Adrenal Fatigue

Abstract

Adrenal insufficiency is a well-defined endocrine disorder with characteristic symptoms, signs, and serum hormone abnormalities on static and dynamic testing. Adrenal fatigue is a fabricated condition that has been promoted by popular websites despite the lack of scientific evidence that the condition exists. It is proposed that the condition can be diagnosed by symptom scoring systems alone or by assessment of daytime salivary cortisol profiles that have never been validated as a testing tool. Treatments can be purchased online from these websites and consist of “adrenal support” supplements, many of which contain actual bovine adrenal extracts. Propagation of this false information about adrenal fatigue endangers the public by diverting their attention away from legitimate evaluations to identify the real causes of their symptoms and by promoting the use of unregulated steroid-containing supplements that can lead to serious suppression of endogenous adrenal function and cause the many known toxicities of steroid hormone excess.

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127© Springer Nature Switzerland AG 2019
M. T. McDermott (ed.), Management of Patients
with Pseudo- Endocrine Disorders,
https://doi.org/10.1007/978-3-030-22720-3_11
Case
A 47-year-old woman has been experiencing fatigue for
about 15years but complains of “total exhaustion” progres-
sively over the past year. She does not sleep well but does not
snore. Her appetite is poor. She only eats full meals occasion-
ally but snacks frequently throughout the day. Mild weight
gain (5lb.) has occurred in the past year. She cannot exercise
due to fatigue. She requests to be treated for adrenal fatigue
for which she has tested positive.
Chapter 11
Adrenal Fatigue
MichaelT.McDermott
M. T. McDermott (*)
University of Colorado Hospital, Aurora, CO, USA
e-mail: michael.mcdermott@cuanschutz.edu
michael.mcdermott@cuanschutz.edu

128
PMH: Mononucleosis at age 18 Meds: Occasional prescription
pain medication
PE: BP 128/70 P 80 Ht 5′8″ Wt 157lb.
(Orthostatic vitals negative)
Complete exam normal
Lab: Full-day salivary cortisol profile– Interpreted as
“adrenal fatigue”
Discussion
True Adrenal Insufficiency
Primary adrenal insufficiency develops as a result of disease
of or damage to the adrenal glands [1]. The most common
cause of primary adrenal insufficiency in the U.S. is autoim-
mune adrenalitis (Addison’s disease). Other, less common,
causes include infections (tuberculosis, deep fungal infec-
tions, HIV), infiltrative disorders (amyloidosis), intra-adrenal
hemorrhage, metastatic cancer, surgical adrenalectomy, and
congenital metabolic disorders (adrenoleukodystrophy, adre-
nomyeloneuropathy). Persons who have primary adrenal
insufficiency usually have deficiencies of all three adrenal
cortical hormones (cortisol, aldosterone, adrenal androgens).
Secondary (central) adrenal insufficiency results from dis-
eases of, damage to, or suppression of the pituitary gland or
hypothalamus [1]. This disorder most commonly develops due
to the administration of exogenous glucocorticoids (“ste-
roids”) to treat systemic or localized inflammatory diseases.
Notably, however, central adrenal insufficiency also frequently
occurs because of the use (widespread) of opioid narcotics for
acute, subacute, or chronic pain management [2, 3]. Other rela-
tively common causes of central adrenal insufficiency include
pituitary and parasellar tumors, surgery or radiation therapy in
the pituitary–hypothalamic regions, traumatic brain injury
(TBI), pituitary infections (syphilis), pituitary hemorrhage/
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apoplexy, infiltrative pituitary diseases, metastatic cancer to the
pituitary gland, various types of idiopathic pituitary inflamma-
tion (hypophysitis– lymphocytic, granulomatous, plasma cell,
xanthomatous, and mixed forms), and hypophysitis induced by
immune checkpoint inhibitor therapy. Secondary (central)
adrenal insufficiency only causes deficient production of corti-
sol and adrenal androgens; aldosterone secretion remains
intact because the renin–angiotensin system, the primary regu-
lator of aldosterone secretion, remains intact.
