Garris David R, Garris Bryan L
Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri-Kansas City, 5007 Rockhill Road, Kansas City, MO 64110, USA.
Reprod Toxicol. 2004 Jul;18(5):641-51. doi: 10.1016/j.reprotox.2004.04.007.
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.
糖尿病（db/db）突变（瘦素受体缺陷）在C57BL/KsJ小鼠中诱发了一种高血糖 - 高胰岛素血症的子宫内膜代谢环境，这种环境促进了高细胞脂质血症、子宫 - 卵巢退化，导致生殖不育和最终的器官萎缩。通过分析相对于油（O）载体处理（HRx）对照（+/？）和（db/db）组的细胞化学、内分泌和组织脂质代谢指标，评估了在明显的糖尿病 - 肥胖综合征（DOS）基因表达之前开始的低剂量17-β-雌二醇治疗（E2-HRx）对预防雌性生殖道退化的有效性。所有HRx治疗均在4周龄（即明显的DOS前期）开始，并持续到16周龄（即慢性DOS表达期），此时评估组织参数。在整个实验期间，相对于（+/？）指标，DOS使（db/db）组的表型肥胖、高血糖和高胰岛素血症显著增加。相比之下，（db/db）组的子宫 - 卵巢重量相对于（+/？）组显著降低。慢性低剂量E2-HRx减轻了（db/db）组中这些由DOS诱导的趋势，维持了较低的体重和正常血糖参数，同时刺激了子宫 - 卵巢重量指标。此外，E2-HRx预防了促进（db/db）小鼠子宫 - 卵巢退化的严重高细胞脂质血症状况，这通过维持正常的生殖细胞结构得以证明。在持续的高胰岛素血症影响下，（db/db）子宫 - 卵巢区室中组织脂肪酶活性的同时适度降低和葡萄糖摄取率的刺激表明，E2-HRx有效地减少了DOS促进（db/db）相关生殖器官萎缩的结构和子宫内膜代谢后果。这些结果表明，（db/db）突变诱导的病理生理改变可能通过低剂量甾体治疗得到改善，其疗效可能是通过膜代谢级联诱导机制或通过生殖靶细胞中的直接核转录调节而发生。随后胰岛素偶联的葡萄糖利用的重新建立以及对脂肪生成的热量分流的抑制促进了C57BL/KsJ-db/db突变体中子宫 - 卵巢结构和代谢稳态的正常化。
