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Adrenal response to glucocorticoid treatment
CORRESPONDENCE
than 25 mg cortisone equivalents/day, there was little or no pituitary or adrenal suppression, leading to the suggestion that the undoubted therapeutic effect of sub-physiological doses of corticosteroids may be by an additive effect.2 Because of this clear evidence that pituitary or adrenal inhibition is associated with the dose of corticosteroid administered, the discrepant findings of Henzen and colleagues is likely to prove methodological. Sam Shuster East Gables, Double Street, Framlingham, IP13 9BN, UK 1
2
Henzen C, Suter A, Lerch E, Urbinelli R, Schorno XH, Briner VA. Suppression and recovery of adrenal reponse after short-term high-dose glucocorticoid treatment. Lancet 2000; 355: 542–45. Shuster S, Williams IA. Pituitary and adrenal function during administration of small doses of corticosteroids. Lancet 1961; ii: 674–458.
Sir—Christoph Henzen and coworkers’ study1 is very important because the transient inhibition of the hypothalamic-piruitary-adrenal axis in such conditions has been underestimated for many years. The return of normal adrenal responsiveness to low-dose corticotropin was observed within 2 weeks in most of the patients. An interesting observation was made in two patients who had suppressed adrenal response to 1 g (1–24) corticotropin, even at 3 months and 6 months. The diminished reserve of adrenal function was probably a result of inhibition of corticotropin releasing hormone (CRH) and corticotropin secretion, however, it is not clear why these two patients had this defect. Henzen and colleagues did not discuss this possibility. In the past 35 years we have treated 103 patients with hormonally active adrenal adenoma and a clinical picture of Cushing’s syndrome, who have had unilateral adrenalectomy.2 Postoperative secondary hypofunction of the remaining adrenal gland was common in this group of patients and adrenal function recovered gradually within 1–12 months in almost all the patients. However, in eight women a long-term (>2 years) secondary adrenal insufficiency was observed and a prolonged replacement therapy was necessary.3 A 2-day stimulation test with (1–24) corticotropin resulted in a good response in all eight patients, while low plasma corticotropin concentrations did not rise significantly during CRH stimulation tests. Concentrations of prolactin, leuteinising hormone, follicle-stimulating hormone, and free thyroxine were found to be
THE LANCET • Vol 355 • April 22, 2000
within normal limits. Prolonged hypothalamic-pituitary-adrenal axis suppression was seen in one patient and a slight hydrocortisone overdosing was suspected as a possible cause. Findings from pituitary-function studies by Gomez and colleagues4 suggest that the pituitary corticotrophy is not the rate limiting step in the postoperative recovery of adrenal activity in patients with Cushing’s syndrome treated by removal of adrenal adenoma. However, it is not clear whether this is the case for all patients in this population. We do not know why seven of over 300 women showed such a delay in the recovery of pituitary function. One may speculate that pituitary recovery depends on genetic factors: a small number of CRH-secreting cells or CRH mRNA in the hypothalamus or a smaller number of corticotroph cells and propiomelanocortin mRNA in the pituitary. We feel sure that our observations and those of Henzen and colleagues1 are not accidental and the rate of pituitary recovery needs to be clarified. Anna A Kasperlik-Saluska, Jadwiga Slowi´nska-Srzednicka Department of Endocrinology, Centre for Postgraduate Medical Education Ceglowska 80, 01-809 Warsaw, Poland 1
2
3
4
Henzen C, Suter A, Lerch E, Urbunelli R, Schomo XH, Briner VA. Supression and recovery of adrenal response after shortterm, high-dose glucocorticoid treatment. Lancet 2000; 355: 542–45. Kasperlik-Zaluska AA, Tolloczo T, Neilubowicz J, Migdalska B. Hormonally active adrenocortical tumours—surgical treatment results. Pol Przegl Chir 1992; 64: 699–706. Kasperlik-Zaluska AA, Makowska AM, Soszy´nski PA, Migdalska BM. Long-term adrenal insufficiency after the removal of adrenal adenoma in Cushing’s syndrome. Endokrynol Pol 1997; 48: 345–53. Gomez MT, Magiakou MA, Mastorakos G, Chrosous GP. The pituitary corticotroph is not the rate limiting step in the preoperative recovery of the hypothamic-pituitary-adrenal axis in patients with Cushing’s syndrome. J Clin Endocrinol Metab 1993; 77: 173–77.