Symptoms of adrenal insufficiency include fatigue, weak-
ness, myalgias, arthralgias, abdominal pain, nausea, vomiting,
headaches, weight loss, postural dizziness, and salt craving.
Physical findings most commonly include hypotension and
tachycardia; cutaneous hyperpigmentation and vitiligo may be
seen but only in primary adrenal insufficiency. Common labo-
ratory features are hyponatremia, hypoglycemia, azotemia,
anemia, and eosinophilia; hyperkalemia occurs only in pri-
mary adrenal insufficiency (due to aldosterone deficiency).
The best screening test for adrenal insufficiency, according
to the current clinical practice guidelines, is a morning serum
cortisol level drawn between 8 and 9 AM. An AM serum
cortisol level <3 ug/dl is diagnostic of adrenal insufficiency; an
AM serum cortisol <5 ug/dl with a plasma ACTH >2 times
the upper normal limit is also supportive of the diagnosis. An
AM serum cortisol level >15 ug/dl rules out adrenal insuffi-
ciency. For those with AM serum cortisol levels between 3
and 15 ug/dl, an ACTH (Cosyntropin 250 mcg) stimulation
test is recommended. A peak serum cortisol level <18 ug/dl 30
minutes after ACTH administration is diagnostic of partial
adrenal insufficiency [1]. A diagram of the relative cortisol
responses to this test in normal subjects and in patients with
partial and complete adrenal insufficiency is drawn in Fig.11.1.
The ACTH stimulation test, however, has some limitations.
A meta-analysis of all published and adequate studies deter-
mined that the sensitivity of the ACTH stimulation test for
detection of primary adrenal insufficiency is 92% (95% confi-
dence interval: 81–94%) but the specificity was not estimable.
For detecting secondary adrenal insufficiency, the existing
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130
data were insufficient to estimate either the sensitivity or the
specificity of the test [4]. In patients with primary adrenal
insufficiency, measurement of anti-adrenal (anti-21-
hydroxylase) antibodies will establish the etiology as autoim-
mune adrenalitis [1].
Impairment of adrenal function occurs gradually in
patients with positive anti-adrenal (anti-21-hydroxylase) anti-
bodies. Four stages of progressive adrenal cortical dysfunc-
tion have been described (Table 11.1) [5]. Others have
suggested that mild plasma ACTH elevations are the first
indicator of impending adrenal gland failure [6]. These data
emphasize that the diagnosis of early adrenal insufficiency
(primary and secondary) may be difficult even with validated
tests and requires significant clinical experience and
judgment.
Hypothalamic–pituitary–adrenal (HPA) physiology is
highly complex. It involves hypothalamic production of
corticotrophin- releasing factor (CRF) and vasopressin to regu-
late the pituitary secretion of corticotropin (ACTH), which
stimulates cortisol secretion from the adrenal glands. Cortisol
Primary adrenal insufficiency
ACTH stimulation test
Serum
cor
tisol
ug/dl
Time (minutes) after ACTH given
Normal
Partial adrenal insufficiency
Complete adrenal insufficienc
y
30
20
10
0 6030
F . Interpretation of the ACTH stimulation test
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131
is then transported in the bloodstream by binding proteins to
peripheral tissues where free (unbound) cortisol crosses cell
and nuclear membranes in target cells and binds to nuclear
glucocorticoid receptors, where it activates or suppresses tran-
scription of target genes. The resulting messenger RNA
(mRNA) is then translated into the cortisol regulated proteins
that ultimately mediate tissue cortisol action. This action
includes feedback of cortisol at the level of the hypothalamus
and pituitary gland to maintain HPA axis homeostasis.
It is certainly possible that some, as yet unrecognized,
inherited, or acquired abnormalities may exist at any of these
multiple sites of cortisol physiology and may or may not be
detectable by our current panel of adrenal axis tests. These
exciting possibilities and the implications they have for
improving patient care are the reasons endocrine research
must be supported and clinicians must stay abreast of the
resulting discoveries and their clinical applications.
