Women develop posttraumatic stress disorder (PTSD) at twice the rate of men, even though fewer women than men experience traumatic events over their lifetimes. Current studies of individuals with PTSD provide evidence of alterations in the neuroendocrine system that involve levels and activity of cortisol and DHEA and changes in immune function that predispose these individuals toward an innate (Th1) immune response. Yet few studies have addressed the possible role of these biologic alterations in women’s increased vulnerability to developing PTSD. In addition, current studies are limited in their ability to link biologic alterations to the observed fourfold increase in medical conditions in women with PTSD as compared to women without PTSD. And finally, few studies have addressed the biologic impact of co-occurring major depressive disorder (MDD) in individuals with PTSD. This critical review provides an update on neuroendocrine and immune perturbations associated with PTSD with and without cooccurring MDD to suggest links to health and possible mechanisms underlying the observed sex disparity in the development of PTSD.
Altemus, M., Cloitre, M., & Dhabhar, F. S. (2003). Enhanced cellular immune response in women with PTSD related to childhood abuse. American Journal of Psychiatry, 160, 1705-1707.
2.
Andrews, R., Herlihy, O., Livingstone, D., Andrew, R., & Walker, J. (2002). Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with glucose intolerance. Journal of Clinical Endocrinology and Metabolism, 87, 5587-5593.
3.
Anisman, H., Griffiths, J., Matheson, K., Ravindran, A. V., & Merali Z. (2001). Posttraumatic stress symptoms and salivary cortisol levels. American Journal of Psychiatry, 158, 1509-1511.
4.
Baker, D. G., Ekhator, N. N., Kasckow, J. W., Hill, K. K., Zoumakis, E., Dashevsky, B. A., et al. (2001). Plasma and cerebrospinal fluid interleukin-6 concentrations in posttraumatic stress disorder. Neuroimmunomodulation, 9, 209-217.
5.
Bjorntorp, P. (1999). Neuroendocrine perturbations as a cause of insulin resistance. Diabetes Metabolism Research Review, 15, 427-441.
6.
Bonne, O., Gilboa, A., Louzoun, Y., Brandes, D., Yona, I., Lester, H., et al. (2003). Resting regional cerebral perfusion in recent posttraumatic stressdisorder. Biologic Psychiatry, 5, 1077-1086.
7.
Boscarino, J. A., & Chang, J. (1999). Higher abnormal leukocyte and lymphocyte counts 20 years after exposure to severe stress: Research and clinical implications. Psychosomatic Medicine, 61, 378-386.
8.
Breslau, N. (2002). Epidemiologic studies of trauma, posttraumatic stress disorder, and other psychiatric disorders. Canadian Journal of Psychiatry, 47, 923-929.
9.
Breslau, N., Chilcoat, H. D., Kessler, R. C., Peterson, E. L., & Lucia, V. C. (1999). Vulnerability to assaultive violence: Further specification of the sex difference in post-traumatic stress disorder. Psychologic Medicine, 29, 813-821.
10.
Breslau, N., Davis, G. C., Andreski, P., Peterson, E. L., & Schultz, L. R. (1997). Sex differences in posttraumatic stress disorder. Archives of General Psychiatry, 54, 1044-1048.
11.
Breslau, N., Davis, G. C., Peterson, E. L., & Schultz, L. (1997). Psychiatric sequelae of posttraumatic stress disorder in women. Archives of General Psychiatry, 54, 81-87.
12.
Breslau, N., Davis, G. C., Peterson, E. L., & Schultz, L. R. (2000). A second look at comorbidity in victims of trauma: The posttraumatic stress disorder-major depression connection. Biologic Psychiatry, 48, 902-909.
13.
Breslau, N., Kessler, R. C., Chilcoat, H. D., Schultz, L. R., Davis, G. C., & Andreski, P. (1998). Trauma and posttraumatic stress disorder in the community: The 1996 Detroit Area Survey of Trauma. Archives of General Psychiatry, 55, 626-632.
14.
Ciechanowski, P. S., Walker, E. A., Russo, J. E., Newman, E., & Katon, W. J. (2004). Adult health status of women HMO members with posttraumatic stress disorder symptoms. General Hospital Psychiatry, 26, 261-268.
15.
Clum, G. A., Calhoun, K. S., & Kimerling, R. (2000). Associations among symptoms of depression and posttraumatic stress disorder and self-reported health in sexually assaulted women. Journal of Nervous and Mental Disorders, 188, 671-678.
16.
Delahanty, D. L., Nugent, N. R., Christopher, N. C., & Walsh, M. (2005). Initial urinary epinephrine and cortisol levels predict acute PTSD symptoms in child trauma victims. Psychoneuroendocrinology, 30, 121-128.
