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Clinical Evidence of Endocrine Disruption Related to Mood Disorders

Major depressive disorder (MDD) is the fourth leading cause of disease burden worldwide (Murray and Lopez 1997; Ustun et al. 2004), and the incidence of MDD in women is twice that of men (Kessler 2003; Kendler et al. 2006). Thus, understanding the pathophysiology of MDD has widespread implications for attenuation and prevention of disease burden (Ustun et al. 2004), particularly in women. Over 40 years of research implicates hormonal dysregulation in mood disorders, with the earliest reports citing elevated cortisol in patients with major depression (Board et al. 1956; Gibbons and McHugh 1962). While in subsequent years a number of hormonal systems have been demonstrated to be associated with depression [i.e., appetite-regulatory, thyroid, and growth hormones (Coplan et al. 2000; Brouwer et al. 2005; Kurt et al. 2007; Barim et al. 2009)], evidence overwhelmingly supports the involvement of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes (Plotsky et al. 1998; Young and Korszun 2002; Swaab et al. 2005) in the development of mood dysregulation. In particular, hormonal dysfunctions in women have been found to precede MDD onset (Nemeroff et al. 1984; Harlow et al. 2003), suggesting that hormonal abnormalities are important in female vulnerability to MDD. Despite the important findings stemming from this critical line of investigation, there is a dearth of literature on sex differences in HPA-/HPG-axis functioning. Further, a number of other confounds (illness state versus disorder trait, treatment and medication status, age, and single episode versus recurrent diagnosis of MDD) present challenges to elucidating the role of sex in the co-occurrence of hormonal dysregulation and mood disorders.

HPA Axis and MDD

There is a long history of work characterizing the HPA system as central to understanding the development of MDD (Nemeroff et al. 1984; Holsboer et al. 1987; Plotsky et al. 1998; Arborelius et al. 1999; Heim et al. 2002; Parker et al. 2003; Raison and Miller 2003; Barden 2004; Swaab et al. 2005; Antonijevic 2006). Depressive symptoms can occur in the context of either endogenously elevated cortisol (i.e., Cushing syndrome; Sonino et al. 1998) or exogenously administered corticosteroids (Kelly et al. 1980), and patients treated with corticosteroids can develop MDD (Ling et al. 1981). Animal and human studies demonstrated consistent HPA axis abnormalities associated with MDD, most notably elevated levels of cortisol in plasma, CSF, and 24-h urine, in addition to high CSF fluid corticotrophin releasing hormone (CRH) levels, blunted responses to CRH administration, and nonsupression of cortisol secretion upon dexamethasone suppression test (Carroll et al. 1976a, b, 1981; Jarrett et al. 1983; Nemeroff et al. 1984; Halbreich et al. 1985; Holsboer et al. 1985; Banki et al. 1987; Evans and Nemeroff 1987; Holsboer et al. 1987; Rubin et al. 1987; Nemeroff et al. 1991; Arborelius et al. 1999; Heim and Nemeroff 2001; Heim et al. 2001; Newport et al. 2003; Oquendo et al. 2003; Raison and Miller 2003; Barden 2004). HPA dysregulation has been related to, among other things, age (Nelson et al. 1984a, b; Bremmer et al. 2007), depression subtype (hypercortisolemia in atypical depression and normal cortisol levels in melancholia; Brouwer et al. 2005), and single versus recurrent episodes (Poor et al. 2004).

Several studies have examined the utility of HPA reactivity as an indicator of treatment response in MDD. For example, while the elevation in CRH has been shown to resolve with treatment (Nemeroff et al. 1991; De Bellis et al. 1993; Veith et al. 1993), some studies report an incomplete resolution to normal levels, suggesting that these HPA abnormalities may be part of the vulnerability to MDD (or a trait) and not only state-related. Although decreases following treatment in abnormally elevated pre-treatment cortisol levels have been widely reported (Gibbons and McHugh 1962; Carroll et al. 1976a, b), a recent meta-analysis found that cortisol levels did not change pre- versus post-treatment in over half of subjects with depression (McKay and Zakzanis 2010). An examination of subject characteristics related to changes in cortisol post-treatment revealed the greatest decreases in those with the melancholic subtype. Time of sample collection, inpatient versus outpatient setting, type of treatment or antidepressant, subject sex, and number of past episodes were not associated with cortisol changes following treatment, although the length of the current episode was negatively associated with change in cortisol levels (McKay and Zakzanis 2010). This finding supported the hypothesis that the nature of HPA axis dysregulation shifts dramatically from acute [overall hypersecretion of corticotrophin releasing hormone (CRH), adrenocorticotropin hormone (ACTH), and cortisol] to chronic (reduced ACTH and hypercortisolemia) phases of depression (Parker et al. 2003).

