The building of life stress, well expressed by the concept of allostatic load, plays an important part in all phases of endocrine illness. Allostatic load refers to the cumulative burden of both stressful life events and chronic stress. When environmental challenges exceed the individual ability to cope, allostatic overload ensues. Assessment of allostatic load/overload by clinical measurements including indices and rating scales, in addition to biomarkers, offers a characterization of the person’s psychosocial environment that is missing from current formulations. Consideration of allostatic load in endocrinology may shed light on a number of clinical issues: interpretation of abnormal hormone values that lack explanations; coping with the various phases of illness; maladaptive illness behavior; response to treatment; presence of residual symptoms; health-damaging lifestyle habits. Addressing allostatic load calls for innovative models of endocrine outpatients with multidisciplinary organization of care, extended time for the interview, focus on rehabilitation. We provide an overview on the mechanisms of allostatic load, how it can be assessed, its potential role in endocrine disturbances, and how its consideration may lead to a needed innovation in patient care.

Exposure to acute and chronic stress can disrupt optimal neuroendocrine activity, resulting in enhanced vulnerability of the individual to a number of medical and psychiatric disorders, as documented by a large body of literature in humans [1, 2]. Stressful life events (discrete changes in the personal or social environment that should be external and verifiable rather than internal or psychological) may be followed by ill health [3, 4]. However, subtle and long-standing life situations should not too readily be dismissed as minor or negligible, since chronic, daily life stresses may be experienced by the individual as taxing or exceeding his/her coping skills with consequences that are of both psychological and physical nature [2, 3, 5].

The concept of allostatic load, introduced by McEwen and Stellar in 1993 [6], reflects the cumulative burden of both stressful life events and chronic stress, as the cost of chronic exposure to fluctuating or heightened neural/neuroendocrine responses resulting from repeated or chronic environmental challenges that an individual reacts to as being particularly stressful [6‒11]. When environmental challenges exceed the individual ability to cope, then allostatic overload may ensue [12].

Allostatic load/overload appears to be a more precise biological concept than “stress” to describe adaptation and maladjustment to “stressors” and includes the physiological effects of health-promoting and health-damaging behaviors [6, 10, 11]. It also encompasses the social determinants of health, as increasingly recognized in the field of diabetes [13].

General population studies indicate that allostatic load is increased by adverse conditions such as low socioeconomic status, living in impoverished neighborhoods, low educational attainment, ethnicity, and racial discrimination [6, 8]. Allostatic load may affect health not only through autonomic and neuroendocrine responses, but also through changes in health behavior. Physiological consequences of the resulting health-damaging behaviors include poor sleep and other aspects of circadian disruption, unhealthy diet, smoking, alcohol consumption, and social isolation [6, 8, 12].

In endocrine research and practice, the term “allostatic load” has been seldom employed so far. However, it clearly pertains to the psychosocial impairment of endocrine patients at large [14].

We provide an overview on the mechanisms of allostatic load, how it can be assessed, its potential role in endocrine disturbances, the clinical implications that it may entail in endocrine practice, and how its consideration may yield a needed innovation in patient care. Search criteria and selection of papers are detailed in the online supplementary Material (for all online suppl. material, see https://doi.org/10.1159/000530691).

The concept of allostatic load refers to the relationship between stress and the processes leading to disease based on allostasis, the ability of the organism to achieve stability through change, anticipating needs, and preparing to satisfy them before they arise [6]. Allostasis complements homeostasis, whose goal is to preserve constancy of the internal milieu by negative feedback regulatory mechanisms [9]. In response to environmental demands, different physiological systems interact at different levels of activity, with the brain as the fundamental organ for predictive regulation [9], and the aftermath depends on individual vulnerability (Fig. 1). The brain does change its circuitry, architecture, and neurochemical functions by both genetic and epigenetic mechanisms [10]. In particular, three brain regions undergo remodeling of dendrites and synapses. The hippocampus, amygdala and prefrontal cortex communicate with each other and mediate cognitive function, fear, and aggression, as well as turning on and off the autonomic nervous system and the hypothalamic-pituitary-adrenal axis responses to environmental stressors [10, 11, 15]. Allostatic load during critical periods of brain development characterized by elevated neuroplasticity and enhanced sensitivity to epigenetic effects, as in childhood and adolescence, may exert long-lasting effects on particular neuronal networks that lead to enduring neuroendocrine alterations [1, 10, 11].

