Axis Suppression Research Articles

Adrenal Suppression in EoE Treated With Budesonide?

See “Adrenal Suppression in Children Treated With Oral Viscous Budesonide for Eosinophilic Esophagitis” by Panagiotopoulos et al on page 190. In this issue of the Journal of Pediatric Gastroenterology and Nutrition, Panagiotopoulos et al (1) report on the results of a quality assurance (QA) project conducted in children with eosinophilic esophagitis (EoE) treated with budesonide. They disclose evidence that adrenal suppression may result from administering therapeutic doses of budesonide for relatively short (<3 months and longer) time periods. During the last decade, the number of children being diagnosed as having EoE has greatly increased. A full understanding of the implications of the diagnosis is lacking. Therefore, an appreciation of the risks and benefits of any 1 therapy, such as glucocorticoids (GCs), is also unclear. That the study was undertaken as a QA project raises issues both of its scientific value and its place in a scientific peer-reviewed journal. Readers should take note that this is not a rigorously designed prospective study of the type all editors like to publish. It does however have a place as a “hypothesis generating” or (as described) a “pilot” study. The authors have felt appropriately compelled to bring to our attention the potential risks inherent in a treatment regarded as relatively benign. Budesonide treats the symptoms of EoE effectively. It is a GC, but because it is rapidly metabolized in the liver, it is considered less likely to result in adverse effects associated with the systemic use of other GCs. It has never been suggested that budesonide is completely safe, but it is possible that clinicians have become too comfortable with its safety profile. The introduction of GC as therapy for various clinical conditions started in the 1950s (2). Currently, they are used as physiologic replacement in adrenal insufficiency and pharmacologic treatment in a variety of conditions including rheumatologic diseases, nephrotic syndrome, asthma, inflammatory bowel diseases, and EoE. As a general rule, treatment with GC requires close monitoring for both undertreatment and overtreatment. Undertreatment can result in adrenal insufficiency, and overtreatment may lead to growth suppression, iatrogenic Cushing syndrome, and hypothalamic-pituitary-adrenal (HPA) axis suppression/secondary adrenal insufficiency. HPA axis suppression can occur with the use of GC therapy of >2 weeks duration, which exceeds physiological doses (the normal endogenous cortisol secretory rate is 6–8 mg · m−2 · day−1 in children and adults (3,4)). HPA axis suppression has been reported in prolonged systemic, topical, and intralesional GC therapy (2,5). The low-dose 1-μg adrenocorticotropic hormone test used by the authors is more sensitive than the standard-dose (250 μg) test (2,6–8); thus, if the findings reported are confirmed, then the screening and testing for secondary adrenal insufficiency in patients being treated with budesonide for an extended time period is warranted. Also, stringent guidelines for the use of budesonide might be considered. The authors did not find significant association with the treatment duration, dose, or concomitant use of inhaled/nasal corticosteroids. This should be interpreted with caution because of the small sample size and study design (or perhaps lack of design.) Other risk factors for adrenal suppression may include efficiency of gastrointestinal absorption related to diet, gastric acidity, bowel transit time, and interindividual sensitivity to GC related to genetic factors (9). A prospective study measuring adrenal suppression in EoE patients matched for disease extent and randomized to receive either budesonide or a nonsteroid treatment is warranted to determine the significance of the findings disclosed. The early symptoms of secondary adrenal insufficiency can be too subtle to note, but until the true incidence and extent of adrenal suppression is known, it is worthy of consideration to provide hydrocortisone supplementation in times of stress (such as major surgery) to any patient who has been treated with budesonide for 3 months in the last year.

Effects of Inhaled Corticosteroids on the Growth Plates of Infant Rats

The most significant adverse effect of inhaled steroid administration in children is suppression of hypothalamic–pituitary–adrenal axis responsiveness and suppression of growth. This study evaluates the effects of inhaled corticosteroids on the growth plates in infant rats. Rats aged 10 days were divided into five groups. Low and high doses of budesonide and fluticasone propionate (50–200–250 mcg/day) were applied with a modified spacer for 10 days. The rat's tibias were then removed and the effects of the steroids on the growth plates were compared. Growth cartilage chondrocyte proliferation and apoptosis rates; IGF-1 and glucocorticoid receptor levels; and resting, proliferative, hypertrophic, and total zone (TZ) measurements were compared using immunohistochemical-staining methods. With high doses of fluticasone, growth plates were affected much more than with high doses of budesonide (p = 0.01). Fluticasone, particularly at a dose of 250 mcg, inhibited the growth plate with an intensive negative impact on all parameters.