The issues of state versus trait (independent of treatment) and underlying vulnerability to relapse in depression have been examined sparingly, with findings initially pointing to hypercortisolemia as a state (not trait) feature of MDD. In remitted patients compared with controls, cortisol levels were reported to be similar (Trestman et al. 1993) or even decreased (Ahrens et al. 2008), although these studies were small (n/group ~20–30). However, a recent well-powered study examined morning and evening salivary cortisol levels in 308 controls, 579 individuals with remitted MDD, and 701 patients currently in an MDD episode (Vreeburg et al. 2009). Results showed that remitted and current MDD subjects demonstrated significantly higher awakening cortisol levels compared to controls, providing compelling evidence that elevated cortisol is not specific to current state but persists following recovery and may therefore be a trait characteristic (Vreeburg et al. 2009). Although findings held when adjusted for sex (57–71 % female, depending on group) and other demographic variables, specific sex differences were not explored. When tracked longitudinally, baseline cortisol and dexamethasone suppression test abnormalities also predicted vulnerability to relapse, necessity for continued medication to sustain remission, and remission rate following hospitalization in MDD (O’Toole et al. 1997; Zobel et al. 1999; Appelhof et al. 2006; Ising et al. 2007).

Further evidence for the role of the adrenal cortex is suggested by work on dehydroepiandrosterone sulfate (DHEA-S) and MDD. DHEA-S, which is produced by the adrenal gland, is considered a weak androgen and has been significantly associated with MDD, depending on age and sex (Orentreich et al. 1984; Schmidt et al. 2002), illness severity, medication status, and time of sampling. In unmedicated MDD patients, DHEA-S had anti-glucocorticoid action in the brain (Young et al. 2002; van Broekhoven and Verkes 2003). In fact, studies demonstrated lower depressive symptoms and better memory function with increased levels of DHEA-S (Wolkowitz et al. 1999; van Broekhoven and Verkes 2003). A high cortisol:DHEA-S ratio, which is a functional indicator of hypercortisolemia (Gallagher and Young 2002), was significantly associated with MDD, emphasizing anti-glucocorticoid DHEA-S action (Young et al. 2002; van Broekhoven and Verkes 2003).

Despite significant advances in understanding the comorbidity of major depression and HPA axis dysregulation as evidenced above, there is a paucity of data on sex differences in the comorbidity. This is striking for three reasons. First, as mentioned previously, there are well-documented sex differences in MDD incidence and prevalence (Kessler 2003; Kendler et al. 2006). Second, substantial data support sex differences in HPA-HPG axes functioning during stress in healthy control populations (Kudielka and Kirschbaum 2005; Goldstein et al. 2010; Andreano et al. 2011) and in MDD women (Holsen et al. 2011). Finally, as discussed below, there are significant interactions of the HPA axis with the HPG axis, which we know is different between the sexes.

Among the few investigations reporting significant sex differences in HPA axis functioning in MDD, the direction of effects is mixed. Men, but not women, with MDD demonstrate abnormal ACTH pulsatility (Young et al. 2007a). Additionally, elevated cortisol has been documented in depressed men versus depressed women (Bremmer et al. 2007) and versus non-depressed men (Hinkelmann et al. 2011), but also in depressed women versus depressed men (Poor et al. 2004) versus non-depressed women (Young and Altemus 2004; Chopra et al. 2009). These conflicting reports on sex differences in cortisol levels may be related to timing of cortisol assessment across studies and/or genetic factors. Recent data suggest an interaction between sex and adrenoreceptor gene polymorphisms in HPA hyperactivity using a dexamethasone/CRH test pre- and post-treatment (Haefner et al. 2008). Specifically, increased ACTH and cortisol responses were seen in males (but not females) homozygotic for the alpha(2)-adrenoreceptor (ADRA2A) gene and females (but not males) homozygotic for the beta(2)-adrenoreceptor (ADRB2) gene (Haefner et al. 2008). Collectively these findings offer initial evidence of sex differences in the role of HPA axis functioning in MDD pathophysiology.

