After extensive suprasellar operations for
hypothalamic tumor removal, some patients develop Cushing-like
morbid obesity while they receive replacement doses of
glucocorticoids. In this study, we examined the hypothesis that target tissue conversion of inactive 11-ketosteroids to active 11 beta-
OH glucocorticoids might explain the
obesity of some patients with hypothalamic lesions. Toward this aim, we studied 10 patients with hypothalamic
obesity and secondary
adrenal insufficiency and 6 control Addisonian patients while they were on
glucocorticoid replacement
therapy. Pituitary
hormone deficiencies were replaced when medically indicated. Twenty-four-hour urine was collected after a single oral dose of 12 mg/m(2)
hydrocortisone acetate. The ratios of free and conjugated
cortisol (F) to
cortisone (E) and their metabolites, [
tetrahydrocortisol (THF)+5 alpha THF]/tetrahyrdocortisone (THE), dihydrocortisols/dihydrocortisones, cortols/cortolones, and (F+E)/(THF+THE+5 alpha THF), were considered to represent
11 beta-hydroxysteroid dehydrogenase (HSD) activity. The 11-
OH/11-oxo ratios were significantly higher in the urine of patients with hypothalamic
obesity. The 11-
OH/11-oxo ratios, however, did not correlate with the degree of
obesity, yet a significant correlation was found between conjugated F/E and the ratio of visceral fat to sc fat measured by computerized tomography at the umbilical level. The consequence of increased 11 beta-HSD1 activity and the shift of the interconversion toward
cortisol may contribute to the effects of the latter in adipose tissue. We propose that deficiency of hypothalamic messengers after
surgical injury induces a paracrine/autocrine effect of enhanced
glucocorticoid activity due to up-regulated 11 beta-HSD1 activity.