12539 Estrogen Type In Contraceptives Matters: Effects On Spatial Memory And Anxiety-Like Behaviors In A Female Rat Model
Authors: Hegwood A P , Kujawa S , Prakapenka A V 
Published: October 2024

Abstract
Disclosure: A.P. Hegwood: None. S. Kujawa: None. A.V. Prakapenka: None.
According to U.S. Centers for Disease Control & Prevention, ∼12% of the U.S. population uses combined oral contraceptives (COCs). Behavioral side effects are common factors in COC discontinuation. Management of COC-related side effects primarily centers around altering the synthetic ethinyl estradiol (EE) dose, the predominant estrogen in COCs. Estradiol valerate (EV) is a recently introduced natural estrogen alternative to EE. EE-containing COCs, such as EE/dienogest (DNG), were found to decrease free steroid hormone serum levels compared to EV-containing COCs, such as EV/DNG. In women and in female rodent models, steroid hormones (e.g., 17-ß estradiol (E2), testosterone) dose-dependently modulate spatial memory and anxiety-related behaviors. We hypothesized that in a rat model of hormonal contraceptive use, EE/DNG differentially modulates spatial memory and anxiety-like behaviors compared to EV/DNG, corresponding to circulating steroid hormone levels. Thirty-six young-adult (3-4-months-old) female rats were randomly assigned to EE/DNG (0.13µg EE and 8.6µg DNG per day), EV/DNG (8.6µg EV and 8.6µg DNG per day), or vehicle treatment (propylene glycol) continuously administered by subcutaneous osmotic pump. At four weeks of treatment, rats were tested on the delayed spontaneous alternation (dSA) task to evaluate spatial memory and the elevated plus maze (EPM) to evaluate anxiety-like behavior. Following EPM, serum was collected and analyzed for E2, progesterone, androstenedione, and testosterone levels using liquid chromatography-mass spectrometry and corticosterone levels using radioimmunoassay. Spontaneous alternation behaviors were similar across all three groups on the dSA. However, EE/DNG increased use of an egocentric navigational strategy, the use of consecutive turns, on the dSA compared to vehicle and EV/DNG. Egocentric strategy is likely mediated by the striatal memory system, engagement of which is elevated with stress and anxiety. Of note, EE/DNG decreased time spent in the open arms of the EPM compared to vehicle and EV/DNG, indicating increased anxiety-like behaviors with EE/DNG. Both EE/DNG and EV/DNG decreased androstenedione, testosterone, and E2 circulating levels compared to vehicle. Steroid hormone serum levels did not differ between EE/DNG and EV/DNG; 58% of EE/DNG serum samples were undetermined/below threshold for E2 levels, limiting statistical analysis. Altogether, we found that, compared to vehicle and the natural EV, the synthetic EE component in hormonal contraceptives elevates anxiety-like behaviors in female rats, an effect that corresponds to increased use of an egocentric navigational strategy on a spatial memory task. Our findings support the notion that estrogen type matters for behavioral outcomes associated with contraceptive use, identifying estrogen type as a possible tool for management of COC-related side effects.
Presentation: 6/1/2024