Steroid Withdrawal Abstracts 1

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Withdrawal from glucocorticosteroid therapy: clinical practice recommendations.
            (Alves et al., 2008) Download
OBJECTIVE:  To present an up-to-date and practical review of how to safely withdraw glucocorticosteroid therapy. SOURCES:  A review of the published literature identified by searching the MEDLINE and LILACS databases (1997-2007), selecting the most representative articles on the subject. SUMMARY OF THE FINDINGS:  Three clinical situations may occur during glucocorticoid withdrawal: adrenal insufficiency secondary to negative feedback on the hypothalamic-pituitary adrenal (HPA) axis, steroid withdrawal syndrome and relapse of the disease for which the glucocorticoids were prescribed. Although there is no consensus on how to best discontinue prolonged glucocorticosteroid therapy, there is agreement that this withdrawal should be gradual. This article updates pediatricians on how to recognize these problems and provides recommendations on how to safely suspend glucocorticosteroid therapy. A brief review of the pharmacology of glucocorticoids is also presented. CONCLUSIONS:  There is no good predictive test for predicting the risk of adrenal insufficiency in patients who have been on corticosteroid therapy chronically. There is a need for prospective studies to assess the true incidence of this problem and to propose rational strategies for preventing it. The current recommendation is that patients who have been on chronic and/or high dose glucocorticoids should be administered glucocorticoids during stress situations unless the integrity of the HPA axis has been established by dynamic tests.

A study of the mechanism of the steroid withdrawal syndrome. Evidence for integrity of the hypothalamic-pituitary-adrenal system.
            (Amatruda et al., 1960) Download
These data indicate that, under the conditions studied, the hypothalamic-pituitary-adrenal system was intact following withdrawal of steroid-ACTH therapjr despite the development of withdrawal symptoms. The etiology and pathogenesis of the withdrawal symptoms in these patients remain to be elucidated.

Certain endocrine and metabolic facets of the steroid withdrawal syndrome.
            (Amatruda et al., 1965) Download
Since the steroid withdrawal syndrome could not be ascribed to either hypoadrenocorticism or hypoadrenocorticotropism, the possibilities of hypervitaminosis A, hypercalcemia, pancreatitis and pseudo- tumor cerebri were considered and excluded. The etiology and pathogenesis of the steroid withdrawal syndrome in these patients and in other clinical and experimental situations remain obscure.

Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself.
            (Dinsen et al., 2013) Download
Glucocorticoid therapy is widely used, but withdrawal from glucocorticoids comes with a potential life-threatening risk of adrenal insufficiency. Recent case reports document that adrenal crisis after glucocorticoid withdrawal remains a serious problem in clinical practice. Partly due to difficulties in inter-study comparison the true prevalence of glucocorticoid-induced adrenal insufficiency is unknown, but it might be somewhere between 46 and 100% 24h after glucocorticoid withdrawal, 26-49% after approximately one week, and some patients show prolonged suppression lasting months to years. Adrenal insufficiency might therefore be underdiagnosed in clinical practice. Clinical data do not permit accurate estimates of a lower limit of glucocorticoid dose and duration of treatment, where adrenal insufficiency will not occur. Due to individual variation, neither the glucocorticoid dose nor the duration of treatment can be used reliably to predict adrenal function after glucocorticoid withdrawal. Also the recovery rate of the adrenal glands shows individual variation, which may be why there is currently insufficient evidence to prove the efficacy and safety of different withdrawal regimens. Whether a patient with an insufficient response to an adrenal stimulating test develops clinically significant adrenal insufficiency depends on the presence of stress and resulting glucocorticoid demand and it is thus totally unpredictable and can change relative fast. Adrenal insufficiency should therefore always be taken seriously. Individual variation in hypothalamic-pituitary-adrenal axis function might be due to differences in glucocorticoid sensitivity and might be genetic. Further awareness of the potential side effect of withdrawal of glucocorticoid and further research are urgently needed.

Natural History Of Pituitary-Adrenal Recovery Following Long-Term Suppression With Corticosteroids.
            (Graber et al., 1965) Download
Plasma ACTH and 17-hy- droxycorticosteroid concentrations were measured at various intervals in patients recovering from prolonged pituitary suppression. Pituitary-adrenal recovery was found to follow a definite pattern requiring several months for completion. Initially, both ACTH and corticosteroid levels were relatively low, a situation similar to that seen in patients with hypopituitarism. Thereafter, plasma ACTH levels gradually increased until they were supernormal, but there was a lag of several months in the recovery of normal adrenal responsiveness. Despite the fact that the pituitary gland could secrete large quantities of ACTH and despite the fact that corticosteroid levels were subnormal, a diurnal rhythm was observed in ACTH levels with a decrease to low values during the latter por- tion of each day. After several months, cor- ticosteroid levels rose to normal, and soon thereafter plasma ACTH concentrations fell again to normal.

Epimedium flavonoids counteract the side effects of glucocorticoids on hypothalamic-pituitary-adrenal axis.
            (Huang et al., 2013) Download
Our previous studies demonstrated that the epimedium herb, when simultaneously used with GCs, counteracted suppressive effects of GCs on the HPA axis without adverse influence on the therapeutic action of GCs. Here, total flavones were extracted from the epimedium flavonoids (EFs) and then used to investigate whether EFs provide protective effects on the HPA axis. We found that GCs induced a significant decrease in body weight gain, adrenal gland weight gain, and plasma adrenocorticotropin (ACTH) and corticosterone levels. After treatment with EFs, body weight gain, adrenal gland weight gain, and plasma corticosterone level were significantly restored, whilst plasma ACTH level was partially elevated. EFs were also shown to promote cell proliferation in the outer layer of adrenal cortex and to enhance the migration of newly divided cells toward the inner layer. To elucidate the underlying mechanisms, the mRNA expression of insulin-like growth factor II (IGF-II) was measured, and EFs significantly upregulated IGF-II expression. Our results indicated that EFs counteract the suppression of the HPA axis induced by GCs. This may involve both the ACTH and IGF-II pathways and thereby promote regeneration of the adrenal cortex suggesting a potential clinical application of EFs against the suppressive effects of GCs on the HPA axis.