An infantile exogenous Cushing syndrome caused by topical steroid

Corticosteroids are widely use for the treatment of various diseases. Long-term use of corticosteroids may lead to development of Cushing syndrome and hypothalamic pituitary adrenal axis suppression. However, iatrogenic Cushing syndrome from absorption of topical steroids to systemic circulation is less common comparing to parenteral or oral use. Infantile age group have greater risks for systemic side effects of the drugs because their skin has poorly developed barrier function and large surface area. We reported a 5-month-old female child was admitted to our hospital with puffiness of face and excessive weight gain after 4 months old. She was born at term with an uneventful pregnancy with a birth weight of 3.4 kg. Her body weight was 8.2 kg (+2SDS), height was 63.5 cm (+0.2SDS). Physical examination showed her was moon face appearance, generalized obesity, hirsutism and buffalo hump. There were few erythema and weeping present at skin fold areas. Blood pressure was 105/68 mmHg (>95th percentile). Past history revealed that the child had diaper dermatitis at 3.5 month of age. She was prescribed a topical combination drug containing nystatin, neomycin, gramicidin and triamcinolone acetonide from private pediatric clinic. Since then she was applying the drug 3-4 times daily on neck, axilla, diaper area and all skin fold areas. Totally drug usage was 30 g in 6 weeks. Investigations showed hemoglobin of 15 g/dL, white blood cell count 18,240/mm3, platelet count 471,000/mm3, blood glucose 74 mg/dL and normal electrolyte, renal and liver function. Ultrasonography of whole abdomen revealed no abnormality. Random PM cortisol was low (0.2 mcg/dL). Secondary adrenal insufficiency was suspected. 1-mcg ACTH stimulation test was done and the peak cortisol was 1.9 mcg/dL. Therefore, exogenous Cushing syndrome and secondary adrenal insufficiency due to overuse of topical combination drug which containing moderate potency steroid was diagnosed. She was promptly treatment by discontinued applying the drug and administered steroid during stress. This report highlights the importance of prolonged use of moderate potency topical steroids can causes hypothalamic pituitary adrenal axis suppression and Cushing syndrome, especially during infantile period. Therefore, limiting the use of moderate- to high-potency topical steroids in children and provide information about potential adverse effects to the caregivers are crucial. Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Medical Testosterone: An Iatrogenic Cause of Male Infertility and a Growing Problem

To determine (1) the frequency of testosterone (T) use in 2 academic male infertility practices, (2) the effect on semen parameters, and (3) the potential for reversibility. We performed a retrospective review. Inclusion criteria were supplemental T usage at the time of initial visit, T cessation, and semen analyses before and after T cessation. From January 2005 to March 2011, 110 of 1540 patients evaluated for infertility (7.1%) were on supplemental T. Thirty-nine patients met the inclusion criteria. Twenty-two of 39 patients (56%) were started on medical recovery by medical treatment. Median sperm concentration increased from 0 to 6.3 million/mL (P <.0001) after T cessation, with median follow-up of 4.5 months. Eight men (21%) remained azoospermic, and 3 men had sperm concentrations of ≤ 0.1 million/mL. Fifteen of 22 men given medical treatment and 16 of 17 men given no treatment had sperm return to the semen, respectively (P = .1061). Final sperm concentration did not differ between those who received medical treatment and those who did not. Exogenous T treatment causes infertility and is common among reproductive-aged men. These effects are transient for some, but not all men had return of sperm to the semen during the study interval, suggesting a possible underlying primary testicular dysfunction or ongoing hypothalamic-pituitary-testicular axis suppression. Education about exogenous T's negative reproductive effects is necessary to avoid this preventable form of infertility. Men with low T levels should have sufficient evaluation to evaluate for underlying pathology before starting T.

Intranasal triamcinolone and growth velocity.