Fig. 1.

Interactions of endocrine and non-endocrine factors in response to allostatic load, resulting in individual vulnerability.

Fig. 1.

Interactions of endocrine and non-endocrine factors in response to allostatic load, resulting in individual vulnerability.

Close modal

There are two distinct methods of assessing allostatic load. One is the use of biological markers related to stress, and the other is concerned with the application of clinimetric tools. Biomarkers include metabolic parameters (glucose, insulin, lipid profiles), indices of inflammation (interleukins, C-reactive protein, fibrinogen), sympathetic nervous system activity (urinary norepinephrine and epinephrine), hypothalamic-pituitary-adrenal axis components (cortisol, dehydroepiandrosterone), insulin-like growth factor 1 [16, 17]. Cumulative indices encompassing both clinical (e.g., blood pressure, waist circumference) and laboratory parameters have also been developed [18]. This methodology relies on biomarkers that express a state of body systems, but does not provide information on the underlying individual causes. Substantial heterogeneity exists across studies as to type and number of parameters to be considered [8, 16‒18]. This approach is not suitable for everyday practice. Moreover, since biological markers include hormonal parameters, such as cortisol, prolactin, dehydroepiandrosterone, epinephrine, norepinephrine, their use in endocrinology appears to be particularly problematic, because of attributional problems (such markers could be altered due to the presence of an endocrine disorder).

In the past decade, help in assessing a state of allostatic load came from clinimetrics, the science of clinical measurements [19‒21], a domain concerned with indices, rating scales and other expressions that are employed to describe or measure symptoms, physical signs, and other clinical phenomena, which do not find room in the customary taxonomy. A first step into the clinimetric assessment of allostatic load was the development of the PsychoSocial Index [22‒24]. This is a short self-rated questionnaire, tailored to a busy clinical setting, for the assessment of stress and related psychological distress. Clinimetric criteria for the determination of allostatic overload by interview methods were introduced in 2010 [7] (Table 1). They were subsequently incorporated in the Diagnostic Criteria for Psychosomatic Research (DCPR) [25] and supplemented by a semi-structured research interview [12].

Table 1.

Clinimetric criteria for the identification of allostatic overload [12, 25]

Criteria A and B are required 
A. The presence of a current identifiable source of distress in the form of recent life events and/or chronic stress; the stressor is judged to tax or exceed the individual coping skills when its full nature and full circumstances are evaluated 
B. The stressor is associated with one or more of the following features, which have occurred within 6 months after the onset of the stressor 
 1. At least two of the following symptoms: difficulty falling asleep, restless sleep, early morning awakening, lack of energy, dizziness, generalized anxiety, irritability, sadness, demoralization 
 2. Significant impairment in social or occupational functioning 
 3. Significant impairment in environmental mastery (feeling overwhelmed by the demands of everyday life) 
Criteria A and B are required 
A. The presence of a current identifiable source of distress in the form of recent life events and/or chronic stress; the stressor is judged to tax or exceed the individual coping skills when its full nature and full circumstances are evaluated 
B. The stressor is associated with one or more of the following features, which have occurred within 6 months after the onset of the stressor 
 1. At least two of the following symptoms: difficulty falling asleep, restless sleep, early morning awakening, lack of energy, dizziness, generalized anxiety, irritability, sadness, demoralization 
 2. Significant impairment in social or occupational functioning 
 3. Significant impairment in environmental mastery (feeling overwhelmed by the demands of everyday life) 

In both general populations and a variety of clinical settings (e.g., cardiology, gynecology), use of biomarkers and/or clinimetric criteria indicated that higher allostatic load is associated with poorer health outcomes [8]. People displaying allostatic load/overload reported marked psychological distress (including psychiatric disorders and suicidal ideations) [8, 26].

