How hormonal contraceptives shape brain and behavior: A review of preclinical studies

Steroid hormones are crucial for normal brain function as they modulate brain development, neurogenesis, neuronal excitability, and neuronal plasticity, thus affecting emotional states, cognition, sociality, and reward. They exert these actions by binding to intracellular steroid receptors that promote gene transcription; in addition, some steroids can modulate ligand-gated ion channels located on the cell membrane thus exerting rapid non-genomic actions (McEwen and Milner, 2017, Porcu et al., 2016). Concentrations of endogenous steroid hormones fluctuate under several physiological conditions including development, puberty, the ovarian cycle, menopause, aging, as well as following several pathological conditions including neuropsychiatric diseases, neurodegenerative, inflammatory diseases. In addition, several pharmacological treatments against these diseases can restore altered levels of steroids. Steroid levels, particularly sex steroids also vary in response to hormonal contraceptives (HC) use (Del Río et al., 2018, Porcu et al., 2016, Porcu et al., 2019).

HC are a combination of synthetic estrogens and progestins, available as pills (combined oral contraceptives), transdermal patches or vaginal rings. Ethinyl estradiol (EE) is still the most used synthetic estrogen, even though some preparations using estradiol valerate or estetrol have the same contraceptive action with fewer side effects than EE (Apter et al., 2017, Nappi et al., 2014). Estrogens are paired to different types of progestins, including androgenic nortestosterone derivatives (levonorgestrel (LNG), norethindrone, desogestrel, gestodene, norgestimate), anti-androgenic progesterone derivatives (cyproterone acetate, chlormadinone acetate, nomegestrol acetate), and the spironolactone derivative drospirenone (Mitchell and Welling, 2020, Sitruk-Ware and Nath, 2010). Progestin-only contraceptives are also available as pills, injections, subdermal implants, and intrauterine devices. Emergency contraception also consists of a single administration of a higher dose of progestins, mostly LNG 1.5 mg or ulipristal acetate 30 mg (Regidor, 2018).

HC are used by 43% of women of reproductive age worldwide, mostly to prevent unintended pregnancies (United Nations, 2019). Since the first oral contraceptive developed in the 1960s, “the pill”, several forms of hormonal contraception are now available, including injectable formulations, subcutaneous implants, skin patches, intrauterine devices, and vaginal rings. Oral contraceptives remain one of the most used forms of hormonal contraception, especially in western countries (United Nations, 2019), mostly due to their high efficacy and rapid reversibility; in addition, they are prescribed as treatment for some gynecological diseases, such as endometriosis, polycystic ovary syndrome, dysmenorrhea, acne, and hirsutism.

