Introduction

A number of epidemiologic survey studies have shown that posttraumatic stress disorder (PTSD) is twice as common in women as in men; in addition, there are gender differences in the type of trauma exposure, presentation of illness, and comorbidities. Some of these differences are clearly societal and nonbiologically based, but it is also clear that the biologic systems altered in PTSD may modulate or be modulated by sex hormones. Rachael Yehuda, PhD,^[1] of the Einstein Medical Center, Bronx, NY, discussed the neuroanatomic, neuroendocrine, and immune-related bases for various gender differences seen in PTSD during this year's Annual Meeting of the American Psychiatric Association.

Neuroendocrine and Neuroanatomic Differences

PTSD is characterized by a number of alterations in stress-related neurotransmitter, neurohormonal, and immune system function. In the biologic model of PTSD, trauma exposure is followed by an unsuccessful neuroendocrine response to trauma. This unsuccessful response is marked by a failure in memory consolidation and symptom restitution. In the normal stress response, a burst of sympathetic nervous system activity constitutes the immediate response. Activation of the hypothalamic/adrenal/pituitary (HPA) axis occurs shortly thereafter. Cortisol is the final mediator of the HPA response, and there is an elevation of cortisol in the normal stress response. In fact, it has been demonstrated that more severe stressors are associated with higher cortisol responses in a "dose-dependent" manner.

In individuals with PTSD, the HPA axis response is dysregulated. Individuals with PTSD have low circulating levels of cortisol. In one study of motor vehicle accident victims, low cortisol levels immediately after the accident were associated with the development of PTSD and high cortisol levels were associated with the development of depression.^[2] Studies using the dexamethasone suppression test have demonstrated that this decrease in cortisol in individuals with PTSD is a result of enhanced sensitivity of the glucocorticoid receptors to negative feedback from circulating cortisol at the level of pituitary. Using labeled hydrocortisone injections to measure glucocorticoid receptors by positron emission tomography (PET) scan, Yehuda and colleagues^[3] have recently demonstrated an enhanced sensitivity of the glucocorticoid receptors at the hippocampal level in individuals with PTSD as well.

Are these HPA axis parameters affected by the gonadal hormones in individuals with PTSD? A number of animal studies have demonstrated a greater acute response of the HPA axis to stress in females vs that in males.^[4] It appears that this increase may be estrogen mediated because ovariectomized females have a stress response which is similar in magnitude to the response of males. There are also changes in the stress response during different phases of the menstrual cycle. The HPA axis stress response during the follicular phase of the cycle is less robust compared with the stress response during the luteal phase. As such, it is important to control for menstrual cycle and menopausal status when studying any gender-specific issues regarding biologic response in PTSD and other disorders.

Dr. Yehuda performed a retrospective analysis of studies concerning biologic changes associated with PTSD. The data indicated that women had lower baseline cortisol levels than men, but PTSD status was not gender related. In other words, women with and without PTSD had lower cortisol as compared to men with and without PTSD. There were some gender differences in the response to the dexamethasone suppression test. There was greater suppression in women than in men, indicating greater dysregulation of the glucocorticoid receptors. In reviewing a number of studies of immune function measures, Dr. Yehuda found no PTSD-specific gender-related differences in cytokine levels.

A number of studies have demonstrated decreases in hippocampal volume in individuals with PTSD. Studies that examined gender differences associated with this finding have demonstrated fairly consistently that hippocampal volume is more decreased in men than in women. In addition, women with PTSD have less memory loss and impairment in cognitive function than their male counterparts.

Dr. Yehuda concluded that there are some PTSD-specific gender differences in the biologic abnormalities seen in individuals with PTSD, but, in general, there are many more similarities than differences. Although there are gender differences in the stress response, many of these differences aren't exaggerated or changed in individuals with PTSD.

Drug Therapy in Women with PTSD

Kathleen Brady, MD, PhD^[5] of the Medical University of South Carolina, Charleston, discussed the prevalence of and drug therapy for PTSD in women.

Risks for Developing PTSD Among Men and Women

There are a number of reasons why PTSD may be more common in women than in men. Different types of traumas carry different risks for the development of PTSD. Rape, in both men and women, carries one of the highest risks for producing PTSD. Approximately 0.7% of men in the United States reported being raped as compared with 9.2% of women.^[6] In 1996, over 300,000 women in the United States were victims of rape or attempted rape. Other forms of sexual abuse and interpersonal violence are also more commonly associated with PTSD when compared to accidents or natural disasters. Rape is far more common in women than in men. A history of depression or anxiety disorder at the time of trauma is also a risk factor for the development of PTSD. A number of epidemiologic surveys have demonstrated that women with PTSD are twice as likely to have depression and anxiety disorders compared with men with PTSD.^[7] As such, much of the increased prevalence of PTSD in women may be mediated by trauma type and comorbidity rather than specific biologic differences per se.

Gender Differences in the Presentation of PTSD

There are also differences between men and women in the presentation of PTSD. Women are more likely to have symptoms of numbing and avoidance and men are more likely to have the associated features of irritability and impulsiveness. Men are more likely to have comorbid substance use disorders and women are more likely to have comorbid mood and anxiety disorders, although many disorders comorbid with PTSD are commonly seen in both men and women.

Gender Differences in Pharmacotherapy

A number of studies have demonstrated the efficacy of the selective serotonin reuptake inhibitors (SSRIs) in the treatment of PTSD. Specifically, there have been 2 large placebo-controlled double-blind studies published demonstrating the efficacy of sertraline in the treatment of PTSD.^[8,9] There is also a double-blind placebo-controlled trial demonstrating the efficacy of 2 doses of paroxetine (20 and 40 mg) in the treatment of PTSD, but this has not yet been published. In a subanalysis of data from the sertraline trial by Brady and colleagues,^[8] it was demonstrated that the efficacy of the drug was more robust in decreasing symptoms of PTSD in women than in men. Similarly, in a recently published gender-specific analysis of data from a large comparison trial of sertraline and imipramine for the treatment of chronic depression^[10] sertraline was significantly more effective than imipramine in premenopausal women; no differences were found in postmenopausal women or in men. Also of interest was a gender difference in drop out rates. Women in the imipramine group were significantly more likely to drop out than women in the sertraline group. Men in the sertraline group were significantly more likely to drop out than men in the imipramine group. It is not clear what the mediator of these gender differences in treatment response is, but estrogen has been demonstrated to enhance serotonergic neurotransmission by increasing synthesis and receptor sensitivity and decreasing metabolism. One study showed that in postmenopausal women with major depression who had a poor response to SSRI treatment, addition of estrogen replacement therapy improved treatment response in most patients.^[11] As such, there may be an estrogen/serotonin connection that is important in determining SSRI response in women.

Psychotherapeutic treatments, particularly cognitive-behavioral therapies, are efficacious in the treatment of PTSD. There are no current studies investigating gender differences in response to psychotherapy. This is likely to be a fruitful area of investigation.

Summary

There are gender differences in the prevalence, comorbidity, presentation, and treatment response in PTSD. Further exploration of these differences and the psychosocial and neurobiologic underpinnings of these differences will be important in improving treatment outcomes for both men and women with PTSD.

References

1. Yehuda R. Immune neuroanatomic neuroendocrine gender differences in PTSD. Program and abstracts of the 154th Annual Meeting of the American Psychiatric Association; May 5-10, 2001; New Orleans, Louisiana. Symposium 12A.
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