Central effectors (hypothalamic hormones and brainstem-derived neurotransmitters) and peripheral effectors (including glucocorticoids, norepinephrine, and epinephrine) modulate the endocrine responses to stress [1]. The stress network regulates the brain cognitive, reward and fear systems, and the wake-sleep centers, and influences the gastrointestinal, cardiorespiratory, metabolic, and immune systems [1].

The endocrine effects of stress were initially examined in healthy people during experimental laboratory sessions, where the stressors can be standardized and allow a better control for known confounding factors [27]. Adrenocortical mechanisms appeared to come into play when individuals were faced with threatening or unpleasant challenges. A key modulator was the degree of novelty, unpredictability, and uncontrollability of the situation. The findings of laboratory stressors, however, can hardly be transferred to real-life challenges.

In clinical settings, recent life events, that is, events in the year before disease onset, may be evaluated by questionnaires or structured interviews with high inter-rater reliability [3, 4]. The role of stressful life events has been investigated in some endocrine disorders (hyperthyroidism, Cushing’s syndrome, hyperprolactinemia). Hyperthyroidism has been the most well-studied condition as to a possible pathogenetic role of stress within a multifactorial frame of reference. In 1991, Winsa et al. [28] mailed a questionnaire about life changes to 219 patients with Graves’ disease and 372 matched control subjects. Scores of negative life events in the 12 months preceding diagnosis were significantly higher in patients than in controls. The findings were replicated by a number of subsequent studies using structured methods of data collection (interviews or questionnaires) in patients with Graves’ disease and matched controls in different countries [29‒33]. Two retrospective studies outlined the role of chronic, daily stresses in patients with Graves’ disease [30, 31], with particular reference to changes in work conditions, increased arguments with spouse or partners, financial difficulties [30]. Daily hassles, such as difficulties in relation with coworkers, were also related to a poor response to antithyroid medications in women [34].

As to endogenous hypercortisolism, a controlled study was performed in a single center in the early 90s: stressful life events in the year before the first signs of disease onset were retrospectively investigated in 66 patients with Cushing’s syndrome of various etiologies and 66 healthy subjects matched for sociodemographic variables [35]. Patients with Cushing’s syndrome reported significantly more losses, undesirable events, and uncontrolled events than normal subjects. Interestingly, when patients with pituitary-dependent Cushing’s disease and patients with pituitary-independent Cushing’s syndrome (primary adrenal hyperfunction and ectopic ACTH production) were evaluated separately and compared with their matched controls, a causal role of stressful life events was found to pertain exclusively to Cushing’s disease, supporting the hypothesis of a limbic-hypothalamic involvement in the pathogenesis of this condition [35, 36].

Studying hyperprolactinemia, 52 consecutive patients (prolactinoma n = 33, idiopathic hyperprolactinemia n = 19) reported significantly more life events than their matched controls [37]. Within the complexity of the mechanisms involved, the findings indicate a potential role of stress in the pathogenesis of either prolactin-secreting pituitary tumors or idiopathic hyperprolactinemia [37].

In three studies [29, 35, 37] using Paykel’s Interview for Recent Life Events [4], the rater made a judgment of the expected stressfulness of the event, when its full nature and particular circumstances are taken into account, ignoring the subjective reaction of the individual. Such rating (objective negative impact) encompasses both chronic stress and life events and has considerable similarities with the clinimetric definition of allostatic overload [12]. All these studies were concerned with a time period preceding the initial symptoms [25, 32, 33, 35, 37] or the diagnosis [28, 30, 31] of the endocrine disorder.

