Diabetes‐associated alterations in uterine structure in the C57BL/KsJ Mouse: Relationship to changes in estradiol accumulation, circulating ovarian steroid levels, and age

Abstract

The effects of the diabetes (D) mutation on utero-ovarian structure and function were examined in match-paired D and control (C) C57BL/KsJ mice between 2 and 16 weeks of age. Between 4 and 8 weeks of age, the uterine epithelium of D mice exhibited a remarkable increase in the amount of cytoplasmic lipid stores as compared with that of C animals. Associated with progressive hyperglycemia between 8 and 16 weeks of age, uterine atrophy and continued lipid accumulation occurred. Both serum progesterone and estradiol levels were lower in D than C mice between 8 and 16 weeks of age. In addition, the uteri of D mice failed to accumulate as much 3H-estradiol as C uteri at 16 weeks of age. These data demonstrate that changes in uterine structure that are attributable to depressed ovarian activity in diabetics underlie the reproductive failure in these animals. The temporal association between the onset of reproductive tract involution and the expressed hyperglycemic condition suggests a causal association between these events in the genetically diabetic C57BL/KsJ mouse.

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

“…In addition, the failure of enhanced tissue noradrenergic counterregulatory responses (12,13) to modulate the observed structural and metabolic indexes, coupled with stimulated lipoprotein lipase enzyme activity indexes, indicates that the progressive lipid insult on cellular integrity promotes or induces cellular lipoatrophy, which then generates endometrial cellular regression and subsequent reproductive tract involution. These results suggest that the reproductive decline characteristic of many type 2 diabetes models, including humans, may be related to the noted cellular lipoadiposity and metabolic alterations that occur after chronic exposure to the hyperglycemic-hyperinsulinemic environment and the inability of recognized counterregulatory systemic factors to correct these homeostatic insults to cellular function (1,3,12,13). Previous studies have indicated that some of the structural features characterized in the present studies may be stabilized in the db/db model by endocrine replacement therapy of the affected female reproductive tract parameters, if therapy is initiated before the early onset of the syndrome expression (5).…”

“…Uteri from control and db/db matchedpaired groups ages 4, 8, 12, and 16 weeks were collected, weighed, and prepared for light and transmission electron microscopic (TEM) examination, as previously described (1)(2)(3)(4)(5). Tissue samples were sectioned and stained with toluidine blue for polychromatic lipid identification (1,3,20) and localization by light microscopic examination or with osmium tetroxide (4,5) before TEM examination. Tissue sections prepared for light microscopic analysis were used for cytoplasmic polychromatic organelle designation, localization of intracellular lipid inclusion accumulations, and subsequent determination of the cytoplasmic volume changes that occur with progressive diabetes, as previously described (5).…”

“…he expression of the diabetes-obesity syndrome in C57BL/KsJ (db/db) mice is accompanied by a progressive cellular atrophy and functional compromise of the female reproductive tract (1)(2)(3). Characterized by ovarian follicular atresia (4), inhibition of follicular recruitment (4), depressed ovarian steroid hormone production (1,3,5), refractory responsiveness to gonadotropin stimulation (6), and failure of corpus luteum formation (4,7,8), the maturation of the reproductive tract is developmentally and structurally impaired as compared with littermate controls (ϩ/?).…”

“…Characterized by ovarian follicular atresia (4), inhibition of follicular recruitment (4), depressed ovarian steroid hormone production (1,3,5), refractory responsiveness to gonadotropin stimulation (6), and failure of corpus luteum formation (4,7,8), the maturation of the reproductive tract is developmentally and structurally impaired as compared with littermate controls (ϩ/?). Uterine structural parameters influenced by the expression of the db/db mutation include a marked depression in uterine epithelial cellular integrity (1,7), depressed responsivity to ovarian steroid hormone therapy (7,9,10), suppressed mitotic indexes (3), and premature tissue involution (2), accompanied by an enhanced cytoplasmic lipid inclusion volume (4).…”

“…Research has indicated that the acute (initial) expression of the mutation-induced cellular alterations continue to expand through chronic expression periods, culminating in tissue and organ involution, depressed metabolic activity (1,3,8,9), inhibition of adrenergic counterregulatory influences (11)(12)(13)(14)(15)(16), and, ultimately, reproductive tract atrophy. The severity of these cellular changes mimic the enhanced blood glucose and triglyceride concentrations that continue to increase across successive time periods (7,17,18).…”