• 11 beta-Hydroxysteroid dehydrogenase activity in Cushing's syndrome: explaining the mineralocorticoid excess state of the ectopic adrenocorticotropin syndrome.

      Stewart, P M; Walker, B R; Holder, G; O'Halloran, Domhnall J; Shackleton, C H; Department of Medicine, Queen Elizabeth Hospital, Birmingham, United Kingdom. (1995-12)
      A characteristic feature of the ectopic ACTH syndrome is a state of mineralocorticoid excess, although the etiology remains obscure. Some forms of endocrine hypertension, such as licorice ingestion, have been explained by cortisol acting as a mineralocorticoid in the setting of inhibition or deficiency of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). This enzyme is responsible for the conversion of cortisol (F) to hormonally inactive cortisone, and its activity in vivo can be inferred from the ratio of the urinary excretion of tetrahydrocortisol (THF) and its isomer (5 alpha THF) to tetrahydrocortisone. Twenty-two patients with Cushing's syndrome (11 pituitary dependent, 9 ectopic, and 2 adrenal adenomas) and 13 controls were studied. Compared to controls. Cushing's patients had a significant increase (P < 0.001) in the excretion of all principal metabolites of F, secondary to a 5- to 6-fold increase in the cortisol secretion rate [median, 34.0 (range, 13.3-327) mg/day in Cushing's vs. 6.1 (range, 2.5-10.3) mg/day in controls]. The THF plus 5 alpha THF/tetrahydrocortisone ratio was significantly increased in Cushing's syndrome regardless of etiology [mean, 1.81 (range, 1.09-9.99) in Cushing's vs. 0.81 (range, 0.51-1.47) in controls; P < 0.001), indicative of defective 11 beta HSD activity. Furthermore, compared to patients with pituitary-dependent Cushing's, this ratio was significantly higher in patients with the ectopic ACTH syndrome (4.12 vs. 1.49; P < 0.01) and was inversely correlated with serum potassium levels (r = -0.57; P = 0.01; n = 22). One explanation for the mineralocorticoid excess state of the ectopic ACTH syndrome appears to be that cortisol gains inappropriate access to the mineralocorticoid receptor through failure of its normal metabolism by 11 beta HSD. The reason for the defective 11 beta HSD activity is unclear, but it may be secondary to substrate saturation, inhibition by other adrenal steroids, or product inhibition.
    • Modulation of cortisol metabolism by low-dose growth hormone replacement in elderly hypopituitary patients.

      Toogood, Andy; Taylor, N F; Shalet, Stephen M; Monson, J P; Department of Endocrinology, Christie Hospital, Manchester, United Kingdom. (2000-04)
      11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) functions as a net reductase converting cortisone to cortisol. GH inhibits 11beta-HSD1, resulting in a shift in cortisol metabolism favoring cortisone, an observation that may have significance in patients with ACTH deficiency who are unable to compensate for such changes. We have studied the effect of three doses of GH replacement (0.17, 0.33, and 0.5 mg each given for 12 weeks in ascending order) on cortisol metabolism in nine patients, aged 62-70 yr, with hypopituitarism who were receiving fixed doses of oral hydrocortisone. Serum insulin-like growth factor I levels rose in a dose-dependent manner over the course of the study. Fat mass decreased significantly at 24 weeks (P = 0.02), a change that was maintained at 36 weeks. Fasting serum insulin levels did not change significantly over the course of the study. The ratio of urine cortisol to cortisone metabolites (Fm/Em) fell significantly at 12 weeks (GH dose, 0.17 mg/day) from 1.32 (0.91-2.20) at baseline to 1.08 (0.89-2.11) (P < 0.05). Although it did not fall further as the dose of GH was increased, the reduction in the Fm/Em ratio persisted at 24 weeks (GH dose, 0.33 mg/day), 1.09 (0.8-2.11) (P < 0.05 vs. baseline), and 36 weeks (GH dose, 0.5 mg/day), 1.19 (0.82-2.31) (P < 0.05 vs. baseline). The Fm/Em ratio did not correlate with serum insulin-like growth factor I, fat mass, or fasting insulin levels at any time during the study. This study confirms the inhibitory effect of GH on 11beta-HSD1 but has shown that the effect occurs maximally at very low GH doses and is not mediated indirectly by change in circulating insulin. Patients with partial or total ACTH deficiency, in whom cortisol replacement is suboptimal, may be at risk of the clinical manifestations of cortisol deficiency when they are commenced on GH therapy.
    • Modulation of cortisol metabolism by the growth hormone receptor antagonist pegvisomant in patients with acromegaly.

      Trainer, Peter J; Drake, William M; Perry, Lesley A; Taylor, N F; Besser, G M; Monson, John; Department of Endocrinology, Christie Hospital, Manchester, United Kingdom M20 4BX. peter.trainer@man.ac.uk (2001-07)
      Pegvisomant is a GH receptor antagonist and highly efficacious new treatment for acromegaly. The two isoenzymes of 11beta-hydroxysteroid dehydrogenase are responsible for the interconversion of cortisol and its inactive metabolite cortisone. We demonstrated previously that the type I isoform, which is principally responsible for conversion of cortisone to cortisol, is partially inhibited by GH. The net activity of the enzyme can be measured by analysis of the urinary ratio of 11-hydroxy/11-oxo cortisol metabolites or of the urinary ratio of tetrahydrocortisol/tetrahydrocortisone [(tetrahydrocortisol + 5alpha-tetrahydrocortisol)/tetrahydrocortisone]. We studied the influence of pegvisomant on cortisol metabolism in patients with active acromegaly. Seven patients (four women and three men; median age, 58 yr; range, 39-72) were studied at baseline and again after a mean of 46 weeks of treatment. The mean insulin-like growth factor I (IGF-I) level at baseline fell from 939.7 +/- 271.1 to 346.9 +/- 379.0 ng/mL on 20 mg/day pegvisomant. The 11-hydroxy/11-oxo ratio increased from a pretreatment mean value of 0.61 +/- 0.18 to 0.88 +/- 0.20 (P < 0.02) and when the six patients in whom serum IGF-I normalized were considered separately, the change was from 0.62 +/- 0.19 to 0.90 +/- 0.21 (P < 0.04). The tetrahydrocortisols/tetrahydrocortisone ratio increased from a pretreatment mean value of 0.64 +/- 0.21 to 0.98 +/- 0.26 (P < 0.02) and in the six patients in whom serum IGF-I normalized, the ratio rose from 0.66 +/- 0.23 to 1.01 +/- 0.26 (P < 0.04). These data 1) indicate that blockade of GH action with pegvisomant in patients with acromegaly is associated with reversal of the inhibition of 11beta-hydroxysteroid dehydrogenase and correction of cortisol metabolism, and 2) suggest that in active acromegaly, cortisol clearance is accelerated and that this is reversed by successful treatment. This is further evidence of the efficacy of pegvisomant in the management of acromegaly and has important implications for determining optimum glucocorticoid replacement.