CHAPTER 39
Adrenal Fatigue
Jacqueline Redmer, MD, MPH
THE NATURAL STRESS RESPONSE
The human body is well equipped to handle stress. A wide
array of hormones and neurotransmitters exist to maintain
homeostasis in response to physical and psychogenic stress-
ors. The adrenal glands, which are located at the top of the
kidney, are at the center of the body’s stress response sys-
tem. The cortex forms approximately 90% of the adrenal
mass, the remaining core being the adrenal medulla. In the
adult, the cortex can be morphologically and functionally
divided into three layers (the glomerulosa, fasciculata, and
reticularis). Each layer has a distinct histological appearance
and secretes different steroid hormones (aldosterone, cor-
tisol, and androgens, respectively). The inner 10%–20%
of the gland is the adrenal medulla, secreting the catechol-
amines epinephrine and norepinephrine1 (Fig. 39.1).
The body responds to physical, emotional, psycho-
logical, and biochemical stresses by releasing cortisol.
Stress is sensed by the hypothalamus, which then releases
corticotropin hormone (CRH). This stimulates the ante-
rior pituitary to produce adrenocorticotropic hormone
(ACTH), which triggers receptors in the adrenal cortex
to release the appropriate amount of cortisol. When the
sympathetic (fight or flight) nervous system is activated,
the adrenals respond by releasing epinephrine, norepi-
nephrine, and cortisol, all of which increase heart rate
and blood pressure diverting blood to the brain, heart,
and skeletal muscle2 (Fig. 39.2).
Adrenal insufficiency is a well-documented condi-
tion in which the adrenals cannot keep up with the stress
response of the body. This can happen if there is destruc-
tion of the adrenal cortex (primary) or if factors outside of
the adrenal glands stimulate them to produce less cortisol
(secondary). In primary adrenal insufficiency, the symp-
toms reflect a loss of glucocorticoid and mineralocorti-
coid hormones, whereas secondary deficiency usually
results only in a loss of cortisol.3
Although not widely accepted by allopathic medicine,
many alternative medicine practitioners believe that a
subclinical adrenal fatigue or burnout can develop when
the adrenals have been working hard to keep up with high
physical, psychological, or emotional stress demands over
time2,4 (Table 39.1). It is hypothesized that sustained lev-
els of high cortisol may lead to decreased responsiveness
in the pituitary and adrenal glands. Changes in hypotha-
lamic-pituitary-adrenal (HPA) axis may be due to the fol-
lowing mechanisms: (1) reduced biosynthesis or release of
the respective hormone on different levels of the HPA axis
(CRH from the hypothalamus, ACTH from the pituitary,
or cortisol from the adrenal glands); (2) hypersecretion of
one hormone with a subsequent downregulation of the
respective target receptors; (3) enhanced sensitivity to the
404
negative feedback of cortisol; (4) a decreased availability of
free cortisol; and/or (5) reduced effects of cortisol on the
target tissue, resulting in a relative cortisol resistance.5,6
Adrenal fatigue and chronic fatigue syndrome (now
recognized as Systemic Exertion Intolerance Disease)
overlap a good deal clinically, and some people view adre-
nal fatigue as a subset of CFS. A meta-analysis of 19 stud-
ies from 2013 on this subject evaluated this relationship.
It was found that 24-hour measures of absolute cortisol
output did not clearly correlate with fatigue symptoms.
However, attenuation of the cortisol diurnal variabil-
ity, particularly with disruption of waking and circadian
rhythms, seems to have more impact on the development
of CFS.9 Other reviews have suggested that HPA axis
activity (or dysfunction) may not be at the core of CFS,
but instead occur as a result of certain behavioral changes
associated with the illness.10
DIAGNOSING ADRENAL FATIGUE
In most cases, a diagnosis of adrenal fatigue is based on
clinical history and the exclusion of other conditions
based on basic lab work. In patients suspected of having
adrenal fatigue, however, it may be reasonable to screen
for frank adrenal insufficiency. With normal diurnal
variations in cortisol, glucocorticoids are lowest at 12
a.m.–1 a.m. and highest at 6 a.m.–8 a.m. In conventional
medicine, cortisol adequacy is usually tested for with an
8 a.m. fasting serum cortisol test. In healthy patients, the
cortisol level is usually 10–20 mcg/dL. An early morning
low serum cortisol concentration less than 3 mcg/dL has
a high specificity (100%) and low sensitivity for adrenal
insufficiency (36%). Using a higher serum cortisol of 10
mcg/dL as the criterion for adrenal insufficiency increases
the sensitivity to 62% and reduces the specificity to 77%.
Thus a low morning serum cortisol concentration alone
is not a reliable predictor of deficient adrenal function.11
Among practitioners, there is controversy regarding
the best measurement of cortisol, with many people feel-
ing strongly that salivary, not serum, levels more accurately
reflect adrenal function.12–15 Controversy exists concerning
the validity of such testing materials and potential confound-
ing variables, such as dietary interference, salivary viscosity,
oral contaminants, and oral diseases such as gingivitis. How-
ever, some data suggest that salivary collection is preferable
because it adjusts for bioavailable cortisol and is unaffected
by cortisol binding globulin level, which rises with oral
contraception pills, hypoalbuminemia, cirrhosis, nephrotic
syndrome, and pregnancy. Salivary cortisol testing is easy
to collect, although testing may not be widely available and
testing criteria have not been uniformly accepted.16