Fetal hormonal programming of sex differences in depression: linking women's mental health with sex differences in the brain across the lifespan

Women’s health has traditionally beenthoughtofintherealmofreproduc-tive health, and that includes women’smental health (i.e., perinatal psychiatry).However, we now know there are sig-niﬁcant sex differences in many chronicdiseases, including brain disorders. Thus,understanding the causes of sex differ-ences in disorders of the brain, withinand outside of reproduction, is criticalto understanding women’s mental healthand healthcare needs. In order to accom-plish this, it is necessary for neuroscienceto adopt a “sex-dependent” and/or “sex-speciﬁc” lens on investigations of thebrain. In this review, we make the case fordepression, which has among the largestsex differences in disorders of the brain.Major depressive disorder (MDD)recently became the number one cause ofdisability worldwide (Murray and Lopez,1997; Ustun et al., 2004; World HealthOrganization, 2012). Importantly, theincidence of MDD in women is twicethat of men (Kessler, 2003; Kendler et al.,2006), and thus understanding its patho-physiology has widespread implicationsfor attenuation and prevention of dis-ease burden, particularly in women. Over40 years of research implicate hormonaldysregulation underlying mood disorders(Boardetal.,1956;GibbonsandMcHugh,1962; Coplan et al., 2000; Brouwer et al.,2005; Kurt et al., 2007; Barim et al., 2009),particularlyinvolvementofhypothalamic-pituitary-adrenal (HPA) and HP-gonadal(HPG) axes (Board et al., 1956; Gibbonsand McHugh, 1962; Plotsky et al., 1998;Young and Korszun, 2002; Swaab et al.,2005). Central dysregulation of hormonalaxes can precede MDD onset suggest-ing a role for hormonal abnormalitiesin female MDD vulnerability. Ours andothers’ work demonstrated that the vul-nerabilityforsex-dependentriskforMDDbegins in

Women's health has traditionally been thought of in the realm of reproductive health, and that includes women's mental health (i.e., perinatal psychiatry). However, we now know there are significant sex differences in many chronic diseases, including brain disorders. Thus, understanding the causes of sex differences in disorders of the brain, within and outside of reproduction, is critical to understanding women's mental health and healthcare needs. In order to accomplish this, it is necessary for neuroscience to adopt a "sex-dependent" and/or "sexspecific" lens on investigations of the brain. In this review, we make the case for depression, which has among the largest sex differences in disorders of the brain.
Major depressive disorder (MDD) recently became the number one cause of disability worldwide (Murray and Lopez, 1997;Ustun et al., 2004;World Health Organization, 2012). Importantly, the incidence of MDD in women is twice that of men (Kessler, 2003;Kendler et al., 2006), and thus understanding its pathophysiology has widespread implications for attenuation and prevention of disease burden, particularly in women. Over 40 years of research implicate hormonal dysregulation underlying mood disorders (Board et al., 1956;Gibbons and McHugh, 1962;Coplan et al., 2000;Brouwer et al., 2005;Kurt et al., 2007;Barim et al., 2009), particularly involvement of hypothalamicpituitary-adrenal (HPA) and HP-gonadal (HPG) axes (Board et al., 1956;Gibbons and McHugh, 1962;Plotsky et al., 1998;Young and Korszun, 2002;Swaab et al., 2005). Central dysregulation of hormonal axes can precede MDD onset suggesting a role for hormonal abnormalities in female MDD vulnerability. Ours and others' work demonstrated that the vulnerability for sex-dependent risk for MDD begins in fetal development (McClellan et al., 2010;Goldstein et al., 2011;Zuloaga et al., 2012a,b;Carbone and Handa, 2013;Seney et al., 2013). Despite these findings, a number of confounds (state vs. trait, treatment, age, and recurrence) present challenges to elucidating the contribution of hormonal or genetic sex (Seney et al., 2013) to the co-occurrence of hormonal dysregulation and mood disorders.
Despite substantial data supporting sex differences in HPA functioning during stress in healthy populations (Kudielka and Kirschbaum, 2005;Goldstein et al., 2010) and MDD women (Holsen et al., 2011(Holsen et al., , 2013, reports of sex differences in the HPA axis and MDD are inconsistent. Men, but not women, with MDD demonstrated increased ACTH pulsatility (Young et al., 2007a) and elevated cortisol compared with nondepressed men and women (Bremmer et al., 2007;Hinkelmann et al., 2012). However, depressed women vs. men (Poor et al., 2004) and non-depressed women (Young and Altemus, 2004;Chopra et al., 2009) also expressed hypercortisolemia. Study inconsistencies may be related to timing of cortisol assessments or may reflect methodological confounds, such as age of study subjects (e.g., post-menopausal women differ from premenopausal women and thus sex differences differ), chronicity of illness (e.g., sustained illness may produce blunted cortisol response rather than hypercortisolemia), or low statistical power to detect sex differences which may vary in effect size, depending on characteristics of the sample (details next paragraph). Further, genetic background likely affects HPA axis dysregulation, as demonstrated in studies showing increased ACTH and cortisol in males (but not females) homozygotic for the alpha(2)adrenoreceptor gene and females (but not males) homozygotic for the beta(2)adrenoreceptor gene (Haefner et al., 2008). Collectively, these findings offer initial evidence of sex differences in the role of HPA axis in MDD pathophysiology and emphasize the importance of considering genetic variation in HPA axis-associated genes.
Some studies report no effect of sex on HPA axis deficits in MDD (Carroll et al., 1976;Nelson et al., 1984b;Dahl et al., 1989;Maes et al., 1994;Deuschle et al., 1998;Brouwer et al., 2005;Vreeburg et al., 2009), although some of these studies were not designed initially to investigate sex differences, introducing potential confounds, such as: oversampling women (thus small samples of men) and low statistical power to test for sex differences (Brouwer et al., 2005;Young et al., 2007a;Vreeburg et al., 2009;Hinkelmann et al., 2012); lack of control for use of oral contraceptives or estrogen-replacement therapy (Brouwer et al., 2005) affecting plasma cortisol levels (Kirschbaum et al., 1999); and disregard for menstrual cycle phase or menopausal status during data collection. These confounds present significant challenges to understanding study inconsistencies on sex differences in HPA-MDD associations and their implications for women's mental health.

