**2. What is stress and what are the physiological responses to stress?**

For a term used frequently in everyday language, stress has proven surprisingly difficult to define. Stress is a term that can appear diffuse, lacking in rigor and certainty of meaning. Nevertheless, most published definitions of stress are concerned with challenges to, or disruptions of, homeostasis. Indeed, our own working definition of stress is "a complex physiological state that embodies a range of integrative physiological and behavioral processes that occur when there is a real or perceived threat to homeostasis" [1, 2]. Certainly, the importance of the maintenance of homeostasis has long been recognized. For example, the ancient Greek philosopher Empedocles (500-430 BC) acknowledged the

Sex Differences and the Role of Sex Steroids in Sympatho-Adrenal

Medullary System and Hypothalamo-Pituitary Adrenal Axis Responses to Stress 117

Fig. 1. Schematic diagram of the sympatho-adrenal medullary system, hypothalamo-pituitary adrenal axis and some opioidergic pathways. The sympatho-adrenal medullary system consists of the sympathetic nervous system and adrenal medulla. Pre-ganglionic neurons

concept of a steady or harmonious state [3] and, in the 19th century, the work of French physiologist Claude Bernard (1813-1878) laid the groundwork for appreciating the importance of adaptive internal mechanisms to challenges [3]. Bernard developed the concept that organisms maintain a stable internal environment (*milieu intérieur*). This concept and understanding was substantially extended by the groundbreaking research of American physiologist Walter Cannon (1871-1945) [3]. It was Cannon who devised the term "homeostasis" and who noted that animals and humans in dangerous situations showed adaptive responses in which they may choose to fight or to escape, termed the "fight or flight" syndrome [4]. Clearly, this requires rapid responses of the body and the physiological system primarily responsible for these adaptive responses is the sympathoadrenal medullary system. The work of Cannon inspired another researcher, Hans Selye (1907 Vienna-1982, Montreal), whose seminal work during the 1930's at McGill University in Montreal, Canada, led to the development of a theory to describe the concept of stress. He developed the "General Adaptation Syndrome", defined as "the sum of all non-specific, systemic reactions of the body which ensue upon long continued exposure to stress" [5]. He depicted three stages in this response: 1) the alarm reaction, which involved activation of the hypothalamo-pituitary adrenal axis, 2) the period of resistance, where the organism "coped" with the challenge and 3) the stage of exhaustion, where the organism's ability to resist or adapt to the challenge declined [5]. A premise of this theory is that organisms have a generalized and non-specific response to all noxious stimuli [5]. While it is now recognized that there may be different types of physiological responses to different stressful environments [1], Selye unquestionably founded the field of stress physiology and provided the framework to define and understand stress. His work continues to stimulate debate and research. Importantly, his work demonstrated the paramount role of the hypothalamopituitary adrenal axis in adaption to stressful situations [5].

It follows from the work of Cannon and Selye that the two most common physiological responses to stress are activation of the sympatho-adrenal medullary system and the hypothalamo-pituitary adrenal axis (Figure 1). The former is activated immediately upon threat or detection of a noxious stimulus and the response is transient, whereas the latter is activated less rapidly and the response is more prolonged. It is common practice to define threats and noxious stimuli that cause stress responses as stressors [1, 2]. While the sympatho-adrenal medullary system and hypothalamo-pituitary adrenal axis are considered the primary means of dealing with stressors, there are other responses, mostly of a neural and neuroendocrine nature, such as the opioidergic system [2], which contribute to an integrated stress response.

The sympatho-adrenal medullary system consists of the sympathetic nervous system and the adrenal medulla (Figure 1). The catecholamines epinephrine and norepinephrine induce the actions of the sympatho-adrenal medullary system which are primarily to stimulate rapid and vigorous neural, behavioral and muscular activity, to stimulate the cardiovascular system to increase cardiac output and redistribute blood flow to the pulmonary blood system and appropriate organs to deal with the stressor [6]. The catecholamines bind to adrenergic receptors, of which there are different subtypes, termed α and β, and this allows for divergent effects in target tissues [6]. The sympathetic component, or "arm", of the sympatho-adrenal medullary system, comprises pre-ganglionic neurons that project from the spinal cord to the various ganglia in the body where they synapse with post-ganglionic neurons that project to, and innervate, target tissues. Acetylcholine from the pre-ganglionic neurons stimulates the post-ganglionic neurons which release norepinephrine into the target tissue. In the adrenal arm of the sympatho-adrenal medullary system, pre-ganglionic

