Role of Ketoconazole Treatment in Urinary-Free Cortisol-to-Cortisone and Tetrahydrocortisol-to-Tetrahydrocortisone Ratios in Nonectopic Cushing's Syndrome

Abstract

We hypothesized that in nonectopic Cushing syndrome there is an insufficient activity of type II (renal) 11beta-hydroxysteroid dehydrogenase (11beta-HSD2) that is related to cortisol excess, rather than to corticotropin (adrenocorticotropic hormone [ACTH]) levels. We measured plasma ACTH and urinary-free cortisol (UFF), urinary-free cortisone (UFE), tetrahydrocortisol (UTHF), and tetrahydrocortisone (UTHE) in 24-h urine samples of 24 healthy subjects and 15 patients diagnosed with nonectopic Cushing syndrome. Then, in the group of patients, a new 24-h urine sample was collected after treatment with 800 mg daily of ketoconazole. The UFF/UFE and UTHF/UTHE ratios were calculated as an estimation of 11beta-HSD2 activity. The patients had an increase in both the UFF/UFE (19.95 +/- 10.3 vs 5.78 +/- 4.72 nmol/24 h; p < 0.0001) and UTHF/UTHE ratios (5.36 +/- 5.23 vs 1.39 +/- 0.95 nmol/24 h; p < 0.001). Both UFF/UFE and UTHF/UTHE ratios decreased after ketoconazole treatment (19.95 +/- 10.3 vs 12.2 +/- 6.9 nmol/24 h; p < 0.005; and 5.36 +/- 5.23 vs 1.62 vs 1.21 nmol/24 h; p < 0.001, respectively). The control subjects had a significant relationship between UFF and UFE (r = 0.70, p < 0.0001), and between UTHF and UTHE (r = 0.75, p < 0.0001) that did not exist in the patient group. After ketoconazole treatment, the decrease in cortisol excretion in the patient group allowed a positive and significant relation between UFF and UFE (r = 0.64, p < 0.01) and between UTHF and UTHE (r = 0.56, p < 0.05) to appear. There was not any significant relationship between either UFF/UFE or UTHF/UTHE ratios and plasma levels of ACTH.

The diagnostic performance of urinary free cortisol is better than the cortisol:cortisone ratio in detecting de novo Cushing's syndrome: the use of a LC–MS/MS method in routine clinical practice

“…Higher UFF:UFE ratios in CS patients suggest that there is 11-b-HSD2 saturation, which is typical of CS (5,8,16). If we divide our CS into two groups whose UFF:UFE ratios are higher or lower with respect to the local upper reference limit of 1.09, the group with the higher ratio showed elevated UFF levels.…”

“…In this study, UFF levels, routinely determined in our centre using the LC-MS/MS method, were compared among healthy subjects, CS patients, and non-CS patients presenting clinical features suggestive of hypercortisolism but with normal LNSC and cortisol !50 nmol/l after 1 mg DST. The diagnostic value of the UFF:UFE ratio was also assessed (5,9,16). This is the first work, to our knowledge, assessing healthy controls and a series of consecutive surgically confirmed CS patients as well as patients in whom the diagnosis of CS was excluded, with the intent of analyzing the sensitivity and specificity of UFF values measured using the LC-MS/MS method.…”

Role of the Renin-Angiotensin System and Aldosterone on Cardiometabolic Syndrome

“…Beside the role of aldosterone in hypertension, different studies have also examined the relationship between the mineralocorticoid receptor activation by steroids other than aldosterone, mainly cortisol, and hypertension. In this respect, we have previously described that cortisol is the steroid that stimulates the mineralocorticoid receptor in patients with Cushing's syndrome through a mechanism involving the saturation of the enzyme 11-hydroxysteroid dehydrogenase; in this case, a positive effect was observed when plasma levels of cortisol were decreased using ketoconazole; these mechanisms were also found to influence the circadian blood pressure pattern in patients with Cushing's syndrome (loss of the normal day-night blood pressure pattern) [77–79]. …”

Cyclic Cushing's syndrome: an overview

“…Currently-available drugs that inhibit steroidogenesis, e.g. mitotane, metyrapone, aminoglutethimide, and ketoconazole, can correct hypercortisolism, quickly normalizing the mean daily plasma cortisol levels in 75% of patients with CS but they have little impact on tumor growth and can induce hepatotoxicity (51,52).…”