How reward and emotional stimuli induce different reactions across the menstrual cycle

Social and Personality Psychology Compass 6/1 (2012): 1–17, 10.1111/j.1751-9004.2011.00415.x How Reward and Emotional Stimuli Induce DifferentReactions Across the Menstrual Cycle Michiko Sakaki* and Mara MatherUniversity of Southern California AbstractDespite widespread belief that moods are affected by the menstrual cycle, researchers on emotionand reward have not paid much attention to the menstrual cycle until recently. However, recentresearch has revealed different reactions to emotional stimuli and to rewarding stimuli across thedifferent phases of the menstrual cycle. The current paper reviews the emerging literature on howovarian hormone fluctuation during the menstrual cycle modulates reactions to emotional stimuliand to reward. Behavioral and neuroimaging studies in humans suggest that estrogen and proges-terone have opposing influences. That is, it appears that estrogen enhances reactions to reward,but progesterone counters the facilitative effects of estrogen and decreases reactions to rewards. Incontrast, reactions to emotionally arousing stimuli (particularly negative stimuli) appear to bedecreased by estrogen but enhanced by progesterone. Potential factors that can modulate theeffects of the ovarian hormones (e.g., an inverse quadratic function of hormones' effects; the struc-tural changes of the hippocampus across the menstrual cycle) are also discussed.
In life, we often encounter hedonic stimuli, such as happy faces, appealing animals,money, car accidents, and stressful events. These hedonic stimuli sometimes induce strongphysiological arousal (i.e., emotional arousal) that modulates subsequent cognitive process-ing (for a review see Mather & Sutherland, 2011). Some hedonic stimuli (e.g., money;high-calorie foods) can also serve as reinforcers (i.e., reward), increasing the frequency ofbehaviors that lead to their acquisition (e.g., Berridge, 2003; Kringelbach, 2005). Giventhe importance of these stimuli in our life, reward and emotion have been intensivelyexamined in many fields, such as social neuroscience, cognitive science, affective neuro-science, behavioral economics, and neuroeconomics.
While traditional studies in these areas examined common patterns across different peo- ple regardless of their sex, a growing body of research demonstrates sex differences inhow people react to and process rewards and emotional stimuli (see Andreano & Cahill,2009; Cahill, 2006; Caldu´ & Dreher, 2007; Hamann & Canli, 2004; Kajantie & Phillips,2006; Kudielka & Kirschbaum, 2005 for reviews). One possible reason for these sex dif-ferences is that ovarian hormones alter reactions to emotional stimuli and to rewards. Forexample, the same emotional stimuli may induce different arousal reactions and neuralresponses in brain regions modulating arousal depending on ovarian hormone levels.
Brain regions involved in reward processing might also respond differently depending onovarian hormone levels. To address these possibilities, in the current paper, we reviewbehavioral and neuroimaging findings on the effects of the menstrual cycle on reactionsto emotional stimuli and to rewards.
Before further discussing the effects of ovarian hormones, we first describe our defini- tions of emotional stimuli and reward. Emotional stimuli are often characterized based ontwo orthogonal dimensions (Russell & Carroll, 1999): valence (positive or negative) and ª 2012 Blackwell Publishing Ltd 2 Emotion, Reward, Menstrual Cycle physiological arousal. Previous studies revealed that the amygdala, which is a key regionfor emotion (Phelps & LeDoux, 2005), responds to the intensity of physiological arousalinduced by positive or negative stimuli (Anderson et al., 2003; Kensinger & Corkin,2004; Shabel & Janak, 2009). However, the amygdala does not respond to the intensityof neutral stimuli (Winston, Gottfried, Kilner, & Dolan, 2005). This valence by intensityinteraction is consistent with the notion that both arousal and valence are importantaspects of emotional stimuli.
In contrast, reward has been defined as an instrumental reinforcer which triggers ‘want- ing' or craving (i.e., incentive salience) and increases the frequency of behaviors contin-gent with it (e.g., Berridge & Robinson, 2003; Berridge, Robinson, & Aldridge, 2009).
Reward has been associated with brain regions involved in dopaminergic processing, suchas the striatum (including nucleus accumbens), globus pallidus, and ventral tegmental area(Berridge, 2003; Berridge et al., 2009). Rewards overlap with emotional stimuli (particu-larly emotionally positive stimuli), as they can produce emotional consequences (e.g.,earning money could be a reinforcer but might also evoke emotional arousal). In fact,rewards sometimes activate the amygdala (Camara, Rodriguez-Fornells, & Munte, 2009).
Likewise, emotionally positive stimuli sometimes activate the reward-related regions inthe brain (Phan, Wager, Taylor, & Liberzon, 2002).
