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Opinion ARTICLE

Front. Neurosci., 08 September 2014 | https://doi.org/10.3389/fnins.2014.00247

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

  • 1Division of Women's Health, Departments of Psychiatry and Medicine, Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital, Boston, MA, USA
  • 2Departments of Psychiatry and Medicine, Harvard Medical School, Boston, MA, USA
  • 3Division of Psychiatric Neuroscience, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
  • 4Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ, USA
  • 5Department of Biomedical Sciences and School of Biomedical Engineering, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA

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 “sex-specific” 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 hypothalamic-pituitary-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.

HPA Axis Implicated in MDD

A central role for the HPA axis in MDD was initially expressed clinically. Depressive symptoms/MDD co-occurred with endogenously elevated cortisol (Sonino et al., 1998) or exogenously administered corticosteroids (Kelly et al., 1980; Ling et al., 1981). Studies demonstrated elevated levels of cortisol in plasma, CSF, and 24-h urine samples, high CSF corticotrophin releasing hormone (CRH) levels, blunted responses to CRH administration, and non-suppression of cortisol secretion on the dexamethasone suppression test in MDD (Carroll et al., 1976, 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; Rubin et al., 1987; Heim et al., 2001; Newport et al., 2003; Raison and Miller, 2003). HPA axis dysregulation was related to age (Nelson et al., 1984a,b; Bremmer et al., 2007), depression subtype (Brouwer et al., 2005), recurrence (Poor et al., 2004), and treatment response, albeit inconsistently (Nemeroff et al., 1991; De Bellis et al., 1993; Veith et al., 1993; McKay and Zakzanis, 2010). One potential confound was whether HPA axis dysregulation reflected clinical state or diagnostic trait. A meta-analysis of >1500 individuals (Vreeburg et al., 2009), demonstrated that hypercortisolemia, present in currently depressed individuals (Trestman et al., 1993; Ahrens et al., 2008), persisted after recovery (Vreeburg et al., 2009), while other studies reported abnormal blunted cortisol response to stress in recurrent cases (Ahrens et al., 2008). In either case, findings suggested HPA dysregulation as a trait. In contrast, some studies showed resolution of hypercortisolemia with treatment (Vythilingam et al., 2004; Lok et al., 2012), arguing that HPA dysregulation was due to clinical state. Elevated baseline cortisol, enhanced CRH sensitivity, and lack of responsivity to dexamethasone suppression also predicted relapse vulnerability and sustained remission (Zobel et al., 1999; Appelhof et al., 2006; Ising et al., 2007). Despite this evidence, HPA-axis targeted treatments are not reliably effective in MDD, although show some success as anti-depressant adjuncts (Jahn et al., 2004) or improvement of cognitive deficits (Young et al., 2004).

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, 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 non-depressed 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).

HPA-HPG Interactions Implicated in MDD

Dysregulation of HPA and HPG axes interact in MDD. Low levels of estradiol with unopposed progesterone in premenopausal MDD was associated with decreased inhibitory feedback on HPA function during stress, resulting in elevated cortisol in MDD compared to healthy women or men (Young and Altemus, 2004). Transient dysregulation of HPA axis during the luteal menstrual phase was reported in premenstrual syndrome (Rabin et al., 1990; Roca et al., 2003). Further, using functional MRI, our group showed hypoactivity in stress-responsive regions in premenopausal MDD women was significantly associated with decreased estradiol and increased progesterone levels during the late follicular menstrual phase (Holsen et al., 2011). In perimenopausal MDD women, these brain regions were associated with hypercortisolemia and hyperactivity (Holsen et al., 2013). These imaging studies suggest a complex interplay between HPA and HPG axes, dependent on age and cycle timing. From a brain circuitry point of view, MDD involves hypothalamic (HYPO) nuclei (paraventricular and ventromedial), central amygdala (AMYG), hippocampus (HIPP), anterior cingulate, medial and orbital prefrontal cortices (ACC, mPFC, OFC) (Dougherty and Rauch, 1997; Mayberg, 1997; Drevets et al., 2002; Sheline et al., 2002; Rauch et al., 2003), regions 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). These regions develop in sex-dependent ways, in part driven by gonadal hormones. There is now a substantial body of functional imaging work relating regulation of mood with endocrine function, e.g., Goldstein et al., 2005, 2010; Protopopescu et al., 2005; Amin et al., 2006; Stark et al., 2006; Dreher et al., 2007; Wang et al., 2007; Pruessner et al., 2008; van Wingen et al., 2008a,b, 2009; Root et al., 2009; Andreano and Cahill, 2010.

Shared Mood and Endocrine Circuitry are Sexually Dimorphic

In vivo imaging and postmortem studies demonstrated sex differences in brain volumes (or nuclei) of regions associated with MDD, although there is little work focused on sexual dimorphisms in MDD per se. In healthy women compared with men, relative to cerebrum size, findings supported greater relative volumes of HIPP (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 relatively greater volumes of AMYG (Giedd et al., 1996; Goldstein et al., 2001), HYPO (Swaab and Fliers, 1985; Allen et al., 1989; Goldstein et al., 2001), and paracingulate gyrus (Goldstein et al., 2001; Paus et al., 1996). Recently, a number of new studies have emerged further characterizing sex-dependent circuitry (Ruigrok et al., 2013), connectivity (Ingalhalikar et al., 2014), and potential mechanisms (Raznahan et al., 2010; Kang et al., 2011; Goldstein et al., 2013; Lenz et al., 2013; Nguyen et al., 2013). Developmental pathways involve, in part, gonadal hormone regulation, seen in model animal (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) and human (Goldstein et al., 2001; Raznahan et al., 2010) development. In fact, preclinical studies demonstrated lasting effects of prenatal adverse events on HPA axis and noradrenergic stress systems (Takahashi et al., 1992; Weinstock et al., 1992; Vallee et al., 1997; Weinstock, 1997). These included hypothalamic and hippocampal structure and function (Takahashi et al., 1992; Matsumoto and Arai, 1997; Weinstock, 1997), with effects that occurred through programming a “hyperactive” system more vulnerable to adult depressive and anxiety-like behaviors and autonomic nervous system deficits, among others (Weinstock et al., 1992; Henry et al., 1994; Barker, 1995; Seckl, 2001; Majdic and Tobet, 2011; Zuloaga et al., 2011; Carbone et al., 2012). Analogous to timing of these events in animals, mid-to-late gestation in humans is a particularly vulnerable time for the impact of prenatal events on sex-dependent brain development (Tobet et al., 2009; Majdic and Tobet, 2011; Zuloaga et al., 2011; Carbone et al., 2012), and recent preclinical and clinical studies implicated earlier gestation (Mueller and Bale, 2008; Howerton et al., 2013).