Inadequate designs and conflicting results from previous studies prompted the US Food and Drug Administration to publish guidelines for the design of clinical trials evaluating the effects of orally inhaled and intranasal corticosteroids on the growth of children. This study conformed to these guidelines to evaluate the effect of triamcinolone acetonide aqueous nasal spray (TAA-AQ) on the growth of children with perennial allergic rhinitis (PAR). This randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluated the effect of once-daily TAA-AQ (110 μg) on the growth velocity (GV) of children aged 3-9 years with PAR by using stadiometry at baseline (4-6 months), during treatment (12 months), and at follow-up (2 months). Hypothalamus-pituitary-adrenal (HPA) axis function was assessed by measuring urinary cortisol levels. Details of adverse events were recorded. Of 1078 subjects screened, 299 were randomized, and 216 completed the study (placebo, 107; TAA-AQ, 109). In the primary analysis (modified intent-to-treat: placebo, 133; TAA-AQ, 134), least-squares mean GV during treatment was lower in the TAA-AQ group (5.65 cm/year) versus placebo (6.09 cm/year). The difference (-0.45 cm/year; 95% confidence interval: -0.78 to -0.11; P = .01), although clinically nonsignificant, was evident within 2 months of treatment and stabilized thereafter. At follow-up, the GV approached baseline (6.70 cm/year) in the TAA-AQ group (6.59 cm/year) and decreased slightly in the placebo group (5.89 cm/year vs 6.06 cm/year at baseline). No HPA axis suppression was observed. By using rigorous Food and Drug Administration-recommended design elements, this study detected a small, statistically significant effect of TAA-AQ on the GV of children with PAR.

Study of hypothalamic pituitary adrenal axis in patients of membranous nephropathy receiving modified Ponticelli regimen.

Pulse methyl prednisolone followed by oral prednisolone and abrupt switch to chlorambucil/cyclophosphamide (Ponticelli/modified Ponticelli regimen) is used in patients with idiopathic membranous nephropathy. This therapy where steroids are stopped abruptly is unphysiologic and expected to have hypothalamic pituitary adrenal (HPA) axis suppression; however, this has not been evaluated. A total of 13 consecutive adult patients with idiopathic membranous nephropathy who had completed modified Ponticelli regimen were studied. The regimen included administration of pulse methylprednisolone 1 g for 3 days followed by oral prednisolone 0.5 mg/kg/day for 27 days followed by oral cyclophosphamide at a dose of 2 mg/kg/day for the next month. This was repeated for three courses. Patients who had received corticosteroids prior to therapy were excluded. The HPA axis was evaluated after 1 month of completing the last course of steroid therapy. The evaluation was done using a low-dose adrenocorticotropic hormone stimulation test. A single intravenous bolus dose of synacthen (1 μg) was given at 9.00 am and the serum cortisol levels were estimated by radioimmunoassay at 0, 30, and 60 min. A peak cortisol level of 550 nmol/L or higher was considered as normal. Mean baseline cortisol levels was 662.3 ± 294.6 nmol/L and peak cortisol level was 767 ± 304.4 nmol/L. A total of 6 patients (46.2%) had low basal cortisol levels, only 3 (23%) had both basal and peak cortisol levels < 550 nmol/L suggestive of HPA axis suppression. To conclude, 23% of patients had suppression of HPA axis after modified Ponticelli regimen.

Psoriatic erythroderma and hypothalamus-pituitary axis suppression due to misuse of systemic steroid: two challenging cases.

Adding corticosteroid in homeopathic pills, self medication of steroid in the backdrop permanent cure in cases of psoriasis is not very uncommon in clinical practice in Indian subcontinent. First case a 52 year man, a known case of psoriasis vulgaris with psoriatic arthropathy of 15 years duration received multiple modalities of therapies without any satisfactory response. He was on self medication of tab prednisolone 10 mg daily with Cushingoid features. Second case a 22 year old boy, a known case of psoriasis from last 06 years was on Homeopathic treatment with Cushinoid features. Tapering of systemic steroid in first case and discontinuation of homeopathic drug in second case resulted in erythroderma and features of adrenal insufficiiency. Investigation revealed low morning cortisol and low cortisol following ACTH stimulation suggestive of HPA axis suppression. Planned withdrawal of steroid under the cover of short acting systemic steroid for short duration along with combination of immunosuppressants and supportive care gave an excellent result in both the cases.