concept of a steady or harmonious state [3] and, in the 19th century, the work of French physiologist Claude Bernard (1813-1878) laid the groundwork for appreciating the importance of adaptive internal mechanisms to challenges [3]. Bernard developed the concept that organisms maintain a stable internal environment (*milieu intérieur*). This concept and understanding was substantially extended by the groundbreaking research of American physiologist Walter Cannon (1871-1945) [3]. It was Cannon who devised the term "homeostasis" and who noted that animals and humans in dangerous situations showed adaptive responses in which they may choose to fight or to escape, termed the "fight or flight" syndrome [4]. Clearly, this requires rapid responses of the body and the physiological system primarily responsible for these adaptive responses is the sympathoadrenal medullary system. The work of Cannon inspired another researcher, Hans Selye (1907 Vienna-1982, Montreal), whose seminal work during the 1930's at McGill University in Montreal, Canada, led to the development of a theory to describe the concept of stress. He developed the "General Adaptation Syndrome", defined as "the sum of all non-specific, systemic reactions of the body which ensue upon long continued exposure to stress" [5]. He depicted three stages in this response: 1) the alarm reaction, which involved activation of the hypothalamo-pituitary adrenal axis, 2) the period of resistance, where the organism "coped" with the challenge and 3) the stage of exhaustion, where the organism's ability to resist or adapt to the challenge declined [5]. A premise of this theory is that organisms have a generalized and non-specific response to all noxious stimuli [5]. While it is now recognized that there may be different types of physiological responses to different stressful environments [1], Selye unquestionably founded the field of stress physiology and provided the framework to define and understand stress. His work continues to stimulate debate and research. Importantly, his work demonstrated the paramount role of the hypothalamo-

It follows from the work of Cannon and Selye that the two most common physiological responses to stress are activation of the sympatho-adrenal medullary system and the hypothalamo-pituitary adrenal axis (Figure 1). The former is activated immediately upon threat or detection of a noxious stimulus and the response is transient, whereas the latter is activated less rapidly and the response is more prolonged. It is common practice to define threats and noxious stimuli that cause stress responses as stressors [1, 2]. While the sympatho-adrenal medullary system and hypothalamo-pituitary adrenal axis are considered the primary means of dealing with stressors, there are other responses, mostly of a neural and neuroendocrine nature, such as the opioidergic system [2], which contribute to

The sympatho-adrenal medullary system consists of the sympathetic nervous system and the adrenal medulla (Figure 1). The catecholamines epinephrine and norepinephrine induce the actions of the sympatho-adrenal medullary system which are primarily to stimulate rapid and vigorous neural, behavioral and muscular activity, to stimulate the cardiovascular system to increase cardiac output and redistribute blood flow to the pulmonary blood system and appropriate organs to deal with the stressor [6]. The catecholamines bind to adrenergic receptors, of which there are different subtypes, termed α and β, and this allows for divergent effects in target tissues [6]. The sympathetic component, or "arm", of the sympatho-adrenal medullary system, comprises pre-ganglionic neurons that project from the spinal cord to the various ganglia in the body where they synapse with post-ganglionic neurons that project to, and innervate, target tissues. Acetylcholine from the pre-ganglionic neurons stimulates the post-ganglionic neurons which release norepinephrine into the target tissue. In the adrenal arm of the sympatho-adrenal medullary system, pre-ganglionic

pituitary adrenal axis in adaption to stressful situations [5].

an integrated stress response.

Fig. 1. Schematic diagram of the sympatho-adrenal medullary system, hypothalamo-pituitary adrenal axis and some opioidergic pathways. The sympatho-adrenal medullary system consists of the sympathetic nervous system and adrenal medulla. Pre-ganglionic neurons

Sex Differences and the Role of Sex Steroids in Sympatho-Adrenal

with the objective of re-establishing homeostasis [17-24].

to stress responses are unknown [1].