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 GABAB 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, 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 post-puberty. 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.

Conflict of Interest Statement

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.

Acknowledgments

This work was supported by the National Institutes of Mental Health, Office of Research on Women's Health (ORWH-NIMH) P50 MH082679 (PIs: Goldstein, Tobet, Handa).

References

Ahrens, T., Deuschle, M., Krumm, B., van der Pompe, G., den Boer, J. A., and Lederbogen, F. (2008). Pituitary-adrenal and sympathetic nervous system responses to stress in women remitted from recurrent major depression. Psychosom. Med. 70, 461–467. doi: 10.1097/PSY.0b013e31816b1aaa

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Allen, L. S., Hines, M., Shryne, J. E., and Gorski, R. A. (1989). Two sexually dimorphic cell groups in the human brain. J. Neurosci. 9, 497–506.

Pubmed Abstract | Pubmed Full Text

Alonso, S. J., Damas, C., and Navarro, E. (2000). Behavioral despair in mice after prenatal stress. J. Physiol. Biochem. 56, 77–82. doi: 10.1007/BF03179902

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Amin, Z., Epperson, C. N., Constable, R. T., and Canli, T. (2006). Effects of estrogen variation on neural correlates of emotional response inhibition. Neuroimage 32, 457–464. doi: 10.1016/j.neuroimage.2006.03.013

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Andreano, J. M., and Cahill, L. (2010). Menstrual cycle modulation of medial temporal activity evoked by negative emotion. Neuroimage 53, 1286–1293. doi: 10.1016/j.neuroimage.2010.07.011

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Angold, A., and Costello, E. J. (2006). Puberty and depression. Child Adolesc. Psychiatr. Clin. N. Am. 15, 919–937, ix. doi: 10.1016/j.chc.2006.05.013

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Appelhof, B. C., Huyser, J., Verweij, M., Brouwer, J. P., van Dyck, R., Fliers, E., et al. (2006). Glucocorticoids and relapse of major depression (dexamethasone/corticotropin-releasing hormone test in relation to relapse of major depression). Biol. Psychiatry 59, 696–701. doi: 10.1016/j.biopsych.2005.09.008

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Baischer, W., Koinig, G., Hartmann, B., Huber, J., and Langer, G. (1995). Hypothalamic-pituitary-gonadal axis in depressed premenopausal women: elevated blood testosterone concentrations compared to normal controls. Psychoneuroendocrinology 20, 553–559. doi: 10.1016/0306-4530(94)00081-K

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Banki, C. M., Bissette, G., Arato, M., O'Connor, L., and Nemeroff, C. B. (1987). CSF corticotropin-releasing factor-like immunoreactivity in depression and schizophrenia. Am. J. Psychiatry 144, 873–877.

Pubmed Abstract | Pubmed Full Text

Barim, A. O., Aydin, S., Colak, R., Dag, E., Deniz, O., and Sahin, I. (2009). Ghrelin, paraoxonase and arylesterase levels in depressive patients before and after citalopram treatment. Clin. Biochem. 42, 1076–1081. doi: 10.1016/j.clinbiochem.2009.02.020

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Barker, D. J. (1995). Intrauterine programming of adult disease. Mol. Med. Today 1, 418–423. doi: 10.1016/S1357-4310(95)90793-9

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bloch, M., Schmidt, P. J., Danaceau, M., Murphy, J., Nieman, L., and Rubinow, D. R. (2000). Effects of gonadal steroids in women with a history of postpartum depression. Am. J. Psychiatry 157, 924–930. doi: 10.1176/appi.ajp.157.6.924

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Board, F., Persky, H., and Hamburg, D. A. (1956). Psychological stress and endocrine functions; blood levels of adrenocortical and thyroid hormones in acutely disturbed patients. Psychosom. Med. 18, 324–333. doi: 10.1097/00006842-195607000-00006

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bremmer, M. A., Deeg, D. J., Beekman, A. T., Penninx, B. W., Lips, P., and Hoogendijk, W. J. (2007). Major depression in late life is associated with both hypo- and hypercortisolemia. Biol. Psychiatry 62, 479–886. doi: 10.1016/j.biopsych.2006.11.033

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Brouwer, J. P., Appelhof, B. C., Hoogendijk, W. J., Huyser, J., Endert, E., Zuketto, C., et al. (2005). Thyroid and adrenal axis in major depression: a controlled study in outpatients. Eur. J. Endocrinol. 152, 185–191. doi: 10.1530/eje.1.01828

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Brummelte, S., and Galea, L. A. (2010). Depression during pregnancy and postpartum: contribution of stress and ovarian hormones. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 766–776. doi: 10.1016/j.pnpbp.2009.09.006

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Carbone, D. L., and Handa, R. J. (2013). Sex and stress hormone influences on the expression and activity of brain-derived neurotrophic factor. Neuroscience 239, 295–303. doi: 10.1016/j.neuroscience.2012.10.073

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Carbone, D. L., Zuloaga, D. G., Hiroi, R., Foradori, C. D., Legare, M. E., and Handa, R. J. (2012). Prenatal dexamethasone exposure potentiates diet-induced hepatosteatosis and decreases plasma IGF-I in a sex-specific fashion. Endocrinology 153, 295–306. doi: 10.1210/en.2011-1601

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Carroll, B. J., Curtis, G. C., and Mendels, J. (1976). Cerebrospinal fluid and plasma free cortisol concentrations in depression. Psychol. Med. 6, 235–244. doi: 10.1017/S0033291700013775

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Carroll, B. J., Feinberg, M., Greden, J. F., Tarika, J., Albala, A. A., Haskett, R. F., et al. (1981). A specific laboratory test for the diagnosis of melancholia. standardization, validation, and clinical utility. Arch. Gen. Psychiatry 38, 15–22. doi: 10.1001/archpsyc.1981.01780260017001

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chopra, K. K., Ravindran, A., Kennedy, S. H., Mackenzie, B., Matthews, S., Anisman, H., et al. (2009). Sex differences in hormonal responses to a social stressor in chronic major depression. Psychoneuroendocrinology 34, 1235–1241. doi: 10.1016/j.psyneuen.2009.03.014