A prospective study of the hypothalamic-pituitary-adrenal axis in children with acute lymphoblastic leukemia receiving chemotherapy

BackgroundGlucocorticoids are essential in protocols of therapy of acute lymphoblastic leukemia (ALL).ObjectivesTo assess the incidence, severity, morbidity, and risk factors of hypothalamic-pituitary-adrenal axis (HPA) suppression in children with ALL, and the time course of recovery.DesignForty standard risk ALL children treated in the Pediatric Hematology/Oncology Unit, Ain-Shams University, Egypt, were classified into dexamethasone (DXM) group: 20 patients on children cancer group protocol and prednisone (PDN) group: 20 patients on modified Berlin-Frankfurt-Muenster (BFM) study group 90 protocol. Patients were followed clinically and by laboratory assessment of morning s.ACTH, basal and after low-dose adrenocorticotrophic hormone stimulation test of cortisol and DHEAS, at diagnosis and every 2 weeks till adrenal recovery.ResultsHPA recovery was earlier in PDN than DXM group (P < 0.05). In induction phases 1 and 2: 65 and 75% of PDN group recovered on week 2, while 45 and 50% of DXM group recovered in week 4. Adrenal recovery was predicted 2 weeks earlier by normalized s.DHEAS. Children below 5 years of age had earlier recovery in PDN group (P = 0.04), no age effect in DXM group.ConclusionAdrenal suppression is an inevitable consequence of ALL therapy. Monitoring of cortisol levels and steroid coverage during stress is recommended, and gradual steroid tapering is suggested.

Steroid-eluting sinus implant for in-office treatment of recurrent polyposis: a pharmacokinetic study.

Long-term use of systemic glucocorticoid therapy has been associated with hypothalamic-pituitary-adrenal axis suppression and other systemic adverse events. This pharmacokinetic study evaluated the systemic safety and performance of a bioabsorbable sinus implant that gradually releases 1350μg of mometasone furoate directly to the sinus mucosa. A prospective, single-center study treating 5 adult patients with recurrent polyposis after bilateral total ethmoidectomy. Each patient received 2 steroid-releasing implants in-office under local/topical anesthesia. Plasma concentrations of mometasone furoate and cortisol were determined before placement and through 30-day follow-up, which also included endoscopic grading and patient-reported outcomes. Five patients (mean age 46.2 ± 9.2 standard deviation [SD] years; 60% male) underwent successful placement in all 10 ethmoid sinuses. There were no serious adverse events. The plasma concentrations of mometasone furoate were generally below the lower limit of quantification (LLOQ) of the assay (30pg/mL). Cortisol concentrations at follow-up ranged from 3.9 to 5.7mg/dL compared to 4.7mg/dL at baseline. At 1 month, there was a significant improvement in bilateral polyp grade (p = 0.037), nasal obstruction score (p = 0.002), and 22-item Sino-Nasal Outcome Test (SNOT-22) (p = 0.010) compared to baseline. The reported 100% placement success, negligible systemic exposure to mometasone furoate released over time, lack of adrenal suppression, and the absence of serious adverse events suggest that the implant provides a valid and safe option for the in-office treatment of recurrent polyposis. Randomized, controlled, blinded clinical studies are underway to provide further evidence of safety and efficacy.

36-Month Treatment Experience of Two Doses of Leuprolide Acetate 3-Month Depot for Children With Central Precocious Puberty

We have recently demonstrated short-term (6-month) efficacy and safety of leuprolide acetate 3-month depot 11.25 and 30 mg in children with central precocious puberty (CPP). To assess long-term (36-month) hypothalamic-pituitary-gonadal axis suppression and safety of leuprolide acetate 3-month depot 11.25 and 30 mg in children with CPP. Open-label, 36-month extension. Twenty pediatric endocrine centers. Seventy-two children (mean age, 8.5 ± 1.6 y; 65 females) with CPP completed and showed maintenance of LH suppression after a 6-month lead-in study. Leuprolide acetate depot (11.25 or 30 mg) administered im every 3 months. Peak-stimulated LH, estradiol, T, growth rate, pubertal progression, and adverse events (AEs). Twenty-nine of 34 subjects in the 11.25-mg group and 36 of 38 subjects in the 30-mg group had LH values < 4 mIU/mL after day 1 at all time points. All seven subjects who escaped LH suppression at any time still maintained sex steroid concentrations at prepubertal levels and showed no signs of pubertal progression. AEs were comparable between groups, with injection site pain being the most common (26.4% overall). No AE led to discontinuation of study drug. The safety profile over 36 months was comparable to that observed during the 6-month pivotal study. The two doses of leuprolide acetate 3-month depot were associated with an acceptable safety profile and provided maintenance of LH suppression in the majority of children with CPP during the 36 months of the study or until readiness for puberty.

