The use of hormonal contraceptives (HCs) has steadily increased among women since their introduction in the 1960s, with nearly one out of three women in the western world using some form of HC as of 2019 (United Nations, 2019). HCs are composed of synthetic progestins that at times are combined with an estrogen (most commonly the synthetic estrogen ethinyl estradiol), providing efficient and reversible contraception with little risk of adverse side-effects (Bitzer and Simon, 2011). HCs are commercially available in a variety of forms such as pills, implants, injections, vaginal rings, and transdermal skin patches. Regardless of the composition or route of administration, HCs achieve contraception by two mechanisms: first, via inhibitory action on the hypothalamic-pituitary-gonadal (HPG) axis that results in decreased release of gonadotropins and ovarian steroid hormones; and second, via changes to secretions from the female’s reproductive tract epithelium that interfere with sperm transport (Rivera et al., 1999, Lobo and Stanczyk, 1994).

The prevalence of HC-use represents a notable shift in the physiological “normal” experienced by women around the world – the suppression of the HPG axis results in an altered ovarian hormonal profile and, for many users, inhibited ovulatory function (Rivera et al., 1999). Over the course of a typical ovulatory cycle levels of the ovarian hormones estrogen and progesterone undergo substantial changes, rising and falling to induce ovulation and menstruation. While some oral HCs attempt to mimic the cyclic nature of the ovarian cycle, most HCs act via continued hormone suppression that may be experienced by users for many years before HC-use is terminated (Robles, 2010). Although HCs act locally on the reproductive tract, their effects can be seen in neurochemical changes to the central nervous system that may suggest a difference in the way HC-users experience and interact with their environment. Epidemiological and human experimental research has connected HC-use with changes in the cognitive and behavioral domains (Allen et al., 2019; Schaffir et al., 2016, Warren et al., 2014); however, the directionality of these effects is oftentimes conflicting. This may be due to differences in the chemical structure and steroid receptor binding affinity of the progestin component of HCs – the development of synthetic progestins for HC use has resulted in multiple generations of progestational agents that have unique binding affinities (Sitruk-Ware and Nath, 2010; Rice, 2006) and may subsequently affect cognition and behavior differently.

Although HCs have notable neurobiological and/or behavioral effects in humans (Warren et al., 2014, Bonenberger et al., 2013; Rapkin et al., 2007), little is understood about the underlying mechanisms that drive these behaviors or how different generations of HCs may result in different behavioral profiles. This type of question is one that might be best answered using non-human animal models of neurobehavior, however, the extant literature examining neurobehavioral outcomes of HC-use in animal models is surprisingly limited, and what is available does not always provide information regarding the fundamental considerations of HCs that go into building a behavior model. As the pharmacological profile of HCs is dynamic and information regarding translatability between animals and humans is more limited for some HCs than others, the following review provides basic methods and considerations researchers may choose to use in designing their experiments using animal models. The provided information is specific to rat models, but most of the basic considerations are universal between species.