Estrogenic stimulation of ovarian follicular maturation in diabetes (db/db) mutant mice: restoration of euglycemia prevents hyperlipidemic cytoatrophy.
The diabetes (db/db) mutation (leptin-receptor defect) induces a hyperglycemic-hyperinsulinemic endometabolic environment that promotes hypercytolipidemic ovarian involution in C57BL/KsJ mice, resulting in reproductive sterility and eventual organoatrophy. The effectiveness of low-dose (1.0 microg/sc/3.5 day intervals), 17- beta-estradiol therapy (E2-HRx), initiated prior to expression of the overt diabetes-obesity syndrome (DOS), on preventing female ovarian follicular cytolipid atrophy was evaluated by analysis of cytochemical, endocrine, and tissue lipo-metabolic indices relative to oil-vehicle treated control (+/?) and (db/db) groups. Chronic low-dose E2-HRx moderated DOS-induced trends in (db/db) groups, maintaining lowered body weights, and systemic euglycemia while stimulating ovarian weight indices. E2-HRx prevented the dramatic hypercytolipidemic condition associated with ovarian follicular involution in (db/db) mice, as evidenced by progressive viable follicular maturation, cytomorphometric analysis of tertiary follicular development, and pre-luteinization indices with diminished follicular atresia rates. The coincident stimulation of tissue lipoprotein lipase and acetyl CoA carboxylase activities in (db/db) ovarian compartments, under persistent hyperinsulinemic influences, indicated that E2-HRx effectively moderated both the structural and hyperlipometabolic consequences of DOS from promoting (db/db)-associated reproductive organoatrophy. Thus, the patho-reproductive alterations induced by the (db/db) mutation can be moderated through low-dose steroidal therapy, the efficacy of which is suspected to occur by steroid-specific nuclear transcription or post-insulin receptor modulation of gluco-metabolic cascades in reproductive target cells.
Garris
David R
DR
Division of Cell Biology and Biophysics, Schools of Biological Sciences and Medicine, University of Missouri-Kansas City, 5007 Rockhill Road, Kansas City, MO 64110, USA. garrisd@umkc.edu
D000818:Animals; D001786:Blood Glucose; D048909:Diabetes Complications / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D004958:Estradiol / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005496:Follicular Atresia; D005786:Gene Expression Regulation / Q000187:drug effects; D006943:Hyperglycemia / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D006949:Hyperlipidemias / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D007279:Injections, Subcutaneous; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009765:Obesity / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D006080:Ovarian Follicle / Q000187:drug effects* / Q000473:pathology
D001786:Blood Glucose; D004958:Estradiol