What factors have impact on glucocorticoid replacement in adrenal insufficiency: a real-life study.

PURPOSE: The impact of patient's characteristics on glucocorticoid (GC) replacement therapy in adrenal insufficiency (AI) is poorly evaluated. Aims of this study were to assess the influence of sex and body weight on GC dosing and to describe the choice of GC in AI of different etiologies. METHODS: We retrospectively evaluated hydrocortisone (HC) equivalent total daily dose (HC-TDD) and per-kg-daily dose (HC-KDD) in 203 patients (104 primary AI [pAI], 99 secondary AI [sAI]) followed up for ≥ 12 months. They were treated with HC, modified-release HC (MRHC) or cortisone acetate (CA) and fludrocortisone acetate (FCA) in pAI. RESULTS: At baseline, CA was preferred both in pAI and sAI; at last visit, MRHC was most used in pAI (49%) and CA in sAI (73.7%). Comparing the last visit with baseline, in pAI, HC-TDD and HC-KDD were significantly lower (p = 0.04 and p = 0.006, respectively), while FCA doses increased during follow-up (p = 0.02). The reduction of HC-TDD and HC-KDD was particularly relevant for pAI women (p = 0.04 and p = 0.002, respectively). In sAI patients, no change of HC-KDD and HC-TDD was observed, and we found a correlation between weight and HC-TDD in males (r 0.35, p = 0.02). CONCLUSIONS: Our real-life study demonstrated the influence of etiology of AI on the type of GC used, a weight-based tailoring in sAI, a likely overdosage of GC treatment in pAI women at the start of treatment and the possibility to successfully increase FCA avoiding GC over-treatment. These observations could inform the usual clinical practice.

Identification of glucocorticoid receptor in Drosophila melanogaster.

BACKGROUND: Vertebrate glucocorticoid receptor (GR) is an evolutionary-conserved cortisol-regulated nuclear receptor that controls key metabolic and developmental pathways. Upon binding to cortisol, GR acts as an immunosuppressive transcription factor. Drosophila melanogaster, a model organism to study innate immunity, can also be immunosuppressed by glucocorticoids. However, while the genome of fruit fly harbors 18 nuclear receptor genes, the functional homolog of vertebrate GR has not been identified. RESULTS: In this study, we demonstrated that while D. melanogaster is susceptible to Saccharomyces cerevisiae oral infection, the oral exposure to cortisol analogs, cortisone acetate or estrogen, increases fly sensitivity to yeast challenge. To understand the mechanism of this steroid-induced immunosuppression, we identified the closest genetic GR homolog as D. melanogaster Estrogen Related Receptor (ERR) gene. We discovered that Drosophila ERR is necessary for cortisone acetate- and estrogen-mediated increase in sensitivity to fungal infection: while ERR mutant flies are as sensitive to the fungal challenge as the wildtype flies, the yeast-sensitivity of ERR mutants is not increased by these steroids. Interestingly, the fungal cortisone analog, ergosterol, did not increase the susceptibility of Drosophila to yeast infection. The immunosuppressive effect of steroids on the sensitivity of flies to fungi is evolutionary conserved in insects, as we show that estrogen significantly increases the yeast-sensitivity of Culex quinquefasciatus mosquitoes, whose genome contains a close ortholog of the fly ERR gene. CONCLUSIONS: This study identifies a D. melanogaster gene that structurally resembles vertebrate GR and is functionally necessary for the steroid-mediated immunosuppression to fungal infections.

Associations between antenatal prednisone exposure and long-term cortisol and cortisone concentrations in children born to women with rheumatoid arthritis: results from a nationwide prospective cohort study.