However, emotional stimuli do not always serve as reinforcers and do not necessarily have strong incentive salience. For example, seeing people cerebrating their victory at theOlympics can induce emotional arousal, but does not necessarily alter one's behavior orinduce craving for victory. Similarly, rewards can serve as reinforcers even when they donot have positively valenced meanings (Berridge, 2003; Berridge et al., 2009). In the cur-rent paper, therefore, ‘‘reward'' is defined as an instrumental reinforcer which increasesthe frequency of contingent behaviors while evoking feelings of ‘wanting' or craving. Incontrast, we use the term ‘‘emotional stimuli'' to refer to valenced stimuli that inducephysiological arousal (regardless of positive or negative valence), affecting cardiovascularactivity, heart rate, skin response, and pupil dilation. Emotional stimuli induce multiplereactions, including physiological arousal, stress hormones, amygdala activity, and subjec-tive feelings. Similarly, rewards can alter physiological states (e.g., heart rate), activity inreward-related regions in the brain, and subjective experiences. In the current paper, wereview the effects of ovarian hormones without discriminating these different aspects ofreactions.
Ovarian Hormone Changes across Menstrual Cycle The human menstrual cycle lasts 28 days on average and is divided into follicular andluteal phases. The follicular phase begins with the onset of menstruation on day 1 andcontinues until ovulation (typically on day 14), and the luteal phase begins at ovulationand continues until the onset of menstruation (typically days 15–28; Figure 1).
The early follicular phase begins with release of gonadotropin-releasing hormone from the hypothalamus, which stimulates the anterior pituitary to secrete follicle-stimulatinghormone (FSH: Barr, 1999; Raven, Johnson, Singer, & Losos, 2005; Rimsza, 2002).
FSH stimulates the growth of a number of ovarian follicles that secrete estrogen as theymature. When one of the developing follicles becomes dominant, it starts to secrete largeamounts of estrogen. This sharp increase in estrogen causes positive feedback effects onthe hypothalamus and the pituitary gland, which results in a surge of luteinizing hormone(LH) and then ovulation. During the luteal phase, the postovulatory dominant ovarianfollicle transforms into a corpus luteum, which in turn produces both progesterone and ª 2012 Blackwell Publishing Ltd Social and Personality Psychology Compass 6/1 (2012): 1–17, 10.1111/j.1751-9004.2011.00415.x Emotion, Reward, Menstrual Cycle The human menstrual cycle. Day 1 of the cycle is defined as the first day of menstruation, with ovula- tion occurring on day 14 in a typical 28-day cycle. The follicular phase starts on day 1 and continues until ovula-tion, which is followed by the luteal phase. The menstrual cycle in healthy women is associated with (a) pituitaryhormone changes, (b) development of ovarian follicles, (c) changes in estrogen and progestrone level, and (d)changes in the thickness of the uterine lining (From The Merck Manual Home Health Handbook, edited by RobertS. Porter. Copyright ª 2004–2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., WhitehouseStation, NJ, USA. Retrieved on 10 May 2011 from: http://www.MerckManuals.com/home).
estrogen. The combination of these two ovarian hormones helps the endometriumthicken and become more vascular. If fertilization does not occur, the corpus luteum can-not survive. As the corpus luteum regresses, estrogen and progesterone levels drop andFSH begins to rise to initiate follicular growth for the next cycle.
Thus, the absolute levels of estrogen and progesterone, and the ratio of these hormone concentrations, change over the regular menstrual cycle. Both progesterone and estrogenlevels are low during the early follicular phase, while the late follicular phase is character-ized by a marked increase in secretion of estrogen. Finally, progesterone levels rise during ª 2012 Blackwell Publishing Ltd Social and Personality Psychology Compass 6/1 (2012): 1–17, 10.1111/j.1751-9004.2011.00415.x 4 Emotion, Reward, Menstrual Cycle the early luteal phase, peaking in the mid-luteal phase, in parallel with a second estrogenpeak.
Research Examining Effects of Ovarian Hormones Although estrogen and progesterone are best known for their effects on the female repro-ductive organs (e.g., uterus; ovary), they cross the blood-brain barrier (Henderson, 1997;Wirth, 2011) and affect brain functions as well (e.g., McEwen, 2002). For example, thehypothalamus, which plays an important role in regulation of the menstrual cycle (asdescribed above), has both estrogen and progesterone receptors. Many other brain regionsthat are not crucial for reproduction also show progesterone receptor expression (Brintonet al., 2008), such as the amygdala, brainstem, hippocampus, cerebellum, and frontal cor-tex. Among those areas, the amygdala is a key region in emotional processing (e.g.,Phelps, 2006). The amygdala also has both ERa and ERb estrogen receptors (e.g., Weiser,Foradori, & Handa, 2008). In fact, the amygdala has one of the highest densities of estro-gen receptors in the brain (Merchenthaler, Lane, Numan, & Dellovade, 2004; Shughrue& Merchenthaler, 2001). These findings suggest that both estrogen and progesteroneinfluence reactions to emotional stimuli. In addition, other brain regions, such as the ven-tral tegmental area, hippocampus, and cerebellum, also express at least one of the estrogenreceptors (McEwen, 2002; Weiser et al., 2008). Given that the ventral tegmental areaplays a crucial role in processing of reward (Berridge, 2003; Berridge et al., 2009), femalesmay show different responses to reward depending on the cycle.
