Steroid Withdrawal Abstracts 2

©

Recovery of Adrenal Function in Patients with Glucocorticoids Induced Secondary Adrenal Insufficiency.
            (Baek et al., 2016) Download
BACKGROUND:  The chronic use of glucocorticoids (GC) suppresses function of the hypothalamic-pituitary-adrenal axis and often results in secondary adrenal insufficiency (AI). The present study aimed to determine the recovery rate of adrenal function in patients with secondary AI within 1 to 2 years and to assess the factors predictive of adrenal function recovery. METHODS:  This was a retrospective observational study that enrolled patients diagnosed with GC-induced secondary AI between 2007 and 2013. AI was defined by peak serum cortisol levels <18 μg/dL during a standard-dose short synacthen test (SST). A follow-up SST was performed after 1 to 2 years, and responders were defined as those with adrenocorticotropic hormone (ACTH)-stimulated peak serum cortisol levels ≥18 μg/dL. RESULTS:  Of the total 34 patients diagnosed with GC-induced secondary AI at first, 20 patients (58.8%) recovered normal adrenal function by the time of the follow-up SST (median follow-up period, 16.5 months). Although the baseline serum ACTH and cortisol levels at the first SST did not differ between responders and non-responders, the incremental cortisol response during the first SST was higher in responders than that of non-responders (7.88 vs. 3.56, P<0.01). Additionally, higher cortisol increments during the first SST were an independent predictive factor of the adrenal function recovery (odds ratio, 1.58; 95% confidence interval, 1.02 to 2.46; P<0.05). CONCLUSION:  In the present study, adrenal function recovery was achieved frequently in patients with GC-induced secondary AI within 1 to 2 years. Additionally, an incremental cortisol response at the first SST may be an important predictive factor of adrenal function recovery.

2014 update of recommendations on the prevention and treatment of glucocorticoid-induced osteoporosis.
            (Briot et al., 2014) Download
OBJECTIVES:  To update the recommendations on the prevention and treatment of glucocorticoid-induced osteoporosis issued in 2003 by the French National Authority for Health (HAS). This update was performed under the aegis of the Bone Section of the French Society for Rheumatology (SFR) and Osteoporosis Research and Information Group (GRIO), in collaboration with four French learned societies (primary-care, gastroenterology, internal medicine, and nephrology). METHODS:  A task force composed of members of the medical specialties involved in managing patients with glucocorticoid-induced osteoporosis conducted a systematic literature review according to the method developed by the HAS then used the results to develop updated recommendations. RESULTS:  These recommendations are intended for all physicians involved in the management of patients who are scheduled to start, or are taking, long-term glucocorticoid therapy (≥ 3 months) in any dose and for any reason. In postmenopausal women and men older than 50 years of age, treatment is warranted in the presence of any of the following risk factors for fracture: history of bone frailty fracture after 50 years of age, bone mineral density T-score ≤ −2.5 at one or more sites, age ≥ 70 years, and dosage ≥ 7.5 mg/d prednisone-equivalent for longer than 3 months. Bisphosphonates can be used in all these situations; teriparatide can be given as first-line therapy in patients at high fracture risk but is reimbursed by the French statutory health insurance system only in patients having two or more prevalent vertebral fractures. The fracture risk is lower in non-menopausal women and in men younger than 50 years of age,in whom treatment decisions should rest on a case-by-case evaluation. CONCLUSION:  These recommendations are intended to clarify the pharmacological management of glucocorticoid-induced osteoporosis.