Several reports have found no effect of sex on HPA dysfunction in MDD (Carroll et al. 1976a, b; Nelson et al. 1984a; Maes et al. 1987, 1989, 1994; Dahl et al. 1989; Deuschle et al. 1998; Brouwer et al. 2005; Rubin et al. 2006; Vreeburg et al. 2009). However, the majority of these studies cited above (including those reporting sex differences and those with null findings) did not initially design their studies to investigate sex differences but rather analyzed the data by sex post hoc. This approach is problematic, since potential confounding (uncontrolled in the initial designs) is typical. For example, the vast majority of studies of MDD oversample women (Maes et al. 1987; Brouwer et al. 2005; Rubin et al. 2006; Young et al. 2007a; Vreeburg et al. 2009; Hinkelmann et al. 2011). Some have matched on sex whereas some included women using oral contraceptives or estrogen-replacement therapy (Brouwer et al. 2005), which have been shown to affect plasma levels of cortisol (Kirschbaum et al. 1999). Further, only a few mention “matching for menstrual status” (Maes et al. 1987; Rubin et al. 2006), and those that do generally refer to including similar numbers of women who are pre- or post-menopausal rather than actually controlling for menstrual cycle phase (for example, conducting study visits only within certain phases such as early follicular or late luteal). These methodological confounds present significant challenges to understanding the inconsistencies in the literature on sex differences in HPA axis dysregulation and MDD comorbidity.

The importance of HPA axis abnormalities in MDD is underscored by human postmortem studies. One human postmortem study found a 25 % decrease in the density of glucocorticoid receptor (GR) mRNA in MDD compared with healthy brains in frontal cortex, dentate gyrus, and subiculum, suggesting a down-regulation of GRs affecting the negative feedback system of the HPA axis resulting in hypercortisolemia (Webster et al. 2002). CRH action on ACTH is potentiated by arginine vasopressin (AVP), which is co-expressed with CRH in some neurons of the paraventricular nucleus of the hypothalamus (PVN) and was enhanced in MDD (von Bardeleben et al. 1989; Muller and Holsboer 2006). A recent postmortem study reported increased AVP mRNA in the PVN and supraoptic nucleus in MDD, particularly with melancholic features (Meynen et al. 2006). This finding is consistent with an increased number of AVP-immunoreactive neurons in PVN (Purba et al. 1996), particularly those co-localizing with increased CRH in PVN in MDD (Raadsheer et al. 1994a, b). It is also consistent with studies of MDD reporting elevated AVP plasma levels (van Londen et al. 1997; van Amelsvoort et al. 2001; de Winter et al. 2003), positive correlations of plasma AVP with cortisol (De Bellis et al. 1994; Inder et al. 1997; de Winter et al. 2003), and increased ACTH and cortisol in MDD and controls with intravenous administration of AVP (Gispen-de Wied et al. 1992), which are findings that were not due to medication confounds (van Londen et al. 1997; van Amelsvoort et al. 2001; Meynen et al. 2006).

HPG Axis and MDD

The relationship between mood disturbances and gonadal hormones was initially recognized, in part, through developmental endocrine disorders such as polycystic ovarian syndrome (PCOS), which is associated with high levels of comorbid depression (Himelein and Thatcher 2006b). The mechanisms behind this comorbidity are not fully understood, as data do not support an association between depressive symptoms and androgen levels, infertility issues, or hirsutism (Keegan et al. 2003; Rasgon et al. 2003; McCook et al. 2005; Himelein and Thatcher 2006a). Further evidence is derived from the abundant literature relating women’s reproductive system to mood fluctuations and depression (Payne 2003; Spinelli 2005; Payne et al. 2009). For example, pubertal onset (Angold and Costello 2006), late luteal menstrual cycle phase (Steiner 1992), chronic use of oral contraceptives (Young et al. 2007b), the postpartum period (Bloch et al. 2000; Brummelte and Galea 2010), and postmenopause (Graziottin and Serafini 2009) are all associated with vulnerability to MDD. However, the establishment of this relationship in women has not been accompanied by parallel examination of possible hormonal deficits linked to mood dysregulation in men at similar ages.

