Feature Review

Molecular Psychiatry (2010) 15, 23–28; doi:10.1038/mp.2009.94; published online 22 September 2009

Sex, trauma, stress hormones and depression

E Young Dr. Elizabeth Young died on September 1, 2009 and that the article on pages 23-28 is the last paper that she wrote?1,maltese cross and A Korszun2

  1. 1Molecular and Behavioral Neurosciences Institute, University of Michigan, Ann Arbor, MI, USA
  2. 2Barts and The London School of Medicine, Queen Mary University of London, London, UK

Correspondence: Professor A Korszun, Centre for Psychiatry, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. E-mail: a.korszun@qmul.ac.uk

maltese crossDeceased.

Received 3 August 2009; Accepted 13 August 2009; Published online 22 September 2009.

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Abstract

Although few studies dispute that there are gender differences in depression, the etiology is still unknown. In this review, we cover a number of proposed factors and the evidences for and against these factors that may account for gender differences in depression. These include the possible role of estrogens at puberty, differences in exposure to childhood trauma, differences in stress perception between men and women and the biological differences in stress response. None of these factors seem to explain gender differences in depression. Finally, we do know that when depressed, women show greater hypothalamic–pituitary–adrenal (HPA) axis activation than men and that menopause with loss of estrogens show the greatest HPA axis dysregulation. It may be the constantly changing steroid milieu that contributes to these phenomena and vulnerability to depression.

Keywords:

depression; sex differences; estrogen; progesterone; HPA axis; stress

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Introduction

Depression is a multifactorial disorder in which adaptation to stressors undoubtedly has a crucial role. Although genetic vulnerability is critical to the development of depression, the incidence of depression is very low in the absence of environmental stressors;1 and in approximately 75% of cases of depression, there is a precipitating life event.2, 3 An understanding of the pathoetiology of depression must provide an explanation for the high predominance of women with depressive disorders. Thus, the relationship between gender, trauma, gonadal steroids stress and depression, and in sex differences in the stress hormone response, comprises both an intriguing and fruitful area of research. Furthermore, there may be gender differences in stress hormones found only in the depressed patients.

The occurrence of gender differences in depression has been replicated in numerous studies across cultures.4 This difference arises at puberty and persists throughout the reproductive years.5 Does estrogen cause depression? Studies by Angold6 have found a relationship between the rise in estrogen and testosterone levels and the rising incidence of depression in girls during adolescence. In women with an earlier episode of depression, the periods of rapidly changing gonadal steroid concentrations, such as those occurring premenstrually or postpartum, mark particularly vulnerable times for the occurrence of depressive symptoms. Studies by O'Hara et al.7, 8 confirm that a history of depressive episodes increases the risk of both postpartum ‘blues’ and postpartum major depression. Recent studies on two epidemiological cohorts9, 10 have found an increased incidence of depressive symptoms and major depression during the menopause transition. The findings of Freeman et al.10, 11 with regard to estrogen showed that both high and low estrogen were associated with depression. More recently, their data suggest that variability in estrogen levels may drive depression, that is, those women who show rapid changes from high to low estrogen and vice versa are those who develop depressive symptoms during the perimenopause transition. Finally, estrogen levels are lower in women with major depression, possibly predisposing women to depression.12

Do sex differences in stress and trauma account for greater incidence of depression?

Given the link between stress and depression, perhaps women are more likely to experience major life stressors. Research does not suggest that this is the case, and the overall incidence of major life stressors is the same between sexes. However, the depressogenic effects of stressors are influenced by gender, and hence women are more susceptible to stressors that affect more distant relationships.13 Kendler et al. found that women were more sensitive to the depressogenic effects of problems in getting along with others in their interpersonal network but men were more sensitive to the depressogenic effects of work problems and separation problems.14 Neither study found that the rate of stressful events could account for excess rates of depression in women.

Perhaps men and women perceive stress differently? In an analysis of a stratified representative sample of 2387 adults, Cohen and Williamson15 found no meaningful sex differences in the perceived stress scale. A large-scale multicountry European study by de Smet et al.,16 consisting of 34972 subjects, found little support for differences in job strain between men and women. There were sex differences in the sense of control but not in the ratings of strain. These studies do not support that differences in stress perception would account for sex differences in depression.