An Under-Recognized and Under-Reported Cause of Adrenal Insufficiency

We report a unique case of potentially life-threatening secondary adrenal insufficiency in a 58year-old female who was maintained on a high dose fentanyl patch and hydrocodone for many years for chronic back pain. She presented to the emergency room (ER) with severe hypotension, weight loss and fatigue. We suspected hypothalamic-pituitary-adrenal (HPA) axis suppression induced by chronic use of opioids. Subsequently, after appropriate laboratory investigations, she was diagnosed with secondary adrenal insufficiency attributed to chronic opiate use. We discontinued the hydrocodone, decreased the dose of her fentanyl patch and began oral prednisone. The patient responded to treatment and her symptoms were resolved as seen on an outpatient follow up visit three months later. Currently, she is off prednisone and is doing well without demonstrating any symptoms or signs of adrenal insufficiency. Physicians must be aware of this potentially life- threatening side effect of opioid medications and should discourage long term opiate use. To the best of our knowledge, this is the first case report in the United States showing opioid-induced secondary adrenal insufficiency.

Hypothalamo–pituitary–adrenal axis, glucose metabolism and TNF‐α in narcolepsy

Narcolepsy with cataplexy is caused by a deficiency in the production of hypocretin/orexin, which regulates sleep and wakefulness, and also influences appetite, neuroendocrine functions and metabolism. In this case-control study, 11 patients with narcolepsy with cataplexy and 11 healthy adults underwent an oral glucose tolerance test, and dexamethasone suppression/corticotropin-releasing hormone stimulation test. The average age of patients and controls was 35.1 ± 13.2 and 41.0 ± 2.9 years, respectively, body mass index was 28.1 ± 6.6 and 25.5 ± 4.7 kg m(-2) . We did not find evidence of a significantly increased prevalence of disturbed glucose tolerance in patients with narcolepsy. After hypothalamo-pituitary-adrenal axis suppression, the number of non-suppressors did not differ between the groups, indicating normal negative feedback sensitivity. The level of cortisol after dexamethasone suppression was significantly lower in patients with narcolepsy, suggesting a slight basal downregulation and/or a slightly increased negative feedback sensitivity of the major endocrine stress system in narcolepsy. Following corticotropin-releasing hormone stimulation, there were no significant differences in levels of adrenocorticotropic hormone or cortisol, and in adrenocortical responsivity to adrenocorticotropic hormone. Finally, patients with narcolepsy displayed significantly higher plasma levels of tumour necrosis factor alpha, soluble tumour necrosis factor receptor p55, soluble tumour necrosis factor receptor p75 and interleukin 6 after adjustment for body mass index. The present study confirms that narcolepsy by itself is not associated with disturbances of glucose metabolism, but goes along with a subtle dysregulation of inflammatory cytokine production. We also found that dynamic hypothalamo-pituitary-adrenal system response is not altered, whereas negative feedback to dexamethasone might be slightly enhanced.

Inhalational Steroids and Iatrogenic Cushing's Syndrome.

