Is Prophylactic Steroid Treatment Mandatory for Subclinical Cushing Syndrome After Unilateral Laparoscopic Adrenalectomy?

OBJECTIVE: This study aimed to provide rational guidelines for patients with subclinical Cushing syndrome (SCS), who are undergoing laparoscopic adrenalectomy, in order to avoid the risk of overtreatment. METHODS: A total of 59 patients diagnosed with SCS caused by unilateral adrenal adenoma, who underwent laparoscopic adrenalectomy from 2010 to 2017, were included into the study. These patients did not receive prophylactic steroid treatment. After discharge, patients with adrenal insufficiency (AI) were treated with glucocorticoid. Then, cortisol levels were reevaluated at three months after surgery by morning serum cortisol. RESULTS: No severe perioperative complications occurred. After unilateral laparoscopic adrenalectomy, no patient developed AI and was readmitted. In the first week after surgery, 10 patients (16.9%) received steroid therapy at the clinic because of mild symptoms of AI. The probability of developing AI was greater in patients with 1-mg dexamethasone midnight suppression test (1 mg-DST) >5 µg/dL than patients with mg-DST ranging within 1.8 to 5.0 µg/dL (P=0.042). The initial dose of hydrocortisone was 20.00±6.67 mg/d (range, 10 to 30), and the duration of treatment was 6.90±3.51 weeks (range, 3 to 12 wk). At three months after surgery, morning cortisol was >5 µg/dL in all patients. CONCLUSIONS: After laparoscopic adrenalectomy, the probability of AI is small in patients with adrenal SCS, and the symptoms of AI were mild. Meanwhile, the HPA axis rapidly recovered. Therefore, prophylactic steroid treatment is not mandatory. Given that AI is more frequent in patients with higher cut-offs of 1 mg-DST, a more precise definition of SCS is necessary to better manage these patients.

MANAGEMENT OF ENDOCRINE DISEASE: Can we cure Cushing's disease? A personal view.

One of today's challenges in endocrinology is the treatment of Cushing's disease: Although pituitary surgery has the potential to 'cure' the patient and restore a completely normal pituitary adrenal axis, there are immediate failures and late recurrences that will ultimately require alternate therapeutic approaches. Their high number is in direct correlation with their serious limitations and they all appear to be 'default options'. This 'personal view' tries to shed some light on the inescapable difficulties of the current treatments of Cushing's disease and to provide some optimistic view for the future where the pituitary adenoma should be the 'reasonable obsession' of a successful therapeutist.

[Drug-induced changes in adrenal cortex function].

Glucocorticoids, commonly used in the treatment of various disorders, particularly if administered at high doses, may lead to the development of iatrogenic Cushing's syndrome, being by far the most common iatrogenic disorder of the adrenal gland. In some cases, however, adrenal cortex function may be affected by other drugs and risk of the development of various clinical entities is dependent on the drug, its dose, as well as on the duration of the treatment. This risk is also related to the baseline function of this gland. Because little is known about the influence of non-hormonal drugs on adrenal cortex function, many physicians are unaware of the existence of these disorders, which, if not detected in the early stages, can pose serious health risk. Although distinguishing endogenous from exogenous adrenal cortex disorders is usually straightforward and based on the patient's history, in rare cases the investigation and differentiation of iatrogenic adrenal cortex disorders may be diagnostically challenging. This article raises awareness of the association between drugs other than adrenal cortex hormones and the function of this gland, and provide the reader with recommendations concerning the diagnosis and treatment of iatrogenic adrenal cortex disorders.

Kombinierte Hoch-/Niedrig-Dosis-Therapie mit systemischen Glukokor-tikoiden bei schweren Verlaufsformen der Alopecia areata im Kindesalter.

