Rethinking Adrenal Fatigue: An Evidence Based Review of Hypocortisolism

By Lena Edwards

The stress response system (SRS) truly rivals the natural wonders of the world in its purpose and level of complexity.  This sophisticated neurobiological network coordinates all physiological processes and maintains internal balance, or homeostasis, in unpredictable or potentially threatening environments^1–3.  Unfortunately, the SRS has not evolved quickly enough to accommodate the ‘human condition’, a dilemma not encountered by other organisms.  Gifted with independent thought, advanced cognition, and the capacity to express emotion, humans can act and react outside of the primitive confines of the innate ‘fight or flight’ response.  Moreover, a plethora of superimposed endogenous and exogenous factors have been shown to alter basal and stress induced SRS activation^4–10.  Consequently, the human SRS is constantly immersed in an unfamiliar and ever-changing physiologic landscape which can ultimately overwhelm its adaptive capacity.

The SRS is not a linear system originating in the hypothalamus and terminating in the adrenal glands.  Rather, this extremely sophisticated system houses numerous other structures, organ systems, chemical mediators, and hormonal modulators whose collaborative efforts drive basal and stress induced SRS function^3,11,12.  The hypothalamic-pituitary-adrenal (HPA) axis is a vital component of the SRS in so far as its effector hormone, cortisol, has widespread influence in regulating all metabolic processes as well as in determining basal SRS tone.  However, it is the elaborate system of checks and balances imposed by other equally influential members of the SRS which prevents autonomous HPA axis hyperactivation and glucocorticoid (GC) induced catabolic tissue damage^3,6,11,12. 

The origins of hypocortisolism are extremely complex and can reflect temporary or permanent impairment in innate HPA axis function under the influence of countless tangential factors.  These factors are unique not only to the individual but also to the stressor itself, and their influence determines the presence, severity, duration, and clinical manifestations of hypocortisolism^4,8,10,13,14.  In viewing the highly convoluted nature of the HPA axis through this lens, it is reasonable to question the anecdotal notion of “adrenal fatigue.”  Despite the lack of scientific validation supporting its existence, adrenal fatigue continues to be widely accepted as a legitimate clinical diagnosis by many medical practitioners and patients who contend that chronic stress can induce hypocortisolism through autonomous adrenal gland ‘exhaustion’ outside of other regulatory controls¹⁵.  This concise review will highlight the primary mechanisms through which hypocortisolism can arise and the clinical consequences thereof.

Pathophysiological Mechanisms of Hypocortisolism

Basal and stress induced cortisol levels can be compromised by any process which impairs the structural or functional integrity of one or more components of the HPA axis.  These conditions can be classified under the categories of primary, secondary, or tertiary adrenal insufficiency depending upon whether the disruption occurs at the level of the adrenal glands, the pituitary gland, or the hypothalamus, respectively¹⁶.  However, relative states of cortisol insufficiency can exist absent conditions that impair one or more components of the HPA axis.  Such is the case when cortisol bioavailability is reduced or if tissue sensitivity to cortisol is impaired (Table 2) ^{3,3,4,6,8,11,13,16–21}. 

In contrast with cortisol insufficiency, hypocortisolism broader in its scope and further encompasses variations in basal and stress induced cortisol release patterns.  Hypocortisolism can manifest as a flattened diurnal cortisol release pattern, a blunted cortisol response to awakening, and/or an insufficient stress induced rise in cortisol levels^4,10.  The mechanisms through which hypocortisolism evolves remain unclear but differ from those which give rise to absolute cortisol insufficiency.  The process is further complicated by the fact that innate HPA axis function can be continuously, and in some cases permanently, altered through exposure to countless endogenous and exogenous factors (Table 1).  Thus, hypocortisolism can evolve at different times and manifest in a variety of ways in the same individual or in similar individuals who are subjected to the same or different stressors¹⁴. 

The paradoxical phenomenon of hypocortisolism has challenged the longstanding belief that chronic stress uniformly causes HPA axis hyperactivation.  Hypocortisolism was first confirmed in otherwise healthy individuals living under conditions of chronic stress¹⁰.  However, the pivotal work of Yehuda and colleagues in 1997 confirmed that chronic stress exposure, in this case in posttraumatic stress disorder (PTSD), could induced blunting of HPA axis activation²².  Subsequent research replicated their findings and additionally demonstrated an association between hypocortisolism and other adult stress related bodily disorders, including chronic fatigue syndrome (CFS), ‘burn out’ and fibromyalgia (FMS)^4,10,23–27. 

