Fatigue, Pain, and Inflammation: The
Clinical Diagnosis and Treatment of
Cortisol Deficiency
Summary
1. Partial cortisol deficiency is common, especially among women and is a frequent cause
of fatigue, pain, depression, anxiety, headaches and cognitive dysfunction.
2. Cortisol deficiency has a much larger role in many medical diseases and disorders than
currently appreciated.
3. The current approaches to the diagnosis and treatment of cortisol deficiency are
ineffective.
4. Saliva cortisol testing is the most accurate and sensitive way to assess cortisol status.
5. The diagnosis and treatment of cortisol deficiency must be based upon clinical criteria.
6. DHEA restoration is medically necessary in all persons on long-term glucocorticoid
therapy.
“It is important to emphasize that none of the tests (for adrenal insufficiency) will be perfect
and therefore, clinical judgment should prevail in patients with significant symptoms and
apparently normal or equivocal biochemical data.”1
1. The Cortisol Connection
Primary care and specialist physicians frequently see patients who suffer from symptoms,
many and varied, for which no medical explanation exists. These patients are most often female
and complain of fatigue, anxiety, pain, headache, irritability, insomnia, and cognitive
dysfunction. Their symptoms worsen premenstrually and under stress. Lacking any causal
explanation, physicians give these patients diagnostic labels and prescribe medications that may
suppress the symptoms. However, the physician should always seek the cause. I contend that
these disorders and many other unexplained symptoms are often due, in full or in part, to
deficient cortisol action in the body and brain; a hormone deficiency is not suspected and
cannot be diagnosed given current assumptions and practices.
1
Cortisol is a major hormone with many known and unknown effects in every tissue in the
body. Many hundreds of genes have been identified which are induced or repressed by cortisol.
Cortisol’s primary function is to maintain homeostasis under stress; to allow the organism to
meet the demands of its environment. Cortisol
assures the availability of glucose by stimulating
Table 1. Symptoms of Cortisol
gluconeogenesis. It moderates our immune system
Deficiency
activity, assuring sufficient response to infection
Fatigue— “adrenal fatigue”
while preventing excessive reactions to the
Depression, anxiety, irritability
environment and our own tissues. Cortisol secretion
Headaches: tension and migraine
has a strong diurnal pattern, levels are highest after
Myalgias and arthralgias
awakening and decline throughout the day. Free
Muscle stiffness and weakness
cortisol levels vary ten-fold in a normal day and can
Cognitive dysfunction-“brain fog”
increase several-fold under stress. ACTH and cortisol
Poor recovery from exertion
secretion are increased by stress, activity, eating,
Insomnia—frequent awakening
infection, inflammation and injury. Cortisol secretion
Hot flashes
is increased by many natural and artificial
Palpitations, tachyarrhythmias
substances. The range and complexity of cortisol’s
Nausea
actions are apparent in the wide variety of physical
Diarrhea, irritable bowel syndrome
and psychiatric problems caused by cortisol
Hypoglycemia
deficiency (CD). (See Table 1.) CD sufferers do not
Hypersensitivity to pain, light, noise
have the physical and mental/emotional stamina
Food and environmental sensitivities
needed to live an active life. They have deep feeling
of fatigue that is usually worse in the daytime and improves in the evening. They do not recover
well from stress or physical activity. They are overly sensitive to environmental stressors—noise,
light, chemicals, heat or cold. They often have pain—usually muscle/joint aches and/or
headaches. They frequently complain of cognitive dysfunction—of not being able to think clearly
or concentrate well during some hours of the day. They often have gastrointestinal disturbances
including nausea, vomiting, diarrhea, bloating or irritable bowel syndrome. In women with
adrenal insufficiency (AI) DHEAS levels are low producing androgen deficiency: low libido, loss of
body hair and muscle weakness. I will discuss the scientific literature and my own experience
with using sensitive laboratory and clinical criteria to diagnose and treat cortisol deficiency.
2. Cortisol-Thyroid Interaction
The diagnosis and treatment of CD is complicated by the very strong interaction between
cortisol and thyroid hormone. Cortisol status cannot be considered in isolation from thyroid
status. Cortisol and T3 are the most powerful hormones in the human body and they both
facilitate and counteract each other in various ways. Of these two hormones, I view cortisol as
more fundamental, as the foundation of the endocrine system because not only T3 but most
major hormones counteract cortisol production and/or action: DHEA, growth hormone,
estradiol, progesterone, and testosterone in descending degrees. Negative constitutional
reactions to the replacement of any of these hormones are usually due to CD. Cortisol also
counteracts all these hormones and their actions in various ways. The apparent hypercortisolism
of many adults (increased visceral fat, hypertension, insulin resistance, etc.) is not due to
excessive cortisol levels but to the age-related declines in hormones that oppose cortisol’s
actions.
2
In CD, both TSH and T4-to-T3 conversion are increased,2 perhaps due to insufficient T3 action
at its nuclear receptors.3 Sufficient cortisol is necessary for thyroid hormone action, but higher
cortisol levels reduce TSH secretion4 and T4-to-T3 conversion.5 Glucocorticoids (GCs) worsen
hypothyroidism and are an effective treatment for hyperthyroidism. Thyroid hormone also
counteracts cortisol. Higher T3 levels and effects increase both the body’s need for cortisol and
metabolism of cortisol. It is well known that
thyroid replacement worsens CD/AI. Thus the
Abbreviations:
appearance of hypocortisolemic symptoms
CD
cortisol deficiency
with thyroid replacement exposes an
CS
cortisol supplementation
underlying CD. Most “negative reactions” to
AI
adrenal insufficiency
thyroid replacement are due to undiagnosed
ACTH
adrenocorticotrophic hormone
CD. Hypothyroidism also masks the clinical
HP
hypothalamic-pituitary
evidence of CD, and vice versa. Classical
HPA
hypothalamic-pituitary-adrenal
hypothyroidism is seen in the presence of
HC
hydrocortisone (cortisol)
cortisol sufficiency and has many of the signs
GC
glucocorticoid
of cortisol excess: edematous appearance,
DHEA(S) dehydroepiandrosterone(sulfate)
hypertension, weight gain, etc. However,
hypothyroid patients who have CD present with atypical signs and symptoms; they are often
thin and have hyperadrenergic symptoms. While hypothyroidism initially raises cortisol levels
through reduced metabolism and negative feedback on the HP system,6 cortisol levels
eventually decline. Prolonged hypothyroidism can produce a relative central CD7 that can be
slowly reversed with thyroid replacement. Thus even in persons with CD, I will often attempt to
gradually restore thyroid levels with T4/T3 therapy in hopes that it will correct the CD and avoid
the need for cortisol replacement therapy.
3. The Spectrum of Cortisol Deficiency
The availability of saliva cortisol testing has given us a new window on cortisol and its role in
many disorders. There is an extensive and rapidly-growing literature that documents lower
cortisol levels in many medical and psychiatric
Table 2. Disorders related to
conditions, and beneficial responses to cortisol
Cortisol Deficiency
supplementation. (Table 2.) The majority of persons with
Severe/Critical Illness
lower cortisol levels in these studies do not have AI that
Autoimmune Disease
could be diagnosed by current approaches. Their cortisol
Allergic disorders
and DHEAS levels are not below the laboratory reference
Chronic Fatigue Syndrome
ranges. They simply have lower cortisol levels and/or
Fibromyalgia Syndrome
effects than controls—a relative or partial CD. They do
Depression
not have disease or damage affecting either the adrenal
Post-Traumatic Stress Disorder
glands or the hypothalamic-pituitary (HP) system. These
Violence/Suicide
studies indicate that most persons with CD do not have
Drug addiction
AI. AI is in fact an archaic term. The adrenal glands are
Premenstrual syndromes
highly complex organs; so the diagnosis should reflect the
Post-partum disorders
precise biochemical problem that is found. The medulla
Hyperemesis Gravidarum
produces catecholamines and the cortex produces
various steroid hormones. Cortisol and related molecules
are made in the zona fasciculata, DHEA and other androgens in the zona reticularis, and
aldosterone and other mineralocorticoids in the zona glomerulosa. Only with complete
destruction of both adrenal glands (Addison’s Disease) are there deficiencies of all three steroids
3
and the catecholamines. In central AI (insufficient ACTH production) only cortisol and DHEAS are
deficient; aldosterone secretion is usually maintained by the renin-angiotensin system. Most CD
is due either to a partial central AI or is isolated—a lack of cortisol effect in the body that may
not be associated with low DHEAS levels. The term “CD” rather than “AI” should be used
whenever referring to the effects of a relative lack of cortisol. More than any other hormone,
cortisol action in the tissues depends upon many hormonal and non-hormonal factors. CD must
always remain a clinical diagnosis based upon evidence of a lack of cortisol effect in the body.
CD may or may not be reflected in lower cortisol levels.