HINTERGRUND: Schwere Verlaufsformen der Alopecia areata (AA) im Kindesalter sind aufgrund limitierter Optionen therapeutisch herausfordernd. Systemische, hochdosierte Glukokortikoide weisen die schnellste Ansprechrate auf, nach dem Absetzen kommt es allerdings zu Rezidiven. Eine längerfristige Hochdosis-Anwendung ist aufgrund der zu erwartenden Nebenwirkungen nicht empfehlenswert. Eine dauerhafte Steroiderhaltungstherapie unterhalb der Cushing-Schwellen-Dosis nach Bolustherapie könnte die Krankheitsaktivität ohne Nebenwirkungen längerfristig unterdrücken. PATIENTEN UND METHODIK: Im Rahmen einer offenen Anwendungsbeobachtung wurden 13 Kinder mit schweren Formen der AA in diese Studie eingeschlossen. Bei sieben Kindern lag eine AA totalis/universalis vor, bei sechs eine multifokale AA mit Befall von mehr als 50 % der Kopfhaut. Das Therapieregime sah eine initiale Prednisolon-Dosierung von 2 mg/kg Körpergeweicht (KG) vor und wurde innerhalb von neun Wochen auf eine Erhaltungsdosierung unter der individuellen Cushing-Schwelle reduziert. Der Nachbeobachtungszeitraum betrug ein bis drei Jahre. ERGEBNISSE: Wir beobachteten in 62 % aller Fälle ein komplettes Nachwachsen der Haare. Die mittlere Dauer bis zum Ansprechen lag bei 6,6 Wochen und konnte mit der Erhaltungstherapie über den gesamten Beobachtungszeitraum aufrechterhalten werden. An Nebenwirkungen wurden ausschließlich eine Gewichtszunahme (1-3 kg) bei allen Behandelten sowie eine milde Steroidakne in 23 % der Fälle beobachtet. SCHLUSSFOLGERUNGEN: Die kombinierte Hoch-/Niedrig-Dosis-Therapie mit systemischen Glukokortikoiden mittels Prednisolon zeigte eine hohe, dauerhafte Ansprechrate ohne signifikante Nebenwirkungen.

Sequential high- and low-dose systemic corticosteroid therapy for severe childhood alopecia areata.

BACKGROUND: Given the limited number of therapeutic options, severe childhood alopecia areata (AA) poses a clinical challenge. The best and most rapid response rates can be achieved with high-dose systemic corticosteroids, however, relapse following treatment discontinuation is inevitable. Due to systemic side effects, long-term high-dose corticosteroid regimens are not feasible. Following initial pulse therapy, continuation of corticosteroid therapy at a dose below the Cushing threshold might be able to suppress disease activity without causing severe side effects. PATIENTS AND METHODS: Thirteen children with severe AA were enrolled in our open observational study. Seven had alopecia totalis or universalis; the remaining six children had multifocal alopecia affecting more than 50 % of the scalp. The treatment regimen consisted of initial pulse therapy with prednisolone 2 mg/kg PO, which was subsequently tapered to a maintenance dose below the individual Cushing threshold within nine weeks. Children were followed-up for one to three years. RESULTS: Sixty-two percent of individuals showed complete hair regrowth. The mean time to response was 6.6 weeks. Said response was sustained with maintenance therapy for the entire follow-up period. Noticeable side effects included weight gain (1-3 kg), which was observed in all children, and mild steroid acne in 23 % of cases. CONCLUSIONS: Sequential high- and low-dose prednisolone therapy is an effective and safe therapeutic option for childhood AA.

Clinical Benefits of Unilateral Adrenalectomy in Patients with Subclinical Hypercortisolism Due to Adrenal Incidentaloma: Results from a Single Center.

INTRODUCTION: This study was designed to evaluate the results of unilateral laparoscopic adrenalectomy in patients with subclinical hypercortisolism (SH) due to adrenal incidentaloma (AI) concerning the main cardiometabolic disorders. METHODS: We have studied between January 2000 to December 2015, 645 patients with AI (283 males and 362 females; mean age 61.9 ± 10 years) and we found 70 patients with SH (27 males and 43 females; mean age 61.9 ± 8.4 years). Twenty-six (37%) SH patients (6 males and 20 females; mean age 58.7 ± 7.1 years) underwent unilateral laparoscopic adrenalectomy, whereas 44 SH patients (21 males and 23 females; mean age 63.9 ± 9.9 years) performed a conservative treatment. All SH patients were evaluated at diagnosis and after follow-up (mean 12 months; range 9-15 months). RESULTS: In only SH patients undergoing unilateral adrenalectomy we found a statistical significant reduction of the arterial hypertension and metabolic syndrome (p < 0.05, respectively). In particular we observed a reduction of 24-h systolic blood pressure and "non-dipper" pattern (p < 0.05, respectively) evaluated with ambulatory blood pressure monitoring (ABPM). CONCLUSIONS: Our study confirm the high prevalence of SH in AI, and the unilateral laparoscopic adrenalectomy seemed to have a beneficial effect on some cardiometabolic disorders.