Human studies of MDD patients have found deficits in gonadal function (Rubinow and Schmidt 1996; Harlow et al. 2003), e.g., androgens (Baischer et al. 1995; Rubinow and Schmidt 1996; Schweiger et al. 1999; Seidman et al. 2001; Weiner et al. 2004) and estradiol (Young et al. 2000), and pituitary function, i.e., low follicle stimulating hormone (FSH; Daly et al. 2003). Women with persistent MDD had two times the risk of earlier perimenopausal transition, and those with a lifetime history of MDD had higher FSH and lower estradiol levels, suggesting an early decline in ovarian function (Young et al. 2000; Harlow et al. 2003). Further reports suggested a relationship between depressive symptom severity and estradiol levels (Baischer et al. 1995) and that ovarian dysfunction preceded the onset of MDD (Harlow et al. 2003). Abnormalities in luteinizing hormone (LH) levels and pulsatility in women with MDD have been consistently documented (Young et al. 2000; Meller et al. 2001; Harlow et al. 2003). LH pulse frequency and testosterone secretion in males with MDD were also lower (Schweiger et al. 1999), although conflicting reports suggested relatively normal HPG axis functioning in MDD males (Rubin et al. 1989).

HPA-HPG Interactions

There is some evidence that inhibition of HPG activity by stress and other factors may be linked to HPA activity (Halbreich and Kahn 2001). CRH inhibits gonadotropin releasing hormone (GnRH) and gonadotropin secretion in model animal studies (Nikolarakis et al. 1986; Olster and Ferin 1987). In fact, the low levels of estradiol seen in MDD premenopausal women may lead to decreased inhibitory feedback of the HPA axis in the presence of increased HPA drive with unopposed progesterone. This may in turn account for elevated levels of cortisol in MDD women compared to MDD men or non-depressed women (Young and Altemus 2004). Although the mood disturbances in premenstrual syndrome do not reach the severity or duration of major depression, transient dysregulation of the HPA axis during the luteal phase has been noted in this population (Rabin et al. 1990; Roca et al. 2003), offering further support for the influence of gonadal steroid hormones on HPA functioning related to mood.

Further, in postmortem studies of MDD, CRH-producing neurons in PVN that co-localized with estrogen receptor alpha (ERα) were enhanced in MDD, again suggesting HPA-HPG interactions in MDD (Bao et al. 2005). In our recent functional imaging study in MDD women, gonadal hormone abnormalities (lower estradiol) were significantly associated with functional brain activity deficits in key regions in the stress response circuitry (e.g., amygdala and hippocampus; Holsen et al. 2011). We are currently testing the hypothesis that the vulnerability for these stress response circuitry deficits and endocrine abnormalities begins during fetal development.

Brain Circuitry Linking MDD, HPA and HPG

The comorbidity between depression and HPA-HPG-axis dysregulation is not surprising from a brain circuitry point of view, given that depression is a disorder that involves hypothalamic nuclei [such as paraventricular (PVN) and ventromedial (VMN)], central amygdala, hippocampus, subgenual anterior cingulate cortex (ACC), and medial and orbitofrontal cortex (mPFC OFC; Dougherty and Rauch 1997; Mayberg 1997; Drevets et al. 2002; Sheline et al. 2002; Rauch et al. 2003), regions that are dense in glucocorticoid and sex steroid hormone receptors (MacLusky et al. 1987; Clark et al. 1988; Handa et al. 1994; Kawata 1995; Tobet and Hanna 1997; Donahue et al. 2000; Östlund et al. 2003). The overlap between these circuitries has been historically noted from behavioral and endocrinological findings but, with the advent of magnetic resonance imaging (MRI) technology, there is a greater focus on the investigation of brain circuitry implicated in the regulation of mood and endocrine functioning. This technology allows for hypothesis-driven in vivo exploration of this shared circuitry.