3.1. The Female Problem with Cortisol
The female hormonal system is adapted to childbearing and breastfeeding, not to optimal
physical and mental performance under stress, as is the male hormonal system. The physician
who makes an effort to diagnose and treat CD will quickly notice that it is much more common
in women. Many studies have found that, compared to men, women make less cortisol, have
lower cortisol levels, and have lower cortisol responses to stress.8,9,10,11,12,13,14 However, one
large study of saliva cortisol levels found higher levels in women than in men.15 Male-to-female
estrogen therapy reduces serum cortisol levels by 50%.16 Estradiol reduces the adrenal
production of cortisol by inhibiting 3-beta
hydroxysteroid dehydrogenase (HSD),17 and reduces
Table 3. Female:Male Ratios
the local, intracellular generation of cortisol from
Non-immune disorders:
cortisone by inhibiting 11-beta HSD-1.18 Estrogen
Fibromyalgia 8:1
supplementation
reduces
cortisol
levels
in
Multiple Chemical Sensitivity 8:1
19
postmenopausal women. This relative lack of cortisol
Chronic fatigue syndrome 4:1
effect allows the progression of inflammation,20,21
Depression 2:1
making women more susceptible to autoimmune
Anxiety 3:2
disorders. This relative CD is a sufficient explanation
Autoimmune diseases:
for women’s greater tendency to suffer from fatigue,
Sjögren’s syndrome 18:1
anxiety, depression, fibromyalgia, and various other
Systemic Lupus Erythematosis 9:1
disorders. (Table 3.) It explains why obsessiveHashimoto's/Graves thyroiditis 5:1
compulsive symptoms in women are worse when
Rheumatoid arthritis 3:1
estrogen levels are higher, after menarche and
Multiple Sclerosis 3:1
premenstrually, or when cortisol levels are lower
Polymyalgia Rheumatica 2:1
postpartum.22 It explains why so many women are
Inflammatory Bowel Disease 1.3:1
prescribed antidepressants that boost cortisol levels
and progestins with glucocorticoid activity,23,24 and the withdrawal syndromes that occur with
stopping antidepressants and some oral contraceptives.25
The premenstrual syndrome and premenstrual dysphoric disorder are related to CD. Women
with PMS have higher DHEAS levels compared to controls,26 and DHEA counteracts estradiol.
Progesterone modulates cortisol actions in the body. Progesterone is a partial agonist at the
cortisol receptor.27 Higher concentrations can reduce cortisol effect by competitive inhibition;
but in the presence of severe CD, progesterone activates the cortisol receptor, alleviating
symptoms. I believe this is why, in some women, progesterone alone can markedly improve
mood and energy. Progesterone can also facilitate cortisol action by increasing cortisol transport
into cells, particularly in the brain.28
In the luteal phase, the higher estradiol and progesterone levels counteract cortisol
production and action producing hypocortisolemic symptoms: irritability, anxiety, fatigue, hot
flashes, myalgias, etc. Women with these disorders have indeed been found to have lower
cortisol levels.29,30,31 Sufficient cortisol antagonizes estrogen’s stimulatory effect on the
4
endometrium;32 so with CD there is excessive endometrial proliferation that can lead to
endometriosis. Endometriosis and pelvic pain have been related to CD.33,34
The female predisposition to CD also explains some of the problems of pregnancy and the
postpartum state. The first trimester of pregnancy is a time of relative hyperthyroidism due to
the TSH-like effect of chorionic gonadotropin.35 Higher thyroid hormone levels produce a
relative CD, and thus the morning nausea in the first trimester. Hyperemesis gravidarum, is
associated with lower cortisol levels36 and is effectively treated with cortisol (hydrocortisone)
supplementation.37,38 Later in pregnancy the placenta produces corticotrophin-releasing
hormone (CRH), doubling maternal free cortisol levels, eliminating the nausea, reducing the
chance of maternal-fetal immune reactions, and preparing the mother for childbirth.39 These
large transformations in cortisol and thyroid production and effects explain why some women
feel much better and some much worse during pregnancy, or during different times in the
pregnancy. After delivery cortisol levels drop because the mother’s CRH-ACTH production was
suppressed during pregnancy and can take time to recover. Cortisol levels can remain low for
weeks and this postpartum CD contributes both to postpartum depression40,41 and the increased
incidence of autoimmune disorders in this period.42,43 Breastfeeding after pregnancy is
efficacious in this regard as it suppresses ovarian function, keeping estradiol and progesterone
levels low for months.
3.2. Severe and Critical Illness
Severely ill patients often improve remarkably with short-term, high-dose GC therapy.
Sufficient cortisol effect is necessary to protect against the lethal effects of cytokines released
during fever, infection or inflammatory stress.44 A majority of critically-ill children have not just
relatively inadequate, but actually low free cortisol levels indicative of CD.45 Severe
hyponatremia is often due to CD and resolves with hydrocortisone therapy.46 Physicians also
prescribe various GCs, by various routes, for severe or persistent allergic reactions,
inflammatory disorders, viral and bacterial infections and pain syndromes. Even in acute
infections the benefits of GC therapy often outweigh the anti-immune effects. Every
prescription for a GC is an endocrine intervention; the physician diagnoses a relative deficiency
of cortisol action in the body and corrects it. Patients who benefit from GC therapy were not
producing sufficient cortisol at the time; additional cortisol effect was required to restore
homeostasis. Viewed in this light, hydrocortisone (HC), the body’s natural GC, may produce
greater benefits with less negative effects in most cases, especially when available in a longacting oral forms of various strengths.
3.3. Chronic Fatigue
Fatigue can have many causes; a common cause in my experience is undiagnosed or
undertreated hypothyroidism. Chronic fatigue syndrome (CFS) has been frequently related to
low cortisol levels and to improvement with cortisol supplementation. Many studies show that
CFS patients tend to have lower cortisol levels than controls,47,48,49,50 lower cortisol responses to
low-dose ACTH stimulation testing,51 and lower DHEA and DHEAS levels.52,53 A majority of
patients with fatigue plus other hypocortisolemic symptoms, AM serum cortisol levels
<14.5mcg/dL (range 5-25mcg/dL), and low or normal ACTH levels had deficient cortisol
responses to insulin tolerance testing; they had partial central CD.54 The CD in CFS is usually due
to HP dysfunction of unknown cause.55,56,57,58 CFS sufferers have lower 24hr. and AM peak ACTH
levels59 and enhanced feedback suppression of cortisol secretion with prednisolone.60 Single
nucleotide polymorphisms have also been found in the glucocorticoid receptor gene61 and
cortisol-binding-globulin (CBG) gene.62
5
Subphysiological doses of HC, 5mg or 10mg daily, reduce disability in CFS patients63 and
replacement doses of 25 to 35mg/day produce significant improvements.64 Some studies show
no benefit.65 There are many pitfalls in the interpretation of studies of endocrine treatment for
various disorders. The patients are usually neither diagnosed with the hormone deficiency nor
given individualized treatment. Physiological cortisol replacement therapy will only help those
with CD, it will not help others and could make them worse; e.g. if they have hypothyroidism.
Fixed-dose endocrine therapy studies are liable to produce underdosing and overdosing in many
patients. Subphysiological cortisol doses can worsen central CD as the unnatural serum peaks
over-suppress ACTH and cortisol production for hours. Any cortisol supplementation reduces
ACTH levels and thereby DHEA and, to a lesser extent, aldosterone production; potentially
causing additional symptoms in some persons. There is no substitute for clinical diagnosis and
individualized treatment. All existing hormone and nutrient deficiencies must be diagnosed and
corrected in an effort to restore the patient’s physiology to a healthy state.
3.4. Fibromyalgia
Fibromyalgia syndrome (FMS) is characterized by diffuse pain, fatigue, reduced exercise
capacity, cold intolerance and sleep disturbances. The vast majority of sufferers are women—
yet medicine has failed to determine the cause. The symptoms of FMS do occur in various
hormone deficiencies: CD, hypothyroidism, androgen deficiency, and growth hormone
deficiency. Persons with certain rheumatic diseases, such as rheumatoid arthritis, systemic lupus
erythematosis or ankylosing spondylitis are more likely to have FMS. FMS has been repeatedly
related to lower serum and saliva cortisol levels,66,67,68,69 lower expression of cortisol receptors
and a higher incidence of cortisol receptor polymorphisms,70 lower peak cortisol responses to
ACTH stimulation and insulin tolerance testing,71 a hyperreactive ACTH response to CRH, and
glucocorticoid feedback resistance.72 Patients often relate the onset of their pain to a physically
or emotionally stressful or traumatic event, such as an automobile accident. It is theorized that
in FMS there is a chronic stress-induced CRH excess that eventually fails to raise cortisol levels
but increases somatostatin secretion, thereby inhibiting both growth hormone and TSH
secretion.73 Many persons with FMS have cortisol, androgen, or growth hormone levels in the
lower part of their reference ranges.74 FMS has also been related to insufficient thyroid
hormone levels or effects.75,76,77
Patients with FMS or rheumatoid arthritis have a higher incidence of thyroid
autoimmunity,78,79 suggesting insufficient cortisol. Like many CFS patients, many FMS patients
have low blood pressure and heart rate responses to tilt table testing.80 This neurally-mediated
hypotension can be produced by cortisol and aldosterone deficiencies. It behooves the physician
to rule out cortisol and thyroid deficiency in any person with CFS or FMS. In my experience,
most patients given such labels have CD, hypothyroidism, iron and/or sex hormone deficiencies
and respond well to their correction. Fibromyalgia is known to be frequently associated with
other disorders painful conditions: chronic fatigue syndrome, endometriosis, inflammatory
bowel disease, interstitial cystitis, temporomandibular joint dysfunction, and vulvodynia. All of
these are causally related to cortisol deficiency.
3.5. Anxiety, Depression, and Anti-Depressants
Increased cortisol secretion is the appropriate and necessary physiological response to stress.