Greater exposure to childhood abuse, including sexual abuse, is another leading explanation for gender differences in depression. Early-life stress and trauma have been found to sensitize animals to later stressors17 and some have suggested that the higher rates of trauma in women might explain the gender differences in depression. However, epidemiological data do not support that women necessarily have more childhood trauma. Studies by Kessler and Magee,18 examining the American Changing Lives longitudinal survey, found greater rates of childhood sexual abuse in women. Furthermore, in general, men are more likely to experience trauma than women. Studies examining population-based samples (generally from school-based samples) of childhood abuse in either young adults18, 19, 20, 21 or late adolescence conclude either no gender difference in exposure to trauma or greater exposure in boys than in girls.19, 20, 21, 22, 23 A recent meta-analysis by Tolin and Foa24 reached similar conclusions that (1) existing studies do not support greater exposure to trauma in women and (2) that overall studies do not support sex differences in childhood trauma. Two studies conducted by a health maintenance organization in San Diego, involving 9460 individuals, analyzed both childhood sexual abuse and other forms of trauma.25, 26 Although the first study, focusing on childhood abuse in women, found a strong association, the second study26 evaluated both men and women with childhood abuse and concluded, ‘For both men and the women, the risk of each outcome was increased at a similar magnitude. For example, compared with no sexual abuse, there was a twofold increased risk for suicide attempts for both men and women (P=0.05) Similarly, there was a 40% increased risk of marrying an alcoholic for both men and women who reported CSA compared with those not reporting CSA (P=0.05)’. It should be further noted that the participants in these studies were all in their mid 50s. It is quite possible that there was some recall bias and those with long histories of depression attributed their depression to events such as childhood abuse when there may well have been other causes. Finally, the study by Breslau et al.,27 analyzing data on adult and childhood trauma from the Detroit Area Study, concluded that trauma does not increase the risk of depression except through post-traumatic stress disorder (PTSD) and that the rates of PTSD are not high enough to account for the excess of depression in women.

It should be noted that the hypothalamic–pituitary–adrenal (HPA) picture shown by women with childhood abuse is not the classic HPA axis picture of major depression. These women show enhanced sensitivity to dexamethasone28 and lower cortisol than their matched control women.29 Although this study by Heim et al.29 did show an exaggerated response to a stressor, the Trier Social Stress Test (TSST), we observed the same exaggerated response to the same stressor in patients with depression plus a comorbid anxiety disorder,30 raising the possibility that it was comorbid anxiety, rather than childhood abuse, that accounted for the differences between groups. Although the study by Breslau et al.,27 analyzing data on adult and childhood trauma from the Detroit Area Study, concluded that trauma does not increase the risk of depression except through PTSD, all studies conclude that women are more sensitive to the development of PTSD after trauma. Furthermore, women are more likely to develop depression in the face of significant life events. This raises the question of sex differences in the biological response to stress.

Sex differences in stress systems

Living organisms survive by maintaining a complex dynamic equilibrium or homeostasis that is constantly challenged by intrinsic or extrinsic stressors. These stressors set into motion responses aimed at preserving homeostasis, including activation of the HPA axis. A hormonal cascade is initiated with the release of corticotropin-releasing hormone (CRH) that triggers the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary corticotrope, and that, in turn, triggers the release of adrenal glucocorticoids. The stress response is turned off by glucocorticoid feedback at the brain and pituitary sites. It has been shown in both rats and humans that the stress response is sexually dimorphic; and studies in rats and humans have suggested that gonadal steroids have an important role in modulating the HPA axis, acting particularly on sensitivity to glucocorticoid negative feedback.31 The effects may be on glucocorticoid receptors, on brain CRH systems or on the responsiveness to CRH.

Studies by Kirschbaum et al.32 have observed sex differences in response to one stress, the TSST. However, the difference is not what would be predicted: men show a greater ACTH response to the stressor. However, the plasma cortisol response is the same in both men and women. Our studies with this same stressor on 96 subjects reached exactly the same conclusions that men show a greater ACTH response to the stressor than women but the cortisol response to the stressor is the same.30 The majority of cortisol in plasma is bound to cortisol steroid-binding globulin. Examining saliva cortisol, the free or active cortisol leads to the conclusions that women show smaller saliva cortisol responses to stress, but it is dependent upon the menstrual cycle phase. Thus, during the follicular phase, women show much smaller responses to the TSST, whereas during the luteal phase their saliva cortisol response to the TSST is the same as men.32 Furthermore, oral contraceptives profoundly decrease the free cortisol response to this stressor.33 We have similar data confirming large menstrual cycle difference in free (saliva) cortisol response to the TSST in normal women, as well as a markedly blunted response in oral contraceptive users (Young, unpublished data).