The foundational groundwork established by Heim, Fries, and other pioneers in stress research has provided invaluable insight into the potential mechanisms leading to chronic stress induced hypocortisolism.  The majority of research suggests that the presence of hypocortisolism during chronic stress exposure likely results from excessive cortisol mediated downregulation, mainly at the pituitary level^{4,10,13,22,28,29}.  Adrenally mediated hypocortisolism has also been demonstrated, however it is occurs subsequent to downregulation of adrenal CRH, AVP, and ACTH receptors rather than to autonomously mediated ‘adrenal fatigue’^{4,8,10,23,24,29–36}.   

Notwithstanding, studies observed that hypocortisolism can be exaggerated by the duration of stress exposure as well as the number and intensity of the concomitant stressors^{1,2,4,13,27,37,37,38}.

It remains unclear whether hypocortisolism occurs as a maladaptive response or as an adaptive mechanism to protect the metabolic machinery from unregulated cortisol mediated tissue damage^4,10,26,39.  Research conducted on pregnant mothers supports the contention that maternal hypocortisolism serves as adaptive safeguard to protect fetal HPA axis growth and development^40,41.  Hypocortisolism observed in those who are critically ill or suffer from chronic infections is also believed to reflect an adaptive counter maneuver to facilitate upregulation of immune defenses in the face of ongoing threat^4,42–47. 

Hypocortisolism and Stress Related Bodily Disorders

Much of the research on hypocortisolism has been conducted in children who experienced traumatic life experiences, including neglect, parental loss or separation, abuse of any kind, institutionalization, natural disasters, and acts of violence^{13,29,31,35,37,38,48–51}.  The development of hypocortisolism during childhood has been associated with higher incidences of abnormal growth and development as well as mood disorders, substance abuse, behavioral disorders, and cognitive dysfunction^{29,31,37,38,48,49,52}.  Moreover, the degree to which these conditions manifest clinically appears to be directly related to the duration and timing of exposure, the nature of the stress, and the timing between assessment and the stress exposure.  In fact, the evidence suggests that earlier and more intense the stress exposure, the greater the risk of permanent alteration in the “set point” of the HPA axis, and the more likely hypocortisolism will persist into adulthood^{8,29,34,38,52,53}. 

Adult hypocortisolism, whether newly emerging or persistent from childhood, has been associated with the development of certain stress related bodily disorders, some of which are listed in Table 3.  In fact, it has been suggested that approximately 25 percent of individuals suffering from stress related bodily disorders have associated hypocortisolism⁴.  Significant overlap has been observed in the clinical symptomatology of stress related bodily disorders, and this is most likely due to the similar pathophysiological processes which give rise to them^{4,10,22,24–26,36,54–57}.  Fries and colleagues coined the term “hypocortisolism triad” to describe the three most prevalent symptoms observed in stress related bodily disorders, namely chronic fatigue, chronic pain, and stress sensitivity⁴. 

PTSD is one of the most well-studied stress related bodily disorders.  It is characterized by symptoms of avoidance, reexperience of the traumatic event, and hyperarousal⁵⁸.  Studies in both children and adults suffering from PTSD  demonstrated not only impairments in HPA axis function but in immune system function as well.  Some of these findings include:

1. Low baseline cortisol secretion
2. Increased GR binding to lymphocytes
3. Enhanced GC negative feedback on ACTH
4. Flattened diurnal cortisol release patterns
5. Blunted ACTH responses to CRH^{4,10,22,26,36,59}

Increased levels of IL-1, IL-6, and TNFα, have also been demonstrated and are believed to contribute to the fatigue, pain, depression, and sleep disturbances frequently seen in these individuals^{10,22,26,29,36,57,58}.  It has been suggested that the extent to which PTSD occurs or persists may be dependent upon the stressor characteristics and the presence concomitant life stressors⁶⁰.  However, individuals who develop hypocortisolism shortly after a traumatic event appear to be more vulnerable to developing subsequent PTSD^22,61.

