Since ethinylestradiol and synthetic progestins act on estrogen and progesterone receptors and OC reduce endogenous testosterone levels (e.g., Jung-Hoffman and Kuhl, 1987; Graham et al., 2007; Hietala et al., 2007), any hormonal contraceptive, irrespective of the progestin component, may show feminizing effects on brain and behavior.

However, hormonal contraceptives do also lead to a reduction of endogenous estradiol and progesterone levels (e.g., Sahlberg et al., 1987). In the presence of high levels of progesterone, testosterone-actions are impaired, because progesterone has a high affinity for the enzyme 5α-reductase, which is responsible for the conversion of testosterone into the physiologically more active dihydrotestosterone (Wright et al., 1983). If progesterone levels are reduced, more testosterone can be converted to dihydrotestosterone. Thus, any hormonal contraceptives, irrespective of the progestin component, may facilitate testosterone actions on the brain, thereby masculinizing brain structure, function and behavior. Alternatively, it has been argued that some masculinizing effects are promoted by estrogen receptors after testosterone has been locally converted to estrogen via the enzyme aromatase (Roselli, 2007). Consequently, estrogenic actions of ethinylestradiol may contribute to possible masculinizing effects of hormonal contraceptives on the brain.

Furthermore, the actions of synthetic progestins on the androgen receptors, may contribute to possible masculinizing and feminizing effects. While androgenic progestins may promote masculinizing effects, anti-androgenic progestins may promote feminizing effects. This distinction has important methodological consequences. The preferable approach to studying the effect of hormonal contraceptives in brain and behavior is a within-subjects design, i.e., comparing women to themselves, before, during and after the period of contraceptive use. Since this is however complicated, costly and time-consuming, hormonal contraceptive dependent effects are often studied by comparing a group of OC users to a group of non-users. If the group of OC users is heterogenous with respect to the androgenicity of the progestin component, possible feminizing and masculinizing effects may counteract each other, leading to results that either under- or over-estimate the actual effects and are hard to compare between different studies. While the first studies in this domain added important explorative impulses, by demonstrating that OCs may indeed influence brain and behavior, we strongly argue that the androgenicity of the progestin component is an important factor that should be controlled in future studies. An interesting observation from our own research experience in that respect may help when comparing findings between studies. We conducted two studies on the effects of OCs only about a year and a half apart, the first one in middle Europe (Austria; Pletzer et al., 2014a), the second one in the US (California, Pletzer et al., 2014b). While in the Austrian sample (Pletzer et al., 2014a), the group of OC users consisted of a majority of women using newer pills containing anti-androgenic progestins, in the US sample (Pletzer et al., 2014b), all OC users were on older pills containing androgenic progestins.

Adult brain structure is not static, but subject to dynamic changes with age. These changes do differentially affect different brain areas, i.e., gray matter volumes in some areas decline more strongly with age than others. A strong age-related decline has for example been demonstrated in the prefrontal cortex, as well as the hippocampus (e.g., Sowell et al., 2003).

Recent results demonstrated that regional gray matter volumes in the prefrontal cortex, as well as the anterior cingulate gyrus are larger in mixed samples of androgenic and anti-androgenic OC users compared to non-users (Pletzer et al., 2010; DeBondt et al., 2013). These regions are already larger in women compared to men (e.g., Good et al., 2001; Pletzer et al., 2010). However, regional gray matter volumes of OC-users were also larger in the cerebellum, hippocampi, parahippocampal and fusiform gyri (Pletzer et al., 2010; DeBondt et al., 2013). Those regions are on the average larger in men compared to women (e.g., Good et al., 2001; Pletzer et al., 2010). Results from rodent hippocampi suggest that these volume increases may be attributed to an increase in synaptic spine density mediated by estrogen receptors (e.g., Murphy et al., 1998; McEwen, 2002; Smith et al., 2009), but an increase in astrocyte volume in response to estradiol has also been suggested (e.g., Spencer et al., 2008).

Newer results from our own lab, suggest that the effects in cerebellum, parahippocampus and fusiform gyri are attributable to OCs containing anti-androgenic progestins, while the results in the prefrontal cortex are to be interpreted with care (Pletzer et al., submitted). We demonstrate that some structural effects increase with the duration of pill use, some interact with the age of the participants and some may not be completely reversible, and hence the duration of previous pill use in the group of non-users plays an important role. Thus, despite the androgenicity of progestins, the duration of (previous) pill use and age are important factors, that should be controlled when studying the effects of OCs on brain and behavior. OCs, in particular those containing anti-androgenic progestins, are commonly used by younger women, while naturally cycling women tend to be on average a few years older.

Synthetic steroids may however, not only cause a structural re-organization of the brain, but—even more importantly—induce changes in neurochemistry and brain function, which are currently relatively unexplored. Despite the relatively robust finding that OC users show altered mate preferences (e.g., Alvergne and Lummaa, 2009), accompanied by changes in brain activation patterns during viewing of erotic stimuli (Abler et al., 2013), OC dependent changes in cognitive performance have not been studied systematically.