Glucocorticoid-induced osteoporosis.
            (Briot and Roux, 2015) Download
Corticosteroid-induced osteoporosis is the most common form of secondary osteoporosis and the first cause in young people. Bone loss and increased rate of fractures occur early after the initiation of corticosteroid therapy, and are then related to dosage and treatment duration. The increase in fracture risk is not fully assessed by bone mineral density measurements, as it is also related to alteration of bone quality and increased risk of falls. In patients with rheumatoid arthritis, a treat-to-target strategy focusing on low disease activity including through the use of low dose of prednisone, is a key determinant of bone loss prevention. Bone loss magnitude is variable and there is no clearly identified predictor of the individual risk of fracture. Prevention or treatment of osteoporosis should be considered in all patients who receive prednisone. Bisphosphonates and the anabolic agent parathyroid hormone (1-34) have shown their efficacy in the treatment of corticosteroid-induced osteoporosis. Recent international guidelines are available and should guide management of corticosteroid-induced osteoporosis, which remains under-diagnosed and under-treated. Duration of antiosteoporotic treatment should be discussed at the individual level, depending on the subject's characteristics and on the underlying inflammation evolution.


 

Why is the management of glucocorticoid deficiency still controversial: a review of the literature.
            (Crown and Lightman, 2005) Download
All endocrinologists would like to make glucocorticoid replacement therapy for their hypoadrenal patients as physiological as possible. Many would like the reassurance of a method of monitoring such treatment to confirm that they are achieving this aim. Advances in our knowledge of the normal physiology are relevant to our attempts to do this. The cortisol production rate in normal subjects is lower than was previously believed. The normal pattern of glucocorticoid secretion includes both a diurnal rhythm and a pulsatile ultradian rhythm. Glucocorticoid access to nuclear receptors is 'gated' by the 11-beta-hydroxysteroid dehydrogenase enzymes, which interconvert active cortisol and inactive cortisone. Such complexities make the target of physiological glucocorticoid replacement therapy hard to achieve. The available evidence suggests that conventional treatment of hypoadrenal patients may result in adverse effects on some surrogate markers of disease risk, such as a lower bone mineral density than age-sex matched controls, and increases in postprandial glucose and insulin concentrations. Although the quality of life of hypoadrenal patients may be impaired, there is no evidence of an improvement on higher doses of steroids, although quality of life is better if the hydrocortisone dose is split up, with the highest dose taken in the morning. Thus the evidence suggests that most patients may safely be treated with a low dose of glucocorticoid (e.g. 15 mg hydrocortisone daily) in two or three divided doses, with education about the appropriate action to take in the event of intercurrent illnesses.

On the various forms of corticosteroid withdrawal syndrome.
            (Dixon and Christy, 1980) Download
Five patients who had received corticosteroids for periods of years experienced steroid withdrawal symptoms when attempts were made to reduce or discontinue the drugs. Summarized herein are studies of hypothalmic-pituitary-adrenocortical (HPA) function in these five people during corticosteroid withdrawal. Analysis of these data and of data in previous reports discloses four subgroups of corticosteroid withdrawal syndrome: Type I, symptomatic and biochemical evidence of HPA suppression; type II, recrudescence of the disease for which the drug was originally described; type III, dependence upon corticosteroids, either physical or psychological, with demonstrably normal HPA function and no recrudescence of underlying disease; and type IV, biochemical evidence of HPA suppression without symptoms and without recurrence of underlying disease. Any combination of types I, II and III may exist. The major conclusions are these five. (1) Some syndromes that clinically suggest HPA suppression are not. (2) Some syndromes that resemble drug-dependence are not. (3) The rapid ACTH test is a clinically useful way to assess HPA function; this test should govern the rate of corticosteroid withdrawal in the absence of steroid-treatable disease. (4) If disease is present, the rate and degree of corticosteroid withdrawal are governed by the status of the disease. (5) Patients have an unpredictable tendency to abuse corticosteroids; physicians should guard against inattentively permitting long-term, unnecessary overdosage to continue.