Medullary System and Hypothalamo-Pituitary Adrenal Axis Responses to Stress 119

evident as widespread effects to mobilize energy stores throughout the body [17-24]. Furthermore, these hormones have far reaching effects on most tissues, organs and systems

The hypothalamo-pituitary adrenal axis is regulated by various neural inputs and negative feedback by the glucocorticoids. There are extensive neuronal pathways within the central nervous system that are activated during stress and there are multiple interactions between these systems (for review see [1]). For example, there are reciprocal connections between noradrenergic neurons located in the brain stem (A1, A2 and A6 noradrenergic cell groups) and CRH and AVP neurons in the paraventricular nuclei of the hypothalamus that are important in mounting a stress response [1]. There are also reciprocal interactions between CRH and AVP neurons and cells in the arcuate nucleus, particularly those expressing peptides derived from POMC, including β-endorphin [1]. It has been shown in rats that serotonergic neurons project from the raphe nucleus of the midbrain to the hypothalamus, and there are interactions between serotoninergic cells, the hypothalamo-pituitary adrenal axis and the sympathetic nervous system [1]. There are also neurons that produce the opioid peptide enkephalin in the paraventricular nucleus but the significance of these with respect

The negative feedback effects of glucocorticoids on the brain are mediated via high affinity mineralocorticoid receptors (MR) and low affinity glucocorticoid receptors (GR). MR are present in the hippocampus and other regions of the limbic system, including the amygdala and lateral septum, and in the hypothalamus [1, 2]. Glucocorticoids act via MR to maintain the basal activity of the hypothalamo-pituitary adrenal axis [25, 26]. The distribution of GR within the brain is much more widespread than for MR and they are found extensively within the hypothalamus and also the anterior pituitary gland [27]. GR are involved in the negative feedback actions of both basal and stress-induced levels of glucocorticoids, particularly the latter and facilitate homeostasis when stress levels of glucocorticoids prevail [25, 26, 28]. The hypothalamo-pituitary adrenal undergoes a circadian rhythm of regulation

While the sympatho-adrenal medullary system and the hypothalamo-pituitary adrenal axis are acknowledged as the front-line physiological systems to deal with stress, the opioids (Figure 1) also have a diverse range of stress-related actions [2]. There are three classes of opioids: β-endorphin, the enkephalins (met-enkephalin and leu-enkephalin) and dynorphin. The opioids act via different receptor subtypes (termed μ, δ and κ) and β-endorphin is the opioid most studied in terms of responses to stress (for review see [2]). As indicated above, β-endorphin is involved in the regulation of the hypothalamo-pituitary adrenal axis and the opioids are generally considered to attenuate and terminate stress responses [2]. Furthermore, these neuropeptides regulate sympathetic, cardiovascular and neural control systems and are involved in the regulation of pain, reinforcement and reward, the release of

Although the opioids clearly play various roles in responses to stress, and in regulating hypothalamo-pituitary adrenal axis responses to stress, it remains the case that most research on stress, particularly with respect to responses to, and impact of, different stressors has been on the sympatho-adrenal medullary system and the hypothalamopituitary adrenal axis. Consequently, we focus on these systems here, while acknowledging the need for a greater understanding of the roles of the opioidergic and other central

systems in stress responses, and in the impact of stress on physiology and behaviour.

and this is evident in the negative feedback actions of the glucocorticoids [17-24].

neurotransmitters and other autonomic and neuroendocrine functions [2].

extend from the spinal cord to ganglia and to the adrenal medulla. When activated the preganglionic neurons release the neurotransmitter acetylcholine (Ach) that stimulates postganglionic neurons to release norepinephrine (NE) directly into target tissue and endocrine cells called chromaffin cells in the adrenal medulla to release epinephrine (E) and NE into the peripheral blood system. The hypothalamo-pituitary adrenal axis is regulated by corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) in the paraventricular nucleus (PVN) of the hypothalamus which are released into the hypophyseal portal blood system and transported to the anterior pituitary. They stimulate the synthesis of pro-opiomelanocortin (POMC) resulting in various products including adrenocorticotropic hormone (ACTH) and the opioid β-endorphin, which are secreted into the peripheral blood system. ACTH acts at the adrenal cortex to stimulate synthesis of the glucocorticoids which are cortisol in humans and non-rodent species (shown here) and corticosterone in rodents and avian species. β-endorphin is also synthesized in the arcuate nucleus (ARC) and the opioid met-enkephalin (Met-enk) in the adrenal medulla in response to stress.