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chung, W. C., Pak, T. R., Weiser, M. J., Hinds, L. R., Andersen, M. E., and Handa, R. J. (2006). Progestin receptor expression in the developing rat brain depends upon activation of estrogen receptor alpha and not estrogen receptor beta. Brain Res. Mol. Brain Res. 1082, 50–60. doi: 10.1016/j.brainres.2006.01.109

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Clark, A. S., MacLusky, N. J., and Goldman-Rakic, P. S. (1988). Androgen binding and metabolism in the cerebral cortex of the developing rhesus monkey. Endocrinology 123, 932–940. doi: 10.1210/endo-123-2-932

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Clayton, J. A., and Collins, F. S. (2014). NIH to balance sex in cell and animal studies. Nature 509, 282–283. doi: 10.1038/509282a

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Coplan, J. D., Wolk, S. I., Goetz, R. R., Ryan, N. D., Dahl, R. E., Mann, J. J., et al. (2000). Nocturnal growth hormone secretion studies in adolescents with or without major depression re-examined: integration of adult clinical follow-up data. Biol. Psychiatry 47, 594–604. doi: 10.1016/S0006-3223(00)00226-2

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Dahl, R., Puig-Antich, J., Ryan, N., Nelson, B., Novacenko, H., Twomey, J., et al. (1989). Cortisol secretion in adolescents with major depressive disorder. Acta Psychiatr. Scand. 80, 18–26. doi: 10.1111/j.1600-0447.1989.tb01295.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Daly, R. C., Danaceau, M. A., Rubinow, D. R., and Schmidt, P. J. (2003). Concordant restoration of ovarian function and mood in perimenopausal depression. Am. J. Psychiatry 160, 1842–1846. doi: 10.1176/appi.ajp.160.10.1842

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

De Bellis, M. D., Gold, P. W., Geracioti, T. D. Jr., Listwak, S. J., and Kling, M. A. (1993). Association of fluoxetine treatment with reductions in CSF concentrations of corticotropin-releasing hormone and arginine vasopressin in patients with major depression. Am. J. Psychiatry 150, 656–657.

Pubmed Abstract | Pubmed Full Text

Deuschle, M., Weber, B., Colla, M., Depner, M., and Heuser, I. (1998). Effects of major depression, aging and gender upon calculated diurnal free plasma cortisol concentrations: a re-evaluation study. Stress 2, 281–287. doi: 10.3109/10253899809167292

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Donahue, J. E., Stopa, E. G., Chorsky, R. L., King, J. C., Schipper, H. M., Tobet, S. A., et al. (2000). Cells containing immunoreactive estrogen receptor-alpha in the human basal forebrain. Brain Res. Mol. Brain Res. 856, 142–151. doi: 10.1016/S0006-8993(99)02413-0

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Dougherty, D., and Rauch, S. L. (1997). Neuroimaging and neurobiological models of depression. Harv. Rev. Psychiatry 5, 138–159. doi: 10.3109/10673229709000299

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Dreher, J. C., Schmidt, P. J., Kohn, P., Furman, D., Rubinow, D., and Berman, K. F. (2007). Menstrual cycle phase modulates reward-related neural function in women. Proc. Natl. Acad. Sci. U.S.A. 104, 2465–2470. doi: 10.1073/pnas.0605569104

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Drevets, W. C., Price, J. L., Bardgett, M. E., Reich, T., Todd, R. D., and Raichle, M. E. (2002). Glucose metabolism in the amygdala in depression: relationship to diagnostic subtype and plasma cortisol levels. Pharmacol. Biochem. Behav. 71, 431–447. doi: 10.1016/S0091-3057(01)00687-6

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Evans, D. L., and Nemeroff, C. B. (1987). The clinical use of the dexamethasone suppression test in DSM-III affective disorders: correlation with the severe depressive subtypes of melancholia and psychosis. J. Psychiatr. Res. 21, 185–194. doi: 10.1016/0022-3956(87)90018-5

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Fameli, M., Kitraki, E., and Stylianopoulou, F. (1994). Effects of hyperactivity of the maternal hypothalamic-pituitary-adrenal (HPA) axis during pregnancy on the development of the HPA axis and brain monoamines of the offspring. Int. J. Dev. Neurosci. 12, 651–659. doi: 10.1016/0736-5748(94)90017-5

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Filipek, P. A., Richelme, C., Kennedy, D. N., and Caviness, V. S. Jr. (1994). The young adult human brain: an MRI-based morphometric analysis. Cereb. Cortex 4, 344–360. doi: 10.1093/cercor/4.4.344

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gibbons, J. L., and McHugh, P. R. (1962). Plasma cortisol in depressive illness. J. Psychiatr. Res. 1, 162–171. doi: 10.1016/0022-3956(62)90006-7

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Giedd, J. N., Vaituzis, A. C., Hamburger, S. D., Lange, N., Rajapakse, J. C., Kaysen, D., et al. (1996). Quantitative MRI of the temporal lobe, amygdala, and hippocampus in normal human development: ages 4-18 years. J. Comp. Neurol. 366, 223–230.

Pubmed Abstract | Pubmed Full Text

Goldstein, J. M., Cherkerzian, S., Buka, S. L., Fitzmaurice, G., Hornig, M., Gillman, M., et al. (2011). Sex-specific impact of maternal-fetal risk factors on depression and cardiovascular risk 40 years later. J. Dev. Orig. Health Dis. 2, 353–364. doi: 10.1017/S2040174411000651

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Goldstein, J. M., Handa, R. J., and Tobet, S. A. (2013). Disruption of fetal hormonal programming (prenatal stress) implicates shared risk for sex differences in depression and cardiovascular disease. Front. Neuroendocrinol. 35:140–158. doi: 10.1016/j.yfrne.2013.12.001

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Goldstein, J. M., Jerram, M., Abbs, B., Whitfield-Gabrieli, S., and Makris, N. (2010). Sex differences in stress response circuitry activation dependent on female hormonal cycle. J. Neurosci. 30, 431–438. doi: 10.1523/JNEUROSCI.3021-09.2010

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Goldstein, J. M., Jerram, M., Poldrack, R., Ahern, T., Kennedy, D. N., Seidman, L. J., et al. (2005). Hormonal cycle modulates arousal circuitry in women using functional magnetic resonance imaging. J. Neurosci. 25, 9309–9316. doi: 10.1523/JNEUROSCI.2239-05.2005

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Goldstein, J. M., Seidman, L. J., Horton, N. J., Makris, N., Kennedy, D. N., Caviness, V. S. Jr., et al. (2001). Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cereb. Cortex 11, 490–497. doi: 10.1093/cercor/11.6.490

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gorski, R. A. (2000). “Sexual differentiation of the nervous system,” in Principles of Neural Science, eds E. R. Kandel, J. H. Schwartz, and Jessell, T. M (New York, NY: McGraw-Hill Health Professions Division), 1131–1146.