Estimation of maximal cortisol secretion rate in healthy humans.
            (Dorin et al., 2012) Download
CONTEXT:  Cortisol secretion is related to ACTH concentration by a sigmoidal dose-response curve, in which high ACTH concentrations drive maximal cortisol secretion rates (CSR(max)). OBJECTIVE:  We sought to estimate CSR(max) and free cortisol half-life in healthy humans (n = 21) using numerical methods applied to data acquired during cosyntropin (250 μg) stimulation. We also evaluated the effect of overnight dexamethasone (DEX; 1 mg) vs. placebo on estimates of CSR(max) and free cortisol half-life. DESIGN:  This study was a double-blind, placebo-controlled, randomized order of overnight DEX vs. placebo, cosyntropin (250 μg) stimulation with frequent serum cortisol sampling and computer-assisted numerical analysis. SETTING:  The study was conducted at a single academic medical center. PARTICIPANTS:  Twenty-one healthy adult subjects (15 females and six males), mean aged 46 yr, participated in the study. INTERVENTION:  Intervention in the study included DEX vs. placebo pretreatment, cosyntropin (250 μg) iv with frequent cortisol sampling. MAIN OUTCOME MEASURES:  CSR(max) and free cortisol half-life estimates, R² for goodness of fit, were measured. RESULTS:  Mean ± sd CSR(max) was 0.44 ± 0.13 nm/second, with free cortisol half-life of 2.2 ± 1.1 min. DEX did not significantly affect estimates of CSR(max) or free cortisol half-life. Our model accounts for most of the variability of measured cortisol concentrations (overall R² = 90.9 ±11.0%) and was more accurate (P = 0.004) during DEX suppression (R² = 94.6 ± 4.6%) compared with placebo (R² = 87.2 ± 8.7%). CONCLUSIONS:  Application of a mass-action model under conditions of cosyntropin stimulation provides a relatively simple method for estimation CSR(max) that accurately predicts measured cortisol concentrations. DEX administration did not significantly affect estimates of CSR(max) or free cortisol half-life.

EULAR evidence-based and consensus-based recommendations on the management of medium to high-dose glucocorticoid therapy in rheumatic diseases.
            (Duru et al., 2013) Download
To develop recommendations for the management of medium to high-dose (ie, >7.5 mg but ≤100 mg prednisone equivalent daily) systemic glucocorticoid (GC) therapy in rheumatic diseases. A multidisciplinary EULAR task force was formed, including rheumatic patients. After discussing the results of a general initial search on risks of GC therapy, each participant contributed 10 propositions on key clinical topics concerning the safe use of medium to high-dose GCs. The final recommendations were selected via a Delphi consensus approach. A systematic literature search of PubMed, EMBASE and Cochrane Library was used to identify evidence concerning each of the propositions. The strength of recommendation was given according to research evidence, clinical expertise and patient preference. The 10 propositions regarded patient education and informing general practitioners, preventive measures for osteoporosis, optimal GC starting dosages, risk-benefit ratio of GC treatment, GC sparing therapy, screening for comorbidity, and monitoring for adverse effects. In general, evidence supporting the recommendations proved to be surprisingly weak. One of the recommendations was rejected, because of conflicting literature data. Nine final recommendations for the management of medium to high-dose systemic GC therapy in rheumatic diseases were selected and evaluated with their strengths of recommendations. Robust evidence was often lacking; a research agenda was created.

Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry.
            (Esteban et al., 1991) Download
Growth retardation as well as the development of Cushingoid features in adrenally insufficient patients treated with the currently accepted replacement dose of cortisol (33-41 mumol/day.m2; 12-15 mg/m2.day) prompted us to reevaluate the cortisol production rate (FPR) in normal subjects and patients with Cushing's syndrome, using a recently developed thermospray liquid chromatography-mass spectrometry method. The stable isotope [9,12,12-2H3]cortisol was infused continuously for 31 h at about 5% of the anticipated FPR. Blood samples were obtained at 20-min intervals for 24 h, spun, and pooled in 4-h groups. Tracer dilution in plasma was determined by liquid chromatography/mass spectrometry. The method was validated with controlled infusions in 6 patients with adrenal insufficiency. Results from 12 normal volunteers revealed a FPR of 27.3 +/- 7.5 mumol/day (9.9 +/- 2.7 mg/day) or 15.7 mumol/day.m2; 5.7 mg/m2. day). A previously unreported circadian variation in FPR was observed. Patients with Cushing's syndrome demonstrated unequivocal elevation of FPR and cortisol concentration correlated during each sample period in normal volunteers, indicating that cortisol secretion, rather than metabolism, is mainly responsible for changes in plasma cortisol. Our data suggest that the FPR in normal subjects may be lower than previously believed.