Bronchial asthma (BA) and Allergic rhinitis (AR) are common clinical problems encountered in day to day practice, where inhalational corticosteroids (ICS) or intranasal steroids (INS) are the mainstay of treatment. Iatrogenic Cushing syndrome (CS) is a well known complication of systemic steroid administration. ICS /INS were earlier thought to be safe, but now more and more number of case reports of Iatrogenic Cushing syndrome have been reported, especially in those who are taking cytochrome P450 (CYP 450) inhibitors. Comparing to the classical clinical features of spontaneous Cushing syndrome, iatrogenic Cushing syndrome is more commonly associated with osteoporosis, increase in intra-ocular pressure, benign intracranial hypertension, aseptic necrosis of femoral head and pancreatitis, where as hypertension, hirsuitisum and menstrual irregularities are less common. Endocrine work up shows low serum cortisol level with evidence of HPA (hypothalamo-pituitary-adrenal) axis suppression. In all patients with features of Cushing syndrome with evidence of adrenal suppression always suspect iatrogenic CS. Since concomitant administration of cytochrome P450 inhibitors in patients on ICS/INS can precipitate iatrogenic CS, avoidance of CYP450 inhibitors, its dose reduction or substitution of ICS are the available options. Along with those, measures to prevent the precipitation of adrenal crisis has to be taken. An update on ICS-/INS- associated iatrogenic CS and its management is presented here.

Cancer-related fatigue: can it be due to adrenal suppression secondary to high-dose steroids used as antiemetic?

To the editor: The use of dexamethasone for cancer-related fatigue (CRF) in patients with advanced cancer is a controversial issue. Beneficial effects of dexamethasone may be counterbalanced by its serious side effects. The exact mechanism of the action of steroids on cancer-related fatigue is unknown. Recently, Yennurajalingam et al. hypothesized that dexamethasone exerts its effects on CRF mainly by interfering with the peripheral effects of proinflammatory cytokines [1]. We believe that this may not be the case for some of patients with CRF. The exact pathogenesis of CRF is unknown. A role of systemic inflammation or imbalance between hypothalamicpituitary-adrenal (HPA) axis and systemic cytokines has been proposed [2, 3]. Advanced stage cancer represents a state of chronic stress. Low levels of endogenous cortisol, which may be associated with symptoms in advanced cancer, had been demonstrated by Lundstrom et al. [4]. Major symptoms of adrenal insufficiency (i.e., fatigue, nausea, loss of appetite) may be misinterpreted as CRF. Indeed, some patients treated for CRF may have unrecognized adrenal insufficiency. High dose of dexamethasone (8–16 mg/day) is commonly used as antiemetic therapy in highly and moderately emetic regimens. Updated ASCO guidelines on antiemetics recommend a 4-day course of dexamethasone (12 mg on day 1 and 8 mg on days 2–4) for highly emetogenic chemotherapy and 1–3-day 8 mg course for moderately emetogenic chemotherapy [5]. Highdose steroids may suppress the hypothalamic pituitary and adrenal axis, even with short-term use [6]. Han et al. published their article on adrenal suppression related to the use of dexamethasone as an antiemetic therapy in patients with cancer in July 2012 [7]. Patients receiving dexamethasone as an antiemetic for at least 3 days per cycle and for more than 3 months were included in this study. Adrenal suppression was demonstrated biochemically in 45 of the 103 patients (43.7 %). Adrenal suppression was more common in patients receiving megestrol acetate concomitantly. Daily replacement therapy with 7.5–10 mg of prednisolone for 1–2 weeks in patients with suppressed HPA axis resulted in the improvement of symptoms associated with adrenal insufficiency. This dose of prednisolone is approximately equivalent to 1 mg of dexamethasone [8]. This is about one eighth of the dose recommended in the study of Yennurajalingam et al. We believe that this lower dose may allow the use of steroid for longer periods and spare some of the patients with CRF from serious side effects of higher doses of steroids. Metabolic (i.e., hyperglycemia, hypokalemia) and muscular side effects (i.e., proximal muscle weakness) of long-term use of steroids may be confused with CRF or even increase the severity of CRF. Lower dexamethasone dose will probably cause less metabolic and muscular side effects. For those patients with continuing symptoms of CRF, steroid dose may be gradually increased. In the current study, no follow up for the quality of life was made after cessation of dexamethasone [1]. As CRF is a chronic problem, symptoms may become worse after cessation of high-dose dexamethasone. Lesser dose of dexamethasone may be used more safely for longer periods of time for some patients with this chronic problem. There are still unanswered questions about CRF: What should be done for patients without biochemical evidence of HPA axis suppression? Should we search for biochemical evidence of inflammation (i.e., C-reactive protein) in this group of patients? Should we start with higher doses of dexamethasone when we have laboratory evidence of both systemic inflammation and HPA axis suppression? Should adrenal insufficiency be in the routine checklist of evaluation O. O. Eren (*) :B. Oyan Medical Oncology Section, Department of Internal Medicine, Yeditepe University Hospital, Devlet yolu, Ankara Caddesi, 102-104 Istanbul, Turkey e-mail: droneren@hotmail.com

