Increased systemic and adipose 11β-HSD1 activity in idiopathic intracranial hypertension

Abstract

Context: Idiopathic intracranial hypertension (IIH) is a disease of raised intracranial pressure (ICP) of unknown etiology. Reductions in glucocorticoid metabolism are associated with improvements in IIH disease activity. The basal IIH glucocorticoid metabolism is yet to be assessed.

Objective: The objective of this study was to determine the basal glucocorticoid phenotype in IIH and assess the effects of weight loss on the IIH glucocorticoid phenotype.

Design: A retrospective case-control study and a separate exploratory analysis of a prospective randomized intervention study were carried out.

Methods: The case-control study compared female IIH patients to BMI, age, and sex-matched controls. In the randomized intervention study, different IIH patients were randomized to either a community weight management intervention or bariatric surgery, with patients assessed at baseline and 12 months. Glucocorticoid levels were determined utilizing 24-h urinary steroid profiles alongside the measurement of adipose tissue 11β-HSD1 activity.

Results: Compared to control subjects, patients with active IIH had increased systemic 11β-hydroxysteroid dehydrogenase (11β-HSD1) and 5α-reductase activity. The intervention study demonstrated that weight loss following bariatric surgery reduced systemic 11β-HSD1 and 5α-reductase activity. Reductions in these were associated with reduced ICP. Subcutaneous adipose tissue explants demonstrated elevated 11β-HSD1 activity compared to samples from matched controls.

Conclusion: The study demonstrates that in IIH, there is a phenotype of elevated systemic and adipose 11β-HSD1 activity in excess to that mediated by obesity. Bariatric surgery to induce weight loss was associated with reductions in 11β-HSD1 activity and decreased ICP. These data reflect new insights into the IIH phenotype and further point toward metabolic dysregulation as a feature of IIH.

Figure 1

Altered glucocorticoid metabolism in patients with IIH. Twenty-four-hour urine steroid metabolomic assessment in control (17) and IIH patients (27). (A) 11β-HSD1 activity was denoted by 5α-THF+THF/THE. (B) 11β-HSD2 activity was denoted by urinary free cortisol/cortisone (F/E). (C) Total glucocorticoid metabolite excretion. (D) Cortisol secretion. (E) 5α-reductase activity. Data are presented as mean ± s.d., Mann–Whitney U-test for A and B, t-test for (C) and t-test with Welch’s correction for (D) and (E). *P < 0.05, **P < 0.01. IIH, idiopathic intracranial hypertension; 11β-HSD1, 11β-hydroxysteroid dehydrogenase; 5α-THF+THF/THE, 5α-tetrahydocortisol+tetrahydrocortisol/tetrahydrocortisone. A full color version of this figure is available at https://doi.org/10.1530/EJE-22-0108.

Figure 2

IIH urinary steroid metabolome following weight loss. Twenty-four-hour urine steroid metabolome profiling at baseline and 12 months in diet (16) and surgical (13) IIH patients. (A) Change in 11β-HSD1, (B), scatter graph of change in 11β-HSD1 activity vs change in intracranial pressure (ICP), (C) change in 11β-HSD2 activity, (D) change in 5α-reductase activity, and (E) scatter graph of change in 11β-HSD1 activity vs change in ICP. Two-way repeated measures ANOVA followed by Sidak’s multiple comparisons test for (A), (B), and (D). Pearson’s correlation for (B) and (E). Data are presented as mean ± s.d. *P < 0.05. cmCSF, centimetres of cerebrospinal fluid; IIH, idiopathic intracranial hypertension; 11β-HSD1, 11β-hydroxysteroid dehydrogenase. A full color version of this figure is available at https://doi.org/10.1530/EJE-22-0108.

Figure 3

Increased 11β-HSD1 activity in subcutaneous adipose tissue explants from patients with IIH and controls. 11β-HSD1 activity as measured by cortisol production in control (4) and IIH (7) subcutaneous adipose explants (unpaired t-test). Data is presented as mean ± s.d.. *P < 0.05. IIH, idiopathic intracranial hypertension; 11β-HSD1, 11β-hydroxysteroid dehydrogenase. A full color version of this figure is available at https://doi.org/10.1530/EJE-22-0108.