Oral steroids in rheumatoid arthritis. Helpful but not remittive.
            (Iannuzzi, 1987) Download
Although low-dose oral corticosteroid therapy cannot be considered remittive, it has earned a place in the therapeutic armamentarium for rheumatoid arthritis. Major clinical trials of a group using corticosteroid compared with a control group have not been done since the 1950s. One of these three large trials showed some slowing of the destructive joint changes of rheumatoid arthritis with use of low doses of corticosteroid. However, these agents have well-known side effects, especially when used long-term. Elderly patients or those who have features of the disease that indicate progression (eg, multiple joint involvement, elevated ESR, early evidence of erosion on x-ray films) are likely to benefit from carefully controlled doses of a corticosteroid. Because these drugs diminish bone formation and arthritis itself accelerates osteoporosis, supplemental calcium and vitamin D are useful adjuncts. A remittive agent and aspirin-like drug should be prescribed along with the corticosteroid. Abrupt withdrawal of even a very low dose of corticosteroids in rheumatoid arthritis patients causes a flare.

Determination of cortisol production rates with contemporary liquid chromatography-mass spectrometry to measure cortisol-d(3) dilution after infusion of deuterated tracer.
            (Klopfenstein et al., 2011) Download
OBJECTIVES:  Measurement of 24-h cortisol production rate (CPR) using steady-state infusion of deuterated cortisol and analysis of stable-isotope dilution by MS is a valuable tool to examine hypothalamic-pituitary-adrenal axis activity in humans. We have developed and validated an improved method for measuring cortisol dilution with contemporary LC-MS technology. DESIGN AND METHODS:  Plasma samples and calibrators were extracted with ethylacetate. LC-MS was performed with a Surveyor HPLC and TSQ Quantum triple-quadrupole mass spectrometer equipped with an atmospheric pressure chemical ionization (APCI) source. RESULTS:  Selectivity was improved over previous methods via elimination of an interferent identified as 20β-dihydrocortisol. The LLOQ for cortisol-d(3) was 2.73nmol/L and LOD 1.37nmol/L. Plasma calibrators were linear over the concentration range 1.5-10% cortisol-d(3), with correlation coefficients >0.995. CONCLUSIONS:  This APCI LC-MS method offers simplified sample work-up and analysis and enables selective detection of the low concentration of cortisol-d(3) infused for determination of 24-h CPR.

Cortisol production rate in childhood and adolescence.
            (Linder et al., 1990) Download
We studied the daily cortisol production rate in 33 normal children and adolescents, using a stable isotope-dilution technique employing high-performance liquid chromatography-mass spectrometry. Two indwelling intravenous catheters were inserted and tracer 9,12,12-2H3-cortisol (deuterated cortisol) was infused continuously for 30 hours. After 6 hours of tracer infusion to allow for equilibration, blood was obtained every 20 minutes for 24 hours. The mean (+/- SD) cortisol production rate was 9.5 +/- 2.5 mg/day (6.8 +/- 1.9 mg/m2/day). Cortisol production rate did not vary with sex or pubertal stage. These results suggest that the cortisol production rate in children and adolescents is significantly lower than previously estimated.


 

