Effects of estradiol and progesterone on diabetes-associated utero-ovarian atrophy in C57BL/KsJ (db/db) mutant mice

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Abstract
The modulating effects of estradiol (E: 1 μg/3.5 days) and progesterone (P: 2 mg/3.5 days) on the obesity and hyperinsulinemic and hyperglycemic components of the diabetes-obesity syndrome in female C57BL/KsJ (db/db) mice, which includes cellular atrophy and adiposity in the reproductive tract, were examined and compared to corresponding control (+?) parameters. All control and diabetic mice received oil (vehicle control), E, or P treatments starting at 4 weeks of age. Body weight, serum insulin levels, blood glucose concentrations, and uteroovarian lipoprotein lipase activites were analyzed at 8 and 16 weeks of age and related to the ultrastructural changes in the steriod-sensitive uterine epithelium during the treatment period. Neither E nor P had any effect on body weights in (+?) or (db/db) mice. The pronounced diabetes-associated elevation in serum insulin levels was enhanced by E, and suppressed by P, in 16-week-old (db/db) mice as compared with controls. By 16 weeks of age, the E therapy normalized blood glucose levels in diabetic mice to control levels, whereas P was ineffective in modulating the hyperglycemia. The reduction in blood glucose levels in E-treated diabetic mice correlated temporally with the return of normal intracellular structure including the disappearance of intracellular lipid vacuoles characteristic of uterine epithelium cells of (db/db) mice. The diabetes-induced rise in utero-ovarian lipoprotein lipase activity was normalized by P-therapy. The reduction in uteroovarian lipoprotein lipase activity coincided temporally with the demonstrated intracellular reorganization in (db/db) reproductive tract tissues. These data indicate that E and P therapies are effective modulators of mutation-induced structural, metabolic, and functional changes in the reproductive tract and peripheral tissues of genetically diabetic C57BL/KsJ (db/db) mice. The ability to restore affected tissue structure and function in this mutant mouse model to that of controls suggests that gonadal steroids may correct, delay, prevent, or suppress the diabetes-associated tissue atrophy and adiposity which characterizes this strain.