Graziottin, A., and Serafini, A. (2009). Depression and the menopause: why antidepressants are not enough? Menopause Int. 15, 76–81. doi: 10.1258/mi.2009.009021

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Haefner, S., Baghai, T. C., Schule, C., Eser, D., Spraul, M., Zill, P., et al. (2008). Impact of gene-gender effects of adrenergic polymorphisms on hypothalamic-pituitary-adrenal axis activity in depressed patients. Neuropsychobiology 58, 154–162. doi: 10.1159/000182891

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Halbreich, U., Asnis, G. M., Shindledecker, R., Zumoff, B., and Nathan, R. S. (1985). Cortisol secretion in endogenous depression. I. Basal plasma levels. Arch. Gen. Psychiatry 42, 904–908. doi: 10.1001/archpsyc.1985.01790320076010

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Handa, R. J., Burgess, L. H., Kerr, J. E., and O'Keefe, J. A. (1994). Gonadal steroid hormone receptors and sex differences in the hypothalamo-pituitary-adrenal axis. Horm. Behav. 28, 464–476. doi: 10.1006/hbeh.1994.1044

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hankin, B. L., Abramson, L. Y., Moffitt, T. E., Silva, P. A., McGee, R., and Angell, K. E. (1998). Development of depression from preadolescence to young adulthood: emerging gender differences in a 10-year longitudinal study. J. Abnorm. Psychol. 107, 128. doi: 10.1037/0021-843X.107.1.128

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Harlow, B. L., Wise, L. A., Otto, M. W., Soares, C. N., and Cohen, L. S. (2003). Depression and its influence on reproductive endocrine and menstrual cycle markers associated with perimenopause: the harvard study of moods and cycles. Arch. Gen. Psychiatry 60, 29–36. doi: 10.1001/archpsyc.60.1.29

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Heim, C., Newport, D. J., Bonsall, R., Miller, A. H., and Nemeroff, C. B. (2001). Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. Am. J. Psychiatry 158, 575–581. doi: 10.1176/appi.ajp.158.4.575

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Henry, C., Kabbaj, M., Simon, H., Le Moal, M., and Maccari, S. (1994). Prenatal stress increases the hypothalamo-pituitary-adrenal axis response in young and adult rats. J. Neuroendocrinol. 6, 341–345. doi: 10.1111/j.1365-2826.1994.tb00591.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Himelein, M. J., and Thatcher, S. S. (2006). Polycystic ovary syndrome and mental health: a review. Obstet. Gynecol. Surv. 61, 723–732. doi: 10.1097/01.ogx.0000243772.33357.84

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hinkelmann, K., Botzenhardt, J., Muhtz, C., Agorastos, A., Wiedemann, K., Kellner, M., et al. (2012). Sex differences of salivary cortisol secretion in patients with major depression. Stress 15, 105–109. doi: 10.3109/10253890.2011.582200

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Holsboer, F., Gerken, A., Stalla, G. K., and Muller, O. A. (1985). ACTH, cortisol, and corticosterone output after ovine corticotropin-releasing factor challenge during depression and after recovery. Biol. Psychiatry 20, 276–286. doi: 10.1016/0006-3223(85)90057-5

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Holsen, L. M., Lancaster, K., Klibanski, A., Whitfield-Gabrieli, S., Cherkerzian, S., Buka, S., et al. (2013). HPA-axis hormone modulation of stress response circuitry activity in women with remitted major depression. Neuroscience 250, 733–742. doi: 10.1016/j.neuroscience.2013.07.042

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Holsen, L. M., Spaeth, S. B., Lee, J. H., Ogden, L. A., Klibanski, A., Whitfield-Gabrieli, S., et al. (2011). Stress response circuitry hypoactivation related to hormonal dysfunction in women with major depression. J. Affect. Disord. 131, 379–387. doi: 10.1016/j.jad.2010.11.024

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Howerton, C. L., Morgan, C. P., Fischer, D. B., and Bale, T. L. (2013). O-GlcNAc transferase (OGT) as a placental biomarker of maternal stress and reprogramming of CNS gene transcription in development. Proc. Natl. Acad. Sci.U.S.A. 110, 5169–5174. doi: 10.1073/pnas.1300065110

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ingalhalikar, M., Smith, A., Parker, D., Satterthwaite, T. D., Elliott, M. A., Ruparel, K., et al. (2014). Sex differences in the structural connectome of the human brain. Proc. Natl. Acad. Sci.U.S.A. 111, 823–828. doi: 10.1073/pnas.1316909110

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ising, M., Horstmann, S., Kloiber, S., Lucae, S., Binder, E. B., Kern, N., et al. (2007). Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression - a potential biomarker? Biol. Psychiatry 62, 47–54. doi: 10.1016/j.biopsych.2006.07.039

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Jahn, H., Schick, M., Kiefer, F., Kellner, M., Yassouridis, A., and Wiedemann, K. (2004). Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial. Arch. Gen. Psychiatry 61, 1235–1244. doi: 10.1001/archpsyc.61.12.1235

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Janssen, J., Hulshoff Pol, H. E., Lampe, I. K., Schnack, H. G., de Leeuw, F. E., Kahn, R. S., et al. (2004). Hippocampal changes and white matter lesions in early-onset depression. Biol. Psychiatry 56, 825–831. doi: 10.1016/j.biopsych.2004.09.011

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Jarrett, D. B., Coble, P. A., and Kupfer, D. J. (1983). Reduced cortisol latency in depressive illness. Arch. Gen. Psychiatry 40, 506–511. doi: 10.1001/archpsyc.1983.01790050032004

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kang, H. J., Kawasawa, Y. I., Cheng, F., Zhu, Y., Xu, X., Li, M., et al. (2011). Spatio-temporal transcriptome of the human brain. Nature 478, 483–489. doi: 10.1038/nature10523

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kawata, M. (1995). Roles of steroid hormones and their receptors in structural organization in the nervous system. Neurosci. Res. 24, 1–46. doi: 10.1016/0168-0102(96)81278-8

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kelly, W. F., Checkley, S. A., and Bender, D. A. (1980). Cushing's syndrome, tryptophan and depression. Br. J. Psychiatry 136, 125–132. doi: 10.1192/bjp.136.2.125

