Diabetes-Induced, Progressive Endometrial Involution Characterization of Periluminal Epithelial Lipoatrophy

Abstract

The present studies detail the cytopathological alterations in uterine epithelial, basal lamina, and stromal endometrial subregions, and associated endocrine parameters that occur during the progressive exacerbation of the diabetes syndrome in this species of mouse. These alterations result in a cellular lipoatrophic condition that compromises uterine tissue integrity and promotes reproductive involution. Uterine tissue samples were obtained from litter-matched control (؉/?) and diabetic (db/db) C57BL/KsJ mice at four designated stages of the progressive expression of the diabetes mutation. In db/db mice between the ages of 4 and 12 weeks, the uterine epithelial cellular architecture exhibited progressive deterioration, characterized by cytoplasmic lipid imbibition (accumulation), organelle disintegration, apical membrane ciliary regression, and peristromal lamina separation from basal membrane surfaces, as compared with control indexes. The cytoplasmic volume occupied by lipid inclusions dominated the epithelial cells in diabetic mice, presenting dense basal pole lipid vacuoles, with perinuclear-intracytoplasmic migration of the inclusions promoting an apical cytoplasmic lipid condensation of increasing volume 8 -12 weeks after mutation expression. These cytoplasmic lipid accumulations occurred under altered metabolic and endocrine conditions characterized by hyperglycemic, hyperinsulinemic, hypertriglyceridemic, and enhanced noradrenergic indexes, which were exacerbated between 4-and 12-week stages. These structural changes were accompanied by enhanced adrenergic counterregulatory metabolic responses as well as elevated lipoprotein and triacylglycerol lipase activities. These data indicate that diabetes-associated uterine involution is characterized by a progressive cellular and peristromal lipoatrophy of epithelial cell cytology and metabolic parameters, promoting stromal separation and ultimate endometrial involution.

Immunohistochemical investigation of endometrial leukocytes in implantation period in rats with streptozotosin-induced diabetes

“…One study performed in 2003 [34] revealed that there were considerable epithelial changes in diabetic rats. In another study on effects of progressive hyperglycemia on the endometrium, a thickened basal membrane, phagocytic blood elements extending into the basal membrane, differentiation in the stromal cells, vacuolization and degeneration were observed [35].…”

Characterization of a novel genetically obese mouse model demonstrating early onset hyperphagia and hyperleptinemia

“…1A). Although it may be difficult to compare body weights between the ICR and C57BL/6 mice, early onset obesity can be observed in ob/ob and db/db mice by 5-7 wk of age (19,31), in contrast to the development of obesity in fat/fat and tub/tub mice at 6 -8 and 10 wk of age, respectively (10). Regarding maximum body weight, the Daruma mice were more similar to ob/ob and fat/fat mice, which attain a weight of 60 -70 g, than to db/db and tub/tub mice, which attain a final body weight of 50 -60 g (10,38,40).…”

Digital Chemospectrophotographic Identification of Intracellular Hyperlipidemia in Diabetic Endometrial Epithelial Cells: Structural and Metabolic Basis of Organoatrophy

“…Suppression of normal reproductive cyclicity, folliculogenesis, ovarian steroid synthesis and release, ovulation, corpus luteum formation and associated endocrine parameters during diabetic states promotes endometrial involution and atrophy [1,3,[8][9][10]. Ultimately, the consequences of the diabetes-associ-ated endopathological and metabolic alterations induce reproductive incompetence and organoatrophy of the female reproductive tract [1,8,10,11].…”

“…Genetically diabetic (db/db) mutant C57BL/KsJ mice have been utilized as an experimental model for the evaluation of the progressive cytopathological changes in endometrial tissue which occur as a result of the nonhomeostatic diabetic metabolic environment [1,8,10]. Of particular interest have been the descriptions of the progressive intracytoplasmic accumulation of triglyceridefree fatty acid pools that accumulate at the cytobasal pole of endometrial epithelial cells [8,10].…”

“…In both experimental animals models [1][2][3][4][5] and humans [6,7], the progressive cytoatrophy of endometrial epithelial cells and stromal tissue layers results in reproductive dysfunction and organoatrophy of the female utero-ovarian axis [8]. Suppression of normal reproductive cyclicity, folliculogenesis, ovarian steroid synthesis and release, ovulation, corpus luteum formation and associated endocrine parameters during diabetic states promotes endometrial involution and atrophy [1,3,[8][9][10]. Ultimately, the consequences of the diabetes-associ-ated endopathological and metabolic alterations induce reproductive incompetence and organoatrophy of the female reproductive tract [1,8,10,11].…”