17.
Delahanty, D. L., Raimonde, A. J., Spoonster, E., & Cullado, M. (2003). Injury severity, prior trauma history, urinary cortisol levels, and acute PTSD in motor vehicle accident victims. Journal of Anxiety Disorders, 17, 149-164.
18.
Dimitrov, S., Lange, T., Tieken, S., Fehm, H. L., & Born, J. (2004). Sleep associated regulation of T helper 1/T helper 2 cytokine balance in humans. Brain Behavior and Immunology, 18, 341-348.
19.
Dobie, D. J., Kivlahan, D. R., Maynard, C., Bush, K. R., Davis, T. M., & Bradley, K. A. (2004). Posttraumatic stress disorder in female veterans: Association with self-reported health problems and functional impairment. Archives of Internal Medicine, 164, 394-400.
20.
Drapeau, V., Therrien, F., Richard, D., & Tremblay, A. (2003). Is visceral obesity a physiological adaptation to stress?Panminerva Medicine, 45, 189-195.
21.
Elzinga, B. M., Schmahl, C. G., Vermetten, E., van Dyck, R., & Bremner, J. D. (2003). Higher cortisol levels following exposure to traumatic reminders in abuse-related PTSD. Neuropsychopharmacology, 28, 1656-1665.
22.
Frayne, S. M., Seaver, M. R., Loveland, S., Christiansen, C. L., Spiro, A., Parker, V. A., et al. (2004). Burden of medical illness in women with depression and posttraumatic stress disorder. Archives of Internal Medicine, 164, 1306-1312.
23.
Gibbs, J. W., Sombati, S., DeLorenzo, R. J., & Coulter, D. A. (2000). Cellular actions of topiramate: Blockade of kainate-evoked inward currents in cultured hippocampal neurons. Epilepsia, 41(Suppl. 1), S10-S16.
24.
Glover, D. A., & Poland, R. E. (2002). Urinary cortisol and catecholamines in mothers of child cancer survivors with and without PTSD. Psychoneuroendocrinology, 27, 805-819.
25.
Gomes, M. B., & Nogueira, V. G. (2004). Acute-phase proteins and microalbuminuria among patients with type 2 diabetes. Diabetes Research and Clinical Practice, 66, 31-39.
26.
Gotovac, K., Sabioncello, A., Rabatic, S., Berki, T., & Dekaris, D. (2003). Flow cytometric determination of glucocorticoid receptor (GCR) expression in lymphocyte subpopulations: Lower quantity of GCR in patients with post-traumatic stress disorder (PTSD). Clinical Experiments in Immunology, 131, 335-339.
27.
Green, B. (2003). Post-traumatic stress disorder: Symptom profiles in men and women. Current Medicine Research Opinion, 19, 200-204.
28.
Heim, C., Newport, D. J., Bonsall, R., Miller, A. H., & Nemeroff, C. B. (2001). Altered pituitary-adrenal axis responses to provocative challenge tests in adult survivors of childhood abuse. American Journal of Psychiatry, 158, 575-581.
29.
Hidalgo, R. B., & Davidson, J. R. (2000). Posttraumatic stress disorder: Epidemiology and health-related considerations. Journal of Clinical Psychiatry, 61(Suppl. 7), 5-13.
30.
Hu, J., Chen, Z., Gorczynski, C. P., Gorczynski, L. Y., Kai, Y., Lee, L., et al. (2003). Sleep-deprived mice show altered cytokine production manifest by perturbations in serum IL-1ra, TNFa, and IL-6 levels. Brain Behavior and Immunology, 17, 498-504.
31.
Inoue-Sakurai, C., Maruyama, S., & Morimoto, K. (2000). Posttraumatic stress and lifestyles are associated with natural killer cell activity in victims of the Hanshin-Awaji earthquake in Japan. Preventive Medicine, 31, 467-473.
32.
Ironson, G., Wynings, C., Schneiderman, N., Baum, A., Rodriguez, M., Greenwood, D., et al. (1997). Posttraumatic stress symptoms, intrusive thoughts, loss, and immune function after Hurricane Andrew. Psychosomatic Medicine, 59, 128-141.
33.
Kanter, E. D., Wilkinson, C. W., Radant, A.D., Petrie, E. C., Dobie, D. J., McFall, M. E., et al. (2001). Glucocorticoid feedback sensitivity and adrenocortical responsiveness in posttraumatic stress disorder. Biologic Psychiatry, 50, 238-245.
34.
Karishma, K. K., & Herbert, J. (2002). Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosterone-induced suppression. European Journal of Neuroscience, 16, 445-453.