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kendler, K. S., Gatz, M., Gardner, C. O., and Pedersen, N. L. (2006). A Swedish national twin study of lifetime major depression. Am. J. Psychiatry 163, 109–114. doi: 10.1176/appi.ajp.163.1.109

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kessler, R. C. (2003). Epidemiology of women and depression. J. Affect. Disord. 74, 5–13. doi: 10.1016/S0165-0327(02)00426-3

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kirschbaum, C., Kudielka, B. M., Gaab, J., Schommer, N. C., and Hellhammer, D. H. (1999). Impact of gender, menstrual cycle phase, and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis. Psychosom. Med. 61, 154–162. doi: 10.1097/00006842-199903000-00006

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kudielka, B. M., and Kirschbaum, C. (2005). Sex differences in HPA axis responses to stress: a review. Biol. Psychol. 69, 113–132. doi: 10.1016/j.biopsycho.2004.11.009

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kurt, E., Guler, O., Serteser, M., Cansel, N., Ozbulut, O., Altinbas, K., et al. (2007). The effects of electroconvulsive therapy on ghrelin, leptin and cholesterol levels in patients with mood disorders. Neurosci. Lett. 426, 49–53. doi: 10.1016/j.neulet.2007.08.018

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lenz, K. M., Nugent, B. M., Haliyur, R., and McCarthy, M. M. (2013). Microglia are essential to masculinization of brain and behavior. J. Neurosci. 33, 2761–2772. doi: 10.1523/JNEUROSCI.1268-12.2013

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ling, M. H., Perry, P. J., and Tsuang, M. T. (1981). Side effects of corticosteroid therapy. Psychiatric aspects. Arch. Gen. Psychiatry 38, 471–417. doi: 10.1001/archpsyc.1981.01780290105011

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lok, A., Mocking, R. J., Ruhe, H. G., Visser, I., Koeter, M. W., Assies, J., et al. (2012). Longitudinal hypothalamic-pituitary-adrenal axis trait and state effects in recurrent depression. Psychoneuroendocrinology 37, 892–902. doi: 10.1016/j.psyneuen.2011.10.005

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

MacLusky, N. J., Clark, A. S., Naftolin, F., and Goldman-Rakic, P. S. (1987). Estrogen formation in the mammalian brain: possible role of aromatase in sexual differentiation of the hippocampus and neocortex. Steroids 50, 459–474. doi: 10.1016/0039-128X(87)90032-8

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Maes, M., Calabrese, J., and Meltzer, H. Y. (1994). The relevance of the in- versus outpatient status for studies on HPA-axis in depression: spontaneous hypercortisolism is a feature of major depressed inpatients and not of major depression per se. Prog. Neuropsychopharmacol. Biol. Psychiatry 18, 503–517. doi: 10.1016/0278-5846(94)90008-6

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Majdic, G., and Tobet, S. (2011). Cooperation of sex chromosomal genes and endocrine influences for hypothalamic sexual differentiation. Front. Neuroendocrinol. 32:137–145. doi: 10.1016/j.yfrne.2011.02.009

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Matsumoto, A., and Arai, Y. (1997). Sexual differentiation of neuronal circuitry in the neuroendocrine hypothalamus. Biomed. Rev. 7, 5–15. doi: 10.14748/bmr.v7.158

CrossRef Full Text

Mayberg, H. S. (1997). Limbic-cortical dysregulation: a proposed model of depression. J. Neuropsychiatry Clin. Neurosci. 9, 471–481.

Pubmed Abstract | Pubmed Full Text

McClellan, K. M., Stratton, M. S., and Tobet, S. A. (2010). Roles for gamma-aminobutyric acid in the development of the paraventricular nucleus of the hypothalamus. J. Comp. Neurol. 518, 2710–2728. doi: 10.1002/cne.22360

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

McCormick, C. M., Smythe, J. W., Sharma, S., and Meaney, M. J. (1995). Sex-specific effects of prenatal stress on hypothalamic-pituitary-adrenal responses to stress and brain glucocorticoid receptor density in adult rats. Brain Res. Dev. Brain Res. 84, 55–61. doi: 10.1016/0165-3806(94)00153-Q

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

McEwen, B. S. (1983). “Gonadal steroid influences on brain development and sexual differentiation,” in Reproductive Physiology IV, ed R. Greep (University Park: Baltimore), 99–145.

McKay, M. S., and Zakzanis, K. K. (2010). The impact of treatment on HPA axis activity in unipolar major depression. J. Psychiatr. Res. 44, 183–192. doi: 10.1016/j.jpsychires.2009.07.012

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Montano, M. M., Wang, M. H., and vom Saal, F. S. (1993). Sex differences in plasma corticosterone in mouse fetuses are mediated by differential placental transport from the mother and eliminated by maternal adrenalectomy or stress. J. Reprod. Fertil. 99, 283–290. doi: 10.1530/jrf.0.0990283

CrossRef Full Text

Mueller, B. R., and Bale, T. L. (2008). Sex-specific programming of offspring emotionality after stress early in pregnancy. J. Neurosci. 28, 9055–9065. doi: 10.1523/JNEUROSCI.1424-08.2008

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Murphy, D. G., DeCarli, C., McIntosh, A. R., Daly, E., Mentis, M. J., Pietrini, P., et al. (1996). Sex differences in human brain morphometry and metabolism: an in vivo quantitative magnetic resonance imaging and positron emission tomography study on the effect of aging. Arch. Gen. Psychiatry 53, 585–594. doi: 10.1001/archpsyc.1996.01830070031007

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Murray, C. J., and Lopez, A. D. (1997). Mortality by cause for eight regions of the world: global burden of disease study. Lancet 349, 1269–1276. doi: 10.1016/S0140-6736(96)07493-4

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Nelson, W. H., Khan, A., Orr, W. W. Jr., and Tamragouri, R. N. (1984a). The dexamethasone suppression test: interaction of diagnosis, sex, and age in psychiatric inpatients. Biol. Psychiatry 19, 1293–1304.

Pubmed Abstract | Pubmed Full Text

Nelson, W. H., Orr, W. W. Jr., Shane, S. R., and Stevenson, J. M. (1984b). Hypothalamic-pituitary-adrenal axis activity and age in major depression. J. Clin. Psychiatry 45, 120–121.