Late-Pregnancy Salivary Cortisol Concentrations of Ghanaian Women Participating in a Randomized Controlled Trial of Prenatal Lipid-Based Nutrient Supplements.

BACKGROUND: High circulating cortisol is associated with miscarriage, preterm birth, and low birth weight. Research in nonpregnant individuals suggests that improved nutrition may lower cortisol concentrations. It is unknown whether nutritional supplementation during pregnancy lowers cortisol. OBJECTIVE: Our objective was to determine whether women receiving a lipid-based nutrient supplement (LNS) throughout pregnancy would have lower salivary cortisol at 36 wk gestation compared with women receiving other nutrient supplements. METHODS: We conducted a randomized controlled trial in 1320 pregnant Ghanaian women at ≤20 wk gestation who were assigned to receive daily throughout pregnancy: 1) 60 mg iron + 400 µg folic acid (IFA), 2) multiple micronutrients (MMNs), or 3) 20 g LNS (containing 118 kcal, 22 micronutrients, and protein). Morning salivary cortisol was collected from a subsample at baseline and at 28 and 36 wk gestation. RESULTS: A total of 758 women had cortisol measurements at 28 or 36 wk gestation. Salivary cortisol at 36 wk gestation did not differ between groups and was (mean ± SE) 7.97 ± 0.199 in the IFA group, 7.84 ± 0.191 in the MMN group, and 7.77 ± 0.199 nmol/L in the LNS group, when adjusted for baseline cortisol, time of waking, and time between waking and saliva collection (P = 0.67). There was an interaction between supplementation group and women's age (continuous variable, P-interaction = 0.03); and when age was dichotomized by the median, significant differences in salivary cortisol concentrations between groups were seen in women ≤26 y of age (IFA = 8.23 ± 0.284 nmol/L, MMN = 8.20 ± 0.274 nmol/L, and LNS = 7.44 ± 0.284 nmol/L; P = 0.03) but not in women >26 y old (IFA = 7.71 ± 0.281 nmol/L, MMN = 7.50 ± 0.274 nmol/L, and LNS = 8.08 ± 0.281 nmol/L; P = 0.13). CONCLUSIONS: We conclude that supplementation with LNSs or MMNs during pregnancy did not affect the cortisol concentration in the study population as a whole, in comparison with IFA, but that LNS consumption among younger women may lead to lower cortisol at 36 wk gestation. This trial was registered at clinicaltrials.gov as NCT00970866.

Long-term study of subclinical Cushing's syndrome shows high prevalence of extra-adrenal malignancy in patients with functioning bilateral adrenal tumors.

Subclinical Cushing's syndrome (SCS) is characterized by subtle autonomous cortisol secretion from adrenal tumors without specific signs and symptoms of hypercortisolism. Patients with SCS have a high prevalence of "lifestyle-related diseases," such as hypertension, diabetes mellitus, dyslipidemia, and osteoporosis. Long-term follow-up of SCS patients is reportedly indispensable for establishing indications for surgical treatment of SCS. We performed a follow-up survey of 27 patients with SCS (median: 5.3 years) and compared those who had undergone surgical treatment (n=15) with those who had not (n=12). The mean diameter of tumors was 31 mm; 16 (59%) patients had unilateral lesions and 11 (41%) carried bilateral ones. In 67% and 60% of the treatment group, respectively, hypertension and diabetes mellitus improved. We also noticed that eight of 11 (73%) SCS patients with bilateral adrenal tumors had extra-adrenal malignancies in various tissues. Interestingly, among nine SCS patients who had malignancies, eight showed bilateral adrenal uptake in ¹³¹I-aldosterol scintigraphy. The results imply that surgical treatment can reduce cardiovascular risks in SCS patients. Screening for malignancy may be necessary in patients with bilateral adrenal tumors suspected of autonomous hypersecretion of cortisol from both sides.