To address these effects of the ovarian hormones in humans, past studies categorized the menstrual cycle into several phases and compared women's reactions to emotional orrewarding stimuli in one phase with other phases. Some studies distinguished the follicu-lar vs. luteal phases. Given that both estrogen and progesterone levels are higher in theluteal than in the follicular phase on the average, however, these studies cannot discrimi-nate the effects of estrogen and progesterone. Thus, other studies have defined menstrualphase more specifically, with smaller ranges of dates of testing. For example, studiesexamining the effects of estrogen compare females in the late follicular mid-cycle phase(high estrogen and low progesterone) with the early follicular phase (low estrogen andlow progesterone). In contrast, studies addressing the effects of progesterone compare theluteal phase (high estrogen and high progesterone) vs. the late follicular phase (high estro-gen and low progesterone). Furthermore, researchers sometimes administer progesteroneor estrogen to females in the early follicular phase. The exogenous administration of theovarian hormones seems especially useful to understand the role of progesterone indepen-dently from estrogen, because there is no phase involving low estrogen and high proges-terone in the regular menstrual cycle.
The phases of the cycle have been defined in various ways. Some studies have relied on self-reports of the dates of menstruation. Other studies have identified the day of ovu-lation by having participants measure their body temperature or their urinary LH levels.
Given possible individual differences and potential menstrual cycle variations within thesame women (e.g., Alliende, 2002), these methods are sometimes combined with hor-mone assays based on plasma or saliva samples to verify the definition of the phase. Whilethese methodological issues are important (see Terner & de Wit, 2006 for a relateddiscussion), the field is new and the number of relevant studies is still small. Therefore,we review studies irrespective of the methods used to define and verify the cycle phases.
In the following sections, we first describe findings from past studies examining the effects of the menstrual cycle on reactions to rewards, and then findings on reactions to ª 2012 Blackwell Publishing Ltd Social and Personality Psychology Compass 6/1 (2012): 1–17, 10.1111/j.1751-9004.2011.00415.x Emotion, Reward, Menstrual Cycle emotionally arousing stimuli in healthy women. Each section starts with reviewing previ-ous studies that simply compared the follicular phase (days 1–14) and the luteal phase(days 15–28). To understand the roles of estrogen and progesterone, we then describestudies examining the effects of these hormones separately with finer cycle categorizationsor exogenous administrations of the ovarian hormones.
Effects of Ovarian Hormones on Reactions to Reward Females showed greater physiological and subjective effects of cocaine (Evans & Foltin,2006; Evans, Haney, & Foltin, 2002), amphetamine (Justice & de Wit, 1999) and nico-tine (Gray et al., 2010) during the follicular phase than during the luteal phase. Neuro-imaging research also revealed that monetary reward induced greater activity in thestriatum in the follicular than luteal phase (Dreher et al., 2007). However, it is not clearwhether the decreased reactions to reward during the luteal phase were due to estrogenor progesterone, both of which are elevated in this period. To address this question, wereview studies examining the effects of these hormones separately.
Estrogen enhances reactions to reward Animal studies suggest that estrogen enhances reactions to rewards (Becker & Hu, 2008;Lynch, Roth, & Carroll, 2002). In one study (Hu, Crombag, Robinson, & Becker,2004), for example, female ovariectomized rats were given estrogen before self-adminis-tration sessions, in which they were allowed to nose poke to obtain a cocaine infusion.
The results indicated that ovariectomized rats with estrogen self-administered largeramounts of cocaine more frequently than did ovariectomized rats without estrogen.
Estrogen was also revealed to increase behavioral sensitization (Becker & Hu, 2008;Galankin, Shekunova, & Zvartau, 2010; Hu & Becker, 2003) and dopamine releasein reward-related regions in the brain (e.g., striatum; Becker, 1990).