Pubmed Abstract | Pubmed Full Text

Nemeroff, C. B., Bissette, G., Akil, H., and Fink, M. (1991). Neuropeptide concentrations in the cerebrospinal fluid of depressed patients treated with electroconvulsive therapy. Corticotrophin-releasing factor, beta-endorphin and somatostatin. Br. J. Psychiatry 158, 59–63. doi: 10.1192/bjp.158.1.59

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Nemeroff, C. B., Widerlov, E., Bissette, G., Walleus, H., Karlsson, I., Eklund, K., et al. (1984). Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 226, 1342–1344. doi: 10.1126/science.6334362

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Newport, D. J., Heim, C., Owens, M. J., Ritchie, J. C., Ramsey, C. H., Bonsall, R., et al. (2003). Cerebrospinal fluid corticotropin-releasing factor (CRF) and vasopressin concentrations predict pituitary response in the CRF stimulation test: a multiple regression analysis. Neuropsychopharmacology 28, 569–576. doi: 10.1038/sj.npp.1300071

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Nguyen, T. V., McCracken, J., Ducharme, S., Botteron, K. N., Mahabir, M., Johnson, W., et al. (2013). Testosterone-related cortical maturation across childhood and adolescence. Cereb. Cortex 23, 1424–1432. doi: 10.1093/cercor/bhs125

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

O'Keefe, J. A., Li, Y., Burgess, L. H., and Handa, R. J. (1995). Estrogen receptor mRNA alterations in the developing rat hippocampus. Brain Res. Mol. Brain Res. 30, 115–124. doi: 10.1016/0169-328X(94)00284-L

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Östlund, H., Keller, E., and Hurd, Y. L. (2003). Estrogen receptor gene expression in relation to neuropsychiatric disorders. Ann. N.Y. Acad. Sci. 1007, 54–63. doi: 10.1196/annals.1286.006

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Park, J. J., Baum, M. J., Paredes, R. G., and Tobet, S. A. (1996). Neurogenesis and cell migration into the sexually dimorphic preoptic area/anterior hypothalamus of the fetal ferret. J. Neurobiol. 30, 315–328.

Pubmed Abstract | Pubmed Full Text

Paus, T., Otaky, N., Caramanos, Z., MacDonald, D., Zijdenbos, A., D'Avirro, D., et al. (1996). In vivo morphometry of the intrasulcal gray matter in the human cingulate, paracingulate, and superior-rostral sulci: hemispheric asymmetries, gender differences and probability maps. J. Comp. Neurol. 376, 664–673.

Pubmed Abstract | Pubmed Full Text

Payne, J. L. (2003). The role of estrogen in mood disorders in women. Int. Rev. Psychiatry 15, 280–290. doi: 10.1080/0954026031000136893

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Plotsky, P. M., Owens, M. J., and Nemeroff, C. B. (1998). Psychoneuroendocrinology of depression. Hypothalamic-pituitary-adrenal axis. Psychiatr. Clin. N. Am. 21, 293–307. doi: 10.1016/S0193-953X(05)70006-X

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Poor, V., Juricskay, S., Gati, A., Osvath, P., and Tenyi, T. (2004). Urinary steroid metabolites and 11beta-hydroxysteroid dehydrogenase activity in patients with unipolar recurrent major depression. J. Affect. Disord. 81, 55–59. doi: 10.1016/S0165-0327(03)00199-X

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Protopopescu, X., Pan, H., Altemus, M., Tuescher, O., Polanecsky, M., McEwen, B., et al. (2005). Orbitofrontal cortex activity related to emotional processing changes across the menstrual cycle. Proc. Natl. Acad. Sci. U.S.A. 102, 16060–16065. doi: 10.1073/pnas.0502818102

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Pruessner, J. C., Dedovic, K., Khalili-Mahani, N., Engert, V., Pruessner, M., Buss, C., et al. (2008). Deactivation of the limbic system during acute psychosocial stress: evidence from positron emission tomography and functional magnetic resonance imaging studies. Biol. Psychiatry 63, 234–240. doi: 10.1016/j.biopsych.2007.04.041

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Rabin, D. S., Schmidt, P. J., Campbell, G., Gold, P. W., Jensvold, M., Rubinow, D. R., et al. (1990). Hypothalamic-pituitary-adrenal function in patients with the premenstrual syndrome. J. Clin. Endocrinol. Metab. 71, 1158–1162. doi: 10.1210/jcem-71-5-1158

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Raison, C. L., and Miller, A. H. (2003). When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am. J. Psychiatry 160, 1554–1565. doi: 10.1176/appi.ajp.160.9.1554

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Rauch, S. L., Shin, L. M., and Wright, C. I. (2003). Neuroimaging studies of amygdala function in anxiety disorders. Ann. N.Y. Acad. Sci. 985, 389–410. doi: 10.1111/j.1749-6632.2003.tb07096.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Raznahan, A., Lee, Y., Stidd, R., Long, R., Greenstein, D., Clasen, L., et al. (2010). Longitudinally mapping the influence of sex and androgen signaling on the dynamics of human cortical maturation in adolescence. Proc. Natl. Acad. Sci. U.S.A. 107, 16988–16993. doi: 10.1073/pnas.1006025107

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Regan, J., Wagner, D., Hamer, G., Wright, A., and White, C. (2004). Latinos and their mental health. Tennessee Med. 97, 218–219.

Pubmed Abstract | Pubmed Full Text

Rhodes, M. E., and Rubin, R. T. (1999). Functional sex differences (“sexual diergism”) of central nervous system cholinergic systems, vasopressin, and hypothalamic-pituitary-adrenal axis activity in mammals: a selective review. Brain Res. Brain Res. Rev. 30, 135–152. doi: 10.1016/S0165-0173(99)00011-9

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Roca, C. A., Schmidt, P. J., Altemus, M., Deuster, P., Danaceau, M. A., Putnam, K., et al. (2003). Differential menstrual cycle regulation of hypothalamic-pituitary-adrenal axis in women with premenstrual syndrome and controls. J. Clin. Endocrinol. Metab. 88, 3057–3063. doi: 10.1210/jc.2002-021570

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Root, J. C., Tuescher, O., Cunningham-Bussel, A., Pan, H., Epstein, J., Altemus, M., et al. (2009). Frontolimbic function and cortisol reactivity in response to emotional stimuli. Neuroreport 20, 429–434. doi: 10.1097/WNR.0b013e328326a031

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Rubin, R. T., Poland, R. E., Lesser, I. M., Winston, R. A., and Blodgett, A. L. (1987). Neuroendocrine aspects of primary endogenous depression. I. Cortisol secretory dynamics in patients and matched controls. Arch. Gen. Psychiatry 44, 328–336. doi: 10.1001/archpsyc.1987.01800160032006

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Rubinow, D. R., and Schmidt, P. J. (1996). Androgens, brain, and behavior. Am. J. Psychiatry 153, 974–884.