Fifty years of experience with cortisone therapy in the study and treatment of rheumatoid arthritis.
            (Neeck, 2002) Download
In 1948 the U.S. rheumatologist Phillip S. Hench administered cortisone for the first time to a patient with rheumatoid arthritis (RA), thereby discovering the therapeutic effects of glucocorticoids. He published this observation together with Kendall, Slocumb, and Polly in 1949, and they received, along with Reichstein and Kendall, the Nobel Prize in Medicine or Physiology in 1950. However, as early as 1949, he rejected the idea that steroids were of etiological significance for RA, and instead stressed their unique place as a tool for pathophysiological research. The discovery of the glucocorticoid receptor and its genomic effects disclosed that there are no qualitative differences between the effects of endogenous cortisol and exogenously applied synthetic glucocorticoids, since all effects are transmitted via the same receptor. Later came the discovery that the hypothalamo-pituitary-adrenal axis is stimulated by cytokines after activation of the immune system. Glucocorticoids are not only the most effective antiphlogistic and immune-suppressive substances with instant effect, but they also show, with low-dosage long-term treatment, clear antiproliferative effects on the cartilage and bone destroying pannus in RA. Little is still known about the precise mechanisms of actions of glucocorticoids in general, and specifically when rheumatic autoimmune diseases are involved. The high effectiveness of these substances and their direct effects via the genomic glucocorticoid receptor allows us to anticipate that uncovering their mechanisms of action will shed deeper insight into the pathomechanisms of these diseases. The use of TNFalpha blockers in the treatment of rheumatoid arthritis and Crohn's disease, with their dramatic immediate effects, comparable with those of the glucocorticoids but without the side effects of the latter, points us in that direction.

Prevalence of oral glucocorticoid usage in the United States: a general population perspective.
            (Overman et al., 2013) Download
OBJECTIVE:  There is little information on oral glucocorticoid use in the general US population. Previously, there have been published estimates of glucocorticoid use in countries outside of the US. This study aimed to estimate the prevalence of glucocorticoid use, duration of use, and concomitant use of antiosteoporosis pharmaceuticals in the US population age ≥20 years. METHODS:  Data from 5 cycles (1999-2008) of the National Health and Nutrition Examination Survey (NHANES) were used to provide nationally representative weighted estimates. Oral glucocorticoids and concomitant use of antiosteoporosis pharmaceuticals (bisphosphonates, calcitonin, calcium, hormone replacement therapies, teriparatide, and vitamin D) were analyzed. RESULTS:  There were 356 NHANES respondents ages ≥20 years who reported use of an oral glucocorticoid in the combined cycles between 1999 and 2008. The weighted prevalence of oral glucocorticoid use was 1.2% (95% confidence interval [95% CI] 1.1-1.4) from 1999-2008, corresponding to 2,513,259 persons in the US. The mean duration of oral glucocorticoid use was 1,605.7 days (95% CI 1,261.2-1,950.1), and 28.8% (95% CI 22.2-35.4) of oral glucocorticoid users reported use for ≥5 years. Concomitant use of a bisphosphonate was reported by 8.6% (95% CI 5.1-11.7) of oral glucocorticoid users, and 37.9% (95% CI 31.7-44.0) reported usage of any antiosteoporosis pharmaceutical. CONCLUSION:  Based on NHANES data from 1999-2008, it is estimated that the prevalence of glucocorticoid use in the US is 1.2%, with a long duration of use and infrequent use of antiosteoporotic medications compared to other estimates.

Association of 24-hour cortisol production rates, cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult men and women.
            (Purnell et al., 2004) Download
The present study was designed to examine the hypothesis that hypothalamic-pituitary-adrenal axis activity as measured by 24-h cortisol production rate (CPR) and plasma levels of free cortisol is linked to increased body fat in adults, and that increased cortisol levels with aging results from increased CPR. Fifty-four healthy men and women volunteers with a wide range of body mass indexes and ages underwent measurement of CPR by isotope dilution measured by gas chromatography-mass spectroscopy, cortisol-binding globulin, and free cortisol in pooled 24-h plasma, body composition, and leptin. Cortisol clearance rates were determined from the 10-h disappearance curves of hydrocortisone after steady-state infusion in a separate group of lean and obese subjects with adrenal insufficiency. Although CPR significantly increased with increasing body mass index and percentage body fat, free cortisol levels remained independent of body composition and leptin levels due to increased cortisol clearance rates. CPR and free cortisol levels were, however, significantly higher in men than women. In addition, 24-h plasma free cortisol levels were increased with age in association with increased CPR, independent of body size. This increase in hypothalamic-pituitary-adrenal axis activity may play a role in the alterations in body composition and central fat distribution in men vs. women and with aging.

