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European Journal of Endocrinology Jul 2023Adrenal incidentalomas are adrenal masses detected on imaging performed for reasons other than suspected adrenal disease. In most cases, adrenal incidentalomas are...
European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors.
Adrenal incidentalomas are adrenal masses detected on imaging performed for reasons other than suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas but may also require therapeutic intervention including that for adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma, or metastases. Here, we provide a revision of the first international, interdisciplinary guidelines on incidentalomas. We followed the Grading of Recommendations Assessment, Development and Evaluation system and updated systematic reviews on 4 predefined clinical questions crucial for the management of incidentalomas: (1) How to assess risk of malignancy?; (2) How to define and manage mild autonomous cortisol secretion?; (3) Who should have surgical treatment and how should it be performed?; and (4) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? Selected Recommendations: (1) Each adrenal mass requires dedicated adrenal imaging. Recent advances now allow discrimination between risk categories: Homogeneous lesions with Hounsfield unit (HU) ≤ 10 on unenhanced CT are benign and do not require any additional imaging independent of size. All other patients should be discussed in a multidisciplinary expert meeting, but only lesions >4 cm that are inhomogeneous or have HU >20 have sufficiently high risk of malignancy that surgery will be the usual management of choice. (2) Every patient needs a thorough clinical and endocrine work-up to exclude hormone excess including the measurement of plasma or urinary metanephrines and a 1-mg overnight dexamethasone suppression test (applying a cutoff value of serum cortisol ≤50 nmol/L [≤1.8 µg/dL]). Recent studies have provided evidence that most patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post dexamethasone >50 nmol/L (>1.8 µg/dL) harbor increased risk of morbidity and mortality. For this condition, we propose the term "mild autonomous cortisol secretion" (MACS). (3) All patients with MACS should be screened for potential cortisol-related comorbidities that are potentially attributably to cortisol (eg, hypertension and type 2 diabetes mellitus), to ensure these are appropriately treated. (4) In patients with MACS who also have relevant comorbidities surgical treatment should be considered in an individualized approach. (5) The appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health, and patient preference. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. (6) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. Furthermore, we offer recommendations for the follow-up of nonoperated patients, management of patients with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses, and for young and elderly patients with adrenal incidentalomas. Finally, we suggest 10 important research questions for the future.
Topics: Aged; Humans; Adrenal Gland Neoplasms; Dexamethasone; Diabetes Mellitus, Type 2; Hydrocortisone
PubMed: 37318239
DOI: 10.1093/ejendo/lvad066 -
JAMA Psychiatry Sep 2021Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy, negatively affecting both mother and child. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Postpartum depression (PPD) is one of the most common medical complications during and after pregnancy, negatively affecting both mother and child.
OBJECTIVE
To demonstrate the efficacy and safety of zuranolone, a neuroactive steroid γ-aminobutyric acid receptor-positive allosteric modulator, in PPD.
DESIGN, SETTING, AND PARTICIPANTS
This phase 3, double-blind, randomized, outpatient, placebo-controlled clinical trial was conducted between January 2017 and December 2018 in 27 enrolling US sites. Participant were women aged 18 to 45 years, 6 months or fewer post partum, with PPD (major depressive episode beginning third trimester or ≤4 weeks postdelivery), and baseline 17-item Hamilton Rating Scale for Depression (HAMD-17) score of 26 or higher. Analysis was intention to treat and began December 2018 and ended March 2019.
INTERVENTIONS
Randomization 1:1 to placebo:zuranolone, 30 mg, administered orally each evening for 2 weeks.
MAIN OUTCOMES AND MEASURES
Primary end point was change from baseline in HAMD-17 score for zuranolone vs placebo at day 15. Secondary end points included changes from baseline in HAMD-17 total score at other time points, HAMD-17 response (≥50% score reduction) and remission (score ≤7) rates, Montgomery-Åsberg Depression Rating Scale score, and Hamilton Rating Scale for Anxiety score. Safety was assessed by adverse events and clinical assessments.