Studies in humans demonstrated similar enhancement effects of estrogen on reactions to rewards. When receiving doses of d-amphetamine, for instance, females reported thatthey liked the effects of drug more strongly in the late follicular phase (high estrogen andlow progesterone) than the early follicular phase (low estrogen and low progesterone; Jus-tice & De Wit, 2000a). In addition, exogenous estrogen administration to females withlow progesterone increased subjective effects of d-amphetamine (e.g., ‘‘want more''; feel-ing ‘‘high''; Justice & de Wit, 2000b; Lile, Kendall, Babalonis, Martin, & Kelly, 2007).
Taken together with findings from animal studies, it appears that estrogen enhances reac-tions to reward stimuli.
Progesterone counters facilitative effects of estrogen However, estrogen no longer has facilitative effects on reactions to rewards when proges-terone is high. As described in previous sections, estrogen administration to ovariecto-mized female rats increased self-administration of cocaine (e.g., Hu et al., 2004). Whenestrogen and progesterone were given together, however, progesterone diminished thefacilitative effects of estrogen (Jackson, Robinson, & Becker, 2006; Larson, Anker,Gliddon, Fons, & Carroll, 2007). These results are consistent with recent findings thatprogesterone down-regulates the estrogen receptor (e.g., Aguirre, Jayaraman, Pike, &Baudry, 2010), and suggest that progesterone counters the facilitative effects of estrogen ª 2012 Blackwell Publishing Ltd Social and Personality Psychology Compass 6/1 (2012): 1–17, 10.1111/j.1751-9004.2011.00415.x 6 Emotion, Reward, Menstrual Cycle (Anker, Larson, Gliddon, & Carroll, 2007; Quinones-Jenab & Jenab, 2010; Yang, Zhao,Hu, & Becker, 2007).
Studies in humans provide additional support that progesterone opposes the effects of estrogen. In line with the facilitative roles of estrogen, estrogen level was positively cor-related with the magnitude of subjective (e.g., feeling ‘‘high''; elation) and physiological(e.g., heart rate) stimulation of amphetamine during the follicular phase (Justice & deWit, 1999; White, Justice, & de Wit, 2002). But when progesterone was high (i.e.,during the luteal phase), the level of estrogen no longer had a positive correlation withthe magnitude of amphetamine's stimulation (Justice & de Wit, 1999; White et al.,2002).
A recent neuroimaging study also reported consistent evidence (Frank, Kim, Krzemien, & Van Vugt, 2010). In this study, female participants viewed images of high-calorie-rewarding foods (e.g., cakes, cookies, ice cream) and of low-calorie foods (e.g., steamedvegetables) when they were hungry. During the late follicular phase, high-calorie foodsinduced greater activity in reward-related regions (e.g., nucleus accumbens) than didlow-calorie foods. However, nucleus accumbens activity did not differ between high-and low-calorie foods in the luteal phase. Given the hormone patterns of the late follicu-lar (high estrogen and low progesterone) and the luteal phase (high estrogen and highprogesterone), these results seem consistent with the idea that progesterone counters facil-itative effects of estrogen.
Progesterone decreases reactions to reward by itself In addition to its countering effects on estrogen, past studies have revealed that progester-one can decrease reactions to reward even when estrogen is low (Evans, 2007; Quinon-es-Jenab & Jenab, 2010). While intact animals show strong preference for a chamberassociated with cocaine, for example, progesterone administration diminished the prefer-ence for the cocaine-paired chambers in ovariectomized female rats (Russo et al., 2003)and in male rats (Romieu, Martin-Fardon, Bowen, & Maurice, 2003). Studies in humansalso reported similar findings. When progesterone was administered to females with lowestrogen, for instance, it attenuated physiological and subjective (e.g., feeling ‘‘high,''‘‘willing to pay'') effects of cocaine (Evans & Foltin, 2006; Sofuoglu, Babb, & Hatsukami,2002). Administration of progesterone also reduced urges to smoke cigarettes in femalesmokers during the early follicular phase (Sofuoglu, Mouratidis, & Mooney, 2011).
Because those studies addressed the effects of progesterone when estrogen is low, theysuggest that progesterone decreases reactions to rewards not only by countering the effectsof estrogen, but also by itself.
In summary, it appears that estrogen and progesterone have opposing effects on reactionsto rewards. That is, both animal and human studies indicate that estrogen enhances reac-tions to rewards. In contrast, studies suggest that progesterone counters the facilitativeeffects of estrogen and decreases reactions to rewards. As we described above, femalestend to show stronger reactions to rewards during the follicular phase than during theluteal phase (Dreher et al., 2007; Evans & Foltin, 2006; Evans et al., 2002; Gray et al.,2010; Justice & de Wit, 1999; Sofuoglu, Dudish-Poulsen, Nelson, Pentel, & Hatsukami,1999). Given studies reviewed in this section, it appears that progesterone is crucial toexplain the decreased reward sensitivity during the luteal phase.
