Using Histopathologic Evidence to Differentiate Reproductive Senescence from Xenobiotic Effects in Middle-aged Female Sprague-Dawley Rats

Abstract

The female reproductive cycle is orchestrated by cyclical and coordinated hormonal changes under the direction of the hypothalamic-pituitary-gonadal (HPG) axis. Any disruption of the HPG axis may lead to functional and structural alterations in the female reproductive system. Test article-related disturbances in the estrous cycle can be recognized in nonclinical toxicity studies by staging the cycle based on microscopic evaluation of female reproductive organs. In chronic rat toxicity studies, an additional complication is the development of reproductive senescence, which is associated with natural alterations in the reproductive cycle leading to changes in the female reproductive system that can potentially be confused with test article effects. The current article describes the features of persistent estrus, one stage of reproductive senescence, in middle-aged Sprague-Dawley rats and discusses elements to help differentiate senescence from induced effects.

The Impact of Age on the Female Reproductive System

“…In addition, there are strain differences in the pattern of changes and timing in the onset of reproductive senescence (vom Saal, Finch, and Nelson 1994). Sprague-Dawley rats can begin to be observed in persistent estrus at 6 to 7 months of age and in the author’s experience as early as 4 to 5 months, especially when singly housed (vom Saal, Finch, and Nelson 1994; Shirai, Houle, and Mirsky 2015). During persistent estrus, there is a characteristic pattern of changes observed histologically including numerous follicular cysts with an absence of corpora lutea and secondary changes in the uterus, cervix, and vagina (Shirai, Houle, and Mirsky 2015).…”

“…Sprague-Dawley rats can begin to be observed in persistent estrus at 6 to 7 months of age and in the author's experience as early as 4 to 5 months, especially when singly housed (vom Saal, Finch, and Nelson 1994;Shirai, Houle, and Mirsky 2015). During persistent estrus, there is a characteristic pattern of changes observed histologically including numerous follicular cysts with an absence of corpora lutea and secondary changes in the uterus, cervix, and vagina (Shirai, Houle, and Mirsky 2015). With prolonged periods of increased circulating estradiol, pituitary lactotrophs are stimulated leading to an increased production of prolactin (Pady, McComb, and Shull 1999).…”

Species Comparison of Postnatal Development of the Female Reproductive System

“…SD rats when examined up to 22 months of age, go from having regular cycles to irregular starting around 7 months of age, with some showing constant estrus before entering a constant period of persistent diestrus (LeFevre and McClintock, ). Although SD rats can be observed in persistent estrus at 6 to 7 months of age, in one of the author's experience, this can occur as early as 4 to 5 months, especially when singly housed (vom Saal, ; Shirai et al, ).…”

“…During persistent estrus, there is a characteristic pattern of changes observed histologically including numerous follicular cysts with an absence of CLs and secondary changes in the uterus, cervix, and vagina (Shirai et al, ). With prolonged periods of increased circulating E2, pituitary lactotrophs are stimulated leading to an increased production of prolactin (Spady et al, ).…”

“…The histologic features in an aging animal are not easily defined and are subject to species and strain differences. Descriptions of common changes in rats are provided in Westwood () and Shirai et al ().…”