Very few data are available as to the presence of allostatic load after the illness has already developed or has been treated. A study was carried out by administration of the PsychoSocial Index [22‒24] to patients with primary aldosteronism (n = 23) in the active phase, comparing them with matched normotensive subjects (n = 23) and also with patients with essential hypertension (n = 23) [38]. Patients with primary aldosteronism displayed significantly higher levels of allostatic load compared to both control groups [38]. Another study was concerned with 86 outpatients cured or in remission from pituitary disease; they were compared with 86 healthy controls and 60 outpatients cured or in remission from nonpituitary endocrine conditions [39]. Patients with pituitary disease displayed significantly higher levels of allostatic load on the PsychoSocial Index [22‒24] than healthy controls, but not compared to nonpituitary endocrine patients [39], suggesting similar degrees of life stress in different types of endocrine disorders. In a study performed in primary care [40], 200 consecutive patients underwent the semi-structured interview for allostatic overload [12] and a state of allostatic overload was identified in 31 (15.5%). In this population of 200 patients, out of 19 with an endocrine condition (thyroid disease in all) 5 (26.3%) presented with allostatic overload.

There is still insufficient research on the role and characteristics of stress in endocrine disease. Nonetheless, the concept of allostatic load appears to have important implications in clinical endocrinology by influencing a number of clinical variables (Fig. 2).

Fig. 2.

Clinical implications of allostatic load.

Fig. 2.

Clinical implications of allostatic load.

Close modal

Interpretation of Hormone Values

Of particular importance in clinical endocrinology are laboratory measurements that may be affected by stressful life situations (e.g., increase of prolactin levels). Such awareness may provide an important clue for interpreting abnormalities in hormone values that lack other explanations.

Phases of Illness

Allostatic load plays an important part in all phases of medical illnesses [12, 25]. For instance, after discharge from the hospital, patients face a transient period of general vulnerability to disease and elevated risk of adverse events (including hospital readmission and mortality), sometimes presenting with the features of posthospital syndrome [41]. This syndrome could also be viewed as a manifestation of allostatic overload (sleep disruption, mobility restriction, pain, fears, psychological distress).

Illness Behavior

The presence of allostatic load does influence illness behavior, the ways in which individuals experience, perceive, evaluate, and respond to their own health status [42]. In clinical endocrinology, there are many aspects of illness behavior that should be taken into account, such as perception and interpretation of symptoms, delay in seeking medical help, treatment adherence [42].

Response to Treatment

Quality of life is variably compromised in different endocrine diseases and does not necessarily improve with successful treatment and normalization of hormone values [14, 36, 39, 43‒48]. Allostatic load may explain why treatments do not always yield the expected results or fail [49]. For example, there are patients who report persistent symptoms despite achieving normal thyroid hormone levels upon thyroid replacement [50]. Resilience (the capacity to overcome adversities and stress while maintaining normal and physical functioning) has been found to modulate quality of life in neuroendocrine neoplasms [51].

Residual Symptoms

Endocrine abnormalities are frequently associated with psychological distress that may reach the threshold of a psychiatric disorder (e.g., major depression, generalized anxiety disorder) [14]. Such disturbances are often found to improve upon normalization of hormone parameters. However, this is not always the case. Both medical and psychiatric symptoms may persist as residual symptomatology. Indeed, in a sample of 146 outpatients cured or in remission from endocrine conditions, 62% presented with at least one psychiatric diagnosis, whereas 66% suffered from at least one of the three DCPR syndromes considered in the study (demoralization, irritable mood, and persistent somatization) [39].

Sleep disturbances may occur as residual symptoms [14]. It has been suggested that circadian disruption may result in neurobehavioral changes that could lead to a reduction in cognitive flexibility and reduce resilience [52, 53].

Health-Damaging Lifestyle Habits

Unhealthy diet, overweight, lack of physical activity, alcohol consumption, smoking habits were all associated with high allostatic load levels [8, 12]. Differences in access to healthcare may influence health attitudes, behavior, and outcomes [54]. In particular, poverty and social inequalities may have an impact, via epigenetic mechanisms, on developmental, affective, and biological variables [49]. The metabolic syndrome is mostly a consequence of harmful lifestyles, frequently associated with allostatic load [5, 16].