Objectives: To identify whether children with antenatal prednisone exposure have chronically elevated cortisol and cortisone concentrations, an altered body composition or higher blood pressure. In addition, to identify whether maternal rheumatoid arthritis disease (RA) activity is associated with these alterations. Methods: In this prospective study, 56 children (mean age=10.0 years) with and 61 children (mean age=9.6 years) without antenatal prednisone exposure, born to women with RA, were included. Hair cortisol and cortisone were analysed using liquid chromatography-tandem mass spectrometry. Linear regression models were built to analyse differences between the two groups, corrected for relevant covariates. Hair cortisol concentrations were also compared between the study population and an age-matched healthy reference group(n=150 children, mean age=9.8 years). Results: Hair cortisol and cortisone concentrations were similar in children with and without antenatal prednisone exposure (median cortisol 1.14 pg/mg (IQR 0.67-1.75) and 1.15 pg/mg (IQR 0.65-2.21) and median cortisone 6.76 pg/mg (IQR 5.42-8.86) and 7.40 pg/mg (IQR 5.39-10.73), respectively). Antenatal prednisone exposure and maternal RA disease activity were also not associated with body composition or blood pressure. Hair cortisol concentrations were not different in children born to mothers with RA compared with children from the reference group. Conclusion: This, in its kind, large and unique long-term prospective study demonstrates that low-dose antenatal prednisone exposure and maternal RA disease activity are not associated with negative consequences in prepubertal childhood. The findings of this study are reassuring and support the assumption that low-dose maternal prednisone use during pregnancy is safe for the offspring, at least until the age of approximately 10 years.

"I would like to tatoo the illness on my arm". The Integrated Personalized Nursing Diagnosis (IPND).

BACKGROUND AND AIM: The nursing diagnosis can based on two different approaches: the standard diagnosis, searching for regularities that can fall within pre-existing categories identified by the nurse, as the expert of the disease; the narrative diagnosis, based on personal meaning attributed to the illness, of which only the patient is the expert. The aim of this work is to underline the usefulness of integration between standard diagnosis and narrative diagnosis, through the Integrated Personalized Nursing Diagnosis (IPND). METHODS: A 31 years old man, suffering from leukaemia, is welcomed at an Italian Oncological Day Hospital, by a nurse trained in the IPND approach. She used the Gordon functional models on objective data, and collected a narration about patient's experience, which has been analyzed with a Grounded Theory methodology. RESULTS: The narrative revealed critical issues and the priorities that patient assigns, which would not have been obtained from a standard diagnosis. From the standard diagnosis, however, emerge several aspects that the patient has neglected to narrate and that does not directly address in his story. The diagnostic integration allowed the nurse to define a conceptual map of problems and resources in a personalized manner. CONCLUSION: The IPND not only gives importance to the priorities of the patient, but also underlines the dynamic path, in which not only the static analysis of needs becomes significant, but also the changes that occur in attributing new meanings to the life experience, as well as the evolution of the person him/herself in this process.

Novel 11ß-hydroxysteroid dehydrogenase 1 inhibitors reduce cortisol levels in keratinocytes and improve dermal collagen content in human ex vivo skin after exposure to cortisone and UV.

Activity and selectivity assessment of new bi-aryl amide 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) inhibitors, prepared in a modular manner via Suzuki cross-coupling, are described. Several compounds inhibiting 11ß-HSD1 at nanomolar concentrations were identified. Compounds 2b, 3e, 7b and 12e were shown to selectively inhibit 11ß-HSD1 over 11ß-HSD2, 17ß-HSD1 and 17ß-HSD2. These inhibitors also potently inhibited 11ß-HSD1 activity in intact HEK-293 cells expressing the recombinant enzyme and in intact primary human keratinocytes expressing endogenous 11ß-HSD1. Moreover, compounds 2b, 3e and 12e were tested for their activity in human skin biopsies. They were able to prevent, at least in part, both the cortisone- and the UV-mediated decreases in collagen content. Thus, inhibition of 11ß-HSD1 by these compounds can be further investigated to delay or prevent UV-mediated skin damage and skin aging.

Impact of maternal steroids during pregnancy.

