A rodent model of human dose-equivalent progestin-only implantable contraception

Abstract

Background Long-acting, reversible contraceptives (LARC; progestin only) are an increasingly common hormonal contraceptive choice in reproductive aged women looking to suppress ovarian function and menstrual cyclicity. The overall objective was to develop and validate a rodent model of implanted etonogestrel (ENG) LARC, at body size equivalent doses to the average dose received by women during each of the first 3 years of ENG subdermal rod LARC use. Methods Intact, virgin, female Sprague-Dawley rats (16-wk-old) were randomized to 1 of 4 groups (n = 8/group) of ENG LARC (high-0.30μg/d, medium-0.17μg/d, low-0.09μg/d, placebo-0.00μg/d) via a slow-release pellet implanted subcutaneously. Animals were monitored for 21 days before and 29 days following pellet implantation using vaginal smears, ultrasound biomicroscopy (UBM), saphenous blood draws, food consumption, and body weights. Data were analyzed by chi-square, non-parametric, univariate, and repeated measures 2-way ANOVA. Results Prior to pellet implantation there was no difference in time spent in estrus cycle phases among the treatment groups (p > 0.30). Following pellet implantation there was a dose-dependent impact on the time spent in diestrus and estrus (p < 0.05), with the high dose group spending more days in diestrus and fewer days in estrus. Prior to pellet insertion there was not an association between treatment group and estrus cycle classification (p = 0.57) but following pellet implantation there was a dose-dependent association with cycle classification (p < 0.02). Measurements from the UBM (ovarian volume, follicle count, corpora lutea count) indicate an alteration of ovarian function following pellet implantation. Conclusion Assessment of estrus cyclicity indicated a dose-response relationship in the shift to a larger number of acyclic rats and longer in duration spent in the diestrus phase. Therefore, each dose in this model mimics some of the changes observed in the ovaries of women using ENG LARC and provides an opportunity for investigating the impacts on non-reproductive tissues in the future.

Toxicological Outcome of Combined Exposure to Potassium Dichromate and Levonorgestrel in the Kidney of Female Rats

“…Group 3 rats were intubated orally with 15 µg/kg body weight, while Group 4 animals were co-exposed to 12 mg/kg body weight PDC and 15 µg/kg /kg body weight levonorgestrel. The dose of PDC in this study has been consistently reported in our laboratory to have toxic effects in rats [15,16], while that of levonorgestrel is similar to a medium dose that was recently reported to mimic contraception related changes in women and useful in evaluating its impacts on non-reproductive tissues [17].…”

The effect of Norethisterone Acetate (NETA) on the uterus of albino rats: Histological, histochemical, immunohistochemical and ultrastructure Study

“…Observations of estrus cyclicity in progestin-only contraceptives treated rats showed a dose-dependent manner in the shift to a larger number of acyclic rats and prolonged diestrus phase 19 . Long-term administration of norethisterone leads to increase of epithelial height and/or epithelial percent in luminal and glandular epithelium.…”

A mouse model of oral contraceptive exposure: Depression, motivation, and the stress response

“…Developing and utilizing animal models is a necessary step towards understanding how HCs modulate the brain and behavior (Hilz, 2022;Tronson & Schuh, 2022). Previous studies have successfully modeled HC exposure in rodents using daily hormone injections, implants, or daily oral gavage protocols to model suppression of ovulation, extensions of fertility, modulation of social and affective behaviors, cognition, and changes in neurochemistry (Allaway et al, 2021;Carrington & Bailey, 1985;Isono et al, 2018;Lacasse et al, 2022;Porcu et al, 2012;Simone et al, 2015). Here we build on these studies to develop and validate a mouse model of HC exposure, specifically targeted to mimic oral contraceptives and the mechanisms by which they regulate the hypothalamic-pituitary-adrenal (HPA) axis, anxiety, and depressionlike behaviors.…”