neurons innervate endocrine cells, called chromaffin cells, in the adrenal medulla, stimulating them to synthesize epinephrine and norepinephrine, and to secrete both catecholamines into the systemic circulation. These catecholamines then act as classic hormones, affecting target tissues throughout the body. It is generally considered that more epinephrine than norepinephrine is released from the adrenal medulla into the systemic circulation [7] because norepinephrine is converted to epinephrine [6]. While this may be the case in various species, possibly including humans, in sheep the adrenal medulla secretes substantially more norepinephrine than epinephrine [8].

The hypothalamo-pituitary adrenal axis is often referred to as the "Stress System" and one might imagine that this is a result of the work of Selye that effectively identified the importance of the adrenal glands in coping with stress. This is a classic neuroendocrine axis where the hypothalamus of the brain controls the activity of the adrenal glands via the anterior pituitary gland (Figure 1). The adrenals are located in the visceral cavity superior to the kidneys. Neurons in each paraventricular nucleus of the hypothalamus synthesize the neuropeptides that are released when stressors activate the hypothalamo-pituitary adrenal axis. These are referred to as hypophysiotropic hormones [9] and in the case of the hypothalamo-pituitary adrenal axis are corticotropic releasing hormone (CRH) [10] and, in all species studied except the pig, arginine vasopressin (AVP) [11]. In the pig, lysine substitutes for arginine to form lysine vasopressin [2]. CRH and AVP are secreted from the terminals of neurons directly into the primary capillary bed of a specialized portal blood system that communicates between the hypothalamus and anterior pituitary gland. This is the hypophyseal portal blood system [9]. CRH and AVP are transported by portal vessels to the secondary capillary bed where they exit and act upon corticotropes, the endocrine cells that produce peptides derived from pro-opiomelanocortin (POMC). These include adrenocorticotropic hormone (ACTH), the opioid β-endorphin and α-melanocyte stimulating hormone [12-16]. Of these, ACTH is of major importance when it comes to regulation of the hypothalamo-pituitary adrenal axis. ACTH acts on the cortex of the adrenal glands to stimulate the synthesis of steroids, including the glucocorticoids, which are essential in responding to stress. In many species, including humans, the predominant glucocorticoid released from the adrenal glands is cortisol. In rodents and avian species it is corticosterone [1]. As the name suggests, glucocorticoids have glucoregulatory actions,

neurons innervate endocrine cells, called chromaffin cells, in the adrenal medulla, stimulating them to synthesize epinephrine and norepinephrine, and to secrete both catecholamines into the systemic circulation. These catecholamines then act as classic hormones, affecting target tissues throughout the body. It is generally considered that more epinephrine than norepinephrine is released from the adrenal medulla into the systemic circulation [7] because norepinephrine is converted to epinephrine [6]. While this may be the case in various species, possibly including humans, in sheep the adrenal medulla secretes