HPA Axis Hormones Associated with Brain Activity

Over the past 5 years, there has been a rapid increase in studies examining the relationship between HPA hormones (more specifically endogenous and exogenous cortisol) and brain activity in subcortical and cortical stress response regions using a variety of functional MRI (fMRI) paradigms in healthy control subjects (generally comprising mixed-gender samples with age ranges between 18 and 35 years). Amygdala and hippocampal activity in response to stimuli of high negative emotionality was positively associated with pre- versus post-scan (Root et al. 2009) and diurnal amplitude (Cunningham-Bussel et al. 2009) salivary cortisol. This relationship between hyperactivation in the amygdala and increased cortisol is supported by additional evidence suggesting that, when categorized by level of endogenous cortisol, individuals with high cortisol demonstrate greater amygdala activity than those with low cortisol levels (van Stegeren et al. 2007, 2008), an effect that is blocked by administration of a noradrenergic antagonist. Cushing syndrome (CS), which is associated with chronic hypercortisolemia, also appears to be associated with hyperactivity in arousal regions. Adolescents with CS compared with age- and gender-matched controls demonstrated increased activation of the amygdala and hippocampus during successful encoding of emotional faces, despite similar memory performance (Maheu et al. 2008). Further, adults with CS showed hyperactivation in the anterior hippocampus, medial frontal gyrus, ACC, caudate, and superior parietal lobule during identification of emotional facial expressions. Accuracy in CS patients was lower and correlated with brain activity, suggesting these differences could be partially explained by compensatory recruitment of these regions (Langenecker et al. 2012). However, in general, these findings point to a pattern of significantly enhanced activation in the presence of heightened endogenous cortisol levels in healthy controls and CS patients.

In cortical stress response circuitry regions, however, somewhat contrasting results emerge. For example, one study reported a negative correlation between ventromedial prefrontal cortical activation to negative (versus neutral) stimuli and pre- versus post-scan cortisol levels (Root et al. 2009). Further, decreased activations in the ACC and OFC were observed in individuals who demonstrated a significant increase in cortisol levels (i.e., “responders”) during a psychosocial stress paradigm (negative feedback during arithmetic problems), as compared to cortisol non-responders (Pruessner et al. 2008). Interestingly, although several of these studies included sex as a covariate in the analyses, only one focused specifically on sex differences. They reported a lateralized pattern of activations in the frontal cortex in males [i.e., increased cerebral blood flow (CBF) in the right PFC and decreased in left OFC, which were associated with cortisol levels] and activations in the ventral striatum, putamen insula, and ACC (unrelated to cortisol level variation) in females (Wang et al. 2007). Taken together, these findings suggest potentially divergent roles of subcortical versus cortical arousal regions in response to stress and cortisol variation, which may be influenced by gonadal steroid hormones given substantial differences in activation patterns between men and women and the importance of HPA and HPG interactions.

Importantly, the literature on changes in endogenous cortisol levels associated with brain responses to emotional and stressful paradigms highlights the significant variability among even healthy individuals in the psychophysiological reaction to stress, as not all study subjects are ultimately classified as cortisol “responders” (Wust et al. 2000; Muehlhan et al. 2011). One methodological alternative to relying on natural variation in cortisol levels is to observe similar phenomena following administration of exogenous cortisol (i.e., hydrocortisone). In general, the amygdala and hippocampus appear to be most sensitive to hydrocortisone, demonstrating significant decreases in activation in comparison to placebo (Lovallo et al. 2010). Striking sex differences in the neural response to hydrocortisone (versus placebo) during fear conditioning have been observed, with increased activation in the ACC, OFC, and mPFC in response to the conditioned (versus unconditioned) stimulus in females and decreases in these same regions in males (Stark et al. 2006; Merz et al. 2010).

HPG Axis Hormones Associated with Brain Activity

Although studies on the HPA hormone-brain relationships occasionally report controlling for menstrual cycle phase in women (Stark et al. 2006), gonadal hormone variation is the primary focus of functional neuroimaging studies of HPG hormone effects on brain activity. A number of investigations have provided evidence of estradiol and progesterone influences on brain activity during cognitive paradigms, including executive functioning (Berman et al. 1997), language processing (Fernandez et al. 2003), and verbal memory (Craig et al. 2008; Konrad et al. 2008) among others (Dietrich et al. 2001; de Leeuw et al. 2006). Here we focus on emotional paradigms, given the role of emotion dysregulation in mood disorders. Activation in stress response circuitry regions has been shown to be modulated across menstrual cycle in healthy women in response to negative arousal images, with greater activation in the anterior hypothalamus, amygdala, hippocampus, ACC, and OFC during the early follicular phase compared with late follicular/midcycle (Goldstein et al. 2005). Further, in healthy women, hyperactivity of the amygdala and hippocampus was present during late luteal compared with early follicular menstrual cycle phase (Andreano and Cahill 2010), with estradiol being negatively associated with amygdala activation (Andreano and Cahill 2010). Direct comparisons between males and females were consistent with these patterns, with greater hyperactivity in men than in women during their late follicular/midcycle compared to when they were in early follicular (Goldstein et al. 2010). Results suggested gonadal hormonal modulation of subcortical arousal by prefrontal circuitry (Goldstein et al. 2005, 2010).