We have also examined sex differences in response to cortisol infusion. Infusion of cortisol ‘turns off’ corticotroph secretion within 15min of the onset of a rise in cortisol in both premenopausal female and age-matched male control subjects.34 After the termination of infusion, men showed a continued inhibition of corticotroph secretion for 60min, whereas women were resistant to cortisol infusion and begin to secrete again in 1h. This difference seems to be dependent on the menstrual cycle phase. Women with follicular phase plasma progesterone concentrations showed patterns of suppression of corticotroph secretion similar to the men. However, women with progesterone concentrations typical of the luteal phase showed rebound corticotroph secretion after termination of cortisol infusion.34

Similar studies by Altemus et al.35 have found decreased cortisol suppression to dexamethasone during the luteal phase of the menstrual cycle, as compared with the follicular phase in the same women. Furthermore, menstrual cycle hormonal changes influenced the expression of glucocorticoid receptor mRNA in lymphocytes, resulting in a decrease in receptors in the luteal phase of the menstrual cycle35 and suggesting that decreases in glucocorticoid receptors may explain the decreased response to dexamethasone. In our studies of basal ACTH and cortisol secretion for 24h, we did not observe any menstrual cycle differences in either ACTH or cortisol.36 Nor have we found menstrual cycle differences in response to metyrapone blockade (Altemus and Young, unpublished data). Taken together, these data suggest that the increased stress responsiveness observed during the luteal phase may well be a function of decreased sensitivity to the glucocorticoid negative feedback.

Which ovarian steroids influence the HPA axis?

Having shown that there are both sex differences and changes across the menstrual cycle in normal subjects, we next turn to an analysis regarding which specific ovarian hormone is the critical hormone. We used rodent models and examined the effects of estrogen antagonists and ovariectomy, with and without estrogen replacement, and found that estradiol decreased stress responsiveness.37 Similar findings have been shown in sheep and humans.38, 39 Treatment of normal men with estradiol for 48h results in increased stress responsiveness.40 However, this could be a function of decreases in testosterone that inhibits stress responsiveness.41 Estradiol administered to postmenopausal women had no effect on the response to the stressor, TSST, but it did decrease the response to the dex-CRH challenge.33

In a clever study design in normally menstruating women, Roca et al.42, 43 analyzed women treated with Lupron, which leads to a loss of all gonadal steroids, followed by estradiol or progesterone add-back phases. They examined the response to exercise stress and found that the exercise stress response was increased during the progesterone ‘add-back’ phase but not during the estrogen ‘add-back’ phase. This supports a role for progesterone in functioning as an antagonist of glucocorticoids. Thus, so far, the data from human studies suggest that estradiol acts as an additional ‘brake’ on the HPA axis but progesterone may impair glucocorticoid negative feedback.

Sex differences in HPA axis regulation in depression

Abnormalities of the HPA axis, as manifested by hypercortisolemia, and disruption of the circadian rhythm of cortisol secretion are well-established phenomena in depression.44, 45 In addition, the failure of cortisol and ACTH suppression with dexamethasone has also been described.44 As HPA dysregulation is the most consistent neuroendocrine abnormality in depression, and depressive disorders occur twice as commonly in women than in men, we asked whether there are sex differences in HPA axis function in depressed patients. We studied baseline cortisol secretion in the morning in 16 depressed patients and 16 age- and sex-matched control patients and found predictably increased cortisol secretion in the group as a whole.34 However, there were also clear sex differences: male patients and their matched controls showed the same plasma cortisol concentration, whereas female depressed patients showed significantly higher mean plasma cortisol concentration than their matched controls. Removal of glucocorticoid negative feedback using metyrapone, a glucocorticoid synthesis inhibitor, showed increased central drive in depressed patients in the evening.46 The response to metyrapone also showed sex differences; only the female depressed patients manifested rebound corticotroph secretion in comparison with their matched controls and the males did not. We conducted 24-h studies with ACTH clamped under metyrapone, and found that depressed women showed significantly increased central drive (presumably because of CRH) only over the 1600–2200 hours time period, replicating our earlier finding. Depressed men showed a significantly decreased response to metyrapone in this same time period compared with the matched control men. The maximum ACTH response using metyrapone was identical between depressed women and their matched controls. In contrast, depressed men showed a significantly decreased maximal ACTH response compared with either their matched controls or with the depressed women. These data argue for a specific circadian time period (late evening) rather than increased CRH–ACTH across the 24-h day as the critical time period in women.47