corticotropin test shows extremely high sensitivity and specificity and generates significant changes from pretest to post-test probability of adrenal dysfunction.1 About a third of our patients received some of their glucocorticoid treatment as outpatients. We did not measure prednisolone to assess adherence to treatment. As Dominique Vanpee and Jean-Bernard Gillet, and Sam Shuster point out, the pharmacokinetics and the route of administration of glucocorticoids have important effects on the function of the hypothalamicpituitary-adrenal (HPA) axis. However, the dose and the duration of glucocorticoid treatment are not reliable indicators of a probable HPA deficiency.2,3 In the patients in our study who received short-term and high-dose glucocorticoid treatment, the adrenal response to corticotropin did not correlate to the duration and dose of glucocorticoid treatment, and there was no correlation to the preparation and administration of the glucocorticoids. In 72% of patients the glucocorticoids were given once a day, in the morning. In response to the comment by Anna Kasperlik-Zaluska and Jadwiga Slowinska-Srzednicka concerning long-term adrenal suppression after endogenous hypercortisolism: the results of a study by Schlaghecke and colleagues,2 in which the CRH test was used to assess the pituitary-adrenal function in patients receiving glucocorticoids, were comparable to our findings, suggesting that the locus of HPA deficiency resides higher than the pituitary corticotroph. However, there is still a lot of uncertainty about the function of the HPA axis in patients treated with glucocorticoids and other factors influencing the adrenal response need to be assessed.3,4 Christoph Henzen Department of Medicine, Kantonsspital Lucerne, CH-6000 Lucerne 16, Switzerland 1
Author’s reply Sir—We appreciate and agree with Donald Payne’s comment that a plasma cortisol concentration below 100 nmol/L is highly suggestive of adrenal suppression. In our study a basal plasma cortisol concentration of less than 185 nmol/L identified 21 of 34 patients with suppressed adrenal response, whereas a basal cortisol concentration of more than 220 nmol/L predicted a normal response in 41 of 52 patients. However, the low dose (1 g)
2
3
4
Thaler LM, Blevins LS. The low dose (1 g) adrenocorticotropin stimulation test in the evaluation of patients with suspected central adrenal insufficiency. J Clin Endocrinol Metab 1998; 83: 2726–29. Schlaghecke R, Kornley E, Santen RT, Ridderskamp P. The effect of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropinreleasing hormone. N Engl J Med 1992; 326: 226–30. Christy NP. Pituitary-adrenal function during corticosteroid therapy. N Engl J Med 1992; 326: 266–67. Livanou T, Ferriman D, James VHT. Recovery of hypothalamo-pituitary-adrenal function after corticosteroid therapy. Lancet 1967; ii: 856–59.
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than 25 mg cortisone equivalents/day, there was little or no pituitary or adrenal suppression, leading to the suggestion that the undoubted therapeutic effect of sub-physiological doses of corticosteroids may be by an additive effect.2 Because of this clear evidence that pituitary or adrenal inhibition is associated with the dose of corticosteroid administered, the discrepant findings of Henzen and colleagues is likely to prove methodological. Sam Shuster East Gables, Double Street, Framlingham, IP13 9BN, UK 1
2
Henzen C, Suter A, Lerch E, Urbinelli R, Schorno XH, Briner VA. Suppression and recovery of adrenal reponse after short-term high-dose glucocorticoid treatment. Lancet 2000; 355: 542–45. Shuster S, Williams IA. Pituitary and adrenal function during administration of small doses of corticosteroids. Lancet 1961; ii: 674–458.
Sir—Christoph Henzen and coworkers’ study1 is very important because the transient inhibition of the hypothalamic-piruitary-adrenal axis in such conditions has been underestimated for many years. The return of normal adrenal responsiveness to low-dose corticotropin was observed within 2 weeks in most of the patients. An interesting observation was made in two patients who had suppressed adrenal response to 1 g (1–24) corticotropin, even at 3 months and 6 months. The diminished reserve of adrenal function was probably a result of inhibition of corticotropin releasing hormone (CRH) and corticotropin secretion, however, it is not clear why these two patients had this defect. Henzen and colleagues did not discuss this possibility. In the past 35 years we have treated 103 patients with hormonally active adrenal adenoma and a clinical picture of Cushing’s syndrome, who have had unilateral adrenalectomy.2 Postoperative secondary hypofunction of the remaining adrenal gland was common in this group of patients and adrenal function recovered gradually within 1–12 months in almost all the patients. However, in eight women a long-term (>2 years) secondary adrenal insufficiency was observed and a prolonged replacement therapy was necessary.3 A 2-day stimulation test with (1–24) corticotropin resulted in a good response in all eight patients, while low plasma corticotropin concentrations did not rise significantly during CRH stimulation tests. Concentrations of prolactin, leuteinising hormone, follicle-stimulating hormone, and free thyroxine were found to be