Insufficient cortisol produces anxiety and an inability to cope with stress. Glucocorticoid
administration and higher endogenous cortisol production reduce fear in response to phobic
stimuli and re-exposure to the stimulus.81 Low saliva cortisol levels combined with stressful life
events are associated with subsequent psychopathology.82 Panic disorder patients show a
6
striking lack of cortisol increase in response to stress.83 Peritraumatic cortisol elevation protects
against the development of post-traumatic stress disorder (PTSD).84,85 Persons with PTSD and
those under chronic stress have lower cortisol levels than controls.86,87,88,89,90,91 PTSD suffers have
lower ACTH responses to metyrapone.92 Low-dose hydrocortisone (<20mg/day) reduces the
cardinal symptoms of PTSD93 and improves brain metabolism and working memory.94
Depressive disorders have been associated with disturbances of the thyroid, adrenal, and
gonadal hormone systems. Dysregulation of mineralocorticoid and glucocorticoid receptors are
causative in the pathogenesis of depression.95 The only biochemical abnormality consistently
seen in major depression is dysregulation of the HPA axis with higher nighttime cortisol levels
and lack of cortisol suppression with dexamethasone. Major depression may be due, in part, to
dysfunction of glucocorticoid receptors in the CNS and a resultant lack of cortisol effect in the
brain.96 Women in remission from a major depression episode have lower morning saliva
cortisol levels and lower ACTH and cortisol responses to stress, indicating a hypoactive HPA
axis.97 Atypical depression is more common than major depression and has been frequently
associated with low cortisol levels.98,99,100 There appears to be an exaggerated negative feedback
regulation of the HPA axis.101 In treatment-resistant depression with fatigue and low-normal
serum cortisol levels, prednisone (7.5mg/day) produces significant improvement.102 Asthma
patients with depression have improved mood during prednisone bursts.103
Antidepressant medications have been repeatedly shown to enhance glucocorticoid
signaling.104,105 They increase the access of cortisol to the brain and reduce CRH production.106
Desipramine, a older tricyclic antidepressant, increases cortisol levels in normals107 and in
patients with atypical depression.108 Monoamine oxidase inhibitors impair the negative
feedback of cortisol, increasing adrenocortical responsiveness to ACTH and reversing the
endocrine and psychiatric manifestations of CD in atypical depression.109 Sertraline, one of the
newer selective serotonin reuptake inhibitors (SSRIs) increases both plasma cortisol and T3
levels in depressed patients110 and increases cortisol levels in controls.111 Paroxetine, citalopram,
escitalopram and fluoxetine increase cortisol levels in controls.112,113,114,115 Consider that many of
the various symptoms that improve with antidepressant therapy are hypocortisolemic: fatigue,
anxiety, panic attacks, myalgias-arthralgias, irritability, insomnia, etc. The induced increase in
ACTH and therefore cortisol production while taking SSRIs also may play a role in their
withdrawal syndromes—which resemble the symptoms of CD.
3.6. Drug Addiction
The secretion of ACTH and cortisol are affected by many natural and artificial substances.
Many legal and illegal drugs boost cortisol levels. High-nicotine cigarette smoking markedly
increases ACTH secretion and cortisol levels116 in both nicotine-naive117 and chronic smokers.118
Nicotine-withdrawal symptoms and the likelihood of relapse have been associated with lower
cortisol levels.119 CD therefore is a likely contributor to nicotine addiction and withdrawal.
Notice that one of the most effective treatments for nicotine addiction and withdrawal is an
SSRI. Our obsession with coffee is also related to cortisol. Two to three cups of coffee raise ACTH
and cortisol levels by 30%.120
The increase in cortisol with legal substances is small compared to some street drugs.
Persons with CD will feel much better with using any drug that raises cortisol levels, and absent
the drug cortisol levels will fall to low levels, motivating then to continue using the drug. Cocaine
increases ACTH and cortisol secretion,121 and this cortisol response is necessary for initiating and
sustaining addiction.122 Ecstasy (MDMA) increases cortisol and DHEAS levels,123 most likely
through serotonin-induced124 increases in ACTH. Cortisol levels rise by 800% when danceclubbing on the drug whereas dance-clubbing alone has no effect.125 Marijuana stimulates ACTH
7
and cortisol secretion acutely in human studies,126,127,128 accounting for its ability to produce a
feeling of calm and well-being. Alcohol addiction is also related to cortisol in a more complex
way. Alcohol levels above 100mg/dl induce higher cortisol levels, which remain high with
continued intoxication.129,130 Abstinent alcoholics have lower cortisol levels than controls131 and
lower ACTH and cortisol responses to insulin and CRH.132 The reduction in HPA reactivity in the
abstinent state contributes to the likelihood of relapse; alcoholics may drink again to increase
their cortisol secretion.133 Dextroamphetamine134 and related drugs (methamphetamine, Ritalin,
Provigil, etc.) raise cortisol levels by a non-ACTH mechanism.135 Methamphetamine doubles
cortisol levels in primates.136 Methamphetamine users have lower basal cortisol levels137 and
when abstinent, have a reduced adrenocortical responsiveness to ACTH.138 In my experience,
many persons with undiagnosed CD or hypothyroidism are often prescribed amphetamines to
alleviate their fatigue and improve their cognitive dysfunction.
3.7. Autoimmune Disease
Persons with active inflammation require higher cortisol levels/effects than healthy persons,
but instead they usually have similar or lower cortisol levels; a relative CD.139 Significantly lower
basal ACTH and cortisol levels are found in Sjögren’s syndrome,140,141 and patients with
ankylosing spondylitis have inadequate responses to low-dose ACTH stimulation testing,
indicating subclinical CD.142 Patients with untreated polymyalgia rheumatica have similar cortisol
but lower DHEAS levels than controls143 and lower cortisol responses to low-dose ACTH
stimulation testing.144 Low cortisol levels are found in systemic lupus erythematosis.145 Patients
with rheumatoid arthritis (RA) also have inappropriately low cortisol levels, elevated IL-6 levels,
and an inadequate cortisol response to surgical stress.146,147 Half of premenopausal women with
RA have lower-quartile serum cortisol and DHEAS levels.148 RA patients have impaired cortisol
secretion in the presence of intact ACTH secretion; probably secondary to the inflammatory
disease process.149 Patients with active juvenile RA also have lower ACTH and cortisol levels.150
Tumor necrosis factor-alpha (TNF) inhibits CRF-stimulated ACTH production.151 The increased
levels of TNF with chronic inflammation reduce ACTH secretion and the cortisol response to
ACTH, thus setting up a vicious cycle of inflammation: more TNF produces lower cortisol and
DHEAS levels, which produce more inflammation and more TNF. The anti-TNF medications
(Humira, Enbrel, etc.) work, to some extent, by interrupting this vicious cycle and thus increasing
cortisol levels/effects. Patients with the lowest baseline cortisol levels and best cortisol response
to anti-TNF therapy have the best therapeutic response.152 Long-term anti-TNF treatment
increases cortisol levels relative to other adrenal hormones,153 increases ACTH secretion and
normalizes adrenal androgen secretion.154 It is plausible that sufficient cortisol and DHEA
supplementation to control inflammation and restore quality of life would be a much more
effective treatment for most patients. Some experts have indeed recommended that the
treatment of RA should include the optimization of cortisol, DHEA, and testosterone levels and
effects.155 Experts have argued that the benefits of low-dose GC treatment in RA and other
autoimmune diseases outweigh the risks.156,157,158 The major impediment to long-term cortisol
supplementation is indeed the fear of the side-effects of long-term GC therapy. I will show
below that these problems can all be minimized or eliminated by prescribing the correct human
hormone, cortisol-hydrocortisone, in clinically-adjusted doses, accompanied by the restoration
of DHEA and the anabolic sex steroids as indicated. In my experience, persons with autoimmune
diseases, particularly those with lower cortisol levels, respond remarkably well to cortisol-DHEA
supplementation.
8
4. The Causes of Cortisol Deficiency
The majority of hormone deficiencies are not due to destruction of the primary gland or HP
system, but are due to dysfunction of HP-primary gland system of unknown cause. This should
be expected: HP function is highly complex and fallible. It is part of the brain and affected by
inputs from many areas of the brain. Both HP and primary gland function deteriorate with age,
producing declines in most major hormones. Most male hypogonadism is central, and the
sensitivity of the HP system to low thyroid levels declines markedly with age. 159 The HPA
system’s complex neurochemistry is altered by many natural and unnatural substances, known
and unknown. We live in a chemical soup; we have hundreds if not thousands of recentlyinvented molecules in our bodies, many of which can act as neural and endocrine disruptors.
When it comes to cortisol, the HP system is not the whole story; the sensitivity of the adrenal
glands to ACTH is affected by direct neural influence via the splanchnic nerve.160
Cortisol is our primary stress-response hormone, and while moderate chronic stress, such as
lower socioeconomic position, causes higher cortisol levels,161 severe chronic stress often causes
lower cortisol levels.162,163,164 On mechanism may be reduction in the catabolism of cortisol in
some tissues, leading to less cortisol production by the HP-adrenal system, and relative
deficiency of cortisol action in the central nervous system. 165 Chronic excessive CRH production
by the hypothalamus leads to downregulation of the pituitary ACTH response and
glucocorticoid-receptor resistance.166,167,168 These maladaptive responses to chronic stress are
explained by a model of the HP system that posits two stable states: a normal state of low
glucocorticoid receptor (GR) concentration, and an abnormal state of high GR concentration. In
the first state stress causes higher cortisol levels and an increase in GR concentration. With the
end of the stress GR concentration returns to normal. However, prolonged stress induces a
permanent high-GR concentration state. The excess of GRs in the HP system causes enhanced
feedback inhibition of ACTH and cortisol secretion resulting in a partial central CD.169 Patients
frequently relate that their problems began after prolonged stress or a serious illness.
We are becoming increasingly aware of the complexity of hormone production, feedback
control, transportation, receptors, effector proteins, etc. Splanchnic innervations of the adrenal
gland has both stimulatory and inhibitory effects on cortisol secretion.170 The suprachiasmatic
nucleus in the brain affect the adrenal cortex’s sensitivity to ACTH via innervation.171 Any one of
the proteins needed for hormone action can be affected by single nucleotide polymorphisms.
These can alter receptor and effector proteins including transcription factors in a tissue-specific
manner. A person may have hormone resistance in some tissues but not in the HP system. They
can have deficient hormone effect in some or most tissues yet normal hormone levels. The
activity of cortisol is modified within cells throughout the body by the amounts and activity of
the isoenzymes 11-beta HSD-1 and 11-beta HSD-2, which interconvert inert cortisone and active
cortisol. These enzymes’ induction and activity are affected by many factors including other
hormones. DHEA inhibits the conversion of inactive cortisone to cortisol via its competition for
binding sites on 11-beta HSD-1, thus reducing peripheral cortisol production.172,173 11-beta HSD2 is prevalent in the kidneys were it inactivates cortisol to cortisone, protecting the
mineralocorticoid receptor from stimulation by cortisol. Aberrant expression or action of these
isozymes is involved in the pathogenesis disorders with excess cortisol effect including
hypertension, insulin resistance and obesity,174 and no doubt also in disorders of deficient
cortisol effect. The extent of this pre-receptor intracellular metabolism and the existence of
polymorphisms of the GR, cortisol-binding globulin (CBG) and other cortisol-related proteins
means that neither serum nor saliva cortisol levels can fully reflect cortisol action in the body as
a whole or in specific tissues. This is consistent with the author’s experience; some persons with
9
marked symptoms of CD and a beneficial response to cortisol supplementation do not have low
saliva and serum cortisol levels.