The hypothalamo-pituitary adrenal axis is often referred to as the "Stress System" and one might imagine that this is a result of the work of Selye that effectively identified the importance of the adrenal glands in coping with stress. This is a classic neuroendocrine axis where the hypothalamus of the brain controls the activity of the adrenal glands via the anterior pituitary gland (Figure 1). The adrenals are located in the visceral cavity superior to the kidneys. Neurons in each paraventricular nucleus of the hypothalamus synthesize the neuropeptides that are released when stressors activate the hypothalamo-pituitary adrenal axis. These are referred to as hypophysiotropic hormones [9] and in the case of the hypothalamo-pituitary adrenal axis are corticotropic releasing hormone (CRH) [10] and, in all species studied except the pig, arginine vasopressin (AVP) [11]. In the pig, lysine substitutes for arginine to form lysine vasopressin [2]. CRH and AVP are secreted from the terminals of neurons directly into the primary capillary bed of a specialized portal blood system that communicates between the hypothalamus and anterior pituitary gland. This is the hypophyseal portal blood system [9]. CRH and AVP are transported by portal vessels to the secondary capillary bed where they exit and act upon corticotropes, the endocrine cells that produce peptides derived from pro-opiomelanocortin (POMC). These include adrenocorticotropic hormone (ACTH), the opioid β-endorphin and α-melanocyte stimulating hormone [12-16]. Of these, ACTH is of major importance when it comes to regulation of the hypothalamo-pituitary adrenal axis. ACTH acts on the cortex of the adrenal glands to stimulate the synthesis of steroids, including the glucocorticoids, which are essential in responding to stress. In many species, including humans, the predominant glucocorticoid released from the adrenal glands is cortisol. In rodents and avian species it is corticosterone [1]. As the name suggests, glucocorticoids have glucoregulatory actions,

extend from the spinal cord to ganglia and to the adrenal medulla. When activated the preganglionic neurons release the neurotransmitter acetylcholine (Ach) that stimulates postganglionic neurons to release norepinephrine (NE) directly into target tissue and endocrine cells called chromaffin cells in the adrenal medulla to release epinephrine (E) and NE into the peripheral blood system. The hypothalamo-pituitary adrenal axis is regulated by corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) in the paraventricular nucleus (PVN) of the hypothalamus which are released into the hypophyseal portal blood system and transported to the anterior pituitary. They stimulate the synthesis of pro-opiomelanocortin (POMC) resulting in various products including adrenocorticotropic hormone (ACTH) and the opioid β-endorphin, which are secreted into the peripheral blood system. ACTH acts at the adrenal cortex to stimulate synthesis of the glucocorticoids which are cortisol in humans and non-rodent species (shown here) and corticosterone in rodents and avian species. β-endorphin is also synthesized in the arcuate nucleus (ARC) and the opioid met-enkephalin (Met-enk) in

the adrenal medulla in response to stress.

substantially more norepinephrine than epinephrine [8].

evident as widespread effects to mobilize energy stores throughout the body [17-24]. Furthermore, these hormones have far reaching effects on most tissues, organs and systems with the objective of re-establishing homeostasis [17-24].

The hypothalamo-pituitary adrenal axis is regulated by various neural inputs and negative feedback by the glucocorticoids. There are extensive neuronal pathways within the central nervous system that are activated during stress and there are multiple interactions between these systems (for review see [1]). For example, there are reciprocal connections between noradrenergic neurons located in the brain stem (A1, A2 and A6 noradrenergic cell groups) and CRH and AVP neurons in the paraventricular nuclei of the hypothalamus that are important in mounting a stress response [1]. There are also reciprocal interactions between CRH and AVP neurons and cells in the arcuate nucleus, particularly those expressing peptides derived from POMC, including β-endorphin [1]. It has been shown in rats that serotonergic neurons project from the raphe nucleus of the midbrain to the hypothalamus, and there are interactions between serotoninergic cells, the hypothalamo-pituitary adrenal axis and the sympathetic nervous system [1]. There are also neurons that produce the opioid peptide enkephalin in the paraventricular nucleus but the significance of these with respect to stress responses are unknown [1].

The negative feedback effects of glucocorticoids on the brain are mediated via high affinity mineralocorticoid receptors (MR) and low affinity glucocorticoid receptors (GR). MR are present in the hippocampus and other regions of the limbic system, including the amygdala and lateral septum, and in the hypothalamus [1, 2]. Glucocorticoids act via MR to maintain the basal activity of the hypothalamo-pituitary adrenal axis [25, 26]. The distribution of GR within the brain is much more widespread than for MR and they are found extensively within the hypothalamus and also the anterior pituitary gland [27]. GR are involved in the negative feedback actions of both basal and stress-induced levels of glucocorticoids, particularly the latter and facilitate homeostasis when stress levels of glucocorticoids prevail [25, 26, 28]. The hypothalamo-pituitary adrenal undergoes a circadian rhythm of regulation and this is evident in the negative feedback actions of the glucocorticoids [17-24].