Pubmed Abstract | Pubmed Full Text

Ruigrok, A. N., Salimi-Khorshidi, G., Lai, M. C., Baron-Cohen, S., Lombardo, M. V., Tait, R. J., et al. (2013). A meta-analysis of sex differences in human brain structure. Neurosci. Biobehav. Rev. 39, 34–50. doi: 10.1016/j.neubiorev.2013.12.004

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Schulz, K. M., Molenda-Figueira, H. A., and Sisk, C. L. (2009). Back to the future: the organizational-activational hypothesis adapted to puberty and adolescence. Horm. Behav. 55, 597–604. doi: 10.1016/j.yhbeh.2009.03.010

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Schweiger, U., Deuschle, M., Weber, B., Korner, A., Lammers, C. H., Schmider, J., et al. (1999). Testosterone, gonadotropin, and cortisol secretion in male patients with major depression. Psychosom. Med. 61, 292–296. doi: 10.1097/00006842-199905000-00007

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Seckl, J. R. (2001). Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms. Mol. Cell. Endocrinol. 185, 61–71. doi: 10.1016/S0303-7207(01)00633-5

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Seidman, S. N., Araujo, A. B., Roose, S. P., and McKinlay, J. B. (2001). Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men. Biol. Psychiatry 50, 371–376. doi: 10.1016/S0006-3223(01)01148-9

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Seney, M. L., Ekong, K. I., Ding, Y., Tseng, G. C., and Sibille, E. (2013). Sex chromosome complement regulates expression of mood-related genes. Biol. Sex Differ. 4, 20. doi: 10.1186/2042-6410-4-20

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sheline, Y. I., Mittler, B. L., and Mintun, M. A. (2002). The hippocampus and depression. Eur. Psychiatry 17(Suppl. 3), 300–305. doi: 10.1016/S0924-9338(02)00655-7

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Simerly, R. B., Chang, C., Muramatsu, M., and Swanson, L. W. (1990). Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study. J. Comp. Neurol. 294, 76–95. doi: 10.1002/cne.902940107

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sonino, N., Fava, G. A., Raffi, A. R., Boscaro, M., and Fallo, F. (1998). Clinical correlates of major depression in Cushing's disease. Psychopathology 31, 302–306. doi: 10.1159/000029054

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Stark, R., Wolf, O. T., Tabbert, K., Kagerer, S., Zimmermann, M., Kirsch, P., et al. (2006). Influence of the stress hormone cortisol on fear conditioning in humans: evidence for sex differences in the response of the prefrontal cortex. Neuroimage 32, 1290–1298. doi: 10.1016/j.neuroimage.2006.05.046

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Steiner, M. (1992). Female-specific mood disorders. Clin. Obstet. Gynecol. 35, 599–611. doi: 10.1097/00003081-199209000-00020

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Stratton, M. S., Searcy, B. T., and Tobet, S. A. (2011). GABA regulates corticotropin releasing hormone levels in the paraventricular nucleus of the hypothalamus in newborn mice. Physiol. Behav. 104, 327–333. doi: 10.1016/j.physbeh.2011.01.003

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Swaab, D. F., Bao, A. M., and Lucassen, P. J. (2005). The stress system in the human brain in depression and neurodegeneration. Ageing Res. Rev. 4, 141–194. doi: 10.1016/j.arr.2005.03.003

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Swaab, D. F., and Fliers, E. (1985). A sexually dimorphic nucleus in the human brain. Science 228, 1112–1125. doi: 10.1126/science.3992248

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Takahashi, A., Sudo, M., Minokoshi, Y., and Shimazu, T. (1992). Effects of ventromedial hypothalamic stimulation on glucose transport system in rat tissues. Am. J. Physiol. 263, R1228–R1234.

Pubmed Abstract | Pubmed Full Text

Tobet, S. A., Basham, M. E., and Baum, M. J. (1993). Estrogen receptor immunoreactive neurons in the fetal ferret forebrain. Brain Res. Dev. Brain Res. 72, 167–180. doi: 10.1016/0165-3806(93)90182-A

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Tobet, S. A., and Hanna, I. K. (1997). Ontogeny of sex differences in the mammalian hypothalamus and preoptic area. Cell. Mol. Neurobiol. 17, 565–601. doi: 10.1023/A:1022529918810

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Tobet, S., Knoll, J. G., Hartshorn, C., Aurand, E., Stratton, M., Kumar, P., et al. (2009). Brain sex differences and hormone influences: a moving experience? J. Neuroendocrinol. 21, 387–392. doi: 10.1111/j.1365-2826.2009.01834.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Trestman, R. L., Coccaro, E. F., Mitropoulou, V., Gabriel, S. M., Horvath, T., and Siever, L. J. (1993). The cortisol response to clonidine in acute and remitted depressed men. Biol. Psychiatry 34, 373–379. doi: 10.1016/0006-3223(93)90181-C

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ustun, T. B., Ayuso-Mateos, J. L., Chatterji, S., Mathers, C., and Murray, C. J. (2004). Global burden of depressive disorders in the year 2000. Br. J. Psychiatry 184, 386–392. doi: 10.1192/bjp.184.5.386

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Vakili, K., Pillay, S. S., Lafer, B., Fava, M., Renshaw, P. F., Bonello-Cintron, C. M., et al. (2000). Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol. Psychiatry 47, 1087–1090. doi: 10.1016/S0006-3223(99)00296-6

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Vallee, M., Mayo, W., Dellu, F., Le Moal, M., Simon, H., and Maccari, S. (1997). Prenatal stress induces high anxiety and postnatal handling induces low anxiety in adult offspring: correlation with stress-induced corticosterone secretion. J. Neurosci. 17, 2626–2636.