Mitigation and Education

Mitigation and Education

Suppressive effects of long-term treatment with inhaled steroids on hypothalamic-pituitary-adrenal axis in asthma

Purpose: Long-term treatment with inhaled steroids (ICS), especially fluticasone that developed lately, may suppress the hypothalamic- pituitary-adrenal (HPA) axis. This study investigated the relationship between ICS use and HPA axis suppression in asthmatics under ICS treatment for average 4.5 years. Methods: The medical records of 129 adult asthmatics who received ICS treatment for 6 months or more and underwent a corticotropin stimulation test from January 2005 to August 2013 were retrospectively reviewed. Results: The patients received ICS only (n=87) were found to have an abnormal response to the corticotropin test in as high as 32.2%, and those received ICS in combination with oral steroids (n=42) had a significantly higher prevalence of the response (71.4%, P<0.001). Abnormal responses to corticotropin occurred depending on ICS daily doses (low, n=8, 12.5%; medium, n=19, 36.8%; high, n=102, 49.0%; X2=4.384, P=0.036). Among the subjects received ICS only, nasal steroid doses (P=0.016) but not ICS doses (P=0.159) were significantly higher in those with abnormal responses than the others. Among all the subjects, oral steroid use (odds ratio [OR], 4.27; 95% confidence interval [CI], 2.35.11.80; P<0.001) and nasal steroid dose (OR, 1.02; 95% CI, 1.00.1.04; P=0.015) were significant risk factors for HPA axis suppression. Conclusion: One-third of asthmatics under long-term treatment with ICS showed a suppression of the HPA axis in a dose-dependent manner. Oral or nasal steroid use may be a risk factor for the suppression. However, since our results may have been overestimated due to subject selection bias, further prospective case-control studies are warranted. (Allergy Asthma Respir Dis 2014;2:285-292)

Epidural Complications and troubleshooting

Epidural corticosteroid infiltrations are an important option for the treatment of pain, though they are not without complications. The present review was based on a PubMed database search of articles covering the period between 1983 and 2014. The described complications can be grouped into the following categories: (1) Infections: The global risk of infections following epidural corticosteroid infiltration is 1%–2%, of which 0.1% prove serious. (2) Neurologic alterations: These complications are due to neurotoxicity (arachnoiditis or aseptic meningitis) or intra-arterial puncture and embolization of particulate corticosteroids in vertebral arteries, resulting in spinal or cerebral infarction. (3) Bleeding: The principal risk factor for epidural hematoma is primary or pharmacologic coagulopathy. Therefore, the decision to suspend treatment must be made according to the consensus-based clinical guides. (4) Post–dural puncture headache: The development of headache in these cases is less frequent than following epidural anesthesia. (5) Pharmacologic effects of corticosteroids: Adrenal axis suppression during 3 weeks may be observed. This has been associated with Cushing-like symptoms, mineralocorticoid effects (arterial hypertension), and blood glucose level elevation in diabetic patients. (6) Others: There have been reports of diminished bone mass in postmenopausal women and isolated cases of chorioretinopathy and Tachon syndrome. Epidural corticosteroid infiltration performed under radioscopic control and with contrast administration can minimize the risk of complications.