While the sympatho-adrenal medullary system and the hypothalamo-pituitary adrenal axis are acknowledged as the front-line physiological systems to deal with stress, the opioids (Figure 1) also have a diverse range of stress-related actions [2]. There are three classes of opioids: β-endorphin, the enkephalins (met-enkephalin and leu-enkephalin) and dynorphin. The opioids act via different receptor subtypes (termed μ, δ and κ) and β-endorphin is the opioid most studied in terms of responses to stress (for review see [2]). As indicated above, β-endorphin is involved in the regulation of the hypothalamo-pituitary adrenal axis and the opioids are generally considered to attenuate and terminate stress responses [2]. Furthermore, these neuropeptides regulate sympathetic, cardiovascular and neural control systems and are involved in the regulation of pain, reinforcement and reward, the release of neurotransmitters and other autonomic and neuroendocrine functions [2].

Although the opioids clearly play various roles in responses to stress, and in regulating hypothalamo-pituitary adrenal axis responses to stress, it remains the case that most research on stress, particularly with respect to responses to, and impact of, different stressors has been on the sympatho-adrenal medullary system and the hypothalamopituitary adrenal axis. Consequently, we focus on these systems here, while acknowledging the need for a greater understanding of the roles of the opioidergic and other central systems in stress responses, and in the impact of stress on physiology and behaviour.

Sex Differences and the Role of Sex Steroids in Sympatho-Adrenal

require some higher cortical processing involving limbic pathways [50].

impact on normal physiological functioning [19, 20, 32].

**5. Sex differences in responses to stress** 

response to stress.

medullary system and the hypothalamo-pituitary adrenal axis.

Medullary System and Hypothalamo-Pituitary Adrenal Axis Responses to Stress 121

are perceived to pose a threat to homeostasis and which result in "anticipatory" glucocorticoid responses to stress. Herman and colleagues [50] asserted that "reactive" glucocorticoid responses to stress are those induced by a genuine challenge to physiological homeostasis that is recognized by sensory pathways. Such challenges may include a change in cardiovascular tone, respiratory distress, pain or circulating cytokines. In such cases, there is a direct neuronal pathway to CRH neurons in the paraventricular nucleus via the brain stem to activate the hypothalamo-pituitary adrenal axis. In contrast, "anticipatory" glucocorticoid responses to stress are not mounted in response to an actual disruption to physiological homeostasis but to the anticipation of such a disruption. These responses

Physiological responses to physical stressors may be considered appropriate since the body is being prepared for a real threat and the elevated heart rate and blood pressure and energy stores mobilised by catecholamines and glucocorticoids (see Section 2) are required to deal with the stressor. For example, a direct physical threat may require vigorous skeletal muscle activity in order to avert detrimental consequences imposed by the stressor. Conversely, physiological responses to psychological stressors are potentially more harmful since the body does not usually need to respond with a physical use of energy, certainly not for a prolonged period. This would be evident where there may be a stressful environment induced without the need for physical exercise, such as being caught in traffic on the way to an important appointment. Heart rate and blood pressure may be elevated, and energy stores mobilized, but with no obvious benefit to dealing with the stressor. An exception would be the possible beneficial effects of increased mental acuity. Nevertheless, it follows that psychological stress may be detrimental to health, particularly if it is prolonged or repeated frequently, because it unnecessarily elevates heart rate and blood pressure and mobilizes energy stores placing unnecessary strain on essential physiological systems. It is important to appreciate that excessive activation of the stress systems can have a negative

Since different types of stressors activate the physiological stress systems via different mechanisms, it is important to consider different types of stressors when considering the roles of sex and the sex steroids in influencing the responsiveness of the sympatho-adrenal

Men and women differ in the prevalence of chronic diseases. For example, men have a higher risk of infectious disease [51] and incidence of cardiovascular disease than women [52, 53] whereas women have a higher incidence of major depression and anxiety [54-56] and autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis [57] than men. Since there are also sex differences in the response to stress, the response to stress poses a potential candidate in the etiology of the chronic disease progression. As indicated above, we will focus on the sympatho-adrenal medullary system and hypothalamo-pituitary adrenal axis when considering sex differences in