5. The Diagnosis of Cortisol Deficiency
The current approach to the diagnosis of CD is extremely insensitive. CD is not even
considered as a primary diagnosis. Conventional endocrinology recognizes only primary or
central AI caused by damage or disease. Isolated ACTH deficiency is assumed to be rare and
confined to persons with HP disease or a genetic abnormality.175 AI is thus believed to be rare
and always severe; so physicians do not suspect CD in any “apparently healthy” patient.
Physicians do not suspect AI much at all, persons with classic AI are typically not diagnosed for
many months or even years after the onset of symptoms. They are given many false diagnoses,
usually psychiatric or gastrointestinal.176
Due to the complexity of endocrine systems, the diagnosis and treatment of hormone
deficiencies must always be clinical—based upon signs and symptoms first and free hormone
levels second. The majority of patients I have diagnosed with CD have a partial central AI of
unknown cause. They usually appear quite healthy in the office. They lack both the hypotension
and hyperpigmentation seen in Addison’s Disease. Saliva cortisol levels are usually low-normal
or low (See below.) at some time or times during the day. Occasionally levels are mid-range,
suggesting some resistance to cortisol. The typical diurnal pattern is usually intact. They make
cortisol, but not enough for their needs. DHEAS levels are usually low within the reference range
(50 to 250mcg/dL), and are low in severe cases. AM ACTH levels are usually low-normal,
indicating that the deficiency is central. CD can exist in persons with mid-range, or even with
high DHEAS levels for age as in non-classical congenital adrenal hyperplasia.
Besides the symptoms listed in Table 1. there are other diagnostic clues to the presence of
CD. Since ACTH and cortisol secretion are affected by so many factors, CD varies over time.
Patients can have hours, days, or weeks when they feel essentially normal, but at other times
can barely function. They typically feel worse in
Table 4. Other Clues for CD
the daytime and better in the evening, perhaps
Variability over days, weeks, months
because cortisol levels are naturally lower during
Worsening of symptoms under stress
those hours. This marked variability is not seen
Feels better in the evenings
with hypothyroidism or many other causes of
Worsening of symptoms with thyroid,
fatigue. A patient’s response to exercise can
DHEA, or estradiol supplementation
provide clues. Some CD patients cannot do any
Improvement on glucocorticoids, SSRIs,
physically-demanding tasks because they cannot
amphetamines, some progestins
recover afterwards. Others are able to raise their
Autoimmune disease or antibodies
cortisol levels with exercise.177 They learn that
Allergic disorders
they must exercise to feel well and become
Needs to exercise to feel well
exercise “addicts”. CD sufferers often have a
history of receiving one or more oral GC courses
or injections for their problems. While on GCs their energy and stamina improve and their aches
disappear. They are sometimes debilitated for weeks after stopping the GC due to the
suppression of their already-weak HP system. CD is suggested by the presence of autoimmune
diseases,178 thyroid antibodies,179,180 vitiligo, eczema, allergies, and psoriasis. Another clue is a
worsening of symptoms with thyroid or DHEA supplementation. Postmenopausal women with
CD may feel worse and have more hot flashes when given estradiol replacement therapy.
Medroxyprogesterone and norethindrone have marked GC activity181 and can ameliorate CD. A
history of improvement in the patient’s hypocortisolemic symptoms on SSRIs, amphetamines or
10
illicit drugs also suggests CD. The presence of many hypocortisolemic symptoms (Table 1.)
combined with other clues (Table 4.) makes the diagnosis of CD highly probable. The diagnosis is
confirmed by a positive response to trial of cortisol supplementation. Before discussing therapy,
I will review the various tests that can be done to assess cortisol production and levels.
5.1. The AM Serum Cortisol Test
The assessment of cortisol status is with serum or saliva testing is difficult because cortisol
secretion has a strong diurnal pattern and is dynamically responsive to stressors, activities and
drugs. The serum cortisol level peaks around 30 minutes after awakening, then declines
throughout the rest of the day, reaching its nadir around 2 am when it begins to rise towards
the post-awakening peak. Most of the day’s cortisol is made between 2am to noon, so an
awakening cortisol should best represent the total production for that day. The initial screening
test most physicians perform is an AM serum cortisol, however, it is insensitive test for a
number of reasons.
Figure 1. 24 hr. serum cortisol levels in two volunteers. 182
First it usually a total, not a free serum cortisol. Free serum cortisol testing is now offered
only by a few laboratories. The AM cortisol level also varies according to the quality of sleep the
previous night. A serum cortisol test is also a stressed test. Driving to the laboratory183 and
anticipating a needle-stick can raise the cortisol levels above what they would be absent such
stressors. The AM cortisol level is also influenced by the awakening and light reflexes. Cortisol
rises by 100% when a person is awakened by an alarm clock, and by 39% with spontaneous
awakening.184 No matter what time of day, awakening is associated with a significant increase in
cortisol levels.185 The transition to bright light increases cortisol levels by 50%, no matter what
time of day.186 The awakening and light reflexes may produce a significant cortisol level briefly in
the AM, even though the level remains low before and afterward. Some CD patients have
normal or even high-normal cortisol levels and some energy in the AM, but very low levels and
fatigue the rest of the day.
11
In addition, the reference ranges reported by laboratories for the AM serum cortisol are,
again, just 95%-inclusive studies of “apparently healthy” adults who were not screened for
hypocortisolemic symptoms. The lower and upper limits represent the 2.5 and 97.5 percentiles,
respectively. The resulting ranges are far too broad: typically 5 to 25mcg/dL. Only persons with
severe AI will fall below such a range. A normal AM cortisol does not exclude AI in symptomatic
persons.187 More than half of patients with hypocortisolemic symptoms and an AM cortisol level
<14.5mcg/dL can have AI.188 Some have argued that one should pursue the diagnosis in
symptomatic patients with a level <12mcg/dL.189
5.2. ACTH Stimulation Testing
Given the problems with a spot AM cortisol level and the fear of “steroids” and their side
effects, physicians have sought an objective test that will reliably identify those patients who
require cortisol supplementation. The they have come to rely on dynamic testing of the HPA
axis. This approach is, however, non-physiological. The fact that a person can produce cortisol
levels in the upper part of the AM reference range when artificially stimulated to do so in no
way proves that they actually produce sufficient cortisol for their needs every day. The first
dynamic test for CD was the insulin tolerance test (ITT). It tests the response of the entire HPA
axis, but to only one stimulus—hypoglycemia. The result does not reflect the HPA response to
other stimuli or to normal day-to-day demands. The ITT is the most sensitive dynamic test, but
due to the risks involved and the monitoring required physicians have largely abandoned it for
the rapid ACTH stimulation test (AST). A synthetic analogue of ACTH (Cortrosyn, Cosyntropin,
Synacthen) is injected to stimulate the adrenal glands to produce cortisol. The AST bypasses the
HP system; it tests only the ability of the adrenal glands to produce adequate AM serum cortisol
levels (18 mcg/dL or 500nmol/L) under maximal ACTH stimulation. Notice that the level that
constitutes are normal response is not far above the 12 to 14.5mcg/dL levels that can be seen in
symptomatic CD patients.
The AST is less sensitive than the ITT. A person will fail an AST only if the zona fasciculata is
severely damaged or atrophied (e.g. from severe ACTH deficiency). The conventional, high-dose
AST is performed with 250 mcg; a supermaximal dose. It can stimulate the adrenal cortex to
produce a high-normal serum cortisol level in patients with known central AI190 and incomplete
Addison’s Disease.191 Given its lack of sensitivity, some experts recommend that the AST be
performed with only 1mcg.192 This low-dose AST test (LAST) is more sensitive, although
technically challenging.193 However, a normal response to a LAST also does not rule out recent
or partial central AI.194 It fails to detect mild AI in children.195 50% of symptomatic persons who
passed a LAST failed an overnight metyrapone challenge test.196 The 1mcg dose is still
superphysiological, producing the same 30 min. cortisol levels in adults as 250mcg.197 The lowest
effective dose of Cosyntropin is around 0.03mcg. A group of patients with suspected primary AI
had a normal response to 250mcg but no response at all to 0.06mcg, whereas controls did
respond to the lower dose.198 Since so many patients, even with known AI, have normal AST
results, some experts assert that the ITT should remain the standard dynamic test.199,200
The AST and ITT tests are both unphysiological; persons do not achieve daily cortisol
sufficiency by injecting ACTH or insulin. These tests have no clinical usefulness. CD can, and must
be diagnosed by history, signs and symptoms first, and relative cortisol and DHEAS levels
second. An AM ACTH level done with serum cortisol level will differentiate primary from central
CD. The diagnosis is ultimately confirmed or refuted by a trial of cortisol supplementation.
12
5.3. Serum DHEAS Level
DHEAS levels are generally low-normal or low in cases of central CD. A low DHEAS is a more
sensitive indicator of central CD than the serum cortisol level.201,202 However, one must consider
the breadth of the DHEAS population reference ranges and the fact that DHEAS levels decline
with age. For persons in their 50s and 60s, the reference ranges are 30 to 300mcg/dL and 20200mcg/dL respectively. A DHEAS level in the lower tertile of these ranges in a symptomatic
person should increase one’s suspicion of CD. A low DHEAS does not necessarily imply CD,
DHEAS may be suppressed for months or even permanently after long-term GC treatment.