ª 2012 Blackwell Publishing Ltd Social and Personality Psychology Compass 6/1 (2012): 1–17, 10.1111/j.1751-9004.2011.00415.x Emotion, Reward, Menstrual Cycle Effects of Ovarian Hormones on Reactions to Emotionally Negative Stimuli Next, we turn to the question whether and how ovarian hormones influence reactions toemotionally arousing stimuli. As we mentioned above, emotional stimuli involve stimuliinducing physiological arousal, irrespective of whether they are positive or negative.
However, the majority of past studies on ovarian hormones employed only negative andneutral stimuli. Therefore, we focus on findings about reactions to negative stimuli in thissection.
As with reward, previous studies revealed that females react to emotionally negative stimuli differently in follicular vs. luteal phases. Compared with the follicular phase, forexample, females in the luteal phase showed increased stress hormones after stressful tasks(Altemus, Roca, Galliven, Romanos, & Deuster, 2001; Childs, Dlugos, & De Wit,2010a; Kirschbaum, Kudielka, Gaab, Schommer, & Hellhammer, 1999; Roca et al.,2003; Tersman, Collins, & Eneroth, 1991), showed stronger amygdala activity whenanticipating pain (Choi et al., 2006), and interpreted mildly negative faces as stronglynegative (Derntl, Kryspin-Exner, Fernbach, Moser, & Habel, 2008). Studies of dailymoods also reported increased negative moods during the luteal phase than the follicularphase (Allen, Allen, & Pomerleau, 2009; Reed, Levin, & Evans, 2008; Sanders, Warner,Backstrom, & Bancroft, 1983). Because these studies cannot discriminate the effects ofthe two ovarian hormones, we review studies examining estrogen and progesterone sepa-rately in the following sections.
Estrogen decreases reactions to emotionally negative stimuli Animal studies indicate estrogen decreases reactions to emotionally negative stimuli. Forexample, exogeneous estrogen administration decreases release of stress hormones at leastwhen estrogen does not reach supra-physiological levels (Dayas, Xu, Buller, & Day,2000; Young, Altemus, Parkison, & Shastry, 2001). Estrogen administration to ovariecto-mized female rats also increased time spent in open arms in the elevated plus maze (anaversive situation for a rat) and reduced duration of freezing after foot-shock (Frye &Walf, 2004), thus reducing the intensity of anxious or depressive responses to aversivesituations (for a review see Walf & Frye, 2006).
Similar patterns were observed in studies in humans as well (e.g., Gasbarri et al., 2008).
Higher levels of estrogen were associated with poorer performance in recognizing angerfaces (Guapo et al., 2009). Estrogen therapy is also known to decrease depressive symp-toms at least in perimenopausal females (Cohen et al., 2003; Soares, Almeida, Joffe, &Cohen, 2001). Furthermore, Goldstein et al. (2005) compared brain activity while view-ing negative or neutral pictures during the early follicular (low estrogen and low proges-terone) vs. late follicular phase (high estrogen and low progesterone). As shown inprevious studies collapsing sex and menstrual cycle phases (e.g., Ochsner et al., 2004;Phan et al., 2002), females in both phases showed enhanced activity in emotion relatedregions, such as the amygdala and orbitofrontal cortex (OFC), when viewing negativepictures than neutral pictures. However, the activity of these areas was modulated by themenstrual cycle phases. That is, females showed greater activity in the amygdala and OFCto negative pictures during the early follicular phase than during the late follicular phase(see also Goldstein, Jerram, Abbs, Whitfield-Gabrieli, & Makris, 2010).
Thus, both animal and human studies suggest that reactions to negative stimuli are decreased by estrogen. Although different studies employed different tasks or measures(e.g., amygdala activity to negative pictures, facial emotion recognition), they have ª 2012 Blackwell Publishing Ltd Social and Personality Psychology Compass 6/1 (2012): 1–17, 10.1111/j.1751-9004.2011.00415.x 8 Emotion, Reward, Menstrual Cycle observed consistent patterns, suggesting that estrogen has similar effects across differentaspects of reactions to negative stimuli. However, this does not mean that estrogen inhib-its any tasks involving negative stimuli. In fact, recent research has revealed the facilitativeeffects of estrogen on one type of learning involving negative stimuli – extinction of fearconditioning (Milad, Igoe, Lebron-Milad, & Novales, 2009; Milad et al., 2010; Zeidanet al., forthcoming).
One possible factor contributing to the contradictory findings is the complexity of tasks being employed. While studies showing inhibitory effects of estrogen measured relativelysimple reactions to negative stimuli (e.g., amygdala activity to negative pictures; facialemotion recognition), extinction learning requires multiple types of processing. Forinstance, recent research indicates that extinction of fear conditioning involves reward-related learning (Holtzman-Assif, Laurent, & Westbrook, 2010; Raczka et al., 2011).
