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11ß-Hydroxysteroid Dehydrogenase Activity in Hypothalamic Obesity

Departments of Pediatrics (D.T., I.E., Z.H.) and Radiology (D.M.), Meyer Children’s Hospital, Haifa 31096, Israel; and National Institute of Child Health and Human Development, Pediatric and Reproductive Endocrinology Branch (G.P.C., Z.H.), Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Ze’ev Hochberg, M.D., D.Sc., Meyer Children’s Hospital, P.O. Box 9602, Haifa 31096, Israel. E-mail: z_hochberg{at}rambam.health.gov.il.

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 11ß-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/m² hydrocortisone acetate. The ratios of free and conjugated cortisol (F) to cortisone (E) and their metabolites, [tetrahydrocortisol (THF)+5THF]/tetrahyrdocortisone (THE), dihydrocortisols/dihydrocortisones, cortols/cortolones, and (F+E)/(THF+THE+5THF), were considered to represent 11ß-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 11ß-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 11ß-HSD1 activity.

Abbreviations: BMI, Body mass index; CT, computerized tomography; E, cortisone; F, cortisol; HSD, hydroxysteroid dehydrogenase; THE, tetrahydrocortisone; THF, tetrahydrocortisol.

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