Using paradigms that examine inhibitory control during cognitive and emotional processing, inhibitory responses to negative (versus neutral) emotional stimuli targets during the luteal phase (versus follicular) are associated with greater activation in the medial OFC (Protopopescu et al. 2005), ACC, DLPFC, and putamen (Amin et al. 2006). In contrast, increased OFC activity during follicular rather than luteal phase was observed in response to male faces judged on sexual desirability (Rupp et al. 2009), which may suggest a significant shift in OFC processing and decision-making related to positive and negative stimuli across the menstrual cycle. However, a study utilizing a reward paradigm recently demonstrated greater follicular than luteal phase activation to anticipation of positive reward delivery in the OFC (Dreher et al. 2007). These discrepancies might be related to differences in menstrual phase definition, with follicular phase defined as days 4–8 (Dreher et al. 2007), 8–12 (Protopopescu et al. 2005), or 10–12 after the start of menstruation (Rupp et al. 2009), and luteal phase defined as 19–23 days following the start of menstruation (Rupp et al. 2009), 6–10 days post LH surge (Dreher et al. 2007), or 1–5 days before menses onset (Protopopescu et al. 2005). Although the healthy control women in these samples had regular cycles, this variation in phase definition across studies could have significant effects on estradiol and progesterone levels, leading to substantial differences reported in these studies in brain activity across the menstrual cycle.

Similar to literature (cited above) on exogenous HPA hormone administration and brain activity, a number of investigations have examined effects of exogenous gonadal hormone regulation of neural responses to emotional stimuli. Compared with placebo, progesterone administration (during early follicular phase when progesterone levels are naturally low) is related to increased amygdala reactivity to emotional face processing, increased amygdala-dorsal ACC connectivity, and decreased amygdala-fusiform gyrus connectivity (van Wingen et al. 2008b). Testosterone administration, contrastingly, increased hippocampus and inferior temporal gyrus activation during memory formation and retrieval of male faces in middle-aged women (van Wingen et al. 2008a). Compared with placebo, testosterone increased amygdala responsivity to levels equivalent to those observed in young women (van Wingen et al. 2009) and reduced functional connectivity between the amygdala and OFC (van Wingen et al. 2010). Thus, administration of exogenous gonadal hormones exerts significant influence on amygdala responsivity in general and coupling between the amygdala and other limbic and cortical regions during evaluation of emotionally salient cues.

Recent Findings in Mood Disorders

A few studies recently demonstrated compelling evidence of links between HPA-HPG hormone dysregulation and brain activity deficits in MDD. Hydrocortisone administration to currently depressed women resulted in increased hippocampal activation during encoding of neutral (versus negative or positive) words in comparison to healthy control women, a trend not observed during placebo (Abercrombie et al. 2011). Importantly, this relationship between exogenous cortisol administration and memory formation did not occur in depressed men, suggesting sex differences in the effect of cortisol on memory processing in depression (Abercrombie et al. 2011). Further, we showed that young women with MDD displayed hypoactivation in a number of regions involved in the stress response circuitry that were significantly associated with gonadal hormone deficits (Holsen et al. 2011), including decreased estradiol and increased progesterone levels in MDD women during late follicular/midcycle phase of the menstrual cycle. Finally, hypoactivation to positive stimuli in the nucleus accumbens and hyperactivations in the amygdala and lateral OFC in response to negative stimuli during the luteal phase (versus late follicular) were reported in women with premenstrual dysphoric disorder compared with healthy controls (Protopopescu et al. 2008b). Findings from these initial studies indicate a complex interaction between HPA (cortisol) and HPG (progesterone, estradiol) dysregulation and brain activation during cognitive and emotional processing (respectively) in women with mood disorders, providing support for mechanisms implicating neuroendocrine systems associated with sex differences in depression.