35.
Kawamura, N., Kim, Y., & Asukai, N. (2001). Suppression of cellular immunity in men with a past history of posttraumatic stress disorder. American Journal of Psychiatry, 158, 484-486.
36.
Kessler, R. C., Sonnega, A., Bromet, E., Hughes, M., & Nelson, C. B. (1995). Posttraumatic stress disorder in the National Comorbidity Survey. Archives of General Psychiatry, 52, 1048-1060.
37.
Kimerling, R. (2004). An investigation of sex differences in nonpsychiatric morbidity associated with posttraumatic stress disorder. Journal of the American Medical Women’s Association, 59, 43-47.
38.
Koenen, K. C., Lyons, M. J., Goldberg, J., Simpson, J., Williams, W. M., Toomey, R., et al. (2003). A high risk twin study of combat-related PTSD comorbidity. Twin Research, 6, 218-226.
39.
Laffaye, C., Kennedy, C., & Stein, M. B. (2003). Post-traumatic stress disorder and health-related quality of life in female victimsof intimate partner violence. Violence Victims, 18, 227-238.
40.
Lang, A. J., Rodgers, C. S., Laffaye, C., Satz, L. E., Dresselhaus, T. R., & Stein, M. B. (2003). Sexual trauma, posttraumatic stress disorder, and health behavior. Behavioral Medicine, 28, 150-158.
41.
Laudenslager, M. L., Aasal, R., Adler, L., Berger, C. L., Montgomery, P. T., Sandberg, E., et al. (1998). Elevated cytotoxicity in combat veterans with long-term post-traumatic stress disorder: Preliminary observations. Brain Behavior and Immunology, 12, 74-79.
42.
Lemieux, A. M., & Coe, C. L. (1995). Abuse-related posttraumatic stress disorder: Evidence for chronic neuroendocrine activation in women. Psychosomatic Medicine, 57, 105-115.
43.
Lindauer, R. J., Vlieger, E. J., Jalink, M., Olff, M., Carlier, I. V., Majoie, C. B., et al. (2004). Smaller hippocampal volume in Dutch police officers with posttraumatic stress disorder. Biologic Psychiatry, 56, 356-363.
44.
Luecken, L. J., Dausch, B., Gulla, V., Hong, R., & Compas, B. E. (2004). Alterations in morning cortisol associated with PTSD in women with breast cancer. Journal of Psychosomatic Research, 56, 13-15.
45.
Maes, M., Lin, A., Bonaccorso, S., van Hunsel, F., Van Gastel, A., Delmeire, L., et al. (1998). Increased 24-hour urinary cortisol excretion in patients with post-traumatic stress disorder and patients with major depression, but not in patients with fibromyalgia. Acta Psychiatry Scandanavia, 98, 328-335.
46.
Maes, M., Lin, A. H., Delmeire, L., Van Gastel, A., Kenis, G., De Jongh, R., et al. (1999). Elevated serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events. Biologic Psychiatry, 45, 833-839.
47.
McElroy, S. L., Kotwal, R., Malhotra, S., Nelson, E. B., Keck, P. E., & Nemeroff, C. B. (2004). Are mood disorders and obesity related? A review for the mental health professional. Journal of Clinical Psychiatry, 65, 634-651.
48.
Miller, R. J., Sutherland, A. G., Hutchison, J. D., & Alexander, D. A. (2001). C-reactive protein and interleukin 6 receptor in post-traumatic stress disorder: A pilot study. Cytokine, 13, 253-255.
49.
Mosnaim, A. D., Wolf, M. E., Maturana, P., Mosnaim, G., Puente, J., Kucuk, O., et al. (1993). In vitro studies of natural killer cell activity in post traumatic stress disorder patients. Response to methionine-enkephalin challenge. Immunopharmacology, 25, 107-116.
50.
Nesto, R. (2004). C-reactive protein, its role in inflammation, type 2 diabetes and cardiovascular disease, and the effects of insulin-sensitizing treatment with thiazolidinediones. Diabetes Medicine, 21, 810-817.
51.
Newport, D. J., Heim, C., Bonsall, R., Miller, A. H., & Nemeroff, C. B. (2004). Pituitary-adrenal responses to standard and low-dose dexamethasone suppression tests in adult survivors of child abuse. Biological Psychiatry, 55, 10-20.
52.
Neylan, T. C., Schuff, N., Lenoci, M., Yehuda, R., Weiner, M. W., & Marmar, C. R. (2003). Cortisol levels are positively correlated with hippocampal N-acetylaspartate. Biological Psychiatry, 54, 1118-1121.