Increased fetal exposure to glucocorticoids is a key mechanism thought to underlie the early life programming of later life disease. There is substantial experimental data in animal models in support of this hypothesis. Emerging evidence suggests glucocorticoid programming may also occur in humans with some studies now linking maternal endogenous cortisol levels with size at birth and gestation at delivery. The dramatic changes to the maternal hypothalamic-pituitary-adrenal axis during pregnancy mean that large-scale studies in humans are challenging to conduct. One of the key regulators of fetal glucocorticoid exposure is the activity of placental "barrier" enzyme 11ß-hydroxysteroid dehydrogenase type 2 (HSD2) which converts active cortisol to inactive cortisone. In animal models, this enzyme is down-regulated by various influences including maternal malnutrition, inflammation or stress but it is not known whether this is a major factor in regulation of human fetal glucocorticoid exposure. More studies are needed to understand the mechanisms whereby altered fetal glucocorticoid exposure may alter fetal growth trajectories and whether changes in the maternal hypothalamic-pituitary-adrenal axis in pregnancy could be suitable as a biomarker to identify those pregnancies most at risk.

[Temporomandibular joint arthropathy in situ steroid injection]. / Arthropathie temporomandibulaire après infiltration cortisonique in situ.

INTRODUCTION: Temporomandibular disorders (TMDs) affect the masticatory muscles and the temporomandibular joints (TMJs). TMDs most often result from occlusal and/or muscular disorders and are then called primary or idiopathic TMDs. Less frequently, TMDs are related to local (trauma, infection) or general (rheumatoid arthritis) causes and are then called secondary TMDs. A little known iatrogenic cause of secondary TDM is the osteoarthritis that may be induced by intra-articular cortisone injections. We report one case of condylar lysis that occurred after one single intra-articular cortisone injection. OBSERVATION: A 62-years-old woman consulted for a long-lasting TMD on the left side manifesting itself through pain and noise. She benefited one year before from an intra-articular injection of cortisone by her rheumatologist for repeated closed lock of her left TMJ. Physical examination showed limited mouth opening with deviation on the left side. Lateral movements on the right side were impossible. The panoramic X-ray showed a condylar lysis on the left side that was on the CT scan. MRI additionally showed an anteriorly displaced and severely reshaped disc and an articular inflammation without intra-articular effusion. DISCUSSION: TMJ osteoarthritis secondary to unique or repeated intra-articular steroid injections are little-known. They are clinically expressed as typical TMDs and characterized on X-rays by condylar lysis and inflammation. Intra-articular injections of steroids are not totally harmless and other treatments must be preferred.

Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Human C1q Deficiency: The Karolinska Experience.

BACKGROUND: Human C1q deficiency is associated with systemic lupus erythematosus (SLE) and increased susceptibility to severe bacterial infections. These patients require extensive medical therapy and some develop treatment-resistant disease. Because C1q is produced by monocytes, it has been speculated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) may cure this disorder. METHODS: We have so far treated 5 patients with C1q deficiency. In 3 cases, SLE symptoms remained relatively mild after the start of medical therapy, but 2 patients developed treatment-resistant SLE, and we decided to pursue treatment with allo-HSCT. For this purpose, we chose a conditioning regimen composed of treosulfan (14 g/m) and fludarabine (30 mg/m) started on day -6 and given for 3 and 5 consecutive days, respectively. Thymoglobulin was given at a cumulative dose of 8 mg/kg, and graft-versus-host disease prophylaxis was composed of cyclosporine and methotrexate. RESULTS: A 9-year-old boy and a 12-year-old girl with refractory SLE restored C1q production after allo-HSCT. This resulted in normal functional properties of the classical complement pathway followed by reduced severity of SLE symptoms. The boy developed posttransplant lymphoproliferative disease, which resolved after treatment with rituximab and donor lymphocyte infusion. Unfortunately, donor lymphocyte infusion induced severe cortisone-resistant gastrointestinal graft-versus-host disease, and the patient died from multiple organ failure 4 months after transplantation. The girl is doing well 33 months after transplantation, and clinically, all signs of SLE have resolved. CONCLUSIONS: Allo-HSCT can cure SLE in human C1q deficiency and should be considered early in subjects resistant to medical therapy.

[Pharmacogenic osteoporosis beyond cortisone. Proton pump inhibitors, glitazones and diuretics]. / Pharmakogene Osteoporose jenseits von Kortison. Protonenpumpenhemmer, Glitazone, Diuretika.