There has been relatively little research on sex differences in the response of the sympathoadrenal medullary system to stress compared to the hypothalamo-pituitary adrenal axis, where most of the effort has been concentrated. We conducted one study comparing plasma catecholamine concentrations in gonadectomized sheep subjected to isolation and restraint

## **3. Stress and health**

Irrespective of the precise definition of stress that one chooses, it is clear that stress embodies a range of physiological and behavioral processes that occur when there is a real or perceived threat to homeostasis. These adaptive responses are designed to re-establish homeostasis and allow coping. For the most part, this is what they do but if the various stress systems are repeatedly or continuously activated over long periods the effects can be deleterious for health [18, 20-24, 29-33]. This is not surprising when one considers the actions of catecholamines and glucocorticoids, as well as other stress hormones and neuropeptides like the opioids. For example, stimulation of the cardiovascular system and mobilization of energy have clear benefits in the short term in dealing with stress but the longer term effects will likely have harmful outcomes, increasing the chance of cardiovascular disease and energy deficits. This premise holds for most body systems as all tissues are affected by stress hormones. Initial benefits can become serious drawbacks, with the stress response becoming pathological.

Severe stress is associated with the increased prevalence of devastating conditions such as major depression, dementia and impaired cognition; cardiovascular disease; impaired immune function with increased vulnerability to disease; impaired growth and reproductive function; osteoporosis; diabetes, the metabolic syndrome and reduced life expectancy [18, 20-24, 29-47]. Some of the conditions associated with severe stress, such as major depression and cardiovascular disease, are amongst the most serious and costly to treat [17][48]. As with most areas of stress research, it is the hypothalamo-pituitary adrenal axis that has received most attention in terms of the impact on health. Nevertheless, as indicated, repeated and chronic activation of the sympatho-adrenal medullary system can lead to disorders and the increased prevalence of ill-health. In addition to stress, there are clinical conditions where the concentrations of glucocorticoids are pathologically high, and this is associated with physiological and behavioral dysfunction similar to that seen during chronic stress. These conditions include Cushing's Syndrome [35, 36], Cushing's Disease [35, 36] obesity [37], metabolic syndrome [37], functional hypothalamic amenorrhea [38, 39], hyperthyroidism [24], Diabetes Mellitus type II [37], hypertension [37] and major depression [37].

It follows that understanding stress responses is important if preventions and treatments of the deleterious effects of stress are to be established. This understanding will need to encompass the mechanisms of responses under a range of conditions, and in response to various stressors, as well as the effects of these responses on the body. The latter is not the focus of the current discussion but the former is. Individuals react to stressors in different ways and various physiological conditions including the sex of an individual will influence stress responses [1, 49]. Given that physiological responses to stress are important determinants for health, we will consider different types of stressors, sex differences in response to stress and the importance of physiological state, particularly reproductive state, in influencing responses to stress.

#### **4. Different types of stressors**

There are many different stressors that we encounter in our daily lives. It is commonly considered that stressors can be categorized as physical stressors or psychological stressors [1]. Physical stressors are those that pose a real threat to homeostasis and which result in "reactive" glucocorticoid responses to stress, whereas psychological stressors are those that

Irrespective of the precise definition of stress that one chooses, it is clear that stress embodies a range of physiological and behavioral processes that occur when there is a real or perceived threat to homeostasis. These adaptive responses are designed to re-establish homeostasis and allow coping. For the most part, this is what they do but if the various stress systems are repeatedly or continuously activated over long periods the effects can be deleterious for health [18, 20-24, 29-33]. This is not surprising when one considers the actions of catecholamines and glucocorticoids, as well as other stress hormones and neuropeptides like the opioids. For example, stimulation of the cardiovascular system and mobilization of energy have clear benefits in the short term in dealing with stress but the longer term effects will likely have harmful outcomes, increasing the chance of cardiovascular disease and energy deficits. This premise holds for most body systems as all tissues are affected by stress hormones. Initial benefits can become serious drawbacks, with