Thus, the facilitative effects of estrogen on extinction recall might be caused by theeffects of estrogen on reward. Furthermore, hippocampal structure is changed by estrogenquite rapidly. For example, higher levels of estrogen result in greater synapse density ofhippocampus within 24 hours in rats (Woolley & McEwen, 1993). Research in humansalso revealed that the same women had increased hippocampal volume during the late-follicular phase than the premenstrual phase (Protopopescu et al., 2008). Since extinctionof conditioning depends not only on emotion-related areas (e.g., OFC), but also on thehippocampus (Milad et al., 2007), structural changes in brain regions critical for extinc-tion learning may also explain enhancing effects of estrogen on extinction. Takentogether, it appears that estrogen decreases reactions to negative stimuli, but can havefacilitative effects when tasks involve reward-related components or hippocampus-relatedprocessing.
Progesterone enhances reactions to emotionally negative stimuli In contrast with estrogen's inhibitory effects on reactions to negative stimuli, past stud-ies suggested that progesterone enhances reactions to negative stimuli at least inhumans (e.g., Andreano, Arjomandi, & Cahill, 2008; Protopopescu et al., 2005).
When females were tested at two timepoints with different level of progesterone, forexample, they experienced more spontaneous intrusive recollections about unpleasantevents when progesterone was high than when progesterone was low (Ferree & Cahill,2009; Ferree, Kamat, & Cahill, forthcoming). Similarly, compared to the late follicularphase (high estrogen and low progesterone), females in the luteal phase (high estrogenand high progesterone) were more sensitive to facial cues signaling contagion andphysical threat (Conway et al., 2007) and increased their heart rates more whilewatching negative videos (Ossewaarde et al., 2010). Furthermore, a neuroimagingstudy (Andreano & Cahill, 2010) revealed increased amygdala activity to negative pic-tures (relative to neutral pictures) when progesterone was high than when progesteronewas low.
Human studies employing exogenous progesterone administration also confirmed the facilitative role of progesterone. For example, females in the follicular phase showedincreased amygdala activity to angry and fearful faces when they were given progesteronecompared with placebo (van Wingen et al., 2008). Progesterone administration alsoincreased physiological reactions to a stress task both in males (Childs, Van Dam, & Wit,2010b) and females (Roca et al., 2003). Furthermore, exogenous progesterone increasednegative moods in women in the early follicular phase (Klatzkin, Leslie Morrow, Light,Pedersen, & Girdler, 2006; Soderpalm, Lindsey, Purdy, Hauger, & de Wit, 2004) as well ª 2012 Blackwell Publishing Ltd Social and Personality Psychology Compass 6/1 (2012): 1–17, 10.1111/j.1751-9004.2011.00415.x Emotion, Reward, Menstrual Cycle as in postmenopausal women (Andre´en et al., 2009). Taken together, it appears thatprogesterone increases reactions to negative stimuli in humans.
However, animal studies provided contradictory findings (for a review see Wirth, 2011). That is, exogeneous progesterone administration was revealed to decrease theintensity of anxious or depressive responses to aversive situations (e.g., elevated plus maze,foot-shock; Auger & Forbes-Lorman, 2008; Frye & Walf, 2004; Llaneza & Frye, 2009).
Furthermore, some studies in humans also observed that progesterone administrationweakened subjective reactions to negative stimuli (e.g., Childs et al., 2010b; de Wit,Schmitt, Purdy, & Hauger, 2001).
One possible reason for this inconsistency is that while increases in progesterone seen during normal menstrual cycles enhance reactions to negative stimuli (as we discussedabove), concentrations of progesterone higher than the normal range might decreaseemotional reactions and have calming effects (see Andre´en et al., 2009 for a review). Infact, when progesterone was administered to post menopausal women, participantsreported the highest negative mood scores with a moderate level of oral micronized pro-gesterone (Andre´en, Sundstro¨m-Poromaa, Bixo, Nyberg, & Ba¨ckstro¨m, 2006). In con-trast, both lower and higher concentrations of progesterone produced less negative moods(Andre´en et al., 2006). Thus, it appears that the effects of progesterone follow an inverse-U function, rather than a linear correlation. Perhaps, if there is too much progesterone,progesterone no longer has facilitative effects and decreases reactions to negative stimuli(see also Andre´en et al., 2005; Gomez, Saldivar-Gonzalez, Delgado, & Rodriguez, 2002).
This might explain why studies with exogenous progesterone administration to animalsand humans sometimes revealed inhibitory effects of progesterone on reactions to nega-tive stimuli.