BACKGROUND: [corrected] There are many drugs which can cause osteoporosis or at least favor its initiation. The effect of hormones and drugs with antihormonal activity, such as glucocorticoids and aromatase inhibitors, on initiation of osteoporosis is well known. In addition, proton pump inhibitors, glitazones and diuretics also influence the formation of osteoporosis. MATERIAL AND METHODS: The results of currently available studies on the correlation between proton pump inhibitors, glitazones and diuretics on formation of osteoporosis were evaluated and summarized. RESULTS: Proton pump inhibitors and glitazones increase the risk for osteoporotic fractures. Loop diuretics may slightly increase fracture risk, whereas thiazides were shown to be osteoprotective by reducing fracture probability on a relevant scale. CONCLUSION: Proton pump inhibitors should not be prescribed without serious consideration and then only as long as necessary. Alternatively, the administration of the less effective H2 antagonists should be considered when possible due to the reduction of acid secretion. Because the long-term intake of thiazides is associated with a clinically relevant reduction in the risk of fractures and they are economic and well-tolerated, prescription can be thoroughly recommended within the framework of differential diagnostic considerations in an appropriate clinical context. The briefly increased risk of falling immediately after starting diuretic therapy is the only point which needs to be considered.

Gastrointestinal bleeding after high intake of omega-3 fatty acids, cortisone and antibiotic therapy: a case study.

Omega-3 fatty acids exert a plethora of physiological actions including triglycerides lowering, reduction of inflammatory indices, immunomodulation, anti- thrombotic effects and possibly promotion of exercise performance. Their use is widespread and for commonly ingested doses their side- effects are minimal. We report a case of a 60 y amateur athlete who consumed about 20 g omega-3 fatty acids daily from supplements and natural sources for a year. After the intake of cortisone and antibiotics he presented duodenum ulcer and bleeding although he had no previous history of gastrointestinal problems. Although several animal data support gastro-protective effects of omega-3 fatty acids in the present case they were not able to prevent ulcer generation. The present observation may be explained by (i) the high dose of omega-3 fatty acids and their effect on bleeding, (ii) the fact that cortisone increases their oxidation and may render them proinflammatory, (iii) other antithrombotic microconstituents included in the consumed cod-oil and/or the diet of the subject and (iv) the differences in the coagulation and fibrinolytic systems of well- trained subjects. Further studies are needed to substantiate any possible interaction of cortisone and omega-3 fatty acids in wide ranges of intake.

[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.

Salivary cortisol day curves in assessing glucocorticoid replacement therapy in Addison's disease.

OBJECTIVE: Patients with Addison's disease require lifelong treatment with glucocorticoids. At present, no glucocorticoid replacement therapy (GRT) can exactly mimic normal physiology. As a consequence, under- and especially overtreatment can occur. Suboptimal GRT may lead to various side effects. The aim of this study was to investigate the use of salivary cortisol day curves (SCDC) in the individual adjustment of GRT in order to approach normal cortisol levels as closely as possible, reduce over- and underreplacement and study the short-term effects on quality of life (QoL). DESIGN AND METHODS: Twenty patients with Addison's disease were included in this prospective study. A SCDC was obtained and compared to normal controls; general and disease specific QoL-questionnaires were completed. Based on SCDC assessment of over- and undertreatment (calculated as duration (h) × magnitude (nmol/L) at different time points, glucocorticoid dose and regime were adjusted. After 4 weeks SCDC and QoL assessment were repeated and the effect of adjusting GRT was analysed. RESULTS: At baseline, underreplacement was present in 3 and overreplacement in 18 patients; total calculated overreplacement was 32.8 h.nmol/L. Overreplacement decreased significantly to 13.3 h. nmol/L (p =0.005) after adjustment of GRT. Overreplacement was found particularly in the afternoon and evening. After reducing overreplacement in the evening, complaints about sleep disturbances significantly decreased. CONCLUSIONS: Individual adjustment of GRT based on SCDC to approach normal cortisol concentrations during the day can reduce overreplacement, especially in the evening. This can lead to a reduction of sleep disturbances and fatigue in patients with Addison's disease. A SCDC is a simple and patient-friendly tool for adjusting GRT and can be useful in the follow-up of patients with Addison's disease.

Granulocyte-colony stimulating factor as treatment option in patients with recurrent miscarriage.