Cushing's syndrome secondary to ectopic ACTH secretion from carcinoid tumor within an ovarian mature teratoma: a case report and review of the literature.

A 46-year-old woman with Cushing's syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) secretion caused by primary ovarian mature teratoma with carcinoid components was presented in our case. The patient manifested sustained hypercortisolemia without circadian rhythm and a lack of suppression of either low-dose dexamethasone suppression test (LDDST) or high-dose dexamethasone suppression test (HDDST). There was no evidence of a pituitary mass or secretion of other hormones. After careful clinical evaluation, no other tumor masses were found. Resection of the ovarian tumors led to sharp reduction of serum ACTH and cortisol concentrations. Immunohistochemistry showed positivity in CgA, Syn, CK, NSE. To the best of our knowledge, there are rare reports of an ACTH-secreting carcinoid components located in an ovarian mature teratoma, and bilateral ovarian mature teratoma makes it rarer.

Prognostic role of overt hypercortisolism in completely operated patients with adrenocortical cancer.

BACKGROUND: Although prognostic parameters are important to guide adjuvant treatment, very few have been identified in patients with completely resected adrenocortical carcinoma (ACC). OBJECTIVE: To assess the prognostic role of clinical symptoms of hypercortisolism in a large series of patients with completely resected ACC. DESIGN, SETTING, AND PARTICIPANTS: A total of 524 patients followed at referral centers for ACC in Europe and the United States entered the study. Inclusion criteria were ≥18 yr of age, a histologic diagnosis of ACC, and complete surgery (R0). Exclusion criteria were a history of other malignancies and adjuvant systemic therapies other than mitotane. INTERVENTION: All ACC patients were completely resected, and adjuvant mitotane therapy was prescribed at the discretion of the investigators. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was overall survival (OS). The secondary end points were recurrence-free survival (RFS) and the efficacy of adjuvant mitotane therapy according to cortisol secretion. RESULTS AND LIMITATIONS: Overt hypercortisolism was observed in 197 patients (37.6%). Patients with cortisol excess were younger (p=0.002); no difference according to sex and tumor stage was observed. The median follow-up of the series was 50 mo. After adjustment for sex, age, tumor stage, and mitotane treatment, the prognostic significance of cortisol excess was highly significant for both RFS (hazard ratio [HR]: 1.30; 95% confidence interval [CI], 1.04-2.62; p=0.02) and OS (HR: 1.55; 95% CI, 1.15-2.09; p=0.004). Mitotane administration was associated with a reduction of disease progression (adjusted HR: 0.65; 95% CI, 0.49-0.86; p=0.003) that did not differ according to the patient's secretory status. A major limitation is that only symptomatic patients were considered as having hypercortisolism, thus excluding information on the prognostic role of elevated cortisol levels in the absence of a clinical syndrome. CONCLUSIONS: Clinically relevant hypercortisolism is a new prognostic factor in patients with completely resected ACC. The efficacy of adjuvant mitotane does not seem to be influenced by overt hypercortisolism.

[Development of Cushing's syndrome during phytotherapy]. / Entwicklung eines Cushing-Syndroms während einer Phytotherapie.

UNLABELLED: HISTORY AND INITIAL FINDINGS: In a 75-year-old woman with unclear weight gain and typical signs of Cushing's syndrome, a pituitary microadenoma and hyperplasia of the left adrenal gland were diagnosed. She was referred for preoperative diagnostics. Her clinical appearance suggested hypercortisolism. INVESTIGATIONS: The lab test suggested external glucocorticoid application. Basal ACTH and cortisol were low. DIAGNOSIS, TREATMENT AND FURTHER COURSE: The patients' phytotherapeutics received from a masseuse were analyzed in a special lab. The analysis showed that the pills were enriched with cortisone and hydrocortisone and were causal for the development of Cushing's syndrome and the symptoms of secondary adrenal insufficiency. CONCLUSION: Symptoms of Cushing's syndrome develop during chronic exposure to glucocorticoids. The development of Cushing's syndrome depends on the patient's sensitivity and on the duration and dose of the glucocorticoid application. Clinical and laboratory studies precede imaging.