CFS is another stress related bodily disorder, which has been strongly associated with hypocortisolism^25,54.  This condition is characterized by persistent fatigue lasting at least six months with at least four of eight additional symptoms⁵⁴.  As in PTSD, concomitant elevations in proinflammatory cytokines contribute to symptoms of malaise, depressed mood, sleep disturbances, and stress sensitivity^25,30.  It has been suggested that CFS may represent a form of subclinical Addison’s Disease given the significant overlap in symptomatology as well as the presence of hypocortisolism in both conditions^62,63.  However, it remains unclear whether CFS occurs as a consequence of hypocortisolism or if hypocortisolism evolves as a delayed clinical consequence related to the symptomatic changes associated with CFS²⁵.  Some studies have even suggested that the hypocortisolism observed in stress related CFS is the consequence of a HPA axis switch, whereby stress induced HPA axis hyperactivation eventually transforms into hypoactivation under the strain of ongoing stress, illness, or infection^30,64. 

Conclusion

The human SRS is a vast and incredibly sophisticated neuroendocrine network designed to maintain physiologic homeostasis and orchestrate diurnal metabolic functions.  Under normal circumstances, the SRS is a dynamic system and exhibits a certain degree of regulatory flexibility.  However, if the its baseline function is exogenously modified or its adaptive capacity is overwhelmed, the very system designed to maintain homeostasis can become the instrument of widespread physiologic chaos.

Addison’s Disease and Cushing’s Disease have long represented the clinical extremes of cortisol production.  However, extensive research has since broadened our understanding of the HPA axis and the many factors which can modify its capacity and functional integrity.  We now know that more subtle versions of hyper- and hypocortisolism manifest clinically and can arise through mechanisms, which do not directly affect the structural integrity of one or more components of the HPA axis.  Furthermore, the presence and extent to which innate HPA axis function is altered is preordained by antenatal factors and continuously reconfigured by countless environmental modifiers.

The paradoxical observation of stress induced hypocortisolism serves as a testament to the extremely complex nature of the SRS.  Moreover, the clinical relevance of hypocortisolism can no longer be discounted because of its association with stress related bodily disorders.  However, an evidence-based approach to hypocortisolism is of paramount importance if diagnostic and therapeutic measures are to be properly implemented.  To this end, we offer the following summary of the scientific evidence:

1. Chronic stress exposure can give rise to hypocortisolism through adaptive downregulation of the central components HPA axis
2. Hypocortisolism has been associated with stress related bodily disorders but can also exist in asymptomatic individuals living in chronically stressful environments
3. Hypocortisolism can reflect an adaptive counter maneuver designed to enhance immune defenses during periods of critical illness, trauma, or infection
4. In the event that hypocortisolism is adrenally mediated, it occurs after downregulation of adrenal AVP, CRH, and ACTH receptors, not through autonomously mediated “adrenal fatigue.”

Tables

Table 1:  Factors Affecting HPA Axis Function and Cortisol Levels

Table 2:  Pathophysiological Mechanisms of Hypocortisolism

Table 3:  Clinical Conditions Associated with HPA Axis Hypofunction

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About the Author

Lena Edwards MD, ABOIM, FAARM, ABAARM

Edwards is an Internist who is also Board Certified in Integrative Medicine, Board Certified and Fellowship Trained in Anti-Aging & Functional Medicine, and Fellowship Trained in Integrative Cancer Therapy.  She is also a fellow of the American Institute of Stress.  Edwards’ is best recognized for her expertise in treating complex Integrative Medicine issues, male and female hormone imbalance, HPA axis and adrenal dysfunction, and stress related bodily disorders.  In addition to her clinical practice, she has also been actively involved in writing, teaching, speaking, and consulting.  She has served as a clinical instructor for the American Academy of Anti-Aging Medicine, the Medical Metabolic Institute, and the George Washington University Integrative Medicine Program.  Her professional affiliations include The American Board of Physician Specialties; The American Board of Integrative Medicine; The American Academy of Anti-Aging and Functional Medicine; The American Institute of Stress; The American College of Physicians; and Alpha Omega Alpha Honor Society.

Edwards has been selected as one of America’s Top Physicians in Internal Medicine, Integrative Medicine, Integrative Cancer Therapy, and as one of the Leading Integrative Medicine Physicians in the World by the International Association of HealthCare Professionals.  She has also authored numerous articles for mass media outlets and peer-reviewed medical journals. Her self-authored book, Adrenalogic: Outsmarting Stress, has sold thousands of copies world-wide.

Editor’s note: William Edwards, a student in Boca Raton, Florida, assisted in review and research for this paper.