Secondary hypoadrenalism.
            (Reimondo et al., 2008) Download
Secondary adrenal insufficiency (SAI) is a clinical disorder that results from hypothalamic or hypophyseal damage or from prolonged administration of supraphysiological doses of glucocorticoids. Since glucocorticoids are widely used for a variety of diseases, the prevalence of SAI is by far exceeding that of primary adrenal insufficiency. Although the presentation of adrenal insufficiency may be insidious and difficult to recognize, an appropriate adrenocortical hormone replacement could lead to a normal quality of life and longevity can be achieved. The spectrum of adrenal insufficiency ranges from overt adrenal crises to subtle dysfunctions in asymptomatic patients who may be at risk of developing acute adrenal insufficiency since their hypothalamic-pituitary-adrenal (HPA) axis cannot appropriately react to stress. Thus, identification of patients with subtle abnormalities of the HPA is mandatory for avoiding this life-threatening event in stressful conditions. The optimal tests and the optimal testing sequence for adrenal insufficiency are still matter of debate. Insulin tolerance test (ITT) could be the gold standard, as it tests the whole HPA axis, but there are some patients who pass the ITT failing the ACTH test. Various alternatives to the ITT, including the standard cosyntropin stimulation test (SST) and low-dose SST, have been proposed since the adrenal gland in SAI loses the capacity for a prompt response to ACTH stimulation. The standard ACTH dose, but not the 1 microg dose, increases adrenal blood flow and this may contribute to produce an early cortisol response of greater magnitude. Moreover, the loss of the early cortisol response to ACTH stimulation could be a specific property of adrenal insufficiency, thus being a sensitive and early marker of failing adrenal function. While the results of the SSTs are often positive in patients with long-standing and severe disease, in patients with mild or recent-onset SAI these tests, using either 250 microg or 1 microg ACTH, tend to give normal results; thus, a negative cosyntropin test result does not rule out the possibility of SAI. Further studies with a systematic comparison of the different tests in large series of patients submitted to a prolonged follow-up are needed to solve the controversy of the optimal diagnostic strategy of SAI.

 

Monitoring adverse events of low-dose glucocorticoid therapy: EULAR recommendations for clinical trials and daily practice.
            (van der Goes et al., 2010) Download
OBJECTIVE:  To develop recommendations on monitoring for adverse events (AEs) of low-dose glucocorticoid (GC) therapy (≤7.5 mg prednisone or equivalent daily) in clinical trials and daily practice. METHODS:  Literature was searched for articles containing information on incidence and monitoring of GC-related AEs using PubMed, EMBASE and Cochrane databases. Second, the authors searched for broad accepted guidelines on the monitoring of certain AEs (eg, WHO guidelines on screening for diabetes). Available data were summarised and discussed among experts (rheumatologists and patients) of the EULAR Task Force to decide which potential AEs should be monitored, how and at which interval. RESULTS:  Data on monitoring proved to be scarce; most articles were focused on therapeutic effects of GCs, not on occurrence and monitoring of AEs. Most recommendations had to be based on consensus. Those for clinical trials aimed at getting insights into incidence, prevalence and clinical relevance of AEs to create a comprehensive and valid AE-profile of GC therapy. The set of AEs to monitor is therefore more extensive, and often consists of assessments at baseline and at end of trials. Recommendations for daily practice are meant to protect patients from real dangers, which can be prevented or treated. Standard care monitoring needs NOT be extended for patients on low-dose GC therapy, except for osteoporosis (follow national guidelines), and baseline assessments of ankle edema, fasting blood glucose and risk factors for glaucoma. CONCLUSION:  Given the incompleteness of literature data, consensus-based recommendations on monitoring for GC-related AEs were created, separately for daily practice and clinical trials.