A prospective observational study evaluating hypothalamic-pituitary-adrenal axis alteration and efficacy of intramuscular triamcinolone acetonide for steroid-responsive dermatologic disease.

BACKGROUND: The lack of recommendations regarding dosing and administration, an undetermined risk of hypothalamic-pituitary-adrenal axis alteration, and the unknown effectiveness of intramuscular (IM) corticosteroid injection to treat dermatologic disease may be deterrents to use. OBJECTIVE: We sought to evaluate presence and duration of iatrogenic Cushing syndrome and secondary adrenal insufficiency in patients receiving IM triamcinolone acetonide (TAC), and to assess physician- and patient-reported outcomes. METHODS: We conducted a prospective observational study of 14 patients given the diagnosis of steroid-responsive dermatologic disease who received either 1 or 2 doses 6 weeks apart of IM TAC. Baseline and follow-up cortisol, adrenocorticotropic hormone, Physician and Subject Global Assessments of Disease Activity Scale score, and the visual analog scale score of pruritus were evaluated at 6-week intervals. RESULTS: Although mean total cortisol was significantly decreased at 6 and 12 weeks compared with baseline, IM TAC did not result in iatrogenic Cushing syndrome or secondary adrenal insufficiency in any patient. Mean Physician and Subject Global Assessments of Disease Activity Scale scores were significantly improved at 6 and 12 weeks compared with baseline. Mean visual analog scale pruritus scores were significantly improved at 6 weeks compared with baseline. LIMITATIONS: The study was limited by the cohort size and a lack of a comparator group. CONCLUSION: IM TAC appears safe when administered as 2 injections at 6-week intervals. Significant improvement was noted across a number of steroid-responsive dermatoses. These results may provide a guide to dosing, frequency, and administration for dermatologists considering the use of IM TAC in the appropriate clinical contexts.

Injecting epidural and intra-articular triamcinolone in HIV-positive patients on ritonavir: beware of iatrogenic Cushing's syndrome.

We report two HIV-positive patients on highly active antiretroviral therapy (HAART) who developed clinical features in keeping with secondary adrenal suppression following epidural and subacromial triamcinolone. Both patients were on ritonavir-boosted protease inhibitor containing HAART and both required maintenance hydrocortisone therapy following diagnosis. This highlights the need for radiologists and clinicians practicing these injections to be aware of this complication, to elicit an accurate drug history, and to take adequate measures to minimize these adverse effects.

Adrenalectomy for adrenocortical adenoma causing Cushing's syndrome in pregnancy: a case report and review of literature.

We present a case of adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome diagnosed in a patient in the third trimester of her pregnancy, with an adrenal mass observed on imaging studies. Laparoscopic adrenalectomy was performed successfully at 32 weeks. To the best of our knowledge, this is the latest gestational age at which laparoscopic adrenalectomy has been reported. We present the various considerations for determining the surgical approach and the optimal timing for surgery. Adrenalectomy during pregnancy for the treatment of Cushing's syndrome caused by adrenocortical adenoma has been reported in 23 patients in the English-language medical literature to date and seems safe and beneficial. According to the data, surgical treatment has led to a reduction in perinatal mortality and maternal morbidity rates, but has not affected the occurrence of preterm birth and intrauterine growth restriction. The best outcome can be achieved by a multidisciplinary approach, with a team comprising a maternal-fetal medicine specialist, an endocrinologist and a surgeon. The timing of surgery and the surgical approach need to be determined according to the surgeon's expertise, the severity of the condition, the patient's preferences, and gestational age. Laparoscopy may prove to be the preferred surgical approach. The small number of cases precludes providing evidence-based recommendations.

Glucose metabolism in patients with subclinical Cushing's syndrome.

This clinical review will summarize the available data regarding the effect of either physiological or increased glucocorticoid concentrations on glucose metabolism and insulin-sensitivity, in order to clarify the role, if any, of subclinical Cushing's syndrome (SCS), a status of altered hypothalamic-pituitary-adrenal axis secretion in the absence of the classical signs or symptoms of overt cortisol excess, in patients with adrenal incidentalomas (AI) and diabetes mellitus type 2. Focusing on patients with SCS associated to AI, while there is convincing evidence in the literature that even a mild hyper cortisolemia is associated with alterations of glucose metabolism, evidence is insufficient to conclude that the simple correction of chronic, even mild, hypercortisolism can completely revert metabolic, mainly glycemic alterations. At the same time, considering the variability of the prevalence of Cushing's syndrome in patients with diabetes mellitus type 2 reported in the literature, no agreement does exist whether screening for CS can be useful and recommended in those patients.