THE LANCET • Vol 355 • April 22, 2000
within normal limits. Prolonged hypothalamic-pituitary-adrenal axis suppression was seen in one patient and a slight hydrocortisone overdosing was suspected as a possible cause. Findings from pituitary-function studies by Gomez and colleagues4 suggest that the pituitary corticotrophy is not the rate limiting step in the postoperative recovery of adrenal activity in patients with Cushing’s syndrome treated by removal of adrenal adenoma. However, it is not clear whether this is the case for all patients in this population. We do not know why seven of over 300 women showed such a delay in the recovery of pituitary function. One may speculate that pituitary recovery depends on genetic factors: a small number of CRH-secreting cells or CRH mRNA in the hypothalamus or a smaller number of corticotroph cells and propiomelanocortin mRNA in the pituitary. We feel sure that our observations and those of Henzen and colleagues1 are not accidental and the rate of pituitary recovery needs to be clarified. Anna A Kasperlik-Saluska, Jadwiga Slowi´nska-Srzednicka Department of Endocrinology, Centre for Postgraduate Medical Education Ceglowska 80, 01-809 Warsaw, Poland 1
2
3
4
Henzen C, Suter A, Lerch E, Urbunelli R, Schomo XH, Briner VA. Supression and recovery of adrenal response after shortterm, high-dose glucocorticoid treatment. Lancet 2000; 355: 542–45. Kasperlik-Zaluska AA, Tolloczo T, Neilubowicz J, Migdalska B. Hormonally active adrenocortical tumours—surgical treatment results. Pol Przegl Chir 1992; 64: 699–706. Kasperlik-Zaluska AA, Makowska AM, Soszy´nski PA, Migdalska BM. Long-term adrenal insufficiency after the removal of adrenal adenoma in Cushing’s syndrome. Endokrynol Pol 1997; 48: 345–53. Gomez MT, Magiakou MA, Mastorakos G, Chrosous GP. The pituitary corticotroph is not the rate limiting step in the preoperative recovery of the hypothamic-pituitary-adrenal axis in patients with Cushing’s syndrome. J Clin Endocrinol Metab 1993; 77: 173–77.
corticotropin test shows extremely high sensitivity and specificity and generates significant changes from pretest to post-test probability of adrenal dysfunction.1 About a third of our patients received some of their glucocorticoid treatment as outpatients. We did not measure prednisolone to assess adherence to treatment. As Dominique Vanpee and Jean-Bernard Gillet, and Sam Shuster point out, the pharmacokinetics and the route of administration of glucocorticoids have important effects on the function of the hypothalamicpituitary-adrenal (HPA) axis. However, the dose and the duration of glucocorticoid treatment are not reliable indicators of a probable HPA deficiency.2,3 In the patients in our study who received short-term and high-dose glucocorticoid treatment, the adrenal response to corticotropin did not correlate to the duration and dose of glucocorticoid treatment, and there was no correlation to the preparation and administration of the glucocorticoids. In 72% of patients the glucocorticoids were given once a day, in the morning. In response to the comment by Anna Kasperlik-Zaluska and Jadwiga Slowinska-Srzednicka concerning long-term adrenal suppression after endogenous hypercortisolism: the results of a study by Schlaghecke and colleagues,2 in which the CRH test was used to assess the pituitary-adrenal function in patients receiving glucocorticoids, were comparable to our findings, suggesting that the locus of HPA deficiency resides higher than the pituitary corticotroph. However, there is still a lot of uncertainty about the function of the HPA axis in patients treated with glucocorticoids and other factors influencing the adrenal response need to be assessed.3,4 Christoph Henzen Department of Medicine, Kantonsspital Lucerne, CH-6000 Lucerne 16, Switzerland 1
Author’s reply Sir—We appreciate and agree with Donald Payne’s comment that a plasma cortisol concentration below 100 nmol/L is highly suggestive of adrenal suppression. In our study a basal plasma cortisol concentration of less than 185 nmol/L identified 21 of 34 patients with suppressed adrenal response, whereas a basal cortisol concentration of more than 220 nmol/L predicted a normal response in 41 of 52 patients. However, the low dose (1 g)
2
3
4
Thaler LM, Blevins LS. The low dose (1 g) adrenocorticotropin stimulation test in the evaluation of patients with suspected central adrenal insufficiency. J Clin Endocrinol Metab 1998; 83: 2726–29. Schlaghecke R, Kornley E, Santen RT, Ridderskamp P. The effect of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropinreleasing hormone. N Engl J Med 1992; 326: 226–30. Christy NP. Pituitary-adrenal function during corticosteroid therapy. N Engl J Med 1992; 326: 266–67. Livanou T, Ferriman D, James VHT. Recovery of hypothalamo-pituitary-adrenal function after corticosteroid therapy. Lancet 1967; ii: 856–59.
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