The Myth ofAdrenal Fatigue
Adrenal fatigue is a proposed condition in which the adrenal
glands, while not insufficient by traditional hormone testing,
become unable to produce adequate amounts of adrenal hor-
mones to meet the requirements of the body to deal with the
T . Proposed stages in the development of overt adrenal
insufciency in patients who have positive serum anti-21- hydroxylase
antibodies (Ref. [5])
Stage Features
1High plasma renin activity (PRA); low/normal plasma
aldosterone (PA)
2Stage 1 plus a reduced peak cortisol response (<18 ug/dl)
to ACTH administration
3Stage 2 plus elevated plasma ACTH
4Clinically overt adrenal insufficiency (baseline serum
cortisol <3 ug/dl)
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daily stresses of life. It is said to occur in patients who are
under chronic high stress (mental, emotional, or physical) in
their work and/or family life; this chronic stress supposedly
exhausts their adrenal glands. It is characterized by nonspe-
cific symptoms such as fatigue, sleep disturbances, difficulty
coping, body aches, digestive problems, and dependency on
caffeine [7–11]. There are numerous practitioners and web-
sites that promote this pseudo-endocrine condition. Adrenal
fatigue was even featured on Dr. Oz on October 22, 2015.
Patients are encouraged to self-diagnose adrenal fatigue
based on symptoms alone; scoring systems are suggested.
Providers or patients themselves can also order a salivary
cortisol profile in which multiple salivary cortisol samples are
collected throughout the day and submitted to a lab for
analysis (for a price); if the salivary cortisol levels fall below
a normative line, the diagnosis of adrenal fatigue is said to be
confirmed.
Importantly, adrenal fatigue has never been scientifically
proven to exist. Furthermore, salivary cortisol profiles have
never been tested scientifically or validated in any way as a
tool to evaluate insufficiency of the HPA axis. As clinician-
scientists, we must be open to novel ideas and proposals. But
rigorous verification by well-designed and well-conducted
scientific investigations must still be the standard by which
we evaluate and clinically apply new and innovative ideas. It
is not sufficient, when patients’ health and wellbeing are con-
cerned, to simply propose a hypothesis and then apply it
without diligent scientific investigation.
Proposed treatment recommendations start with a healthy
well-balanced diet, regular exercise, good sleep habits, stress
reduction, and cessation of smoking and alcohol use. Most of
us would never object to any of these measures. This is the
same advice we give to almost all patients, regardless of the
diagnosis. Patients are certainly likely to feel better and have
improved quality of life if they follow these recommenda-
tions. But adrenal fatigue websites and promoters also sug-
gest that patients take supplements. Once again, there is
likely no harm in taking vitamin and mineral supplements as
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long as some (fat-soluble vitamins A, D, E, and K, for exam-
ple) are not taken in excess. But adrenal supplements that
contain whole adrenal tissue or adrenal extracts are also
strongly promoted [12].
The Endocrine Society (Hormone Foundation) has taken
the lead in opposing the promotion of adrenal fatigue by
practitioners and websites [7–10]. The Hormone Foundation
website and its printed literature provide patients with the
following clear warnings: “No scientific proof exists to
support adrenal fatigue as a true medical condition.” “Doctors
are concerned that if you are told you have this condition, the
real cause of your symptoms may not be found and treated
correctly.” “Doctors urge you not to waste precious time
accepting an unproven diagnosis such as ‘adrenal fatigue’ if
you feel tired, weak, or depressed. If you have these symp-
toms, you may have adrenal insufficiency, depression, obstruc-
tive sleep apnea, or other health problems. Getting a real
diagnosis is very important to help you feel better and over-
come your health problem.” And finally, “If you take adrenal
hormone supplements when you don’t need them, your adre-
nal glands may stop working and become unable to make the
hormones you need when you are under physical stress.
