Diabetes ( db/ db) mutation-induced female reproductive tract hypercytolipidemia: estrogenic restoration of utero-ovarian indices.
The diabetes ( db/ db) mutation (leptin-receptor defect) induces a hyperglycemic-hyperinsulinemic endometabolic environment that promotes hypercytolipidemic, utero-ovarian involution in C57BL/KsJ mice, resulting in reproductive sterility and eventual organoatrophy. The effectiveness of low-dose, 17-B-estradiol therapy (E2-HRx), initiated prior to the genetic expression of the overt diabetes-obesity syndrome (DOS) on preventing female reproductive tract involution was evaluated by analysis of cytochemical, endocrine and tissue lipo-metabolic indices relative to oil (O)-vehicle treated (HRx) control (+/?) and ( db/ db) groups. All HRx treatments started at 4 weeks of age (i.e., pre-overt DOS stage) and continued through 16 weeks of age (i.e., chronic DOS expression) when tissue parameters were evaluated. The DOS promoted a dramatic increase in phenotypic obesity, hyperglycemia and hyperinsulinemia in ( db/ db) groups, relative to (+/?) indices, throughout the experimental period. In contrast, utero-ovarian weights were dramatically reduced in ( db/ db) groups relative to (+/?). Chronic low-dose E2-HRx moderated these DOS-induced trends in ( db/ db) groups, maintaining lowered body weights and normoglycemic parameters while stimulating utero-ovarian weight indices. In addition, E2-HRx prevented the dramatic hypercytolipidemic condition which promotes utero-ovarian involution in ( db/ db) mice as evidenced by the maintenance of normal reproductive cytoarchitecture. The concurrent moderation of tissue lipase activity and stimulated glucose uptake rates by ( db/ db) utero-ovarian compartments, under persistent hyperinsulinemic influences, indicated that E2-HRx effectively reduced both the structural and endometabolic consequences of the DOS from promoting ( db/db)-associated reproductive organoatrophy. These results indicate that the pathophysiological alterations induced by the ( db/ db) mutation may be ameliorated through low-dose steroidal therapy, the efficacy of which is suspected to occur via membrane metabolic cascade induction mechanisms or by direct nuclear transcription modulation in reproductive target cells. The subsequent re-establishment of insulin-coupled glucose utilization and suppressed caloric shunting towards lipogenesis promotes the normalization of utero-ovarian structural and metabolic homeostasis in C57BL/KsJ-db/ db mutants.[1]References
- Diabetes (db/db) mutation-induced female reproductive tract hypercytolipidemia: estrogenic restoration of utero-ovarian indices. Garris, D.R., Garris, B.L. Reprod. Toxicol. (2004) [Pubmed]
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