Clinical Implications for Gender Differences in Stress Responses

Hans Selye’s work in the 1940s also introduced the concept that stress accelerates the onset of disease through pathophysiological changes in endocrine and autonomic regulatory systems. Stress alone does not cause disease, but it is hypothesized to increase an individual’s susceptibility to disease.

In the past quarter century, this concept has been supported by results from numerous clinical and epidemiological studies related to cardiovascular disease, affective disorders, gastrointestinal disorders, diabetes, and physiological disorders associated with normal aging.

The mechanisms linking stress to disease states in humans are not fully understood, but hormonal changes, induced by the stress response, are recognized as a major influence. Glucocorticoids have a primary role but one that is modulated by gonadal steroid hormones. Androgen receptors, ERs, and GRs are found in many tissues that are stress-responsive. Some of these include the heart muscle, blood vessels, and immune tissues such as the spleen, thymus, and bone marrow.

Gonadal steroid hormone receptors are also found in brain regions that mediate emotional and autonomic responses to stress, such as the hippocampus, hypothalamus, and amygdala. Thus gender differences in stress-related disease susceptibility appear to involve an interaction between glucocorticoid and gonadal hormones.

The role of stress in psychological and physiological disorders is complex. Animal studies have demonstrated that adult stress responsiveness is influenced developmentally by both genetics and the early environment. This bidirectional influence of both factors makes it difficult to predict the stress-related susceptibility to disease in individuals. However, physiological gender differences are still evident in humans regardless of early environment.

Many of these differences parallel sex differences in animals. For instance, the unstressed basal heart rate in women is greater than in men. Women also exhibit a larger exercise-induced increase in heart rate. However, in response to anger and psychological stress, men exhibit greater emotional and cardiovascular lability with respect to both heart rate and blood pressure.

This lability, resulting in larger increases in systolic pressure, is thought to contribute significantly to the greater risk in men for cardiovascular morbidity. Protection from heart disease in women is also related to estrogen, which provides protection against arteriosclerosis until menopause. The anti-atherosclerotic effects of estrogen also appear to involve the presence of ERs in cardiovascular tissue.

Physical or psychologically stressful stimuli also produce a greater stimulation of the HPA axis in women than in men, similar to the stress effects observed in other mammals. Administering CRH to women induces a greater release of ACTH and a prolonged elevation of cortisol than administering it to men, indicating that these gender differences probably involve processes directly under the regulation of the central nervous system.

However, unlike animals, gender differences in the human HPA axis responsiveness to psychological stressors appear to be much more dependent on the type of psychological stress and the environmental circumstances in which it occurs. Studies suggest that psychological factors associated with social stress, such as taking care of an elderly parent, have more impact on HPA reactivity in women than in men, perhaps placing women’s health at greater risk under such circumstances.

A primary factor underlying gender differences in the HPA response to stress appears to be higher estrogen levels in women. During the normal menstrual cycle, HPA activity is enhanced during the follicular phase, when estrogen levels peak, and is reduced during the luteal phase, when progesterone levels are elevated.

The removal of the ovaries prior to menopause reduces the HPA sensitivity to CRH stimulation. The effect of estrogen on HPA reactivity is not gender-specific because normal men who were administered a short-term regimen of estrogen also exhibited increased HPA activity. One possible explanation for such effects of estrogen is provided by observations that estrogen therapy increases circulating levels of CBG in women.

Although not yet shown to be the case, such increases in CBG, and the resulting decreases in free cortisol, could play a role in the elevated HPA activity in response to stress reported in women (due to a decrease in cortisol bioavailability). Similarly, it remains to be determined whether men and women are equally sensitive to the influence of estrogen on the HPA and whether organizational influences of gonadal steroids confer a differential sensitivity to the later hormonal modulation of HPA activity.

The incidence of autoimmune disease is also sexually dimorphic, and the severity and onset are exacerbated by life stress. The overall incidence in women is approximately 2.5-fold greater then in men. In contrast to the protective role estrogen plays in cardiovascular disease, it appears to be a major contributory factor to the gender difference observed in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and lupus.

Estrogen can regulate immune responses through ERs present on thymocytes, macrophages, and endothelial cells, all of which also express GRs. The interaction between estrogen and glucocorticoids on immunomodulation is a rapidly expanding area of research interest and one that is likely to underlie the gender difference in autoimmune disease susceptibility.

Numerous clinical studies have reported a greater incidence of depression in women. The reasons underlying this gender difference are controversial, but both hormonal status and stress may be involved. Women have been reported to be more susceptible to depression during periods of fluctuations in estrogen and progesterone levels.

However, although such changes have often been cited as causes of mood disorders in women, the literature does not provide strong support for a direct causal relationship between gonadal hormone status and depression or anxiety disorders. An additional mediating factor may be life stress.

The onset of clinical depression is well known to be exacerbated by life stress, and data suggest that a link to a gender bias in mood disorders involves an increased susceptibility in some women to the combined effects of stress and hormonal status. Thus, fluctuations in estrogen and progesterone during the menstrual cycle have been proposed to confer a susceptibility to depression in women that can be exacerbated by life stress.

A gender difference is also observed in the incidence of posttraumatic stress disorder (PTSD), which is a stress-induced pathological condition that is clinically distinct from depression or other affective disorders. Long-term physiological changes are observed in PTSD patients that involve increased adrenergic tone and alterations in HPA function.

Following exposure to prolonged psychological trauma, women exhibit PTSD symptoms twice as frequently as men, even when the type of trauma is equivalent. The organizational effects of hormones may also play a role in gender differences in the incidence of PTSD.

This stems from findings showing that experiencing psychologically traumatizing events prior to puberty greatly increases the susceptibility to PTSD in adulthood in females compared to males. This increased susceptibility appears to relate specifically to experiencing childhood psychological trauma because accidents or injury during this period do not increase the risk for PTSD in either gender when later psychological trauma is experienced.

In summary, current research studying the interrelationships among gender, stress, and pathophysiology strongly implicate a role for gonadal hormones in predicting gender differences related to disease or psychopathology.

However, a definitive understanding of the role of gender in the elicitation of stress-induced pathophysiology awaits a better understanding of the complex relationship among the environment, steroid hormones, and other stress-induced biochemical factors.