Testosterone and glucose metabolism in men: current concepts and controversies

A wealth of observational studies show that low testosterone is associated with insulin resistance and with an increased risk of diabetes and the metabolic syndrome. Experimental studies have identified potential mechanisms by which low testosterone may lead to insulin resistance. Visceral adipose tissue is an important intermediate in this relationship. Actions of testosterone or its metabolite oestradiol on other tissues such as muscle, liver, bone or the brain, and body composition-independent effects may also play a role. However, definitive evidence from randomised controlled trials (RCTs) to clarify whether the association of low testosterone with disordered glucose metabolism is causative is currently lacking. It therefore remains possible that this association is due to reverse causation, or simply originates by association with common health and lifestyle factors. RCTs of testosterone therapy in men with or without diabetes consistently show modest metabolically favourable changes in body composition. Despite this, testosterone effects on glucose metabolism have been inconsistent. Recent evidence suggests that the hypothalamic-pituitary-testicular axis suppression in the majority of obese men with metabolic disorders is functional, and may be, at least in part, reversible with weight loss. Until further evidence is available, lifestyle measures with emphasis on weight reduction, treatment of comorbidities and optimisation of diabetic control should remain the first-line treatment in these men. Such measures, if successful, may be sufficient to normalise testosterone levels in men with metabolic disorders, who typically have only modest reductions in circulating testosterone levels.

Hypothalamo–pituitary–adrenal axis, glucose metabolism and TNF-α in narcolepsy

Narcolepsy with cataplexy is caused by a deficiency in the production of hypocretin, which regulates sleep and wakefulness and also influences appetite, neuroendocrine functions and metabolism. In this case-control study 11 patients with narcolepsy and cataplexy and 11 healthy adults underwent an oral glucose tolerance test and dexamethason-inhibition cortisol releasing hormone stimulation test. The average age of patients and controls was 35.1 ± 13.2 and 41.0 ± 2.9 years, respectively, the body mass index (BMI) 28.1 ± 6.6 and 25.5 ± 4.7. We did not find evidence of a significantly increased prevalence of disturbed glucose tolerance in narcolepsy patients. After hypothalamo-pituitary–adrenal axis suppression, the number of non-suppressors did not differ between the groups, indicating normal negative feedback sensitivity. The level of cortisol after dexamethason suppression was significantly lower in narcoleptic patients suggesting a slight basal down-regulation and/or a slightly increased negative feedback sensitivity of the major endocrine stress system in narcolepsy. Following CRH stimulation, there were no significant differences in levels of ACTH or cortisol, and in adrenocortical responsivity to ACTH. Finally, narcoleptic patients displayed significantly higher plasma levels of TNF- α , solubleTNFR p55, soluble TNFR p75 and IL-6 after adjustment for BMI. The present study confirms that narcolepsy by itself is not associated with disturbances of glucose metabolism, but goes along with a subtle dysregulation of inflammatory cytokine production. We also found that dynamic HPA system response is not altered, whereas negative feedback to dexamethasone might be slightly enhanced. This study was supported by the grant of the Czech Ministry of Health NT 13238-4/2012, PRVOUK-P26/LF1/4 and by the European Union Framework 6 (MCRTN-CT-2004-512362).

Recommendations for pimecrolimus 1% cream in the treatment of mild-to-moderate atopic dermatitis: from medical needs to a new treatment algorithm

Pimecrolimus 1% cream is an effective, non-corticosteroid, topical anti-inflammatory treatment for atopic dermatitis (AD). The aim of this article was to review published clinical data that have examined how pimecrolimus can address the medical needs of AD patients. Clinical studies have demonstrated that early treatment with pimecrolimus decreases the progression to disease flares, rapidly improves pruritus and significantly enhances quality of life. Patients find the formulation easy to apply, which may result in improved adherence with the treatment regimen. Pimecrolimus, in contrast to topical corticosteroids (TCSs), does not induce skin atrophy or epidermal barrier dysfunction and is highly effective for the treatment of AD in sensitive skin areas. Furthermore, pimecrolimus reduces the incidence of skin infections compared with TCSs and is not associated with other TCS-related side effects such as striae, telangiectasia and hypothalamic-pituitary-adrenal axis suppression. An additional benefit of pimecrolimus is its substantial steroid sparing effect. On the basis of these data, a new treatment algorithm for patients with mild-to-moderate AD is proposed in which pimecrolimus is recommended as a first line therapy for patients with established mild AD at the first signs and symptoms of disease. Pimecrolimus is also recommended for mild-to-moderate AD after initial treatment with a TCS. After resolution of lesions, maintenance treatment with pimecrolimus may effectively prevent subsequent disease flares. In conclusion, the clinical profile of pimecrolimus suggests that it may be considered the drug of choice for the treatment of mild-to-moderate AD in children as well as adults and particularly in sensitive skin areas.