Dexamethasone non-suppression and menopause
 

We also examined the effect of loss of gonadal steroids at menopause on HPA axis regulation in depressed women,31 using corticotroph secretion as our end point. We conducted these studies on 51 depressed women; 36 of whom were premenopausal and 15 postmenopausal. The premenopausal women showed a significantly lower incidence of corticotroph non-suppressors (44%) than the postmenopausal women (non-suppressor=81%). Using a step-wise regression with a number of independent variables and corticotroph non-suppression to dexamethasone as the dependent variable, we found that only age and baseline cortisol had a significant effect on corticotroph non-suppression; but when age and menopausal status were compared, menopausal status showed a stronger correlation and, combined with cortisol, yielded a correlation coefficient of 0.817. This suggests that menopausal status, in conjunction with cortisol hypersecretion, is a critical variable in the development of HPA dysregulation in women, as manifested by resistance to dexamethasone, and accounts for 65% of the variance. Furthermore, the lower rate of cortisol non-suppression in premenopausal women suggests that gonadal steroids may modulate the HPA axis and exert some protective effect against the high levels of endogenous glucocorticoids (cortisol).

In his formulation of the glucocorticoid cascade hypothesis, Sapolsky48 has suggested that stress and repeated bouts of hypercortisolemia lead to downregulation of glucocorticoid receptors, which in turn results in further glucocorticoid hypersecretion, eventually leading to loss of hippocampal neurons, that is, a ‘glucocorticoid feedforward cascade’.48 His studies in rats have suggested that aging is a critical variable, and that aging rats showed downregulation of glucocorticoid receptors, failure to shut off stress-induced glucocorticoid secretion and hippocampal neuronal loss. Aging is also associated with HPA axis dysregulation in depression.49, 50, 51 We tested the hypothesis that the recurrent episodes of hypercortisolemia, occurring in recurrent depression, lead to progressive HPA axis dysregulation. We divided patients into first episode versus recurrent unipolar depression and examined differences in the rates of pituitary non-suppression. We found no effect of recurrent episodes but observed that, within both recurrent and first-episode subgroups, aging was associated with a higher incidence of HPA axis dysregulation. As 16 of the 20 subjects over 50 years were women, we cannot determine if aging is also a factor in men. However, in women, aging seemed to be a more important factor than the absolute number of episodes, and the previous analysis suggested that menopausal status was the critical variable in aging.

In summary, menopause itself is not associated with increases in plasma cortisol concentrations in depressed women, but it is associated with an increase in dexamethasone resistance. Resistance to dexamethasone suppression is strongly associated with an increased baseline cortisol secretion, in combination with age or menopause, and thus seems to reflect the development of glucocorticoid receptor resistance in the context of low estrogen.

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Conclusions

Women are more likely to develop depression than men with the onset of depression beginning during puberty. They are also more likely than men to develop PTSD after exposure to trauma,52 despite similar rates of trauma exposure. Gender differences in exposure to trauma, in the number of significant life stressors experienced or in the perception of stress, do not explain gender differences in depression. Gender differences between the magnitude of the biological stress response also do not explain the increased sensitivity of women to the psychiatric sequelae of stress. However, it is clear that ovarian hormones do regulate the magnitude of the ACTH and cortisol responses to stressors. Furthermore, they strongly influence the HPA axis picture in depressed women. The interactions of organizational differences in female brains with cyclical gonadal steroid hormone changes after puberty, followed by menopause and the loss of these same steroids, suggest that stress responsiveness and susceptibility to stress-related disorders could vary substantially over the lifetime of women. Among patients with major depression, depressed women show greater HPA axis dysregulation than depressed men. There is certainly evidence that the increased vulnerability to depression in women arises at puberty, when gonadal steroids first begin to regularly influence the HPA axis of girls. Although this review focused on the HPA axis, ovarian steroids influence many other brain systems and all of these systems are exposed to cyclic changes in ovarian steroids on a monthly basis; the major increases in these steroids are followed by steep decreases with pregnancy and childbirth, and then finally loss of the steroid effects at menopause. It may be that the continually changing steroid milieu is the major factor sensitizing women to stress.

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Conflict of interest

The authors declare no conflict of interest.

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Acknowledgements

We acknowledge the support of NIH grants MH50030, MH078975 and UL1RR024986 that support the Michigan Clinical Research Unit, which supported all our studies.

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