Some persons with insufficient cortisol levels/effects have normal or high DHEAS levels,
suggesting some defect in their adrenal cortisol production or cortisol receptor/effector
systems. As DHEA counteracts cortisol’s effects in the body, high-normal or high DHEAS levels
can produce symptomatic CD even when cortisol levels appear sufficient.
5.4. Saliva Cortisol
The ideal screening laboratory test for CD would allow us to see the person’s free cortisol
levels throughout a normal day. It would be painless and easy to perform at home. Fortunately
such at test is available. Many studies have shown that saliva cortisol levels are an excellent
indicator of free serum cortisol levels, circumventing changes in CBG caused by medications or
other hormonal disorders.203,204,205,206 Salivary cortisol levels best represent the free, biologically
active, free fraction of cortisol in the serum.207,208,209 and correlate very well with serum cortisol
concentrations throughout the 24hr period.210 Saliva testing can be used to screen for CD211 and
a late-night saliva cortisol is a valuable screening tool for
Table 5: LabCorp’s LC/MS/MS
Cushing’s syndrome/disease.212,213,214 Saliva cortisol testing
Saliva Cortisol Ranges
is also useful in conjunction with dexamethasone
8 am: 0.02-0.60mcg/dL
suppression testing215 and ACTH stimulation testing.216,217,218
Noon: <0.01-0.33mcg/dL
Is it a practical means for assessing HPA function during and
4 pm: 0.01-0.20mcg/dL
after glucocorticoid therapy;219 as useful as the AST.220,221
11pm: <0.01-0.09mcg/dL
Saliva testing is now the gold standard for the assessment
of cortisol deficiency or excess. All major laboratories offer saliva cortisol testing. LabCorp222
provides saliva collection kits with instructions and labels to indicate the time of each sample.
Physicians are generally unaware of the efficacy of saliva testing for cortisol. Even if they
order it, the reference ranges they see are of no use in diagnosing CD. The daytime ranges have
Before lunch: 0.08 to 0.2
lower limits that are incompatible with health. (See
Table 6:dinner:
ZRT’s Immunoassay:
Before
0.04 to 0.13
Table 5.) This is due to the use of the classical 2
Classicalbedtime:
vs. Diagnostic
Ranges
Before
0.02 to
standard deviations from the mean method,
Morning: 0-1.44 vs. 0.37-0.95mcg/dL
applied to an unscreened population whose values
0.07
Noon:
0-0.46 vs. 0.12-0.30mcg/dL
are not normally-distributed but are skewed
Evening: 0-0.32 vs. 0.06-0.19mcg/dL
towards lower levels. ZRT Labs223 have attempted
Night:
0-0.21 vs. 0.04-0.10mcg/dL
to produce meaningful diagnostic ranges using
their extensive database of saliva test results accompanied by histories and symptom ratings.
They excluded persons with a high probability of CD or of Cushing’s syndrome/disease,224 and
chose a 20-80 percentile range. (Table 6.) Using a similar immunoassay, other researchers found
classical AM ranges for males of 0.395-1.46mcg/dL and for females 0.337-1.46mcg/dL).225
There are only a few studies regarding saliva cortisol levels in CD, and these generally used
immunoassays whose values that are about 40% higher than those obtained with mass
spectroscopy. In patients with secondary AI, AM saliva cortisol levels were 0.26mcg/dL
compared with 0.44mcg/dL in controls.226 AM saliva cortisol levels in Addison’s Disease were
13
0.15mcg/dL, vs. 0.67mcg/dL in controls.227 In a study of patients with known HP disease vs.
controls, the authors suggested a diagnostic range of 0.18-0.76 mcg/dL. The lower cutoff was
highly specific for AI by ITT, but not sensitive as it included only one-fourth of patients with
abnormal ITT results. The mean AM saliva cortisol for those with abnormal ITT results was
0.355mcg/dL vs. 0.69mcg/dL in controls, yet the classical range in controls had a lower limit of
0.13 mcg/dL, far too low to exclude AI.228
A single AM saliva test is still insensitive, 229 for many or the same reasons that an AM serum
cortisol is insensitive. I have seen many symptomatic persons a high-normal awakening saliva
cortisol levels, but low levels the rest of the day, who responded well to cortisol
supplementation. The noon-time is the next more important test for CD. It best represents
cortisol levels during most of the day. An LC/MS/MS value below 0.08mcg/dL at mid-day
supports the diagnosis of CD in a symptomatic patient. In some cases of CD, only the evening
and bedtime levels are below the ranges suggested in Table 7. I have constructed these ranges
based upon LabCorp’s ranges, ZRT’s research, and my
Table 7: Suggested LC/MS/MS
own experience. I have patients collect samples on a
Diagnostic Saliva Cortisol Ranges
non-working day (typically Sunday). The first saliva
Post awakening: 0.25-0.60mcg/dL
sample is collected 30mins after awakening. I have
Before lunch:
0.08-0.20mcg/dL
them withhold any SSRIs or amphetamines the day of
Before dinner: 0.04-0.13mcg/dL
the saliva collection and until after blood is drawn the
Before bedtime: 0.02-0.07mcg/dL
following morning for serum cortisol, ACTH, and
DHEAS.
A problem with saliva testing for steroid hormones is that any transdermal application of the
hormone with the last several weeks or months causes elevated saliva levels of the steroid—far
above normal values and out of proportion to both serum levels and physiological
effects.230,231,232 This appears to be caused by steroid saturation of red blood cell membranes as
the cells squeeze through the dermal capillaries. This membrane saturation somehow causes
more of the steroid to enter the saliva. Saliva cortisol levels will be falsely elevated if the patient
has applied any over-the-counter, 1% hydrocortisone cream to their skin within the last several
months. Serum cortisol levels are not affected.
As accurate and sensitive as diurnal saliva cortisol testing is, it is still not a measurement of
cortisol effect in the tissues, which depends upon many other mechanisms. Thus a person with
clinical evidence of CD should be offered a trial of cortisol supplementation even if saliva cortisol
levels are within or above the ranges suggested in Table 7.
6. Physiological vs. Pharmacologic Glucocorticoid Therapy
Sufficient cortisol is necessary for our quality of life and long-term health, yet no other
hormone is so misunderstood and feared. Physicians have seen the deleterious effects of GCs,
and assume that hydrocortisone (HC) therapy is no different. Indeed, the U.S. Food and Drug
Administration lists HC as a drug and applies to it all the warnings, drug interactions, etc.
associated with the entire corticosteroid drug class. It even designates HC as a pregnancy
category C drug (risk cannot be ruled out); even though it is naturally present in every pregnant
woman’s body and must be replaced if deficient! The widespread use of GCs to treat various
symptoms and disorders caused by CD also blinds physicians to the prevalence of CD. They see
themselves as treating diseases and disorders with a drug. However, by definition, disorders and
diseases that improve with GC therapy are due, at least in part, to a relative deficiency of
cortisol. The physician prescribes a GC because he/she has decided that the patient has a
relative deficiency of cortisol effect. This is not the case only in relatively trivial situations where
14
GCs are prescribed to produce a pharmacologic anti-inflammatory effect—such as to suppress a
poison ivy reaction. In every case, however, GC therapy is endocrine therapy.
Many, many more persons have a degree of CD than physicians realize. They have so often
seen marked improvements in constitutional symptoms, mood and energy in patients given GCs
that they have come to believe that “steroids make anyone feel better”. In fact they are
unknowingly diagnosing and treating persons who have CD. Healthy persons, with sufficient
cortisol, do not feel better when given HC or GCs, and are likely to experience negative effects
from superphysiological doses. Healthy persons do not ask the physician to put them back on
the GC. The prevalence and significance of CD are evidenced by the fact that GCs are among the
most powerful and oft-prescribed drugs in medicine. Scores of different altered versions of
cortisol are found in pills, inhalers, injections, topical creams/gels, eye drops, etc. Prednisone,
Medrol (methylprednisolone), dexamethasone, betamethasone and other GCs are prescribed to
suppress inflammation and improve the body’s response to stress. These drugs’ structures,
actions, pharmacokinetics and pharmacodynamics differ significantly from those of HC.
Cortisol (Hydrocortisone)
Prednisone
Methylprednisolone
Dexamethasone
Figure 2. Arrows mark the significant structural alterations of commonly prescribed
glucocorticoids. (Images from Wikipedia)
Table 8. Relative potencies of various glucocorticoids
Name
Glucocorticoid
potency
Mineralocorticoid
potency
Duration of action
(half-life in hours)
Cortisol (hydrocortisone)
1
1
8
Prednisone
3.5-5
0.8
16-36
Methylprednisolone
5-7.5
0.5
18-40
15
Dexamethasone
25-80
0
36-54
Fludrocortisone
15
200
24
The patented glucocorticoids are not natural to our biosphere. They are not human
hormones. They do not have the same benefits as HC and they do have excessive and
unexpected deleterious effects. GCs generally have much stronger glucocorticoid effect and
higher ratios of glucocorticoid-to-mineralocorticoid effect than HC. As they are different
molecules, the quoted potency ratios are misleading. Research shows that GCs have greater
deleterious effects than expected at such ratios. Prednisone’s chemical structure is most like
that of cortisol and 1mg of prednisone is said to have a GC potency 4 times greater than HC, but
for bone loss the ratio is more like 5:1 or 6:1.233 The prednisolone:HC ratio for growth
suppression in children is 15:1.234 Methylprednisolone is said to be 5 times more potent than
HC, but in this ratio it causes insulin levels to rise twice as high,235 and causes a much greater
reduction in the phagocytic and bacteriocidal activities of human granulocytes than does HC.236
Dexamethasone, with its more altered structure, is said to be 40 times more potent than HC, yet
in producing insulin resistance, the ratio is more like 70:1.237 Dexamethasone (4mg/day) given to
healthy men produces emotional arousability and negative feelings of anger and sadness;
adding HC to the dexamethasone counteracts negative feelings and improves mood.
