Addison’s disease or primary adrenal insufficiency is a syndrome characterized by wasting of and hyperpigmentation, due to destruction of the adrenal glands resulting in inadequate secretion of mineralocorticoids and glucocorticoids (1). The goal of the treatment is to replace glucocorticoid that will permit a reasonable quality of life (2, 3). However, with the current replacement strategies, physiological replacement cannot be restored and also no objective laboratory parameter has proven to be reliable for monitoring replacement quality. Here, we describe a case not only with high plasma ACTH level also with symptoms of both hypercortisolism and hypocortisolism together under the conventional therapy and which was successfully treated by mimicking physiological diurnal cortisol secretion of the patient.

Case Report

A 24-year-old man with a diagnosis of Addison’s disease and who was on replacement therapy with oral administration of 7.5 mg prednisolone (5 mg in the morning and 2.5 mg in the afternoon) and 0.05 mg fludrocortisone daily) for about two years was admitted to our clinic with complaints of weakness and progressive darkening of his skin. His past medical history was unremarkable except for a liver biopsy under steroid coverage due to high liver function tests and HbsAg positivity a year ago. The result was macro and microvascular type steatohepatitis. On physical examination, his skin was deeply pigmented as were his mucous membranes and, on his abdomen and axilla, there were pink purple striae which were >1 cm in depth (Figure 1). Central obesity was also observed. Supine blood pressure was 120/70 mmHg, and he had no orthostatic hypotension. Initial laboratory examination showed normal urinalysis, blood chemistry, and basal pituitary hormones with secondary peripheral hormones except low plasma cortisol and elevated ACTH levels under the prednisolone therapy (Table 1). There was no anemia, total and differential leukocyte counts were normal. He was transferred to Baskent University Hospital to investigate the cause of high ACTH. First, urinary 17-hydroxycorticosteroid (17 OHCS) level was measured which was normal (11.72 mg/day, normal: 9.00-22.00 mg/day). Plasma ACTH levels were not suppressed to less than 10 pg/ml by the administration of 2 mg and 8 mg dexamethasone (divided into four times a day) (18.5 pg/ml and 11.9 pg/ml, respectively). Plasma levels of cortisol were suppressed to 0.7 µg/dl either by 2 mg or 8 mg dexamethasone. Daily profiles of ACTH and cortisol during 7.5 mg prednisolone treatment and after withdrawal of the therapy showed that ACTH was high all day and cortisol was high in a short period (Figure 2 and 3). When morning prednisolone replacement was stopped, plasma ACTH levels elevated throughout a 24-hour period. With exogenous prednisolone replacement, plasma ACTH levels fell slightly above normal in the morning but not in the afternoon. Gadolinium-diethylene triamine penta-acetic acid (Gd-DTPA)-enhanced magnetic resonance imaging (MRI) of the pituitary showed microadenoma or hyperplasia measuring 6 x 4 mm on the right side of the pituitary gland (Figure 4). Pituitary imaging was totally normal a year before. Therapy was changed to 20 mg hydrocortisone (10 mg in the morning, 5 mg at noon and 5 mg in the afternoon) and 0.25 mg dexamethasone at 23:00 instead of 7.5 mg prednisolone. Fludrocortisone was continued at the same dose. ACTH levels were suppressed to 543 pg/ml, 218 pg/ml and 251 pg/ml 1, 3 and 6 months later, respectively. After the 6 months of new replacement therapy, MRI of the brain showed no microadenoma or hyperplasia. Systemic pigmentation, abdominal obesity and straie faded and weakness improved during therapy.


In this report, we describe a case of hypersecretion of ACTH during replacement therapy with prednisolone in a patient with Addison’s disease. In those patients, although 24-hour ACTH level is high, circadian ACTH periodicity is intact (4). In our patient, when prednisolone replacement was stopped, plasma ACTH levels elevated throughout the day as expected. However, during therapy, ACTH was highest in the morning and fell slightly after prednisolone and started to rise in the early morning, meaning that circadian ACTH periodicity was not intact. Furthermore, plasma ACTH levels were not suppressed to less than 10 pg/ml by the administration of 2 mg and 8 mg dexamethasone. This inadequate ACTH suppression could be due to reduced sensitivity of the corticotrophs in the pituitary gland in which microadenoma or hyperplasia was illustrated in our case. The noteworthy difference between our case and the literature is hypercortisolemic findings with pituitary hyperplasia or adenoma.

Like in our patient, the most commonly used glucocorticoid replacement regimen is in two daily doses of administration, with a half to two-thirds administered in the morning and second dose 6-8 hour after the first one to mimic the physiological cortisol secretion pattern. Nevertheless, recent studies concluded that most patients require only a daily dose of hydrocortisone ~20 mg t.i.d (5,6) to obtain as optimal daytime cortisol profiles as possible and also improved quality of life. However, Plat et al. (7) have demonstrated a more unfavorable metabolic response to evening administration of hydrocortisone.

Long-acting glucocorticoids are also recommended for replacement therapy due to more stable glucocorticoid effect throughout the day and night (8). Similar to that in our country, some do not have access easily to hydrocortisone or cortisone acetate, and therefore, have to resort to long-acting synthetic glucocorticoids. However, prednisolone and dexamethasone have much longer biological half-lives than hydrocortisone and cortisone acetate, resulting in unfavorably high night-time glucocorticoid activity with potentially detrimental effects, especially on insulin sensitivity and bone mineral density (9,10). In our case, with two doses of prednisolone therapy plasma cortisol was >10 µg/dl only after morning dosage. Therefore, use of synthetic glucocorticoids for replacement therapy in adrenal insufficiency is not recommended generally.

Since monitoring of glucocorticoid replacement is mainly based on clinical grounds, a reliable biomarker for glucocorticoid activity has not yet been identified. In primary adrenal insufficiency, ACTH is invariably high before the morning dose and rapidly declines with increasing cortisol levels after glucocorticoid ingestion (11). Aiming at ACTH levels within the normal range, therefore, would result in over replacement. Urinary cortisol excretion shows considerable interindividual variability in patients on chronic glucocorticoid replacement (12). By some authors, serum cortisol day curves have been advocated as the best objective measures of the glucocorticoid replacement therapy (5,6). Also in our case, cortisol day curve findings were relieved to manage new glucocorticoid replacement regimen that resulted with disappearance of pituitary hyperplasia or adenoma although the ACTH levels were higher than 80 pg/ml during follow-up.

In almost all cases, ACTH-producing hyperplasia or adenoma were appeared with high plasma ACTH level and persistent hyperpigmentation after several years of conventional steroid replacement and most of these were treated with transsphenoidal surgery. The risk-bearing group for such situation is patients with long disease duration, hypethyroidism, drug usage that increase clearance of corticosteroids, physical or emotional stress and pregnancy. In our patient, inappropriate secretion of ACTH from a corticotroph adenoma or hyperplasia in a brief period may be described by inappropriate replacement with synthetic glucocorticoid. In such cases, early serum cortisol day curve should be used to treat the patient medically without surgery.

However, there is no evidence to show if one treatment option is better than the other. Comparative studies of different glucocorticoids are therefore clearly warranted. None of these glucocorticoid replacement regimens satisfactorily mimic the normal diurnal biorhythm of cortisol, therefore, development of sustained-release hydrocortisone tablets would probably prove beneficial.


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