Sexual Dimorphisms in Shared Mood and Endocrine Circuitry

Extant literature suggests that the circuitry shared between mood regulation and endocrine functioning also includes highly sexually dimorphic regions and therefore may help us understand sex differences in MDD. In vivo imaging and postmortem studies have demonstrated sex differences in brain volumes (or nuclei) of regions associated with MDD. In women, relative to cerebrum size, findings support greater relative volumes of hippocampus (Filipek et al. 1994; Giedd et al. 1996; Murphy et al. 1996; Goldstein et al. 2001), ACC (Paus et al. 1996; Goldstein et al. 2001) and OFC (Goldstein et al. 2001). In men, there are greater volumes (relative to cerebrum size) of the amygdala (Giedd et al. 1996; Goldstein et al. 2001), hypothalamus (Swaab and Fliers 1985; Allen et al. 1989; Goldstein et al. 2001), and paracingulate gyrus (Paus et al. 1996; Goldstein et al. 2001). Thus women tend to have relatively larger volumes of hippocampus, OFC, and ACG, whereas men have relatively larger amygdala and hypothalamic volumes. Recent findings offer additional evidence that regional brain volumes in women vary across the menstrual cycle, with hippocampal gray matter volume increased and dorsal basal ganglia gray matter volume decreased during follicular rather than luteal phase (Protopopescu et al. 2008a). Further, estradiol, progesterone, and testosterone levels in young adults explained 13 %, 13 %, and 2 % in the variation of superior parietal gyrus, medial temporal pole, and inferior frontal gyrus gray matter volume, respectively (Witte et al. 2010), suggesting significant associations between gonadal hormone levels and neuroanatomic variation in humans.

One potential factor involved in human sexual dimorphisms may be the role of gonadal hormones on brain development, as seen in particular in model animal work by collaborators Tobet and Handa (McEwen 1983; Simerly et al. 1990; Tobet et al. 1993, 2009; O’Keefe et al. 1995; Park et al. 1996; Tobet and Hanna 1997; Gorski 2000; Chung et al. 2006). Our findings in humans indirectly suggested that this factor might also, in part, contribute to understanding human sexual dimorphisms in adulthood (Goldstein et al. 2001). In animals, nuclei of the corticomedial amygdala, PVN, VMN, hippocampus, OFC, and ACG express high concentrations of gonadal and/or adrenal hormone receptors compared with other brain regions (Handa et al. 1994; Pacak et al. 1995; Koob 1999; Solum and Handa 2002; Tobet 2002; Östlund et al. 2003; Lund et al. 2004, 2006; Suzuki and Handa 2004). These brain regions have been implicated in MDD and HPA function. Our hypotheses are in part based on the premise, supported by our work on sex differences in another disorder with fetal origins, schizophrenia (Goldstein et al. 2002), that normal sexual dimorphisms during fetal development in MDD may go awry in brain regions associated with MDD and HPA function and that mechanisms involved in understanding normal sexual dimorphisms, such as the roles of gonadal and adrenal hormones (in association with genes; Handa et al. 1994; Majdic and Tobet 2011), will contribute to understanding sex differences in MDD in adulthood.

Prenatal Stress Models of Understanding Sex Differences in MDD and Comorbid Endocrine Dysregulation

Preclinical and clinical studies have demonstrated lasting effects of prenatal adverse events on the HPA axis and noradrenergic stress systems (Takahashi et al. 1992; Weinstock et al. 1992; Vallee et al. 1997; Weinstock 1997). These include conditioned stress responses such as heightened glucocorticoid, norepinephrine, and autonomic response to novel stressors and altered dopaminergic, gamma aminobutyric acid (GABA)-ergic, and serotonergic function (Heim et al. 2000; Heim and Nemeroff 2001). Animal studies demonstrated the impact of prenatal stress on hypothalamic and hippocampal structure and function (Takahashi et al. 1992; Matsumoto and Arai 1997; Weinstock 1997), with lasting effects on the HPA axis in adult offspring by programming a “hyperactive” system that was vulnerable to adult depression, anxiety, and autonomic nervous system deficits among others (Weinstock et al. 1992; Henry et al. 1994; Barker 1995; Arborelius et al. 1999; Seckl 2001). Our current work has demonstrated that mid-to-late gestation is a particularly vulnerable time for the impact of prenatal events on sex-specific brain development (Tobet et al. 2009; Majdic and Tobet 2011) and development of the hormonal systems such as HPA (Celsi et al. 1998; Slotkin et al. 1998; Tronche et al. 1999; Sandau and Handa 2007; Zuloaga et al. 2011). Thus preclinical studies, including our own work, have demonstrated the vulnerability of the HPA system to adverse prenatal events with sex-specific effects on HPA function and affect.

