Elsevier

Psychoneuroendocrinology

Volume 31, Issue 2, February 2006, Pages 151-178
Psychoneuroendocrinology

Review
The effects of sex and hormonal status on the physiological response to acute psychosocial stress

https://doi.org/10.1016/j.psyneuen.2005.07.002Get rights and content

Summary

Whether one is male or female is one of the most important determinants of human health. While males are more susceptible to cardiovascular and infectious disease, they are outnumbered by women for many autoimmune disorders, fibromyalgia and chronic pain. Recently, individual differences in the physiological response to stress have emerged as a potentially important risk factor for these disorders. This raises the possibility that sex differences in prevalence of disease could at least in part be explained by sex differences in the nature of the physiological response to stress.

In a psychophysiological laboratory, the autonomic nervous system response can be provoked by many different stressors including physical, mental and psychosocial tasks, while the hypothalamic–pituitary–adrenal axis (HPAA) response seems to be more specific to a psychosocial challenge incorporating ego involvement. The responses of both systems to different psychosocial challenges have been subject to extensive research, although in respect of sex differences the HPAA response has probably been more systematically studied. In this review, we focus on sex differences in HPAA and autonomic nervous system responses to acute psychosocial stress. Although some differences are dependent on the stressor used, the responses of both systems show marked and consistent differences according to sex, with the phase of the menstrual cycle, menopausal status and pregnancy having marked effects. Between puberty and menopause, adult women usually show lower HPAA and autonomic responses than men of same age. However, the HPAA response is higher in the luteal phase, when for example poststress free cortisol levels approach those of men. After menopause, there is an increase in sympathoadrenal responsiveness, which is attenuated during oral hormone replacement therapy, with most evidence suggesting that HPAA activity shows the same trends. Interestingly, pregnancy is associated with an attenuated response of the sympathoadrenal and HPAA systems at least as assessed by biochemical stimulation.

It is likely that these sex differences in autonomic function are a result of estrogen exposure which attenuates sympathoadrenal responsiveness. The HPAA is however somewhat more complex and evidence now suggests the influence of other modifiers such as arginine vasopressin (AVP) and the regulation of circulating cortisol bioavailability by corticosteroid-binding globulin (CBG).

The pronounced and multi-faceted sex differences in stress responsiveness suggest that they are a product of a strong evolutionary pressure. We hypothesise that this has to a great deal been driven by the need to protect the fetus from the adverse effects of maternal stress responses, in particular excess glucocorticoid exposure. Studying this hypothesis may have a fundamental impact on our understanding about how adult health is set during early life and how adult disease could be prevented in men and women.

Introduction

Being male or female is one of the most important predictors of an individual's health. Compared with women of similar age, men have a higher risk of arteriosclerosis (Kalin and Zumoff, 1990) and infectious disease (Klein, 2000), while women outnumber men for several autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis (Beeson, 1994, Whitcare et al., 1999), as well as many stress-related bodily complaints such as fibromyalgia (Wolfe et al., 1995) and chronic pain (Verhaak et al., 1998). Knowing what biological mechanisms underlie such profound differences may be extremely helpful in elucidating the pathogenesis of various common disorders, a step crucial in developing their prevention and treatment. However, despite recent progress, the mechanisms behind these sex differences remain insufficiently understood.

Individuals react to stressful events in different ways, and differences in the physiological stress response are important determinants of health. A stressful stimulus results in the activation of several physiological pathways including the hypothalamic–pituitary–adrenal axis (HPAA) and the autonomic nervous system. A considerable body of research during recent years has linked the function of both of these systems with the pathogenesis of several common disorders including coronary heart disease, type 2 diabetes, the metabolic syndrome, depression and stress-related bodily complaints (Stoney et al., 1990, Schobel et al., 1996, Phillips et al., 1998, Phillips et al., 2000, Heim et al., 2000, Yang et al., 2000, Kajantie et al., 2002, Kajantie et al., 2003a, Tsigos and Chrousos, 2002, Treiber et al., 2003, Kreier et al., 2003, Schwartz et al., 2003, Brown et al., 2004). Importantly, both systems show a clear sex-specific pattern of response. Therefore, stress reactivity is a major candidate for a mechanism explaining why some diseases are more common in males and others in females.

Some recent reviews have been published related to sex-differences in stress responsiveness. Based on their long-term programmatic work in the field, Kudielka and Kirschbaum (2005) review sex differences in HPAA responsiveness providing in particular a thorough discussion on methodological issues. Otte et al. (2005) have performed a meta-analysis of studies on the effect of age and sex on HPAA response to physiological, pharmacological or psychosocial challenge. In contrast, the objective of our review is to provide a systematic and comprehensive description of human studies assessing how sex and hormonal status affect HPAA and autonomic nervous system responsiveness to acute psychological stressors. This has led the development of the hypothesis that the origin of these sex differences arises from the need to protect the developing fetus from excessive exposure to stress hormones in utero. To elucidate potential mechanisms of these relationships, we refer to selected human studies using other stimulators of these systems as well as a number of elegant animal models important in understanding the overall framework; however, a comprehensive evaluation of these studies remains outside the scope of this review.

Section snippets

Measuring the stress response

The assessment of stress responsiveness requires a reproducible stressor that is severe enough to produce a detectable response but moderate enough to reveal differences between individuals. This prerequisite is easier to fulfil in a laboratory setting rather than in normal living conditions. However, to be meaningful a laboratory stressor should bear some resemblance to stressful events in everyday life. Two types of stressors are commonly used: psychosocial tasks such as public speaking,

Sex differences in stress responsiveness

In a 1987 meta-analysis of 12 psychophysiological studies examining the relationship between sex and stress responsiveness, Stoney et al. concluded that there was only limited support for sex differences in response (Stoney et al., 1987). Whereas women had lower systolic blood pressure responses, the urinary catecholamine data were equivocal and the glucocorticoid responses did not differ. One of the major criticisms of these early studies was that the psychological stressors employed, while

HPAA

The use of psychological stress stimuli such as public speaking tasks are probably the best approximations to real-life stressors. Studies using these methods have consistently shown pronounced sex differences in the physiological stress response. However, it is of note that these stressors stimulate the HPAA at the central level and do not necessarily distinguish between different levels of the axis. Such data are however obtainable from studies using specific biochemical tests of the HPAA.

Evolutionary benefit—a hypothesis

Despite the recent advances in the understanding of mechanisms behind these profound sex differences, their ultimate cause remains poorly understood. In human biology, explanations for complex phenomena are often provided by teleological considerations—consideration of the evolutionary advantage of developing sex differences in behavioural and metabolic responses during stressful situations. Many such evolutionary pressures, such as those related to mating behaviour, are likely to have been

Acknowledgements

The work has been supported by the Academy of Finland, British Heart Foundation, Finnish Medical Society Duodecim, Jalmari and Rauha Ahokas Foundation, Novo Nordisk Foundation, Signe and Ane Gyllenberg Foundation, The Royal Society and Yrjö Jahnsson Foundation.

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