Bone involvement in exogenous hypercortisolism.

Corticosteroids remain a key component in the management of many disorders. Bone loss resulting from long-term administration of these drugs is common and osteoporosis induced by corticosteroids is the most frequent cause of secondary osteoporosis in nearly 50% of individuals on chronic corticosteroid therapy suffering from an osteoporotic fracture at some point. This article reviews the epidemiology and pathogenesis of glucocorticoid-induced osteoporosis.

Correction of cortisol overreplacement ameliorates morbidities in patients with hypopituitarism: a pilot study.

CONTEXT: Hypopituitarism in adults is known to be associated with deleterious effects on body composition, lipid profile and quality of life (QoL). This was attributed to GH deficiency. The potential role of glucocorticoid overreplacement had never been investigated. OBJECTIVE: To investigate whether reduction in glucocorticoid replacement dose to more physiological one could ameliorate the "AO-GHD"-attributed symptomatology in patients with hypopituitarism. Design Eleven patients with panhypopituitarism taking 20-30 mg/day of hydrocortisone, but on no GH replacement were switched to 10-15 mg of hydrocortisone daily. Both basally and 6-12 months later, their body mass index, body composition by dual-energy X-ray absorptiometry, lipid profile, and the score of quality of life, QOL-AGHDA were measured. RESULTS: Within 6-12 months of lower hydrocortisone dose, subjects lost an average of 7.1 kg of total body fat and 4.1 kg of abdominal fat. No changes were seen in lean body mass, bone mineral content and HOMA-IR. Plasma total cholesterol and triglyceride concentrations decreased significantly (< 0.05) and the QoL improved (P = 0.018). CONCLUSIONS: Our pilot study suggests that decreasing the glucocorticoid replacement dose to approximately 15 mg/day is beneficial in terms of patients' body composition, lipid profile and quality of life.

Intervention at the level of the neuroendocrine-immune axis and postoperative pneumonia rate in long-term alcoholics.

RATIONALE: Postoperative pneumonia is three to four times more frequent in patients with alcohol use disorders followed by prolonged intensive care unit (ICU) stay. Long-term alcohol use leads to an altered perioperative hypothalamus-pituitary-adrenal (HPA) axis and immunity. OBJECTIVES: The aim of this study was to evaluate HPA intervention with low-dose ethanol, morphine, or ketoconazole on the neuroendocrine-immune axis and development of postoperative pneumonia in long-term alcoholic patients. METHODS: In this randomized, double-blind controlled study, 122 consecutive patients undergoing elective surgery for aerodigestive tract cancer were included. Long-term alcohol use was defined as consuming at least 60 g of ethanol daily and fulfilling the Diagnostic and Statistical Manual of Mental Disorders IV criteria for either alcohol abuse or dependence. Nonalcoholic patients were included but only as a descriptive control. Perioperative intervention with low-dose ethanol (0.5 g/kg body weight per day), morphine (15 mug/kg body weight per hour), ketoconazole (200 mg four times daily), and placebo was started on the morning before surgery and continued for 3 d after surgery. Blood samples to analyze the neuroendocrine-immune axis were obtained on the morning before intervention and on Days 1, 3, and 7 after surgery. MEASUREMENTS AND MAIN RESULTS: In long-term alcoholic patients, all interventions decreased postoperative hypercortisolism and prevented impairment of the cytotoxic T-lymphocyte type 1:type 2 ratio. All interventions decreased the pneumonia rate from 39% to a median of 5.7% and shortened intensive care unit stay by 9 d (median) compared with the placebo-treated long-term alcoholic patients. CONCLUSIONS: Intervention at the level of the HPA axis altered the immune response to surgical stress. This resulted in decreased postoperative pneumonia rates and shortened intensive care unit stay in long-term alcoholic patients.