Models for investigation of HPA compromise have included prenatal stress and infection during mid-to-late gestation that have demonstrated sex-specific effects in preclinical studies. From preclinical studies, sex effects (i.e., greater in females than males) include (1) greater glucocorticoid transfer across the placenta in female mice (Montano et al. 1993; Fameli et al. 1994); (2) greater immobility in standard tests associated with MDD phenotypic behavior (Alonso et al. 2000); (3) increased ACTH corticosterone and glucocorticoid receptor (GR) binding (Weinstock et al. 1992; McCormick et al. 1995; Regan et al. 2004); (4) increased corticosterone sensitivity (Rhodes and Rubin 1999); (5) greater susceptibility to changes following loss of GABAB receptor function (McClellan et al. 2010; Stratton et al. 2011); (6) greater susceptibility to cell death in the amygdala following developmental exposure to the glucocorticoid agonist dexamethasone (Zuloaga et al. 2011); and (7) greater susceptibility to diet-induced hepatosteatosis and insulin growth factor (IGF)-1 deficits (Carbone et al. 2011). In humans, MDD females compared with MDD males show (1) increased GR and MR mRNA in temporal and PFC regions (Watzka et al. 2000); (2) higher levels of cortisol (Frederiksen et al. 1991; Heuser et al. 1994; Laughlin and Barrett-Connor 2000); and (3) decreased volume of hippocampus and increased amygdala (Vakili et al. 2000; Janssen et al. 2004; Weniger et al. 2006). Thus we have been testing the hypothesis that sex differences in the impact of adverse fetal HPA programming demonstrated in preclinical studies, contribute to sex differences in adult MDD.

Receptors responsible for the expression and/or regulation of expression of HPA hormones reside in brain regions implicated in MDD. Hypothalamic nuclei (such as PVN and ventromedial nucleus) and hippocampus are involved in the regulation of HPA hormones, as demonstrated in earlier work by Tobet and Handa (Tobet and Hanna 1997; Brown et al. 1999; Lund et al. 2006; Sandau and Handa 2006; Foradori and Handa 2008; McClellan et al. 2010; Stratton et al. 2011). They are dense in CRH and glucocorticoid receptors, vasopressin, GABA receptors, and sex steroid receptors (Keverne 1988; Handa et al. 1994; Pacak et al. 1995; Koob 1999; Tobet et al. 1999; Dellovade et al. 2001; Davis et al. 2002; Solum and Handa 2002; Tobet 2002; Östlund et al. 2003; Lund et al. 2004, 2006; Suzuki and Handa 2004; Weiser and Handa 2009). Studies have argued that the effects of prenatal stressors on the brain are mediated by neurotransmitter systems that interact with glucocorticoids and gonadal steroid receptors such as GABA and glutamate (Tobet et al. 1999; Seckl and Walker 2001; Owen et al. 2005; McClellan et al. 2008, 2010; Zuloaga et al. 2011), which we have demonstrated in our current program project [National Institute of Health Office for Research on Women’s Health-National Institute of Mental Health P50 MH082679].

In Summary

MDD is a major public health problem with substantial economic, social, and disease burden worldwide. Women are approximately two times more likely than men to present with a lifetime history of MDD. Moreover, this sex difference starts in early adolescence and persists through the mid-50s. Thus, understanding the pathophysiology of this disorder, particularly for women, has important implications for attenuation of suffering worldwide. There is substantial literature supporting the notion that MDD (at least some forms) is a disorder whose vulnerability begins during fetal development. A number of potential pathways may connect adverse conditions arising during fetal development and sex differences in MDD in adulthood. We are currently investigating prenatal stress models that focus on disruption of the development of the fetal HPA circuitry―during periods in which the sexual differentiation of the brain occurs―that we hypothesize place the male or female fetus at differential risks for MDD in adulthood. Further, we have been testing the hypothesis that the fetal hormonal programming will be significantly associated with sex differences in brain activity deficits in stress response circuitry and adult HPA and HPG deficits in MDD. Finally, the demonstration of altered neuroendocrine regulation in relation to sex differences in brain activity in MDD may contribute to understanding the higher prevalence of endocrine disorders in MDD than in the general population, thus promoting further inquiry into development of neuroendocrine treatment modalities. We believe that an understanding of the mechanisms involved in sex differences in the dysregulation of gonadal and adrenal hormones during fetal development in MDD will have etiologic implications and importance for the psychopharmacologic, hormonal and immunoregulatory treatment and prevention of MDD, particularly in women.