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.

Keywords: Estrus cycle; Etonogestrel; Hormonal contraception; Long-acting reversible contraception; Ovarian function; Progestin; Ultrasound biomicroscopy.

Fig. 1

Images of ovarian follicles and corpora lutea in rats using ultrasound biomicroscopy. Legend: Arrows with black outline define the external boundary of the ovary; Arrow-heads indicate follicles; White arrows indicate corpora lutea

Fig. 2

Body weight (a) and food consumption (b) varied with time across the study. Legend: Arrow = day of pellet insertion, # = different from week 1, * = different from week 2, ^ = different from week 3, % = different from week 4, $ = different from week 5

Fig. 3

Proportion of time spent in a specific cycle phase prior to (a) or following pellet insertion (b). Legend: # = different from Placebo dose within cycle phase, * = different from Low dose within cycle phase

Fig. 4

Cycle type classifications (a-c), ultrasound biomicrocope measurements (d-k), and estradiol concentrations (l). Legend: Arrow = day of pellet insertion, lines with # = difference between days (all treatment groups combined), lines with * = difference between treatment groups within one day, lines with & = difference between study days within the placebo group, lines with $ = difference between study days within the low dose group, lines with ^ = difference between study days within the high dose group