In 1-5% of patients during childbearing years recurrent miscarriages (RM) occur. There are established risk factors like anatomical, endocrine and hemostatic disorders as well as immunological changes in the maternal immune system. Nevertheless, further elucidation of the pathogenesis remains a matter of debate. In addition, there are no standardized immunological treatment strategies. Recent studies indicate possible effects of tumor necrosis factor α blocker and granulocyte-colony stimulating factor (G-CSF) concerning live birth rate (LBR) in RM patients. Therefore, we performed a retrospective cohort study in patients undergoing assisted reproductive treatment (ART) with known RM analysing the possible benefits of G-CSF application. From January 2002 to December 2010, 127 patients (199 cylces) with RM (at least 2 early miscarriages) 49 (72 cycles) receiving G-CSF and 78 (127 cycles) controls receiving either no medication (subgroup 1) or Cortisone, intravenous immunoglobulins or low molecular weight heparin (subgroup 2) undergoing ART for in vitro fertilisation/intracytoplasmic sperm injection were analysed. G-CSF was administered weekly once (34 Mill) in 11 patients, 38 patients received 2 × 13 Mill G-CSF per week until the 12th week of gestation. Statistical analysis was performed with SPSS for Windows (19.0), p < 0.05 significant. The mean age of the study population was 37.3 ± 4.4 years (mean ± standard deviation) and differed not significantly between patients and subgroups. However, the number of early miscarriages was significantly higher in the G-CSF group as compared to the subgroups (G-CSF 2.67 ± 1.27, subgroup 1 0.85 ± 0.91, subgroup 2 0.64 ± 0.74) and RM patients receiving G-CSF had significantly more often a late embryo transfer (day 5) (G-CSF 36.7%, subgroup 1 12.1%, subgroup 2 8.9%). The LBR of patients and the subgroups differed significantly (G-CSF 32%, subgroup 1 13%, subgroup 2 14%). Side effects were present in less than 10% of patients, consisting of irritation at the injection side, slight leukocytosis, rise of the temperature (<38 °C), mild bone pain and hyperemesis gravidarum. None of the newborn showed any kind of malformations. According to our data, G-CSF seems to be a safe and promising immunological treatment option for RM patients. However, with regard to the retrospective setting and the possible bias of a higher rate of late embryo transfers in the G-CSF group additional studies are needed to further strengthen our results.

[Cortisone-induced humerus head necrosis in acute myeloid leukemia: cartilage-preserving arthroscopic spongioplasty]. / Cortison-induzierte Humeruskopfnekrose bei akuter myeloischer Leukämie : Knorpelerhaltende arthroskopisch unterstützte Spongiosaplastik.

Osteonecrosis is a long known side effect in patients receiving cortisone or chemotherapy. A young patient was diagnosed with acute myeloid leukemia (AML) in 2005. After receiving combined cortisone and chemotherapy the patient was in complete remission. In 2007 a total hip replacement was necessary due to femoral head necrosis. Years after the joint replacement the patient reported acute shoulder pain without trauma. In this article an alternative procedure to an endoprothesis in a young patient with a humeral head osteonecrosis is presented.

Arterial and venous thromboses in patients with idiopathic (immunological) thrombocytopenia: a possible contributing role of cortisone-induced hypercoagulable state.

Immunological thrombocytopenias, as other forms of thrombocytopenia, are associated with bleeding. Occasionally, these patients manifest thrombotic events. A total of at least 29 patients were reported to have had either arterial (20 cases) or venous (9 cases) thrombosis while platelet count was less than 50 × 10(3)/µL. The most frequent clinical manifestation was a myocardial infarction. Thrombosis occurred in the large majority of patients during prednisone therapy. Patients receiving cortisone or patients with Cushing syndrome show a hypercoagulable state characterized by elevated factor VIII levels, decreased fibrinolysis, and abnormal von Willebrand factor multimers composition. The same is probably true for prednisone-treated patients with thrombocytopenia. However, the 2 conditions are not identical since prednisone is a mainly glycoactive compound, whereas cortisol produced in excess in Cushing syndrome is mainly mineraloactive. The presence of large, young, hyperactive platelets may also play a role. Prednisone-treated patients with thrombocytopenia have to be considered as potentially thrombophilic.