Animal models for glucocorticoid-induced postmenopausal osteoporosis: An updated review.
            (Zhang et al., 2016) Download
Glucocorticoid-induced postmenopausal osteoporosis is a severe osteoporosis, with high risk of major osteoporotic fractures. This severe osteoporosis urges more extensive and deeper basic study, in which suitable animal models are indispensable. However, no relevant review is available introducing this model systematically. Based on the recent studies on GI-PMOP, this brief review introduces the GI-PMOP animal model in terms of its establishment, evaluation of bone mass and discuss its molecular mechanism. Rat, rabbit and sheep with their respective merits were chosen. Both direct and indirect evaluation of bone mass help to understand the bone metabolism under different intervention. The crucial signaling pathways, miRNAs, osteogenic- or adipogenic- related factors and estrogen level may be the predominant contributors to the development of glucocorticoid-induced postmenopausal osteoporosis.

 


References

Baek, JH, et al. (2016), ‘Recovery of Adrenal Function in Patients with Glucocorticoids Induced Secondary Adrenal Insufficiency.’, Endocrinol Metab (Seoul), 31 (1), 153-60. PubMed: 26676337
Briot, K, et al. (2014), ‘2014 update of recommendations on the prevention and treatment of glucocorticoid-induced osteoporosis.’, Joint Bone Spine, 81 (6), 493-501. PubMed: 25455041
Briot, K and C Roux (2015), ‘Glucocorticoid-induced osteoporosis.’, RMD Open, 1 e000014. PubMed: 26509049
Crown, A and S Lightman (2005), ‘Why is the management of glucocorticoid deficiency still controversial: a review of the literature.’, Clin Endocrinol (Oxf), 63 (5), 483-92. PubMed: 16268798
Dixon, RB and NP Christy (1980), ‘On the various forms of corticosteroid withdrawal syndrome.’, Am J Med, 68 (2), 224-30. PubMed: 7355893
Dorin, RI, et al. (2012), ‘Estimation of maximal cortisol secretion rate in healthy humans.’, J Clin Endocrinol Metab, 97 (4), 1285-93. PubMed: 22337905
Duru, N, et al. (2013), ‘EULAR evidence-based and consensus-based recommendations on the management of medium to high-dose glucocorticoid therapy in rheumatic diseases.’, Ann Rheum Dis, 72 (12), 1905-13. PubMed: 23873876
Esteban, NV, et al. (1991), ‘Daily cortisol production rate in man determined by stable isotope dilution/mass spectrometry.’, J Clin Endocrinol Metab, 72 (1), 39-45. PubMed: 1986026
Iannuzzi, LP (1987), ‘Oral steroids in rheumatoid arthritis. Helpful but not remittive.’, Postgrad Med, 82 (5), 295-8, 300. PubMed: 3313340
Klopfenstein, BJ, et al. (2011), ‘Determination of cortisol production rates with contemporary liquid chromatography-mass spectrometry to measure cortisol-d(3) dilution after infusion of deuterated tracer.’, Clin Biochem, 44 (5-6), 430-34. PubMed: 21185275
Linder, BL, et al. (1990), ‘Cortisol production rate in childhood and adolescence.’, J Pediatr, 117 (6), 892-96. PubMed: 2104527
Neeck, G (2002), ‘Fifty years of experience with cortisone therapy in the study and treatment of rheumatoid arthritis.’, Ann N Y Acad Sci, 966 28-38. PubMed: 12114256
Overman, RA, JY Yeh, and CL Deal (2013), ‘Prevalence of oral glucocorticoid usage in the United States: a general population perspective.’, Arthritis Care Res (Hoboken), 65 (2), 294-98. PubMed: 22807233
Purnell, JQ, et al. (2004), ‘Association of 24-hour cortisol production rates, cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult men and women.’, J Clin Endocrinol Metab, 89 (1), 281-87. PubMed: 14715862
Reimondo, G, et al. (2008), ‘Secondary hypoadrenalism.’, Pituitary, 11 (2), 147-54. PubMed: 18418713
van der Goes, MC, et al. (2010), ‘Monitoring adverse events of low-dose glucocorticoid therapy: EULAR recommendations for clinical trials and daily practice.’, Ann Rheum Dis, 69 (11), 1913-19. PubMed: 20693273
Zhang, Z, et al. (2016), ‘Animal models for glucocorticoid-induced postmenopausal osteoporosis: An updated review.’, Biomed Pharmacother, 84 438-46. PubMed: 27685786