Studies reviewed in this section indicate that estrogen and progesterone have opposinginfluences on reactions to emotionally negative stimuli. In other words, reactions to nega-tive stimuli appear to be decreased by estrogen but enhanced by progesterone. These pat-terns were observed across different studies employing different types of tasks or measures(e.g., amygdala activity to negative pictures; stress hormones; facial emotion recognition).
However, studies sometimes observed different patterns. Potential factors for these incon-sistencies are an inverse quadratic function of progesterone's effects, reward-related com-ponents involved in tasks being employed, and structural changes of the brain across themenstrual cycle.
Effects of Ovarian Hormones on Reactions to Emotionally Positive Stimuli The amygdala, a key region for emotional processing, responds to emotionally arousinginformation, regardless of whether it is positive or negative (e.g., Anderson et al., 2003;Kensinger & Schacter, 2006; Sergerie, Chochol, & Armony, 2008). Thus, one mightexpect that estrogen and progesterone have similar influences on positive and negativestimuli. However, previous studies in humans provided mixed results regarding ovarianhormone effects on reactions to positive stimuli.
Consistent with facilitative effects of progesterone on reactions to negative stimuli, for example, progesterone administration increased positive emotional states in postmenopausalwomen (de Wit et al., 2001). Higher progesterone was also associated with a greaterincrease in cortisol after positive emotion induction in males (Wirth, Meier, Fredrickson, ª 2012 Blackwell Publishing Ltd Social and Personality Psychology Compass 6/1 (2012): 1–17, 10.1111/j.1751-9004.2011.00415.x 10 Emotion, Reward, Menstrual Cycle & Schultheiss, 2007). However, opposite patterns have also been reported. That is, pro-gesterone administration reduced amygdala activity to happy or neutral faces (van Wingenet al., 2007) and decreased positive emotional states, such as friendliness or confidence, infemales in the early follicular phase (Klatzkin et al., 2006; de Wit et al., 2001). Resultson estrogen were also mixed. Researchers sometimes observed increased activity in emo-tion-related areas to positive stimuli when estrogen was low than high (Zhu et al., 2010).
However, other research provided evidence for facilitative effects of estrogen on reactionsto positive stimuli (Amin, Epperson, Constable, & Canli, 2006; Gizewski et al., 2006).
One possible reason for this inconsistency is the role of reward. Although rewards and emotionally positive stimuli can be defined separately (as discussed above), they also over-lap with each other. For example, positive but non-rewarding stimuli sometimes activatereward-related regions, such as striatum, in addition to the amygdala (Hamann & Mao,2002). Recent research also revealed that viewing positive emotional stimuli can increasesubsequent striatum activity to monetary rewards (Wittmann, Schiltz, Boehler, & Duzel,2008). These results suggest that positive emotional stimuli not only evoke emotionalarousal, but also prime reward-related processing.
This complex nature of positive stimuli might explain the mixed findings of estrogen and progesterone on reactions to positive stimuli. That is, estrogen might facilitatereward-related aspects of reactions to positive stimuli, but decrease their aspects related toemotional arousal. Similarly, progesterone might decrease reward-related aspects of reac-tions to positive stimuli, but have facilitative effects on their aspects related to emotionalarousal. Thus, ovarian hormones might have opposing influences on the reward-relatedand arousal-related aspects of positive emotion, which could result in unclear effects ofthe ovarian hormones on reactions to positive stimuli.
Questions for Future Research and Conclusions In summary, the current paper suggests that estrogen and progesterone have opposinginfluences on both reactions to emotionally arousing negative stimuli and reactions torewarding stimuli. In other words, reactions to negative stimuli seem to be decreased byestrogen, but enhanced by progesterone. In contrast, the opposite effects were observedin reactions to rewarding stimuli. That is, it appears that estrogen enhances reactions torewards, while progesterone decreases reactions to rewards not only by itself, but also bycountering the facilitative effects of estrogen. In addition to this overall pattern, thecurrent paper also highlights several important questions for future studies.
The first question concerns the effects of the ovarian hormones on reactions to positive stimuli. As we pointed out in the previous section, past studies reported mixed findingson the effects of estrogen and progesterone on reactions to positive stimuli. Given apotential link between reward and positive emotion (e.g., Wittmann et al., 2008), reac-tions to positive stimuli might reflect not only emotional arousal-related processing, butalso reward-related processing. Future studies should tease apart these two aspects of posi-tive emotion to clarify how the ovarian hormones modulate reactions to positive stimuli.