All the variables indicated in Figure 2 are intertwined in practice. For instance, allostatic overload may trigger sleep disturbances and psychological distress that in turn affect quality of life and illness behavior, influencing the treatment outcome of an endocrine disorder. It is not simply a matter of including allostatic load in the evaluation of patients, but of finding new modalities of assessment and treatment in clinical endocrinology. The insights we gained with an innovative model of outpatient clinic [55] provide the basis for a number of suggestions, as outlined below.

In recent years, there has been increasing awareness of the unsatisfactory degree of remission that current therapeutic strategies entail in a variety of endocrine disorders [14, 36, 43‒48, 56]. There may be different reasons for a delayed or impaired process of recovery. The presence of stressful life situations may interact with a number of variables, such as persistent alterations of hormone values, unrealistic expectations of a quick recovery, hormone replacement that does not fully restore optimal endocrine balance, impairment in self-esteem, body image distortion, disruption in interpersonal relationships, social withdrawal [56]. Such factors may hinder work performance, and economic deterioration may ensue [57], which then becomes the source of additional allostatic load.

We envisioned rehabilitation of endocrine patients as the sum of activities required to ensure them the best physical, mental, and social conditions so that they may progress to an optimal state of health [58]. Its main indications are delayed recovery after a surgical intervention or radiotherapy; impaired quality of life with discrepancy between endocrine status and current functioning, as it may occur in patients receiving replacement therapy, e.g., thyroid [50]; decline in physical and social functioning [14]; persistence of important comorbidity with reference to psychological disturbances [14]; maladaptive illness behavior that includes poor adherence to treatment and difficulties in self-management [42]; problems with lifestyle and risk behavior [12, 25]. These clinical situations may build into a state of allostatic load that should be addressed using individualized strategies [12].

The importance of addressing psychosocial determinants of health in endocrine disease is increasingly recognized [59]. Including allostatic load in the clinical evaluation allows to view illness within the interaction between the person and the environment that has a lot to do with the increasing rate of metabolic abnormalities (obesity, diabetes, metabolic syndrome) worldwide [5, 13, 49, 60‒62].

The allostasis model defines health as optimal predictive fluctuation, since increased demand calls for increased response capacity [9]. McEwen emphasized the importance of using allostasis optimally and maintaining a healthy balance that promotes positive aspects of brain and body health through health-promoting behaviors [63]. It has been argued that enduring lifestyle changes can only be achieved with a personalized approach that targets euthymia, as the presence of positive affect and psychological well-being [64]. The concept of euthymia is seldom addressed in clinical endocrinology [51], but it is attracting interest in the domain of diabetes [65, 66].

In clinical endocrinology, there is often the tendency to rely on “hard data,” mainly expressed as hormone measurements, excluding “soft information,” such as psychological distress. This soft information can now, however, be reliably assessed by clinimetric tools [19‒21]. Considering allostatic overload may help demarcate substantial clinical differences among patients who otherwise seem deceptively similar because they share the same medical diagnosis [12]. The evidence that we have summarized should lead endocrinologists to a multidimensional assessment, encompassing also allostatic load. The difficulties patients encounter in coping with endocrine illness and its psychological consequences have led to the development of many patient associations in the past decades [14, 67].

As it happened in other fields of clinical medicine, a conceptual shift from a merely biomedical approach to a psychosomatic consideration of the person and his/her quality of life appears to be necessary for improving therapeutic effectiveness [14, 36, 56, 59]. In this view, we introduced the concept of rehabilitation in endocrinology [56, 58] and tried to translate into operational terms the acquisitions of current psychosomatic research, starting an innovative outpatient service [55]. Applying interdisciplinary expertise and addressing allostatic load issues in current endocrine practice are likely to improve final outcomes.

The authors have no conflicts of interest to declare.

The authors have no funding to declare.

Nicoletta Sonino, Giovanni A. Fava, Marcella Lucente, and Jenny Guidi provided a substantial contribution to the conception and writing of the paper.

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