Tissue-specific increases in 11beta-hydroxysteroid dehydrogenase type 1 in normal weight postmenopausal women

Abstract

With age and menopause there is a shift in adipose distribution from gluteo-femoral to abdominal depots in women. Associated with this redistribution of fat are increased risks of type 2 diabetes and cardiovascular disease. Glucocorticoids influence body composition, and 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) which converts inert cortisone to active cortisol is a putative key mediator of metabolic complications in obesity. Increased 11betaHSD1 in adipose tissue may contribute to postmenopausal central obesity. We hypothesized that tissue-specific 11betaHSD1 gene expression and activity are up-regulated in the older, postmenopausal women compared to young, premenopausal women. Twenty-three pre- and 23 postmenopausal, healthy, normal weight women were recruited. The participants underwent a urine collection, a subcutaneous adipose tissue biopsy and the hepatic 11betaHSD1 activity was estimated by the serum cortisol response after an oral dose of cortisone. Urinary (5alpha-tetrahydrocortisol+5beta-tetrahydrocortisol)/tetrahydrocortisone ratios were higher in postmenopausal women versus premenopausal women in luteal phase (P<0.05), indicating an increased whole-body 11betaHSD1 activity. Postmenopausal women had higher 11betaHSD1 gene expression in subcutaneous fat (P<0.05). Hepatic first pass conversion of oral cortisone to cortisol was also increased in postmenopausal women versus premenopausal women in follicular phase of the menstrual cycle (P<0.01, at 30 min post cortisone ingestion), suggesting higher hepatic 11betaHSD1 activity. In conclusion, our results indicate that postmenopausal normal weight women have increased 11betaHSD1 activity in adipose tissue and liver. This may contribute to metabolic dysfunctions with menopause and ageing in women.

Figure 1. Subcutaneous adipose tissue 11βHSD1.

A 11βHSD1 transcript levels were normalized to endogenous control Cyclophilin A. *P<0.05, ** P<0.01, N = 19, 17, and 23 for the premenopausal follicular (□), luteal (▪), and postmenopausal (▴) groups, respectively. One woman in follicular phase and three in the luteal phase of the menstrual cycle did not have the biopsy and three women in each premenopausal group were found not to be in the correct phase. Data were natural log-transformed to achieve normal distribution. B Correlation between adipose 11βHSD1 activity after 24 hr incubation (percent conversion) and adipose 11βHSD1 mRNA expression (relative to Cyclophilin A). Premenopausal follicular (□), luteal (▪), and postmenopausal women (▴). Linear regression line is shown for the postmenopausal group, dotted lines denotes the 95% confidence interval. C Subcutaneous adipose tissue 11βHSD1 activity was measured as percent conversion of cortisol to cortisone over time in tissue homogenates, protein concentration 3 mg/ml. N = 13, 10, and 20 for premenopausal follicular (□), luteal (▪), and postmenopausal women (▴), respectively. There were no significant differences between the groups. Data were ln-transformed to achieve normal distribution and are shown as means±SEM.

Figure 2. Hepatic 11βHSD1 activity.

Serum cortisol levels after overnight dexamethasone suppression and oral cortisone intake (25 mg). Postmenopausal women (▴, N = 23) had higher serum cortisol levels at 30 min post cortisone intake than premenopausal women in follicular phase of the menstrual cycle (□, N = 17). *P<0.05 and **P<0.01 for postmenopausal vs. premenopausal follicular phase. Luteal phase, ▪, N = 16. Data are means±SEM.