Severe stress is associated with the increased prevalence of devastating conditions such as major depression, dementia and impaired cognition; cardiovascular disease; impaired immune function with increased vulnerability to disease; impaired growth and reproductive function; osteoporosis; diabetes, the metabolic syndrome and reduced life expectancy [18, 20-24, 29-47]. Some of the conditions associated with severe stress, such as major depression and cardiovascular disease, are amongst the most serious and costly to treat [17][48]. As with most areas of stress research, it is the hypothalamo-pituitary adrenal axis that has received most attention in terms of the impact on health. Nevertheless, as indicated, repeated and chronic activation of the sympatho-adrenal medullary system can lead to disorders and the increased prevalence of ill-health. In addition to stress, there are clinical conditions where the concentrations of glucocorticoids are pathologically high, and this is associated with physiological and behavioral dysfunction similar to that seen during chronic stress. These conditions include Cushing's Syndrome [35, 36], Cushing's Disease [35, 36] obesity [37], metabolic syndrome [37], functional hypothalamic amenorrhea [38, 39], hyperthyroidism [24],

It follows that understanding stress responses is important if preventions and treatments of the deleterious effects of stress are to be established. This understanding will need to encompass the mechanisms of responses under a range of conditions, and in response to various stressors, as well as the effects of these responses on the body. The latter is not the focus of the current discussion but the former is. Individuals react to stressors in different ways and various physiological conditions including the sex of an individual will influence stress responses [1, 49]. Given that physiological responses to stress are important determinants for health, we will consider different types of stressors, sex differences in response to stress and the importance of physiological state, particularly reproductive state,

There are many different stressors that we encounter in our daily lives. It is commonly considered that stressors can be categorized as physical stressors or psychological stressors [1]. Physical stressors are those that pose a real threat to homeostasis and which result in "reactive" glucocorticoid responses to stress, whereas psychological stressors are those that

Diabetes Mellitus type II [37], hypertension [37] and major depression [37].

**3. Stress and health** 

the stress response becoming pathological.

in influencing responses to stress.

**4. Different types of stressors** 

are perceived to pose a threat to homeostasis and which result in "anticipatory" glucocorticoid responses to stress. Herman and colleagues [50] asserted that "reactive" glucocorticoid responses to stress are those induced by a genuine challenge to physiological homeostasis that is recognized by sensory pathways. Such challenges may include a change in cardiovascular tone, respiratory distress, pain or circulating cytokines. In such cases, there is a direct neuronal pathway to CRH neurons in the paraventricular nucleus via the brain stem to activate the hypothalamo-pituitary adrenal axis. In contrast, "anticipatory" glucocorticoid responses to stress are not mounted in response to an actual disruption to physiological homeostasis but to the anticipation of such a disruption. These responses require some higher cortical processing involving limbic pathways [50].

Physiological responses to physical stressors may be considered appropriate since the body is being prepared for a real threat and the elevated heart rate and blood pressure and energy stores mobilised by catecholamines and glucocorticoids (see Section 2) are required to deal with the stressor. For example, a direct physical threat may require vigorous skeletal muscle activity in order to avert detrimental consequences imposed by the stressor. Conversely, physiological responses to psychological stressors are potentially more harmful since the body does not usually need to respond with a physical use of energy, certainly not for a prolonged period. This would be evident where there may be a stressful environment induced without the need for physical exercise, such as being caught in traffic on the way to an important appointment. Heart rate and blood pressure may be elevated, and energy stores mobilized, but with no obvious benefit to dealing with the stressor. An exception would be the possible beneficial effects of increased mental acuity. Nevertheless, it follows that psychological stress may be detrimental to health, particularly if it is prolonged or repeated frequently, because it unnecessarily elevates heart rate and blood pressure and mobilizes energy stores placing unnecessary strain on essential physiological systems. It is important to appreciate that excessive activation of the stress systems can have a negative impact on normal physiological functioning [19, 20, 32].

Since different types of stressors activate the physiological stress systems via different mechanisms, it is important to consider different types of stressors when considering the roles of sex and the sex steroids in influencing the responsiveness of the sympatho-adrenal medullary system and the hypothalamo-pituitary adrenal axis.