Given that HC are mostly used by young, healthy women, much attention has been paid to their side effects. For instance, cardiovascular adverse effects have been reported, especially in women with other predisposing factors (i.e. smoking), but the lower HC formulations markedly reduce or abolish this risk (Levin et al., 2018, Williams and MacDonald, 2021), and evidence of improved cardiovascular outcomes following HC use has also been reported (Horvath et al., 2018). Likewise, potential risks for cervical and breast cancer are low and may depend on other variables related to duration of HC intake, reproductive history, increased risk due to genotype or to papilloma virus infection (Barańska et al., 2021; Brabaharan et al., 2022, Gierisch et al., 2013, Levin et al., 2018). On the other hand, HC use decreases the incidence of endometrial, ovarian and colorectal cancers, as well as benign breast disease (Brabaharan et al., 2022, Horvath et al., 2018, Levin et al., 2018). In addition, HC use in some women is also associated with headache, weight gain, nausea, changes in menstrual flow and decreased sexual desire, suggestive of an effect at the level of the central nervous system. Furthermore, emotional lability, irritability, and episodes of affective disorders such as depression or mood changes are also common reasons given by women for discontinuing effective HC use, often within the first three months, suggesting psychological effects of these drugs (Kulkarni, 2007, Kurshan and Epperson, 2006). Nonetheless, despite the large number of studies, there is still a lack of agreement on the effect of HC on mood disturbances, with evidence for mood deterioration as well as mood improvement or stabilization (Bitzer et al., 2018, Böttcher et al., 2012, Cheslack-Postava et al., 2015, Fruzzetti and Fidecicchi, 2020, Hall et al., 2012, Keyes et al., 2013, Lewis et al., 2019, Lundin et al., 2017, Montoya and Bos, 2017; Rapkin, Biggio, et al., 2006; Rapkin, Morgan, et al., 2006; Robakis et al., 2019, Skovlund et al., 2016; Sundstrom Poromaa and Segebladh, 2012, Toffol et al., 2012). Indeed, brain imaging studies showed increased mean diffusivity in the fornix of HC users compared to non-users, suggestive of microstructural changes in white matter (De Bondt et al., 2013), as well as modified volumes in specific brain regions, along with altered functional connectivity in the frontal nodes of the executive network between HC users and non-users, with important consequences for emotional regulation (Engman et al., 2018, Gingnell et al., 2013, Lisofsky et al., 2016, Petersen et al., 2021, Petersen et al., 2014, Petersen et al., 2015, Pletzer et al., 2016, Pletzer et al., 2019, Pletzer et al., 2010, Taylor et al., 2021). Some of these effects differ between adolescent and adult HC users (Sharma, Fang, et al., 2020; Sharma, Smith, et al., 2020), may depend on duration of HC use and type of progestin, and may not be completely reversible (Pletzer et al., 2015).

Although it is now accepted that HC affect brain function, the mechanisms underlying such effects are not completely understood. Animal models may aid in investigating the neurobiological mechanisms behind HC actions on brain function, but insofar very few studies have examined the effects of HC in animals’ brains. Here, we describe the current literature on preclinical studies in animals focused on the effects of HC on the central nervous system. Animal models to study effects of HC on brain and behavior have mostly used female rats or mice (see Table 1 for summary and references) and consist of administration of an estrogen-progestin combination, usually EE and LNG, or administration of a single synthetic steroid. Among progestins, LNG is the most studied; it is a second generation progestin that binds with high affinity to progesterone, androgen and mineralocorticoid receptors, but not estrogen receptors (Schindler et al., 2008). LNG is widely used in currently prescribed HC formulations and, besides “the pill”, it is also the primary component of most emergency contraceptive pills, intra-uterine devices and subdermal implants (Regidor, 2018). Some older studies have tested mestranol in combination with other progestins such as norethindrone, norethisterone acetate, medroxyprogesterone acetate, or lynestrenol; however, studies examining the new generation of progestins with anti-androgenic effects (i.e. drospirenone, dienogest, trimegestone) are still lacking. Drugs are administered in a wide range of doses meant to mimic the HC formulations used by women. The route of administration is mostly subcutaneous or oral; the subcutaneous administration allows a slow rate of absorbance compared to other routes of delivery, while the oral route better mimics the one used by women; oral gavage via orogastric feeding needle is preferred to other oral delivery methods (i.e. voluntary intake; feeding syringe) to ensure each animal takes the same amount of drug. Implantable minipumps could also provide a suitable HC delivery system that allows constant delivery of the drug and could mimic subdermal implants used by women; however, this route of delivery is less common in preclinical research. Duration of treatment ranges from 1 day (rare) to 2 months, but the majority of the studies reported chronic treatments of 28-30 days, thus encompassing approximately 7 estrous cycles. Lifespan differs substantially between rats/mice and women; thus it is not simple to mimic duration of treatment. Studies using a short-term treatment, which encompasses approximately 1-3 estrous cycles, can provide useful information on the neurobiological effects of HC, but might be less relevant from a translational point of view, given that women usually take HC for longer periods of time. The majority of preclinical studies have examined HC effects during chronic exposure or the day after the last administration; studies examining putative long-term effects that may persist after weeks from drug discontinuation are very few and more research is needed. Overall, these studies showed that HC can alter neuroactive hormones, neurotransmitters, neuropeptides, as well as emotional states, cognition, social and sexual behaviors, as detailed in the next sections.

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