Hydrocortisone binds to mineralocorticoid receptors in the central nervous system while
dexamethasone does not.238 Since dexamethasone does not easily cross the blood-brain barrier
and can deplete the brain of cortisol-effect.239 Common sense dictates that the only “steroid”
that should be routinely given for systemic therapy, especially for any extended period, is HC. An
impediment to the use of HC has been the lack of a long-acting oral preparation. That has been
addressed by slow-release products now available in Europe (Plenadren and Chronocort),240,241
and hopefully soon to be available in the United States.
There is another problem with the long-term use of GCs. Whenever a GC or HC is prescribed,
ACTH is suppressed to some degree. This reduces both cortisol and DHEA production. Serum
DHEA and DHEAS levels can fall to undetectable levels, and this iatrogenic hormone deficiency is
a major contributor to the morbidity seen GC- and HC-treated patients. (See below.)
7. Cortisol Supplementation
Every patient whose history, signs and symptoms are consistent with CD deserves a clinical
trial of cortisol supplementation (CS). Patients with CFS and FM who have other indicators of CD
deserve a trial of CS.242 CS, given at the lowest dose that provides sufficient clinical benefit, and
combined with DHEA replacement, is both safe and effective. In CD, CS improves mood, energy,
mental function, muscle function, and sleep. It reduces pain, anxiety, and inflammation. CS is
both more effective and more safe than the many drugs used to treat the signs and symptoms
of CD or the inflammation associated with CD. CS may be the only treatment needed for many
allergic and autoimmune disorders. Clinical success is more certain when the saliva cortisol and
serum DHEAS levels are clearly low, but is probable in symptomatic persons with normal levels.
Cortisol is, however, the most difficult hormone to replace for many reasons. In the United
States only short-acting HC tablets are available; 2 to 4 doses are required each day and there
are marked swings in serum levels and hormone effects. It is impossible to mimic the diurnal
pattern, let alone the dynamic nature of cortisol production. There are unphysiological peaks
followed by troughs within hours of ingestion, constituting a kind of pulse therapy. If the dose is
16
too low, the unnatural peak can still over-suppress the dysfunctional HP system, leaving levels
too low when the dose wears off.
As cortisol is a major stress-response hormone, patients must learn to stress-dose; to mimic
a functional HP system by increasing their HC doses for additional physical activity, illness, or
emotional stress. Tasks such as traveling, doing yard work, public speaking, etc. require higher
doses. During an uncomplicated viral illness the dose
Table 8. Challenges in Cortisol
should be increased by at least 25%, and with fever
Supplementation
by 100%. Endogenous cortisol secretion rates are
Short-acting tablets, multiple doses
much higher during and after surgery. Guidelines
Suppression of cortisol production
exist for HC dosing prior to and after surgical
Emergency/accident coverage
procedures. From the start of therapy, patients must
Need for stress-dosing
have timely access to professional advice concerning
No test to determine proper dose
their doses and symptoms. This task can be
Suppression of DHEA production
performed by e-mail or telephone contact with the
Overnight cortisol deficiency
physician or nurse or with trained counselors who
Reduction in aldosterone secretion
themselves have CD.
Worsens hypothyroidism
Adjusting cortisol doses is an art and involves
much trial-and-error. The clinician needs to know
that the serum half life of cortisol is 1 to 1.5 hrs, but the biological half-life is closer to eight
hours, and there is a longer period over which cortisol sufficiency operates. At any given time,
the cortisol status of the patient is dependent not just on their cortisol dose or level at the
moment, but on their dosing history over the hours, days and even weeks. A person who has
received sufficient cortisol in the preceding hours may have sufficient cortisol effect to last for
many hours afterwards even though their serum levels drop low. This fact allows most persons
to tolerate low overnight cortisol levels and not need a bedtime dose. A common scenario is a
patient who has sufficient cortisol to feel well initially, and continues to feel while under more
stress or while more active for days or weeks but then “crashes”, indicating that a cumulative
CD had developed. They suffer hypocortisolemic and hyperadrenergic symptoms that can last
for many days in spite of additional cortisol replacement. They do recover with time.
Taking cortisol or a GC lowers ACTH production. Since ACTH stimulates cortisol, DHEA, and
aldosterone production,243 CS can cause deficiencies of these other adrenal hormones, which
may produce symptoms or long-term morbidity. DHEA will be discussed below. Aldosterone
production is stimulated by ACTH to a lesser extent, and also by the renin-angiotensin system. A
person with a functional adrenal gland will usually produce enough aldosterone to retain
sufficient salt and water, but some persons with central CD who are given cortisol will develop
signs and symptoms of aldosterone deficiency (i.e., lightheadedness, low blood pressure, and
orthostatic hypotension). As aldosterone is only available through compounding pharmacies and
is quite expensive, the usual treatment for aldosterone deficiency is fludrocortisone. It is
hydrocortisone with a fluoride atom added so that it cannot be deactivated by 11-beta HSD2 in
the kidneys. Hopefully in the future long-acting aldosterone tablets will be available.
7.1. What is physiological cortisol supplementation?
The conventional treatment of CD with low-fixed doses of hydrocortisone results in a lower
quality of life and greater disability.244,245 Treated patients have a higher rate of premature death
from cardiovascular, malignant and infectious causes.246 Chilren and patients under 40 have a
higher risk of death from adrenal insufficiency itself,247,248 suggesting inadequate treatment.
Some experts today recommend very low doses, like 10mg in the AM, 5mg in the PM, based on
known cortisol production rates and peak serum levels. However, such does are rarely sufficient
17
in my clinical experience. Clinicians who adjust the dose by symptoms typically prescribe 30 to
40mg on average.249
How much cortisol does the body actually make each day? The mean cortisol production rate
in children is estimated to be 6.8mg/m2/day250 and in young men 9-11mg/m2/day.251 If we
accept a cortisol production range of 6–11mg/m2/day, that yields 9-18mg/day for average-sized
women (1.6m2) and 12-22mg/day for average-sized men (2.0m2). Oral dosing must be higher
than endogenous production due to imperfect absorption, first-pass metabolism by the liver,
and urinary dumping of HC during peak levels when cortisol-binding-globulin (CBG) is saturated.
For a given daily HC dose, fewer and higher HC doses
lead to more urinary cortisol secretion than a
Table 9. Signs, symptoms and tests
greater number of more smaller doses.252 The
of excess cortisol dosing
bioavailability of oral cortisol varies from 26 to
Fluid retention
91%.253 By subcutaneous infusion, a person with AI
Excessive weight gain
typically needs 8–15mg/m2/day to restore normal
Facial flushing
diurnal salivary and serum cortisol levels; 30%
Palpitations
higher than the endogenous production rate. The
Cushingoid face, fat distribution
daily infusion dose a patient needs is about one-half
Neuropsychological symptoms
of the clinically-adjusted oral dose.254
Muscle weakness, wasting
As the typical twice-daily oral doses must amount
High blood pressure
to more than twice the endogenous production, oral
Insulin resistance
replacement doses should be around 16-36mg/day
for women and 28-44mg/day for men—that is in persons who make no cortisol or in whom
endogenous production is completely suppressed. Some with partial central CD do well,
however with subreplacement doses that boost their levels temporarily in the daytime. Dr.
William Jefferies, who pioneered the clinical diagnosis and treatment of mild-to-moderate CD,255
obtained consistent improvements and no long-term morbidity in patients with HC doses of 20
to 30mg daily in 4 equal divided doses. A current textbook states that most persons with AI
require 15 to 25mg of HC daily.256 In hypopituitary adults, 20mg of HC daily (15mg+5mg) does
not increase endogenous glucose production or insulin resistance compare to a physiological HC
infusion.257,258 A study of cortisol area-under-the curve with oral HC led to recommendations of
only 10mg/day for persons weighing 50-54kg up to 25mg/day for persons weighing 115 to
120kg. Strangely, the authors failed to include the 2 to 8am overnight cortisol production, when
about one third of the daily cortisol production occurs (Figure 3.).259
Figure 3. Circadian rhythm of serum cortisol in normal subjects from published data (solid line):
(a) simulated cortisol profile for a patient (broken line) following thrice-daily hydrocortisone
18
administration (10 mg at 06·00 h, 5 mg at 12·00 h and 2·5 mg at 18·00 h, shown as solid
arrows). (reproduced by permission Mah)
Such attempts to find the physiological dose by measuring serum levels are interesting, but
in clinical practice CS must be always be adjusted by clinical criteria. The physician cannot
adhere to any fixed ideas about the proper dose when that means leaving the patient
symptomatic. Healthy adults have a large range of both cortisol production (5-fold) and 24-hr
plasma free cortisol levels (3-fold).260 Hereditary abnormalities in the glucocorticoid receptor
gene make 6.6% of the normal population relatively hypersensitive to glucocorticoids and 2.3%
are relatively resistant.261 Interindividual variations in GC sensitivity can be tissue-specific in
healthy subjects.262 Some persons are rapid metabolizers of cortisol. A male patient who
required 80mg/day of HC orally needed 40mg/day by infusion to achieve normal diurnal serum
and saliva cortisol levels.263 A young male with CAD required 33mg per day by infusion (equiv. to
66mg orally) to normalize ACTH levels and adrenal androgen production.264
The amount and timing of HC doses must be individualized; determined by clinical criteria.
The ultimate guide for oral CS is the person’s signs and symptoms. In all cases, the physician
must try to find the lowest daily HC dose that eliminates the symptoms and signs of CD (Table
1.) while producing no signs, symptoms, or other laboratory evidence of cortisol excess (Table
9.). Serum or saliva cortisol levels are of little use due to the pulsatile nature of the therapy with
short-acting tablets but may help the physician detect gross over- or under-dosing. Saliva testing
may be affected by retention of cortisol in the oral cavity after swallowing a tablet.265 Checking
serum or saliva cortisol levels at 2 hrs after a dose, or just prior to the next dose may be useful
adjunct when the clinical situation is uncertain. The patient and clinician will usually be able to
detect overdosing—more so with HC than with GCs because of HC’s great mineralocorticoid
effect. The patient will generally not tolerate receiving too much cortisol. Early signs of
overdosing include fluid retention and weight gain. Early symptoms include facial flushing and a
feeling of overstimulation: often described by the patient as jitteriness or shakiness. Palpitations
or a bounding heart rate may be felt. Excessive cortisol in the evening can make it hard to fall
asleep. Long-term overdosing can produce the well-known Cushingoid features including moonface, central obesity, stretch marks, hypertension, insulin-resistance and muscle-wasting, These
are unlikely to occur with physician-monitored therapy.