When these supplements are stopped, a person’s adrenal
glands can remain ‘asleep’ for months. People with this prob-
lem may be in danger of developing a life-threatening condi-
tion called adrenal crisis.”
The Mayo Clinic website also has the following strong
statements [11]: “The term often shows up in popular health
books and on alternative medicine websites, but it isn’t an
accepted medical diagnosis.” And, “It’s frustrating to have
persistent symptoms your doctor can’t readily explain. But
accepting a medically unrecognized diagnosis from an
unqualified practitioner could be worse. Unproven remedies
for so-called adrenal fatigue may leave you feeling sicker,
while the real cause– such as depression or fibromyalgia–
continues to take its toll.”
Despite this public criticism, proponents of adrenal fatigue
continue to advertise and promote (and financially benefit
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from) this fabricated disorder. Websites openly display sleep-
ing men and women, young people who are so completely
exhausted (from adrenal fatigue) that they have fallen asleep
on their couches, at their desks, and on logs out in the forest.
They promote symptom scores and the unvalidated salivary
cortisol profile to make the diagnosis. And they entice vulner-
able patients with online access (for a price) to unproven and
potentially dangerous products labeled as “Made from raw,
cold-processed bovine glandular tissue”; “Raw Adrenal
Glandular Concentrate”; “Natural glandular”; “Blend of
glandulars, herbs, vitamins, and more” [12]. This type of
pseudo-science circus is well described and denounced as
fraudulent and harmful by Dr. Lisa Pryor in her excellent
article in the New York Times (Jan 5, 2018) [13].
Back toOur Patient
This patient has severe fatigue and poor quality of life. She is
not responsible for the misinformation she has received or
believed about adrenal fatigue from other practitioners or
the Internet. She has just come to ask for help. She deserves
respect, honesty, and compassion like all other patients. We
should listen carefully to her symptoms, concerns, and frustra-
tions and assure her that we are committed to helping her
find relief for her symptoms. A complete and skillful physical
examination is always an important component of the evalu-
ation. We should then review previous lab tests and order
additional lab tests, if appropriate, especially if the prior labs
showed equivocal results, were done at the wrong time of day,
were run in an unfamiliar laboratory, or if there is any ques-
tion about possible assay interference from supplements. An
ACTH stimulation test (see above) may be considered. If not
already done, testing for other endocrine-related and meta-
bolic conditions, such as diabetes mellitus, calcium abnor-
malities, hypogonadism, celiac disease, vitamin D deficiency,
vitamin B12 deficiency, sleep apnea, and depression can be
considered. Some testing may be more appropriately done by
the patient’s primary care provider.
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Regardless of the diagnosis, we should always emphasize
the importance of healthy lifestyle measures to include good
nutrition, regular exercise, good sleep habits, smoking cessa-
tion, moderation or cessation of alcohol consumption, stress
reduction and stress management, and treatment of other
coexisting illnesses (endocrine, general medical, psychiatric),
if present. Management of non-endocrine related conditions
by the primary care provider should be strongly encouraged.
We should also educate patients regarding medical infor-
mation they find on the Internet and that they should always
verify the source of the information in order to evaluate its
credibility. This patient should be informed, but not lectured,
that adrenal fatigue is not a real disorder and that salivary
cortisol profiles have never been validated as a tool to evalu-
ate adrenal insufficiency, whether they are ordered by another
practitioner or are self-ordered from a website. And she
should be advised that there is no credible evidence that adre-
nal supplements are beneficial. Furthermore, those products
that contain whole adrenal glands or adrenal extracts actually
contain steroid hormones that can suppress their own natural
adrenal function and can also, depending on the amount of
steroid hormones present, lead to steroid-related complica-
tions such as diabetes mellitus, osteoporosis, hypertension,
hyperlipidemia, peptic ulcer disease, and glaucoma. We should
respect the patient’s initiative to investigate and implement
measures to improve her/his quality of life but must empha-
size our core value of practicing evidence-based medicine and
the ethical responsibility we have to recommend tests and
treatments that have proven efficacy and safety.