Scattered over several countries and decades, it has been reported that OC users show enhanced verbal memory (Mordecai et al., 2008), recognition working memory during sleep deprivation (Wright and Badia, 1999), a lack of memory impairment due to cortisol (Kuhlmann and Wolf, 2005) and better dream recall (Sheldrake and Cormack, 1976) compared to non-users. These verbal abilities and memory are usually thought to favor women (e.g., Andreano and Cahill, 2009). However, non-significant effects were reported for other measures of verbal abilities, like verbal fluency (Mordecai et al., 2008) or a verbosequential task (Gordon and Lee, 1993), while verbal reaction times were slower in OC users compared to non-users in an older study (Garrett and Elder, 1984). First evidence for brain functional differences between OC users and non-users has also been reported in the verbal domain. A German brain imaging study (Rumberg et al., 2010) observed that during a word generation task OC users showed stronger activations in right-hemispheric task-specific areas than non-users. This is of particular interest, since the peak coordinates of the task-specific activations were left-lateralized in all participants and sex differences in lateralization have long been discussed in particular with respect to verbal tasks (e.g., Renteria, 2012).

On the other hand, some studies report better mental rotation performance in OC users compared to non-users (Wright and Badia, 1999; Wharton et al., 2008), although other studies report non-significant effects on visuospatial tasks (Gordon and Lee, 1993; Mordecai et al., 2008). Spatial abilities have robustly been observed to favor men (Andreano and Cahill, 2009). Wharton et al. (2008) nicely demonstrated that mental rotation performance does not only correlate with hormonal contraceptive use, but also with the androgenicity of the progestin component. Users of drospirenone-containing contraceptives performed worse on the mental rotation task than non-users. Neuroimaging studies exploring functional differences in spatial tasks between OC-users and non-users are still lacking. However, it has been demonstrated that brain activation patterns are masculinized in numerical tasks (Pletzer et al., 2014a), which have been related to spatial abilities (e.g., Hubbard et al., 2005).

Furthermore, OC users perform like men in an emotional memory paradigm, designed by Cahill and coworkers (Nielsen et al., 2011, 2013) and in a Navon paradigm (Pletzer et al., 2014b), both studies conducted on US samples. Brain functional differences between OC users and non-users have also been reported during the resting state (Petersen et al., 2014), during face processing (Mareckova et al., 2012) and during reward processing (Bonenberger et al., 2013). However, further more systematic studies are needed to reveal the true nature of OC-dependent effects on cognition as well as the impact of synthetic steroids on the neuronal correlates. Importantly, it has been demonstrated that endogenous sex hormones, in particular estrogen, affect cognitive performance differentially in different subpopulations of women, as some neurotransmitters (e.g., dopamine) affect behavior in an inverse U-shaped manner (Jacobs and D'Esposito, 2011; Colzato and Hommel, 2014). Hence, like in the study of menstrual cycle dependent effects (Colzato and Hommel, 2014), it might be worth considering neurotransmitter baseline levels, when studying the effects of hormonal contraceptives on brain and behavior.

Reports on OC-related mood changes are inconsistent, ranging from beneficial in most women (Oinonen and Mazmanian, 2002) to increased rates of depression, anxiety, fatigue, neurotic symptoms, compulsion and anger (Robinson et al., 2004; Kulkarni, 2007). Repeated findings of beneficial mood changes may however be biased by data sampling. Only women, who continue the intake of oral contraceptives (“survivor effect”) are included in those studies, while women, who discontinue the use of oral contraceptives due to negative emotional side effects, do not contribute to these results (Oinonen and Mazmanian, 2002).

Possible physiological mechanisms underlying both positive and negative mood swings in oral contraceptive users are manifold and at the moment speculative. Elevated levels of estradiol have anti-depressive effects (Moses-Kolko, 2009; Estrada-Camarena, 2010), presumably due to its serotonin (5-HT) enhancing property (e.g., Bethea et al., 2002). A decline in estradiol at the end of the menstrual cycle, post-partum or in the menopause has been associated with negative mood changes and depressive symptoms during these phases (Moses-Kolko, 2009). On the one hand combined OCs contain ethinyl-estradiol as synthetic agonist for estradiol receptors, which could promote positive mood changes. Antagonistic properties for the 5-HT3 receptor have been demonstrated not only for estradiol, but also for ethinylestradiol (Wetzel et al., 1998). On the other hand the levels of endogenous estradiol decline as a consequence of OCs (e.g., Sahlberg et al., 1987), which could result in negative mood changes. In female cynomolgus monkeys on OCs a decreased prolactin response was observed, suggesting reduced serotonergic activity (Henderson and Shively, 2004). Progesterone, however, may promote positive mood changes at low concentrations and negative mood changes at high concentrations due to biphasic effects on GABAergic neurons (Andréen et al., 2009). Again, synthetic progestins as contained in OCs simultaneously act as progesterone receptor agonist and reduce the level of endogenous progesterone (Wright et al., 1983; Sahlberg et al., 1987). In a meta-analysis Oinonen and Mazmanian (2002) suggest that the progesterone/estrogen ratio correlates to the direction of emotional changes.

In summary, these results suggest that there are (at least) two populations of women with differential emotional responses to oral contraceptive use. Interestingly, the majority of studies focused on depressive symptoms, while other emotional and personality dimensions, like aggression or empathy, have hardly been investigated.

First and foremost, we conclude that there is a strong demand for additional studies on how hormonal contraceptives affect the brain from the molecular to the behavioral level. Thus, future studies aiming to investigate “normal” brain functioning, should control for the use of hormonal contraceptives among their participants. At both the structural as well as behavioral level, feminizing and masculinizing effects of hormonal contraceptives have been observed simultaneously. However, these changes may show differential manifestation at the behavioral level in different subpopulations of women. As the number of women using oral contraceptives constantly increases, while the age of first contraceptive use constantly decreases down to sensitive neuroplastic periods during puberty, the associated changes in personality and social behavior imply significant consequences for society.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.