Pubmed Abstract | Pubmed Full Text

van Wingen, G. A., van Broekhoven, F., Verkes, R. J., Petersson, K. M., Backstrom, T., Buitelaar, J. K., et al. (2008a). Progesterone selectively increases amygdala reactivity in women. Mol. Psychiatry 13, 325–333. doi: 10.1038/sj.mp.4002030

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

van Wingen, G. A., Zylicz, S. A., Pieters, S., Mattern, C., Verkes, R. J., Buitelaar, J. K., et al. (2009). Testosterone increases amygdala reactivity in middle-aged women to a young adulthood level. Neuropsychopharmacology 34, 539–547. doi: 10.1038/npp.2008.2

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

van Wingen, G., Mattern, C., Verkes, R. J., Buitelaar, J., and Fernandez, G. (2008b). Testosterone biases automatic memory processes in women towards potential mates. Neuroimage 43, 114–120. doi: 10.1016/j.neuroimage.2008.07.002

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Veith, R. C., Lewis, N., Langohr, J. I., Murburg, M. M., Ashleigh, E. A., Castillo, S., et al. (1993). Effect of desipramine on cerebrospinal fluid concentrations of corticotropin-releasing factor in human subjects. Psychiatry Res. 46, 1–8. doi: 10.1016/0165-1781(93)90002-X

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Vreeburg, S. A., Hoogendijk, W. J., van Pelt, J., Derijk, R. H., Verhagen, J. C., van Dyck, R., et al. (2009). Major depressive disorder and hypothalamic-pituitary-adrenal axis activity: results from a large cohort study. Arch. Gen. Psychiatry 66, 617–626. doi: 10.1001/archgenpsychiatry.2009.50

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Vythilingam, M., Vermetten, E., Anderson, G. M., Luckenbaugh, D., Anderson, E. R., Snow, J., et al. (2004). Hippocampal volume, memory, and cortisol status in major depressive disorder: effects of treatment. Biol. Psychiatry 56, 101–112. doi: 10.1016/j.biopsych.2004.04.002

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wang, J., Korczykowski, M., Rao, H., Fan, Y., Pluta, J., Gur, R. C., et al. (2007). Gender difference in neural response to psychological stress. Soc. Cogn. Affect. Neurosci. 2, 227–239. doi: 10.1093/scan/nsm018

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Weiner, C. L., Primeau, M., and Ehrmann, D. A. (2004). Androgens and mood dysfunction in women: comparison of women with polycystic ovarian syndrome to healthy controls. Psychosom. Med. 66, 356–362. doi: 10.1097/01.psy.0000127871.46309.fe

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Weinstock, M. (1997). Does prenatal stress impair coping and regulation of hypothalamic-pituitary-adrenal axis? Neurosci. Biobehav. Rev. 21, 1–10. doi: 10.1016/S0149-7634(96)00014-0

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Weinstock, M., Matlina, E., Maor, G. I., Rosen, H., and McEwen, B. S. (1992). Prenatal stress selectively alters the reactivity of the hypothalamic-pituitary adrenal system in the female rat. Brain Res. Mol. Brain Res. 595, 195–200. doi: 10.1016/0006-8993(92)91049-K

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Weniger, G., Lange, C., and Irle, E. (2006). Abnormal size of the amygdala predicts impaired emotional memory in major depressive disorder. J. Affect. Disord. 94, 219–229. doi: 10.1016/j.jad.2006.04.017

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

World Health Organization. (2012). Depression, a hidden burden (Fact sheet). Available online at: http://www.who.int/mental_health/advocacy/en/

Young, A. H., Gallagher, P., Watson, S., Del-Estal, D., Owen, B. M., and Ferrier, I. N. (2004). Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder. Neuropsychopharmacology 29, 538–545. doi: 10.1038/sj.npp.1300471

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Young, E. A., and Altemus, M. (2004). Puberty, ovarian steroids, and stress. Ann. N.Y. Acad. Sci. 1021, 124–133. doi: 10.1196/annals.1308.013

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Young, E. A., Kornstein, S. G., Harvey, A. T., Wisniewski, S. R., Barkin, J., Fava, M., et al. (2007b). Influences of hormone-based contraception on depressive symptoms in premenopausal women with major depression. Psychoneuroendocrinology 32, 843–853. doi: 10.1016/j.psyneuen.2007.05.013

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Young, E. A., and Korszun, A. (2002). The hypothalamic-pituitary-gonadal axis in mood disorders. Endocrinol. Metab. Clin. North Am. 31, 63–78. doi: 10.1016/S0889-8529(01)00002-0

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Young, E. A., Midgley, A. R., Carlson, N. E., and Brown, M. B. (2000). Alteration in the hypothalamic-pituitary-ovarian axis in depressed women. Arch. Gen. Psychiatry 57, 1157–1162. doi: 10.1001/archpsyc.57.12.1157

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Young, E. A., Ribeiro, S. C., and Ye, W. (2007a). Sex differences in ACTH pulsatility following metyrapone blockade in patients with major depression. Psychoneuroendocrinology 32, 503–507. doi: 10.1016/j.psyneuen.2007.03.003

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Zobel, A. W., Yassouridis, A., Frieboes, R. M., and Holsboer, F. (1999). Prediction of medium-term outcome by cortisol response to the combined dexamethasone-CRH test in patients with remitted depression. Am. J. Psychiatry 156, 949–951.

Pubmed Abstract | Pubmed Full Text

Zuloaga, D. G., Carbone, D. L., and Handa, R. J. (2012a). Prenatal dexamethasone selectively decreases calretinin expression in the adult female lateral amygdala. Neurosci. Lett. 521, 109–114. doi: 10.1016/j.neulet.2012.05.058

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Zuloaga, D. G., Carbone, D. L., Hiroi, R., Chong, D. L., and Handa, R. J. (2011). Dexamethasone induces apoptosis in the developing rat amygdala in an age-, region-, and sex-specific manner. Neuroscience 199, 535–547. doi: 10.1016/j.neuroscience.2011.09.052

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Zuloaga, D. G., Carbone, D. L., Quihuis, A., Hiroi, R., Chong, D. L., and Handa, R. J. (2012b). Perinatal dexamethasone-induced alterations in apoptosis within the hippocampus and paraventricular nucleus of the hypothalamus are influenced by age and sex. J. Neurosci. Res. 90, 1403–1412. doi: 10.1002/jnr.23026

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Keywords: major depression, sex differences, women's health, stress, mood, fetal programming

Citation: Goldstein JM, Holsen L, Handa R and Tobet S (2014) Fetal hormonal programming of sex differences in depression: linking women's mental health with sex differences in the brain across the lifespan. Front. Neurosci. 8:247. doi: 10.3389/fnins.2014.00247

Received: 21 May 2014; Accepted: 24 July 2014;
Published online: 08 September 2014.

Edited by:

Belinda Pletzer, University of Salzburg, Austria

Reviewed by:

Margaret Altemus, Cornell Universtiy, USA

Copyright © 2014 Goldstein, Holsen, Handa and Tobet. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: jill_goldstein@hms.harvard.edu