However, none of the aforementioned studies or recommendations regarding physiological
HC dosing included replacement of DHEA to youthful levels or effective T4/T3 thyroid
replacement. Replacing these hormones significantly increases the daily HC dose requirement.
DHEA counteracts and balances cortisol’s effects in the body. (See below) With adding DHEA to
HC therapy, the patient will have a return of hypocortisolemic symptoms and the HC dose must
be increased to compensate. The HC-dosing literature includes some patients on TSHnormalizing doses of levothyroxine, but none on clinically-optimized T4/T3 thyroid replacement
therapy. Higher thyroid levels/effects increase the body’s demand for and metabolism of
cortisol. Oral T3 also particularly increases cortisol metabolism. The major site of cortisol
metabolism is the liver, where cortisol is reduced, oxidized, or hydroxylated. Thyroid hormone
increases cortisol metabolism primarily by increasing 5 alpha- and 5 beta-reductase activity.266
The liver’s intracellular T3 comes primarily from the circulation, and oral T3 therapy produces
highly superphysiological T3 levels in the portal circulation during absorption, and
superphysiological serum levels for several hours. This overstimulation increases the rates of
many hepatic processes including cortisol metabolism. Persons receiving both DHEA and T4/T3
thyroid replacement therapy will require higher HC doses than seen in any existing studies.
19
7.2. Cortisol Dosing Strategies
Oral HC doses affect the patient’s well-being substantially from hour-to-hour. The clinician
must work closely with the patient to find the doses and timing that will allow the patient to feel
and function well throughout the day and to sleep well at night. With any hormone therapy it is
always best to mimic Nature whenever possible.
Patients usually do best with taking the largest dose
Table 10. Principles of HC Therapy
of HC upon awakening to simulate the AM rise, and
Start with AM and afternoon doses
then lower doses as the day goes on. Often only two
Highest dose upon awakening, lower
doses are needed, a large morning dose and a
doses as day goes on
smaller afternoon dose. After an HC dose, serum
Add evening and/or bedtime doses
levels peak at 1.2hrs on average, and back to
only if necessary
baseline in around 6 hrs. Taking hydrocortisone after
Find the lowest effective daily dose
eating a meal delays and lowers the peak level and
Restore DHEAS to youthful levels
prolongs the serum elevation.267 (Figure 4.) A good
Add fludrocortisone if indicated
strategy to take the AM dose on an empty stomach
Maintain thyroid/cortisol balance.
soon after awakening to increase cortisol levels
Optimize sex hormone levels
rapidly to start the day. A sufficiently large AM dose
will last until noon. Then the patient can take a smaller dose after lunch to slow absorption and
produce a more prolonged effect. The half-life of HC is prolonged in the evening and
overnight,268 so smaller doses then produce greater effect. Postponing the second dose until
dinner will usually cause an afternoon nadir.269 At the start of therapy, the patient must be
informed about the timing of the peaks and of troughs. The patient will then begin to
understand how he/she feels when levels are higher vs. lower after doses. The patient will be
better able to understand the effect of cortisol on their symptoms. They need to know that if
they feel badly several hours after a dose, it is because their levels-effects have fallen low;
otherwise they my believe that they are having a side effect or negative reaction to cortisol. The
patient must be given permission to take additional doses whenever needed, and told to
increase the usual doses the following day accordingly. The physician should take the person’s
lifestyle and schedule into account when suggesting or adjusting a dosing schedule; for example,
a person who works late into the evening or has a stressful evening commute will need more HC
in the afternoon than one who spends quite evenings at home.
Some patients can get by with subphysiological dosing—a couple small HC doses during
daytime. Their endogenous still rises overnight. Evening or bedtime doses in these persons can
suppress the overnight production and cause them to wake up in a state of deficiency. So it is
usually best to try the two daytime doses only before resorting to evening and bedtime doses.
Patients with little endogenous cortisol production on oral HC will have very low cortisol levels
during the night. Some will not tolerate this and will awaken with hypocortisolemic symptoms.
They will not feel well during the day unless the overnight deficiency is resolved. This usually
requires a bedtime dose and sometimes also a 2 to 3 am dose. For persons who need the
additional doses, typical ratios are 1, 0.5, 0.25, 0.25 (e.g. 20, 10, 5, 5mg) The dose should be
increased in anticipation of adding DHEA supplementation or starting T4/T3 replacement. With
two daily doses, typical doses are 15+5mg without DHEA or thyroid, and 20+10mg to 30+20mg
daily with DHEA and thyroid.
20
Figure 4. Mean serum cortisol concentrations following a fixed dose of 10 mg hydrocortisone,
in fasting and fed states.270
The most physiological form of cortisol supplementation is continuous subcutaneous
infusion. This can be done with the same pumps and infusion sets used for insulin delivery for
diabetics. A normal diurnal serum and saliva cortisol profile can be obtained than with oral
tablets.271,272
7.3. Troubleshooting Cortisol Supplementation
A few patient may have typical symptoms of cortisol deficiency (fatigue, headaches) but fail
to improve with cortisol supplementation. In some this could be due to polymorphisms of the
cortisol-binding globulin gene. Their free cortisol levels are usually normal and they don’t
improve with cortisol supplementation.273,274
7.4. Fear of Adrenal Suppression
Many physicians believe that they should not prescribe HC to patients, even when they
believe that the patient suffers from CD, because they fear suppressing the person’s
endogenous cortisol production. This is neither a logical nor ethical reason for withholding
effective treatment. If a hormone deficiency exists that is impairing a person’s quality of life and
health, the physician is obligated to treat the deficiency whenever possible. For almost all
endocrine deficiencies, effective treatment provides full hormone sufficiency and thus
necessarily suppresses the dysfunctional endogenous production system partially or fully. In CD,
the physician will improve the patient’s daily and emergency stress responses by prescribing
cortisol and by educating the patient about the need for additional cortisol under stress and in
emergencies. The patient just has to be informed that they are dependent upon exogenous
cortisol. They must carry hydrocortisone with them at all times, increase the dose for greater
stress, activity, or illness. They should wear some sort of medical alert jewelry and carry a
medical alert card informing medical personnel of their condition and containing their
physician’s name and contact information. The patient has the right to choose whether to bear
the risks of CS in order to enjoy the benefits. Most persons will are happy to bear the risks of
adrenal suppression if CS greatly improves their quality of life.
21
8. The Importance of DHEA
DHEA, like thyroid hormone, has very important interactions with cortisol, and a patient’s
cortisol status cannot be understood apart from his/her DHEA status. When ACTH secretion
increases both cortisol and DHEA are secreted in greater amounts. CS and GC therapy reduce
ACTH secretion and therefore DHEA(S) secretion.275 This iatrogenic suppression of DHEA is
deleterious as DHEA is both a major source of anabolic steroids and an antagonist of cortisol
levels and effects within various tissues. In a healthy person, DHEA supplementation reduces
serum cortisol levels,276,277,278 explaining why persons with CD cannot tolerate DHEA. DHEA
improves insulin sensitivity279 by antagonizing cortisol, thus helping to prevent or alleviate Type
II diabetes. DHEA has anti-inflammatory effects; reducing levels of inflammatory molecules such
interleukin-6 and tumor necrosis factor alpha. The
Table 11. DHEA-DHEAS
suppression of DHEA is a thus a major cause of the
Most abundant steroids in the body
deleterious effects of oral glucocorticoids, and
DHEAS and DHEA are interconvertible
DHEA supplementation is necessary to help
Anabolic prohormone
prevent these effects.280 DHEA is also a
Anti-inflammatory
neurosteroid; it protects hippocampal neurons
Neurosteroid
from glucocorticoid-induced neurotoxicity,281 and is
Levels decline with age, stress, disease
a non-competitive antagonist of the gammaLower levels associated with mortality
aminobutyric (GABA) receptor.282.283
The adrenal glands secrete large amounts of
and DHEA and DHEAS, estimated at 4mg and 7-15mg/day respectively.284 Youthful serum DHEAS
levels are 20 times higher than cortisol (300mcg/dL vs. 15mcg/dL), 400 times higher than
testosterone in men (0.8mcg/dL), and 3000 times higher than estradiol in women (0.01mcg/dL).
Active DHEA circulates in amounts similar to male testosterone (0.5mcg/dL). The much more
abundant DHEAS can be converted into DHEA in peripheral tissues that contain steroid
sulfatases.285 DHEA is converted into androgens and estrogens with various tissues; the enzymes
that do so are expressed in a cell-specific fashion, permitting local control of steroid formation
and action.286 The study of this process has been called “intracrinology.”287 DHEA is has been
considered to be a prohomone only, but DHEA receptors have been found on endothelial cells288
and T-cells.289
Adrenal DHEA(S) is the source of the majority of androgens in females.290 Before menopause,
75% of a woman’s androgens come from DHEA
Table 12. Benefits of DHEA-DHEAS
and after menopause nearly 100%. After
Maintains bone mass
menopause, DHEA is the source of all estrogens.
Opposes deleterious effects of cortisol
Therefore the loss of DHEA has a more profound
Reduces pain and inflammation
effect
upon
women’s
health.