53.
Oquendo, M. A., Echavarria, G., Galfalvy, H. C., Grunebaum, M. F., Burke, A., Barrera, A., et al. (2003). Lower cortisol levels in depressed patients with comorbid post-traumatic stress disorder. Neuropsychopharmacology, 28, 591-598.
54.
Pederson, C. L., Maurer, S. H., Kaminski, P. L., Zander, K. A., Peters, C. M., Stokes-Crowe, L. A., et al. (2004). Hippocampal volume and memory performance in a community-based sample of women with posttraumatic stress disorder secondary to child abuse. Journal of Traumatic Stress, 17, 37-40.
55.
Petrovsky, N. (2001). Towards a unified model of neuroendocrine-immune interaction. Immunology and Cell Biology, 79, 350-357.
56.
Pico-Alfonso, M. A., Garcia-Linares, M. I., Celda-Navarro, N., Herbert, J., & Martinez, M. (2004). Changes in cortisol and dehydroepiandrosterone in women victims of physical and psychological intimate partner violence. Biological Psychiatry, 56, 233-240.
57.
Plotsky, P. M., Owens, M. J., & Nemeroff, C. B. (1998). Psycho-neuroendocrinology of depression. Hypothalamic-pituitary-adrenal axis. Psychiatric Clinicsof North America, 21, 293-307.
58.
Rasmusson, A. M., Lipschitz, D. S., Wang, S., Hu, S., Vojvoda, D., Bremner, J. D., et al. (2001). Increased pituitary and adrenal reactivity in premenopausal women with posttraumatic stress disorder. Biological Psychiatry, 50, 965-977.
59.
Rasmusson, A.M., Vasek, J., Lipschitz, D.S., Vojvoda, D., Mustone, M. E., Shi, Q., et al. (2004). An increased capacity for adrenal DHEA release is associated with decreased avoidance and negative mood symptoms in women with PTSD. Neuropsychopharmacology, 29, 1546-1557.
60.
Resnick, H. S., Yehuda, R., Pitman, R. K., & Foy, D. W. (1995). Effect of previous trauma on acute plasma cortisol level following rape. American Journal of Psychiatry, 152, 1675-1677.
61.
Rohleder, N., Joksimovic, L., Wolf, J. M., & Kirschbaum, C. (2004). Hypocortisolism and increased glucocorticoid sensitivity of pro-inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder. Biological Psychiatry, 55, 745-751.
62.
Rohleder, N., Schommer, N. C., Hellhammer, D. H., Engel, R., & Kirschbaum, C. (2001). Sex differences in glucocorticoid sensitivity of proinflammatory cytokine production after psychosocial stress. Psychosomatic Medicine, 63, 966-972.
63.
Schnurr, P. P., & Green, B. L. (2004). Understanding relationships among trauma, post-traumatic stress disorder, and health outcomes. Advanced Mind and Body Medicine, 20, 18-29.
64.
Seedat, S., Stein, M. B., Kennedy, C. M., & Hauger, R. L. (2003). Plasma cortisol and neuropeptide Y in female victims of intimate partner violence. Psychoneuroendocrinology, 28, 796-808.
65.
Shin, L. M., Shin, P. S., Heckers, S., Krangel, T. S., Macklin, M. L., Orr, S. P., et al. (2004). Hippocampal function in posttraumatic stress disorder. Hippocampus, 14, 292-300.
66.
Sondergaard, H. P., Hansson, L. O., & Theorell, T. (2002). Elevated blood levels of dehydroepiandrosterone sulphate vary with symptom load in posttraumatic stress disorder: Findings from a longitudinal study of refugees in Sweden. Psychotherapy and Psychosomatics, 71, 298-303.
67.
Sondergaard, H. P., Hansson, L. O., & Theorell, T. (2004). The inflammatory markers C-reactive protein and serum amyloid A in refugees with and without posttraumatic stress disorder. Clinics of Chim Acta, 342, 93-98.
68.
Sondergaard, H. P., & Theorell, T. (2003). A longitudinal study of hormonal reactions accompanying life events in recently reset-tled refugees. Psychotherapy and Psychosomatics, 72, 49-58.
69.
Spivak, B., Shohat, B., Mester, R., Avraham, S., Gil-Ad, I., Bleich, A., et al. (1997). Elevated levels of serum interleukin-1 beta in combat-related posttraumatic stress disorder. Biological Psychiatry, 42, 345-348.
70.
Stein, M., & Kennedy, C. (2001). Major depressive and post-traumatic stress disorder comorbidity in female victims of intimate partner violence. Journal of Affective Disorders, 66, 133-138.