Systemic glucocorticoid therapy and adrenal insufficiency in adults: A systematic review.
            (Joseph et al., 2016) Download
OBJECTIVES:  The aim of this systematic literature review was to summarize the current knowledge regarding the prevalence of, time to recovery from, and influence of glucocorticoid dose and duration on glucocorticoid-induced adrenal insufficiency (AI). METHODS:  Eligible studies were original research articles, which included adult patients with an indication for glucocorticoids and measured adrenal function following exposure to systemic glucocorticoids. Searches were performed in Web of Science and MEDLINE, with further articles identified from reference lists. Screening was performed in duplicate. Data were extracted for each group of glucocorticoid-exposed patients within eligible studies. The reported proportion of patients with AI was summarized as median and inter-quartile range. Results were then stratified by daily dose, cumulative dose, duration of exposure and time since last glucocorticoid use. The risk of bias within and across studies was considered: for randomised controlled trials risk of bias was assessed using the tool developed by the Cochrane Collaboration. RESULTS:  Overall, 73 eligible studies were identified out of 673 screened. The percentage of patients with AI ranged from 0% to 100% with a median (IQR) = 37.4% (13-63%). Studies were small-median (IQR) group size 16 (9-38)-and heterogeneous in methodology. AI persisted in 15% of patients retested 3 years after glucocorticoid withdrawal. Results remained widely distributed following stratification. AI was demonstrated at <5mg prednisolone equivalent dose/day, <4 weeks of exposure, cumulative dose <0.5g, and following tapered withdrawal. CONCLUSIONS:  The heterogeneity of studies and variability in results make it difficult to answer the research questions with confidence based on the current literature. There is evidence of AI following low doses and short durations of glucocorticoids. Hence, clinicians should be vigilant for adrenal insufficiency at all degrees of glucocorticoid exposure.

The steroid withdrawal syndrome: a review of the implications, etiology, and treatments.
            (Margolin et al., 2007) Download
Steroid therapy is frequently used for chronic pain, particularly inflammatory pain states. Steroid withdrawal syndrome can produce a broad array of signs and symptoms, some of which are not well recognized. High fever is among these. We describe several cases with this clinical scenario and review the syndrome in broader terms.

[Nicotinamide as an effective agent against endogenous hypocorticism during prolonged corticosteroid therapy].
            (Vinogradov et al., 1981) Download
Radioimmunoassay was used in 30 patients (aged 19-40 years) with stage II rheumatism to examine ACTH level in blood plasma after one-week treatment with prednisolone (0.005 g 4 times a day per os) alone and in combination with nicotinamide (2 ml of 2.5% solution twice a day intramuscularly). It was shown that the stimulant action of nicotinamide on the hypophyseo-adrenocortical system distinctly manifested under the conditions of the patients’ body saturation with endogenous corticosteroids. Continuation of nicotinamide administration after withdrawal of hormonal therapy promoted the maintenance of the increased ACTH level in plasma and averted the development of hypocrticoidism.

 


References

Alves, C, TC Robazzi, and M Mendonça (2008), ‘Withdrawal from glucocorticosteroid therapy: clinical practice recommendations.’, J Pediatr (Rio J), 84 (3), 192-202. PubMed: 18535733
Amatruda, TT, et al. (1960), ‘A study of the mechanism of the steroid withdrawal syndrome. Evidence for integrity of the hypothalamic-pituitary-adrenal system.’, J Clin Endocrinol Metab, 20 339-54. PubMed: 13793101
Amatruda, TT, MM Hurst, and ND D’Esopo (1965), ‘Certain endocrine and metabolic facets of the steroid withdrawal syndrome.’, J Clin Endocrinol Metab, 25 (9), 1207-17. PubMed: 4284084
Dinsen, S, et al. (2013), ‘Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself.’, Eur J Intern Med, 24 (8), 714-20. PubMed: 23806261
Graber, AL, et al. (1965), ‘Natural History Of Pituitary-Adrenal Recovery Following Long-Term Suppression With Corticosteroids.’, J Clin Endocrinol Metab, 25 11-16. PubMed: 14252277
Huang, J, et al. (2013), ‘Epimedium flavonoids counteract the side effects of glucocorticoids on hypothalamic-pituitary-adrenal axis.’, Evid Based Complement Alternat Med, 2013 938425. PubMed: 24174984
Joseph, RM, et al. (2016), ‘Systemic glucocorticoid therapy and adrenal insufficiency in adults: A systematic review.’, Semin Arthritis Rheum, 46 (1), 133-41. PubMed: 27105755
Margolin, L, et al. (2007), ‘The steroid withdrawal syndrome: a review of the implications, etiology, and treatments.’, J Pain Symptom Manage, 33 (2), 224-28. PubMed: 17280928
Vinogradov, VV, et al. (1981), ‘[Nicotinamide as an effective agent against endogenous hypocorticism during prolonged corticosteroid therapy].’, Vopr Pitan, (5), 20-23. PubMed: 6274098