those who remained alive. RESULTS: From August 2012 to June 2017, 26 deaths occurred (8 PAI, 18 SAI) from cardiovascular disease (n = 9), infection (n = 4), suicide (n = 2), drug-induced hepatitis (n = 2), and renal failure, brain tumour, cachexia and AC (each n = 1); cause of death was unclear in 5 patients. Patients who died were significantly older at baseline than alive patients. Causes of AI were representative of patients with SAI; however, 3-quarters of deceased patients with PAI had undergone bilateral adrenalectomy (3 with uncontrolled Cushing's disease, 3 with metastatic renal cell cancer). There were no significant differences in body mass index, blood pressure, low-density lipoprotein cholesterol, total cholesterol or electrolytes between deceased and alive patients. Deceased patients with SAI were more frequently male individuals, were receiving higher daily doses of hydrocortisone (24.0 ± 7.6 vs 19.3 ± 5.7 mg, P = .0016) and experienced more frequent ACs (11.1 vs 2.49/100 patient-years, P = .0389) than alive patients. CONCLUSIONS: This is the first study to provide detailed characteristics of deceased patients with AI. Older, male patients with SAI and frequent AC had a high mortality risk.

Management of glucocorticoid replacement in adrenal insufficiency shows notable heterogeneity - data from the EU-AIR.

CONTEXT AND OBJECTIVE: Treatment for adrenal insufficiency (AI) remains suboptimal. Despite glucocorticoid replacement, patients with AI have reduced life expectancy and quality of life. This study aimed to describe the spectrum of management of glucocorticoid replacement in patients with AI enrolled in the European Adrenal Insufficiency Registry (EU-AIR). DESIGN, SETTING AND PATIENTS: EU-AIR is a prospective, multinational, multicentre, observational study initiated in August 2012 to monitor the long-term safety of glucocorticoid replacement in routine clinical practice in Germany, the Netherlands, Sweden and the UK (ClinicalTrials.gov identifier: NCT01661387). This analysis included 1166 patients with primary and secondary AI (mean disease duration 16·1 ± 11·6 years) receiving long-term glucocorticoid replacement therapy. MAIN OUTCOME MEASURE: Glucocorticoid type, dose, frequency and treatment regimen were examined. RESULTS: Most patients (87·4%) were receiving hydrocortisone. The most common dose range, taken by 42·2% of patients, was 20 to <25 mg/day; however, 12·6% were receiving doses of ≥30 mg/day. Hydrocortisone was being taken once daily by 5·5%, twice daily by 48·7%, three times daily by 43·6% and four times daily by 2·1%. Patients with primary AI received higher replacement doses than those with secondary AI (23·4 ± 8·9 and 19·6 ± 5·9 mg/day, respectively). Twenty-five different regimens were being used to deliver a daily hydrocortisone dose of 20 mg. CONCLUSIONS: We have shown significant heterogeneity in the type, dose, frequency and timing of glucocorticoid replacement in real-world clinical practice. This reflects dose individualization based on patient symptoms and lifestyle in the absence of data supporting the optimal regimen.

Immediate versus modified release hydrocortisone in mitotane-treated patients with adrenocortical cancer.

OBJECTIVE: Mitotane induces hepatic CYP3A4 activity, resulting in accelerated cortisol inactivation, and also increases cortisol binding globulin (CBG). Therefore, higher hydrocortisone doses are required in patients with adrenocortical cancer (ACC) on mitotane treatment. Modified release hydrocortisone has not been used in mitotane-treated ACC patients yet. AIM: Case series to compare serum cortisol, calculated free serum cortisol and ACTH levels in ACC patients on mitotane treatment with immediate and modified release hydrocortisone. DESIGN: Pharmacokinetics of immediate and modified release hydrocortisone, each administered at a dose of 40-20-0 mg, in nine patients with ACC and adjuvant mitotane treatment. For comparison, ten patients with secondary adrenal insufficiency (SAI) on three different hydrocortisone regimens and ten healthy males were included. METHODS: Serum cortisol and plasma ACTH were measured by chemiluminescent enzyme immunoassay, and CBG by RIA, followed by calculation of free cortisol. RESULTS: Calculated free serum cortisol levels after 40 mg immediate release hydrocortisone in ACC patients (46 ± 14 nmol/l) were similar to those after 10 mg immediate release hydrocortisone intake in men with SAI (64 ± 16 nmol/l) or to the physiological morning free cortisol levels in healthy subjects (31 ± 5 nmol/l). Compared to immediate release hydrocortisone, free cortisol levels after 40 mg modified release hydrocortisone in ACC patients were significantly lower (12 ± 3 nmol/l; P = 0·03) resulting in a generally lower AUC (98 ± 21 vs 149 ± 37 nmol h/l; P = 0·02). CONCLUSIONS: 40-20-0 mg immediate release, but not modified release hydrocortisone, resulted in sufficient glucocorticoid coverage in patients with ACC receiving mitotane treatment. The use of equivalent doses of modified release hydrocortisone preparation should be avoided in patients on mitotane treatment.