A second question is which aspects of reward and emotion are affected by estrogen and progesterone. Reward is not a unitary concept and has been decomposed into twoaspects (Berridge & Robinson, 2003; Berridge et al., 2009): a) hedonic consequences ofconsumption (‘liking') and b) incentive salience (i.e., ‘wanting'; craving). Studiesreviewed in this paper demonstrated similar effects of estrogen and progesterone on thesetwo aspects. That is, incentive salience (e.g., ‘‘want more'') is enhanced by estrogen (e.g.,Justice & de Wit, 2000b), but decreased by progesterone (Gray et al., 2010). Hedonic ª 2012 Blackwell Publishing Ltd Social and Personality Psychology Compass 6/1 (2012): 1–17, 10.1111/j.1751-9004.2011.00415.x Emotion, Reward, Menstrual Cycle consequences (e.g., ‘‘like drug'') is also enhanced by estrogen (e.g., Justice & De Wit,2000a), but decreased by progesterone (e.g., Evans & Foltin, 2006). However, these twoaspects often correlate with each other (e.g., Epstein et al., 2004). Thus, it is possible thatthe ovarian hormones influence only one of the aspects, and that the affected aspect mod-ulates the other aspect, which results in similar patterns between them. Likewise,although previous research on negative emotion observed similar effects of the ovarianhormones across different aspects of emotional reactions (e.g., amygdala activity; stresshormone, subjective mood states), there might be some aspects that are more stronglymodulated by ovarian hormones than others. Future studies need to clarify which aspectsof emotional and reward reactions are modulated by the ovarian hormones, while consid-ering detailed neurobiological mechanisms of the influences of estrogen and progesterone(e.g., Hudson & Stamp, 2011; Quinones-Jenab & Jenab, 2010).
Another question for future research is how ovarian hormones influence social behav- iors or one's personality. The construct of personality relies on the assumption that indi-viduals can be characterized by qualities that are relatively invariant over time. However,many personality traits are related with emotion or rewards (e.g., trait anxiety, neuroti-cism, self-esteem, and reward sensitivity). Thus, the same woman might show cyclic vari-ations in their emotion-related or reward-related personality tendencies. Similarly, theovarian hormones might influence within-individual processes and social behaviors, suchas emotion regulation, well-being, consumption behaviors, and attitudes toward otherpeople, all of which are relevant to emotion or reward. Future studies need to addressthe effects of the ovarian hormones on those complex intra- and inter-personal processes,while combining traditional psychology research methods (e.g., personality assessment,behavioral experiment), with physiological measures (e.g., hormone assay) and neuro-imaging methods. This multimethodological approach should provide better understand-ing of our behaviors in everyday life.
In conclusion, from the studies included in this review, it appears that the menstrual cycle and ovarian hormones modulate how people react to emotional and rewardingstimuli. Given the core importance of emotion and reward processing in our lives, suchdifferences are important and further investigation is needed to better understand themechanisms of the effects. These hormonal effects might explain why specific phases ofthe cycle are related to depressive symptoms (Farage, Osborn, & MacLean, 2008) orhigher risks in addiction (Becker & Hu, 2008; Terner & de Wit, 2006). Thus, examiningthe effects of menstrual cycle or ovarian hormones may have theoretical implications inmany fields, while providing practical suggestions on how to improve females' well-beingin real life.
This project was supported by grants K02 AG032309, R01 AG025340, and R01AG038043.
Short Biographies Michiko Sakaki received her PhD from the University of Tokyo and is an AssistantResearch Professor of Gerontology at the University of Southern California. Her researchfocuses on the effects of emotion on cognition. Utilizing neuroimaging and behavioralmethods, she addresses how emotion influences cognitive processing (e.g., memory,attention, problem solving) and how individual's characteristics (e.g., age, sex) modulate ª 2012 Blackwell Publishing Ltd Social and Personality Psychology Compass 6/1 (2012): 1–17, 10.1111/j.1751-9004.2011.00415.x 12 Emotion, Reward, Menstrual Cycle the emotional effects on cognition. She has authored and coauthored papers on these top-ics for ‘‘Journal of Personality'', ‘‘Journal of Cognitive Neuroscience'', ‘‘Cognitive, Affective, &Behavioral Neuroscience'', ‘‘Social, Cognitive, Affective Neuroscience'' and ‘‘Gerontology.'' Mara Mather's research focuses on how emotion and stress affect memory and deci- sions and how such influences differ depending on one's age and gender. Her researchelucidating the interaction of emotion, cognition, and aging has been recognized withthe American Psychological Association Distinguished Scientific Award for Early CareerContribution to Psychology and the Springer Early Career Achievement Award inResearch on Adult Development and Aging. She also received a National Institutes ofHealth K02 Career Development award and the Richard Kalish Innovative PublicationAward from the Gerontological Society of America. She is Associate Professor of Geron-tology and Psychology at the University of Southern California and holds an A.B. in psy-chology from Stanford University and a Ph.D. in cognitive psychology from PrincetonUniversity.
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