Consistent with these views, Dr. Rashmi Mullur published
an excellent commentary on the management of adrenal
fatigue in 2018 [14]. Stemming from her own experiences, she
advises against lengthy or detailed explanations of adrenal
physiology and the absence of evidence for the existence of
adrenal fatigue and focusing instead on the actual needs of
the patient with compassionate listening, an emphasis on
healthy lifestyle measures and discussion of alternative
approaches to reduce stress and mitigate the lingering effects
of past emotional and/or physical trauma [14].
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Satisfactory outcomes for these patients are clearly facili-
tated by the development of an honest, respectful, supportive,
and compassionate relationship with their physician. As I
have emphasized before, it is an honor that patients entrust
their health to us and value our expertise. In return, our goal
should be to do our best to improve their quality of life, even
if there is no apparent endocrine disorder. This doesn’t mean
that we should take over the management of areas that are
more appropriate for their primary care provider or other
specialists. But it does mean that we should make it clear that
we believe they are struggling with their symptoms, that we
are concerned about their health and welfare, that we would
like to be part of the solution if their condition is endocrine
based, and that, while we strongly believe in innovative and
individualized solutions, we have an obligation to provide
them with the best evidence-based advice possible.
References
1. Bornstein SR, Allolio B, Arlt W, etal. Diagnosis and treatment
of primary adrenal insufficiency: an Endocrine Society clinical
practice guideline. J Clin Endocrinol Metab. 2016;101:364–89.
2. Oltmanns KM, Fehm HL, Peters A. Chronic fentanyl appli-
cation induces adrenocortical insufficiency. J Intern Med.
2005;257:478–80.
3. Donegan D, Bancos I. Opioid-induced adrenal insufficiency.
Mayo Clin Proc. 2018;93(7):937–44.
4. Ospina NS, Nofal AA, Bancos I, etal. ACTH stimulation tests
for the diagnosis of adrenal insufficiency: systematic review and
meta-analysis. J Clin Endocrinol Metab. 2016;101:427–34.
5. De Bellis A, Bizzaro A, Rossi R, etal. Remission of subclinical
adrenocortical failure in subjects with adrenal autoantibodies. J
Clin Endocrinol Metab. 1993;76:1002–7.
6. Baker PR, Nanduri P, Gottlieb PA, et al. Predicting the onset
of Addison’s disease: ACTH, renin, cortisol and 21-hydroxylase
autoantibodies. Clin Endocrinol. 2012;76(5):617–24.
M. T. McDermott
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137
7. Hormone Foundation (Endocrine Society) Website – Adrenal
Fatigue. https://www.hormone.org/-/media/hormone/files/myth-
vs-fact/mfsadrenalfatigue-520.pdf?la=en.
8. Hormone Health Network Adrenal Fatigue Fact Sheet. www.
hormone.org/diseases-and-conditions/adrenal/adrenal-fatigue.
9. Schaffer R. In age of Internet diagnoses, endocrinologists
confront myth of “adrenal fatigue”. Endocrine Today, April
2018:1–12.
10. Seaborg E.The myth of adrenal fatigue. Endocrine News, Sept
2017: 29–32.
11. Mayo Clinic Website – Adrenal Fatigue. https://www.mayo-
clinic.org/diseases-conditions/addisons-disease/expert-answers/
adrenal-fatigue/faq-20057906.
12. Akturk HD, Chindris AM, Hines JM, Singh RJ, Bernet
VJ. Over-the-counter “adrenal support” supplements contain
thyroid and steroid-based adrenal hormones. Mayo Clin Proc.
2018;93(3):284–90.
13. Pryor L.How to counter the circus of pseudoscience. NewYork
Times, Jan 5, 2018.
14. Muller RS.Making a difference in adrenal fatigue. Endocr Pract.
2018;24(12):1103–5.
Chapter 11. Adrenal Fatigue
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