Outcome after resection of Adrenocortical Carcinoma liver metastases: a retrospective study.

BACKGROUND: Metastatic Adrenocortical Carcinoma (ACC) is a rare malignancy with a poor 5-year-survival rate (<15%). A surgical approach is recommended in selected patients if complete resection of distant metastasis can be achieved. To date there are only limited data on the outcome after surgical resection of hepatic metastases of ACC. METHODS: A retrospective analysis of the German Adrenocortical Carcinoma Registry was conducted. Patients with liver metastases of ACC but without extrahepatic metastases or incomplete tumour resection were included. RESULTS: Seventy-seven patients fulfilled these criteria. Forty-three patients underwent resection of liver metastases of ACC. Complete tumour resection (R0) could be achieved in 30 (69.8%). Median overall survival after liver resection was 76.1 months in comparison to 10.1 months in the 34 remaining patients with unresected liver metastases (p < 0.001). However, disease free survival after liver resection was only 9.1 months. Neither resection status (R0/R1) nor extent of liver resection were significant predictive factors for overall survival. Patients with a time interval to the first metastasis/recurrence (TTFR) of greater than 12 months or solitary liver metastases showed significantly prolonged survival. CONCLUSIONS: Liver resection in the case of ACC liver metastases can achieve long term survival with a median overall survival of more than 5 years, but disease free survival is short despite metastasectomy. Time to recurrence and single versus multiple metastases are predictive factors for the outcome.

Changes in Body Mass Index in Pheochromocytoma Patients Following Adrenalectomy.

Catecholamine excess from pheochromocytoma results in cardiovascular symptoms such as arterial hypertension and tachycardia and induces metabolic alterations including glucose intolerance and increase in resting metabolic rate. The objective of our study was to investigate the effect of surgical cure of pheochromocytoma on body-mass-index and the correlation of body-mass-index changes to preoperative endocrine parameters. Pheochromocytoma patients from the Munich ENSAT Registry were matched (1:2) for age and gender to patients from the German Conn's Registry, who had undergone surgery for aldosterone-producing-adenomas. Thereby, 43 pheochromocytoma patients (17 males/26 females) and 86 aldosterone-producing-adenoma patients were analyzed for body-mass-index, blood pressure, and catecholamine levels before and one year after adrenalectomy. Seventy-four percent of pheochromocytoma patients were hypertensive preoperatively and 48% one year postoperatively. Systolic blood pressure did not differ significantly in pre- and postoperative measurements whereas diastolic blood pressure was significantly reduced over time. Moreover, pheochromocytoma patients gained body weight (p<0.001) one year following adrenalectomy accompanied by significant increases in body-mass-index, whereas aldosterone-producing adenoma patients displayed a slight weight loss. Despite weight gain, diagnosis of diabetes mellitus dropped from 9 of 43 investigated pheochromocytoma patients at baseline to 4 at follow-up. A significant correlation between body-mass-index changes to the preoperative catecholamine levels was found only for urinary normetanephrines. These data suggest that normalization of chronic catecholamine excess by adrenalectomy is associated with an increase in body-mass-index, which is more pronounced in patients with high preoperative levels of urinary normetanephrines.

The Role of Fludrocortisone in Cognition and Mood in Patients with Primary Adrenal Insufficiency (Addison's Disease).

BACKGROUND: Primary adrenal insufficiency (AI) requires hormone replacement therapy with fludrocortisone and hydrocortisone stimulating glucocorticoid (GR) and mineralocorticoid receptors (MR). Evidence from animal and human studies shows that MR function is crucial for cognitive function and mood. Regarding patients with AI, very little is known about the role of MR in cognitive function and mood. METHODS: A repeated-measures within-subject design was used to determine whether cognitive function and mood are related to MR occupation in patients with AI. Intraindividually, patients were examined twice, with 1 week between testing days: once with fludrocortisone (high MR occupation) and once without fludrocortisone (low MR occupation). All patients kept their stable regimen of hydrocortisone. The assessment of cognitive function included executive function, attention, and verbal, visuospatial and working memory. Additionally, mood and blood pressure were measured. RESULTS: Verbal memory improved significantly during high MR occupation (after fludrocortisone intake) compared to low MR occupation [without fludrocortisone, t(29) = -2.1, p = 0.046]. There were trend level differences in the Number-Combination test [t(29) = -1.9, p = 0.074] and in the Stroop interference task [t(29) = -1.9, p = 0.068]. No significant differences in visuospatial and working memory were found. Furthermore, the current mood state was better during high MR occupation compared to low MR occupation [t(29) = -2.4, p = 0.023] as was diastolic blood pressure [F(2, 29) = 3.6, p = 0.07]. CONCLUSIONS: Cognitive function and mood in patients with AI depend in part on MR occupation. Because the medium effect size indicates a potential clinical significance, further studies should systematically examine which dosages of fludrocortisone are associated with optimal cognitive function and mood in AI patients.