71.
Stein, M. B., Walker, J. R., Hazen, A. L., & Forde, D. R. (1997). Full and partial posttraumatic stress disorder: Findings from a community survey. American Journal of Psychiatry, 154, 1114-1119.
72.
Stein, M. B., Yehuda, R., Koverola, C., & Hanna, C. (1997). Enhanced dexamethasone suppression of plasma cortisol in adult women traumatized by childhood sexual abuse. Biological Psychiatry, 42, 680-686.
73.
Surtees, P., Wainwright, N., Day, N., Brayne, C., Luben, R., & Khaw, K. T. (2003). Adverse experience in childhood as a developmental risk factor for altered immune status in adulthood. International Journal of Behavioral Medicine, 10, 251-268.
74.
Tucker, P., Beebe, K. L., Burgin, C., Wyatt, D. B., Parker, D. E., Masters, B. K., et al. (2004). Paroxetine treatment of depression with posttraumatic stress disorder: Effects on autonomic reactivity and cortisol secretion. Journal of Clinical Psychopharmacology, 24, 131-140.
75.
Vanitallie, T. B. (2002). Stress: A risk factor for serious illness. Metabolism, 51, 40-45.
76.
Walker, B. R., Soderberg, S., Lindahl, B., & Olsson, T. (2000). Independent effects of obesity and cortisol in predicting cardiovascular risk factors in men and women. Journal of International Medicine, 247, 198-204.
77.
Walker, E. A., Katon, W., Russo, J., Ciechanowski, P., Newman, E., & Wagner, A. W. (2003). Health care costs associated with posttraumatic stress disorder symptoms in women. Archives of General Psychiatry, 60, 369-374.
78.
Watson, I. P., Muller, H. K., Jones, I. H., & Bradley, A. J. (1993). Cell-mediated immunity in combat veterans with post-traumatic stress disorder. Medical Journal of Australia, 159, 513-516.
79.
Weisberg, R. B., Bruce, S. E., Machan, J. T., Kessler, R. C., Culpepper, L., & Keller, M. B. (2002). Nonpsychiatric illness among primary care patients with trauma histories and posttraumatic stressdisorder. Psychiatric Services, 53, 848-854.
80.
Wilson, S. N., van der Kolk, B., Burbridge, J., Fisler, R., & Kradin, R. (1999). Phenotype of blood lymphocytes in PTSD suggests chronic immune activation. Psychosomatics, 40, 222-225.
81.
Yehuda, R. (2001). Biology of posttraumatic stress disorder. Journal of Clinical Psychiatry, 62, 41-46.
82.
Yehuda, R. (2002). Current status of cortisol findings in post-traumatic stress disorder. Psychiatric Clinics of North America, 25, 341-368.
83.
Yehuda, R., Boisoneau, D., Lowy, M. T., & Giller, E. L. Jr. (1995). Dose-response changes in plasma cortisol and lymphocyte glucocorticoid receptors following dexamethasone administration in combat veterans with and without posttraumatic stress disorder. Archives of General Psychiatry, 52, 583-593.
84.
Yehuda, R., Golier, J., Yang, R., & Tischler, L. (2004). Enhanced sensitivity to glucocorticoids in peripheral mononuclear leukocytes in posttraumatic stress disorder. Biologic Psychiatry, 55, 1110-1116.
85.
Yehuda, R., Halligan, S. L., Grossman, R., Golier, J. A., & Wong, C. (2002). The cortisol and glucocorticoid receptor response to low dose dexamethasone administration in aging combat veterans and holocaust survivors with and without posttraumatic stress disorder. Biologic Psychiatry, 52, 393-403.
86.
Yehuda, R., Teicher, M. H., Trestman, R. L., Levengood, R. A., & Siever, L. J. (1996). Cortisol regulation in posttraumatic stress disorder and major depression: A chronobiological analysis. Biologic Psychiatry, 40, 79-88.
87.
Young, E. A., & Breslau, N. (2004). Cortisol and catecholamines in posttraumatic stress disorder: An epidemiologic community study. Archives of General Psychiatry, 61, 394-401.
88.
Young, E. A., Tolman, R., Witkowski, K., & Kaplan, G. (2004). Salivary cortisol and posttraumatic stress disorder in a low-income community sample of women. Biologic Psychiatry, 55, 621-626.
89.
Zlotnick, C., Bruce, S. E., Weisberg, R. B., Shea, M. T., Machan, J. T., & Keller, M. B. (2003). Social and health functioning in female primary care patients with post-traumatic stress disorder with and without comorbid substance abuse. Comprehensive Psychiatry, 44, 177-183.