HPG AXIS IMPLICATED IN MDD
Post-puberty adolescence is a key period during which sex differences in MDD begin to emerge, initially during ages 13-15, with the largest increase in late adolescence (e.g., Hankin et al., 1998). However, few studies have focused on understanding why the higher rate of MDD in girls than boys is initiated during this period. This is unfortunate since puberty is an important critical period for brain plasticity likely arising from differential flooding of the brain with gonadal hormones (Schulz et al., 2009), and further sexual differentiation of the brain as the prefrontal cortex fully develops during ages 18-22 years. Evidence for HPG axis-MDD associations also came from studies of polycystic ovarian syndrome (Himelein and Thatcher, 2006) and literature relating women's reproductive biology to mood fluctuations and depression (Steiner, 1992;Bloch et al., 2000;Payne, 2003;Angold and Costello, 2006;Young et al., 2007b;Graziottin and Serafini, 2009;Brummelte and Galea, 2010). Although there has been less examination of HPG deficits in MDD in men, lower testosterone has been reported (Schweiger et al., 1999;Seidman et al., 2001). HPG dysregulation in MDD has included androgens (Baischer et al., 1995;Rubinow and Schmidt, 1996;Schweiger et al., 1999;Seidman et al., 2001;Weiner et al., 2004), estrogens (Young et al., 2000), and pituitary function (Daly et al., 2003). Women with persistent MDD had two times the risk of earlier perimenopausal transition, higher FSH, and lower estradiol levels, suggesting an early decline in ovarian function (Young et al., 2000;Harlow et al., 2003). Further, depressive symptom severity was associated with low estradiol levels (Baischer et al., 1995).
Preclinical studies also demonstrated sex differences (greater in females than males) in a number of domains, including: (1) greater placental glucocorticoid transfer (Montano et al., 1993;Fameli et al., 1994); (2) greater immobility in tasks associated with MDD phenotypic behavior (Alonso et al., 2000); (3) increased ACTH, corticosterone, and glucocorticoid receptor 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 GABA B receptor function (McClellan et al., 2010;Stratton et al., 2011); (6) greater susceptibility to cell death in AMYG following developmental exposure to dexamethasone (Zuloaga et al., 2011);and (8) greater susceptibility to diet-induced hepatosteatosis and insulin growth factor-1 deficits (Carbone et al., 2012). In humans, at the level of the brain, there have been fewer studies of sex differences in MDD, although some reported decreased HIPP and increased AMYG volumes, greater in females than males (Vakili et al., 2000;Janssen et al., 2004;Weniger et al., 2006). Collectively, preclinical studies support the hypothesis that prenatal exposures (particularly those implicating stress circuitry pathways) facilitate altered programming of stress-related endocrine and neural circuits implicated in the sex-dependent development of depressive-like behavior. Although parallel studies in humans are still in their infancy, we and others are currently testing the hypothesis that prenatal maternal disruption of stress-immune pathways will, in the context of genetic background, result in vulnerability for the sex-dependent risk for MDD in the offspring (Handa et al., 1994;Majdic and Tobet, 2011).

CONCLUSIONS
The number one cause of disability worldwide is MDD, and women are two times the risk of men. This represents ∼350 million people worldwide, approximately 16 million in the U.S. alone (WHO October 2012 Fact Sheet). Depression is comorbid with many chronic diseases that are also associated sex differences in risk (Goldstein et al., 2011(Goldstein et al., , 2013. Thus, depression is a major public health problem with substantial economic, social and disease burden that, we argue, requires a sex-dependent lens to understand its pathophysiology. There are key naturalistic opportunities for the study of this higher risk in women, and that is when the brain is differentially flooded with or depleted of gonadal hormones, i.e., fetal development, puberty, pregnancy, and perimenopausal-menopause transition. The evidence briefly discussed here supports the hypothesis that the etiology of sex differences in MDD begins in fetal development and emerges postpuberty. Its onset can be catalyzed by pregnancy (postpartum depression) and the menopausal transition (when there is an increase in MDD onset). The fact that these particular periods during the lifespan have significant implications for MDD onset is consistent with an important role for steroid hormones in MDD. This underscores the importance of promoting further inquiry into the development of adjunctive neuroendocrine treatments, dependent on timing across the lifespan. This lifespan approach to studying sex differences in disorders, like depression, also illustrates how maternal health (e.g., pregnancy), women's mental health, and sex differences in disorders of the brain are linked. Thus, we have argued the importance for preclinical and clinical neuroscience to incorporate a sex-dependent and/or sex-specific lens on investigations ranging from the cellular-molecular level to circuitry, systems, and behavior, an argument that recently was underscored by the new directive from NIH to incorporate this perspective in designs of preclinical studies (Clayton and Collins, 2014). We believe this will provide the basis for the development of sex-dependent therapeutics which will enhance progress to greater efficacy.