RESULTS
Of 153 randomized patients, the efficacy set comprised 150 patients (mean [SD] age, 28.3 [5.4] years), and 148 (98.7%) completed treatment. A total of 76 patients were randomized to placebo, and 77 were randomized to zuranolone, 30 mg. Zuranolone demonstrated significant day 15 HAMD-17 score improvements from baseline vs placebo (-17.8 vs -13.6; difference, -4.2; 95% CI, -6.9 to -1.5; P = .003). Sustained differences in HAMD-17 scores favoring zuranolone were observed from day 3 (difference, -2.7; 95% CI, -5.1 to -0.3; P = .03) through day 45 (difference, -4.1; 95% CI, -6.7 to -1.4; P = .003). Sustained differences at day 15 favoring zuranolone were observed in HAMD-17 response (odds ratio, 2.63; 95% CI, 1.34-5.16; P = .005), HAMD-17 score remission (odds ratio, 2.53; 95% CI, 1.24-5.17; P = .01), change from baseline for Montgomery-Åsberg Depression Rating Scale score (difference, -4.6; 95% CI, -8.3 to -0.8; P = .02), and Hamilton Rating Scale for Anxiety score (difference, -3.9; 95% CI, -6.7 to -1.1; P = .006). One patient per group experienced a serious adverse event (confusional state in the zuranolone group and pancreatitis in the placebo group). One patient in the zuranolone group discontinued because of an adverse event vs none for placebo.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, zuranolone improved the core symptoms of depression as measured by HAMD-17 scores in women with PPD and was generally well tolerated, supporting further development of zuranolone in the treatment of PPD.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02978326.
Topics: Adolescent; Adult; Depression, Postpartum; Depressive Disorder, Major; Double-Blind Method; Female; GABA Modulators; Humans; Middle Aged; Outcome Assessment, Health Care; Postpartum Period; Pregnancy; Pregnancy Trimester, Third; Pregnanes; Pyrazoles; Young Adult
PubMed: 34190962
DOI: 10.1001/jamapsychiatry.2021.1559 -
Journal of Pain and Symptom Management Feb 2017Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is... (Review)
Review
Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ([email protected]).
Topics: Diuretics; Edema; Hospice Care; Humans; Palliative Care; Spironolactone
PubMed: 28024992
DOI: 10.1016/j.jpainsymman.2016.12.320 -
The Cochrane Database of Systematic... Dec 2017Pneumonia is a common and potentially serious illness. Corticosteroids have been suggested for the treatment of different types of infection, however their role in the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Pneumonia is a common and potentially serious illness. Corticosteroids have been suggested for the treatment of different types of infection, however their role in the treatment of pneumonia remains unclear. This is an update of a review published in 2011.
OBJECTIVES
To assess the efficacy and safety of corticosteroids in the treatment of pneumonia.
SEARCH METHODS
We searched the Cochrane Acute Respiratory Infections Group's Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS on 3 March 2017, together with relevant conference proceedings and references of identified trials. We also searched three trials registers for ongoing and unpublished trials.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that assessed systemic corticosteroid therapy, given as adjunct to antibiotic treatment, versus placebo or no corticosteroids for adults and children with pneumonia.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Two review authors independently assessed risk of bias and extracted data. We contacted study authors for additional information. We estimated risk ratios (RR) with 95% confidence intervals (CI) and pooled data using the Mantel-Haenszel fixed-effect model when possible.
MAIN RESULTS
We included 17 RCTs comprising a total of 2264 participants; 13 RCTs included 1954 adult participants, and four RCTs included 310 children. This update included 12 new studies, excluded one previously included study, and excluded five new trials. One trial awaits classification.All trials limited inclusion to inpatients with community-acquired pneumonia (CAP), with or without healthcare-associated pneumonia (HCAP). We assessed the risk of selection bias and attrition bias as low or unclear overall. We assessed performance bias risk as low for nine trials, unclear for one trial, and high for seven trials. We assessed reporting bias risk as low for three trials and high for the remaining 14 trials.Corticosteroids significantly reduced mortality in adults with severe pneumonia (RR 0.58, 95% CI 0.40 to 0.84; moderate-quality evidence), but not in adults with non-severe pneumonia (RR 0.95, 95% CI 0.45 to 2.00). Early clinical failure rates (defined as death from any cause, radiographic progression, or clinical instability at day 5 to 8) were significantly reduced with corticosteroids in people with severe and non-severe pneumonia (RR 0.32, 95% CI 0.15 to 0.7; and RR 0.68, 95% CI 0.56 to 0.83, respectively; high-quality evidence). Corstocosteroids reduced time to clinical cure, length of hospital and intensive care unit stays, development of respiratory failure or shock not present at pneumonia onset, and rates of pneumonia complications.Among children with bacterial pneumonia, corticosteroids reduced early clinical failure rates (defined as for adults, RR 0.41, 95% CI 0.24 to 0.70; high-quality evidence) based on two small, clinically heterogeneous trials, and reduced time to clinical cure.Hyperglycaemia was significantly more common in adults treated with corticosteroids (RR 1.72, 95% CI 1.38 to 2.14). There were no significant differences between corticosteroid-treated people and controls for other adverse events or secondary infections (RR 1.19, 95% CI 0.73 to 1.93).
AUTHORS' CONCLUSIONS
Corticosteroid therapy reduced mortality and morbidity in adults with severe CAP; the number needed to treat for an additional beneficial outcome was 18 patients (95% CI 12 to 49) to prevent one death. Corticosteroid therapy reduced morbidity, but not mortality, for adults and children with non-severe CAP. Corticosteroid therapy was associated with more adverse events, especially hyperglycaemia, but the harms did not seem to outweigh the benefits.
Topics: Adrenal Cortex Hormones; Ampicillin; Anti-Bacterial Agents; Budesonide; Dexamethasone; Humans; Hydrocortisone; Pneumonia; Prednisolone; Randomized Controlled Trials as Topic
PubMed: 29236286
DOI: 10.1002/14651858.CD007720.pub3 -
Frontiers in Neuroendocrinology Oct 2020Estradiol is the "prototypic" sex hormone of women. Yet, women have another sex hormone, which is often disregarded: Progesterone. The goal of this article is to provide... (Review)
Review
Estradiol is the "prototypic" sex hormone of women. Yet, women have another sex hormone, which is often disregarded: Progesterone. The goal of this article is to provide a comprehensive review on progesterone, and its metabolite allopregnanolone, emphasizing three key areas: biological properties, main functions, and effects on mood in women. Recent years of intensive research on progesterone and allopregnanolone have paved the way for new treatment of postpartum depression. However, treatment for premenstrual syndrome and premenstrual dysphoric disorder as well as contraception that women can use without risking mental health problems are still needed. As far as progesterone is concerned, we might be dealing with a two-edged sword: while its metabolite allopregnanolone has been proven useful for treatment of PPD, it may trigger negative symptoms in women with PMS and PMDD. Overall, our current knowledge on the beneficial and harmful effects of progesterone is limited and further research is imperative.
Topics: Emotions; Female; Humans; Pregnanolone; Premenstrual Dysphoric Disorder; Progesterone
PubMed: 32730861
DOI: 10.1016/j.yfrne.2020.100856 -
Breast Cancer Research : BCR Oct 2022Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between...
BACKGROUND
Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association.
METHODS
Genetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses.
RESULTS
We found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09-1.21, OR 1.19, 95% CI 1.07-1.33 and OR 1.03, 95% CI 1.01-1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12-1.27, OR 1.25, 95% CI 1.11-1.40 and OR 1.06, 95% CI 1.03-1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03-1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC.
CONCLUSIONS
TT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC.
Topics: 17-alpha-Hydroxyprogesterone; Adult; Aldosterone; Androstenedione; Breast Neoplasms; Dehydroepiandrosterone Sulfate; Estradiol; Female; Genome-Wide Association Study; Gonadal Steroid Hormones; Humans; Hydrocortisone; Longitudinal Studies; Mendelian Randomization Analysis; Progesterone; Sex Hormone-Binding Globulin; Testosterone
PubMed: 36209141
DOI: 10.1186/s13058-022-01553-9 -
Journal of Neuromuscular Diseases 2022Deflazacort and prednisone/prednisolone are the current standard of care for patients with Duchenne muscular dystrophy (DMD) based on evidence that they improve muscle... (Review)
Review
Deflazacort and prednisone/prednisolone are the current standard of care for patients with Duchenne muscular dystrophy (DMD) based on evidence that they improve muscle strength, improve timed motor function, delay loss of ambulation, improve pulmonary function, reduce the need for scoliosis surgery, delay onset of cardiomyopathy, and increase survival. Both have been used off-label for many years (choice dependent on patient preference, cost, and geographic location) before FDA approval of deflazacort for DMD in 2017. In this review, we compare deflazacort and prednisone/prednisolone in terms of their key pharmacological features, relative efficacy, and safety profiles in patients with DMD. Differentiating features include lipid solubility, pharmacokinetics, changes in gene expression profiles, affinity for the mineralocorticoid receptor, and impact on glucose metabolism. Evidence from randomized clinical trials, prospective studies, meta-analyses, and post-hoc analyses suggests that patients receiving deflazacort experience similar or slower rates of functional decline compared with those receiving prednisone/prednisolone. Regarding side effects, weight gain and behavior side effects appear to be greater with prednisone/prednisolone than with deflazacort, whereas bone health, growth parameters, and cataracts appear worse with deflazacort.
Topics: Humans; Muscular Dystrophy, Duchenne; Prednisolone; Prednisone; Pregnenediones; Prospective Studies
PubMed: 35723111
DOI: 10.3233/JND-210776 -
The Australasian Journal of Dermatology Aug 2018Derivatives of hydrocortisone, such as mometasone furoate, a (2') furoate-17 ester with chlorine substitutions at positions 9 and 21, have been designed to improve... (Review)
Review
Derivatives of hydrocortisone, such as mometasone furoate, a (2') furoate-17 ester with chlorine substitutions at positions 9 and 21, have been designed to improve efficacy and reduce the incidence of adverse effects. An extensive literature search of MEDLINE, Embase and other databases was conducted to review the safety and efficacy of various formulations of topical mometasone furoate. Mometasone furoate exhibits high potency with greater anti-inflammatory activity and a longer duration of action than betamethasone. In clinical trials, mometasone furoate shows comparable or significantly better efficacy, depending on the comparator, in all indications studied in both adults and children. It is well tolerated with only transient, mild to moderate local adverse effects. It is characterised by low systemic availability due to its high lipophilicity, low percutaneous absorption and rapid hepatic biotransformation, and consequently has no significant effect on the hypothalamic-pituitary-adrenal axis. The molecular biotransformation of mometasone furoate in the skin results in a lower affinity with dermal cells than epidermal cells, which contributes to its low atrophogenicity. Sensitisation to mometasone furoate is low. Overall, mometasone furoate is a highly efficacious potent corticosteroid with a low risk of both local and systemic adverse effects.
Topics: Administration, Topical; Betamethasone; Dermatologic Agents; Humans; Mometasone Furoate
PubMed: 29411351
DOI: 10.1111/ajd.12762 -
CNS Drugs Mar 2019Postpartum depression is one of the most common complications of childbirth. Untreated postpartum depression can have substantial adverse effects on the well-being of... (Review)
Review
Postpartum depression is one of the most common complications of childbirth. Untreated postpartum depression can have substantial adverse effects on the well-being of the mother and child, negatively impacting child cognitive, behavioral, and emotional development with lasting consequences. There are a number of therapeutic interventions for postpartum depression including pharmacotherapy, psychotherapy, neuromodulation, and hormonal therapy among others, most of which have been adapted from the treatment of major depressive disorder outside of the peripartum period. Current evidence of antidepressant treatment for postpartum depression is limited by the small number of randomized clinical trials, underpowered samples, and the lack of long-term follow-up. The peripartum period is characterized by rapid and significant physiological change in plasma levels of endocrine hormones, peptides, and neuroactive steroids. Evidence supporting the role of neuroactive steroids and γ-aminobutyric acid (GABA) in the pathophysiology of postpartum depression led to the investigation of synthetic neuroactive steroids and their analogs as potential treatment for postpartum depression. Brexanolone, a soluble proprietary intravenous preparation of synthetic allopregnanolone, has been developed. A recent series of open-label and placebo-controlled randomized clinical trials of brexanolone in postpartum depression demonstrated a rapid reduction in depressive symptoms, and has led to the submission for regulatory approval to the US Food and Drug Administration (decision due in March 2019). SAGE-217, an allopregnanolone analog, with oral bioavailability, was recently tested in a randomized, double-blind, placebo-controlled phase III study in severe postpartum depression, with reportedly positive results. Finally, a 3β-methylated synthetic analog of allopregnanolone, ganaxolone, is being tested in both intravenous and oral forms, in randomized, double-blind, placebo-controlled phase II studies in severe postpartum depression.
Topics: Animals; Depression, Postpartum; Drug Combinations; Drug Development; Female; GABA Modulators; Humans; Neurosteroids; Pregnanes; Pregnanolone; Pyrazoles; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration; beta-Cyclodextrins
PubMed: 30790145
DOI: 10.1007/s40263-019-00605-7 -
JAMA Apr 2022Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage. (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage.
OBJECTIVE
To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy.
DESIGN, SETTING, AND PARTICIPANTS
Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019).
INTERVENTIONS
Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66).
MAIN OUTCOMES AND MEASURES
The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017.
RESULTS
Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]).
CONCLUSIONS AND RELEVANCE
Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01603407.
Topics: Child; Child, Preschool; Female; Glucocorticoids; Humans; Male; Muscular Dystrophy, Duchenne; Prednisone; Pregnenediones
PubMed: 35381069
DOI: 10.1001/jama.2022.4315