The
Improves fertility and sexual function
postmenopausal ovary makes some DHEA:
Improves insulin sensitivity
postmenopausal women with intact ovaries
Reduces visceral fat
have 20% higher DHEAS levels than those
Inhibits platelet aggregation
without ovaries. This explains some of negative
Prevents oxidation of LDL cholesterol
effects of oophorectomy.291 DHEA is important
Improves immune function
to the maintenance of female sexuality.292 Low
Increases growth hormone secretion
DHEAS has been more closely correlated with
decreased sexual function in menopausal
293,294
women than low testosterone.
Females with AI and low DHEAS levels lose axillary and
pubic hair, have dry skin and low libido. In women with hypopituitarism, oral DHEA restores
22
axillary and pubic hair growth, sexual relations, alertness, stamina and initiative.295,296,297 DHEA
may play a role in preventing breast cancer.298
8.1. DHEA in Adrenal Disorders
Persons with congenital adrenal hyperplasia (CAH) require long-term GC therapy to lower
ACTH and DHEAS levels to the normal range. They have a much better quality of life than
patients with primary adrenal gland failure, especially women.299 The difference is DHEA. AI
patients have low DHEAS levels initially that are further suppressed with GC therapy. Likewise in
Cushing’s Disease DHEAS levels are preserved as excessive ACTH stimulates both cortisol and
DHEA secretion. In Cushing’s Syndrome ACTH and DHEA are suppressed, causing much more
bone loss.300 In women with hypercortisolism, the best predictor of vertebral fracture is not the
cortisol level, but the cortisol-to-DHEAS ratio.301 In AI patients, DHEA supplementation in lowers
cholesterol levels and increases insulin sensitivity.302 It enhances self-esteem and improves
mood and energy.303
8.2. DHEA and Aging
There is a dramatic decline in circulating levels of DHEA-S/DHEA with age. From its peak in
the 20-30yr age group, DHEAS/DHEA declines by 70% by age 50-60yrs, and more slowly
afterwards.304,305,306,307,308 The zona reticularis of the adrenal cortex atrophies with aging; the
cause is unknown.309 As cortisol levels do not decline significantly with aging, this loss of DHEA
produces a relative glucocorticoid excess—a pseudo-Cushing’s syndrome: increased visceral fat,
reduced insulin sensitivity and hypertension. DHEA loss with age contributes to sarcopenia,
osteopenia, atherosclerosis, impairment of cognitive and affective function and deterioration of
immunocompetence. This clinical state has been called “adrenopause.”310 A person’s DHEAS
level serve as a general indicator of aging and health status.311 Lower DHEAS has been correlated
with the risk of death in both sexes.312 DHEA supplementation has been shown to beneficial in
older persons in many studies. In postmenopausal women DHEA supplementation enhances
insulin sensitivity, lowers serum triglycerides, improves cholesterol profiles, and increases IGF1/IGFBP-3 levels.313,314,315 It increases IGF-1 levels and perceived physical and psychological wellbeing.316,317,318 In elderly women, DHEA supplementation improves bone mass, libido, and skin
quality,319,320 and reduces visceral fat and insulin levels.321 DHEA supplementation lowers leptin
and C-reactive protein levels.322 DHEA supplementation has a salutary effect on the immune
system, increasing natural killer cell population and cytotoxicity.323,324 It improves cognitive
function and activities of daily living scores in women with dementia.325 Both DHEAS and
estradiol therapy in postmenopausal women restore pituitary beta-endorphin responses to
stimuli to those of a young person, improving both mood and pain levels.326
8.3. DHEA in Cardiovascular Disease
People who are given glucocorticoids for long periods have 2.5 times the risk of
cardiovascular disease.327 The iatrogenic DHEA deficiency plays a role. Naturally-low DHEAS
levels in men are associated with increased risk of death from any cause and death from
ischemic heart disease,328 independent of lipid levels.329 Lower DHEAS levels are found in men
with a history of a premature myocardial infarction330 and in postmenopausal women with
coronary artery disease.331 Lower DHEAS levels are associated with vascular disease in grafted
blood vessels.332 Elevated insulin levels reduce the production of DHEA and increase its
elimination; this may contribute to the negative effects of hyperinsulemia including
atherogenesis.333
23
Low density lipoprotein (LDL), is atherogenic only when oxidized. Oxidized LDL is taken up by
macrophages and endothelial cells, initiating the atherogenic process. DHEA is an integral part
of LDL and HDL and exerts anti-oxidative effects on LDL.334,335 DHEAS is associated with improved
flow-mediated dilation, suggesting a protective effect on the endothelium.336 DHEA protects
vascular endothelial cells from apoptosis337 while also inhibiting their excess growth.338 The loss
of DHEA contributes to the pro-clotting diathesis of aging. DHEA retards platelet aggregation339
and lowers fibrinogen levels.340 It inhibits vascular smooth muscle cell proliferation and
enhances large and small vessel endothelial cell function, apparently via a DHEA-specific
receptor.341 DHEA decreases the levels of plasminogen activator inhibitor type 1 (PAI-1).342 DHEA
supplementation Increases platelet cGMP production, testosterone and estradiol levels and
decreases PAI-1 and LDL cholesterol levels. These anti-atherogenic effects may be particularly
beneficial in elderly persons with low levels.343
8.4. DHEA in Psychiatry
Low DHEAS had been frequently associated with psychiatric disorders and DHEA
supplementation found to be efficacious, especially in middle-aged and elderly individuals.
DHEA is essential for adaptation to acute stress.344 Lower DHEAS levels are associated with
depression in abstinent alcoholics,345 with autism,346 and with relapse in cocaine addiction.347
Anorexic women have low DHEAS levels and DHEA supplementation improves weight gain, bone
density, IGF-1 levels, and psychological parameters.348 DHEA supplementation is an effective
treatment for major and minor depression,349 depression in AIDS patients,350 and schizophrenia,
especially in women.351,352 DHEA supplementation improves mood and memory in young men.353
8.5. DHEA in Rheumatology
In chronic autoimmune inflammatory diseases, cortisol and DHEAS levels are typically either
inappropriately normal or low, whereas both hormones should be elevated in response to
chronic inflammation. This relative or absolute AI exacerbates the inflammatory disease. The
treatment of autoimmune and other chronic inflammatory diseases should include the
optimization of both cortisol and DHEAS levels.354 The antiinflammatory effects of cortisol are
well-known and exploited with GC therapy. However, DHEA also has potent anti-inflammatory
effects. The decline in DHEAS levels with age is linked to the rise in IL-6 levels, promoting a proinflammatory state in aging persons.355 Higher IL-6 levels are seen in a wide variety of
inflammatory disorders, malignancies, and autoimmune diseases and are correlated with bone
loss and increased disability.356 DHEA supplementation reduces IL-6 levels.357 In SLE, DHEA
supplementation reduces IL-10 levels by 70%.358 DHEA downregulates several proinflammatory/resorptive cytokines In human osteoblastic cells.359 DHEA supplementation in
diabetic patients reduces reactive oxygen species, increases glutahione and Vitamin E levels, and
downregulates the tumor-necrosis-factor-alpha (TNF-a) system.360 In SLE, DHEA
supplementation reduces the signs and symptoms of the disease and allows a reduction GC
dose.361,362 It improves mental well-being and sexuality.363
8.6. Bone density: The Importance of DHEA and Sex Steroids
Cortisol and GC therapy promote bone loss in a dose-related manner. This is not a side effect
but an expected physiological consequence. The solution is not to withhold cortisol from those
who need it, but to optimize the levels of the anabolic hormones that counteract cortisol and
increase bone density: estradiol, testosterone, DHEA, and growth hormone. These hormones all
decline with age beginning around age 30, which is when age-related bone loss begins. Men
continue to secrete testosterone in significant amounts as they age and have higher estradiol
24
levels and less bone loss than postmenopausal women. Women begin losing bone at age 30 and
suffer a rapid loss of up to 25% of bone density within 5 yrs of menopause. Persons who are
already in a bone-losing state are more susceptible to bone loss with glucocorticoid treatment;
peri- and postmenopausal women are at particular risk.364,365 Adult women have a significant
decrease in bone mineral density (BMD) with just a 12-week course of physiological CS.366
DHEA helps maintain and build bone mass both by its anti-cortisol effects and its ability to
increase levels of estradiol367 testosterone, and IGF-1.368 In men with inflammatory bowel
disease low BMD was correlated to low DHEAS levels, not to testosterone levels.369 DHEA
protects against osteoporosis by being converted into estrogens by aromatase activity,370 and by
raising IGF-I and reducing osteolytic IL-6.371 Women with osteoporosis have much lower DHEAS
levels than those with normal BMD.372 Long-term DHEA supplementation in post-menopausal
women can increase BMD by 3.6%.373 DHEA supplementation in menopauses has the additional
benefits of alleviating menopausal symptoms without thickening the uterine lining.374
In persons on GC therapy, BMD can be maintained if both DHEAS and sex hormone levels are
optimized. In women with high cortisol levels, both higher sex hormone and DHEAS levels
protect against fractures.375 Women with systemic lupus erythematosis (SLE) receiving GC
therapy gain bone mass when DHEA is added.376 Women on long-term GC therapy also gain
bone density with estrogen and estrogen/progestin therapy.377,378 Vitamin D, calcium and
growth hormone should also be replaced as indicated in order to maintain bone density with GC
therapy. 1000mg of calcium carbonate and 500IU of Vitamin D3 stops and even reverses bone
loss in RA patients.379 The treatment of growth hormone deficiency increases BMD, most
markedly in men and in women who also receive sex hormone replacement.380 Adding growth
hormone to estrogen therapy in postmenopausal women increases BMD by up to 14% in 18
months.381
8.7. Principles of DHEA Supplementation
Due to its many health benefits, it is good to optimize restore DHEAS to youthful levels in
every person where possible. DHEA supplementation is medically necessary for those on HC or
GC therapy. The negative effects of DHEA are of two kinds: androgenic and hypocortisolemic.
Women are much more likely than men to experience both kinds unwanted effects. Androgenic
effects include acne, hirsutism, oily skin-seborrhea, and thinning of scalp hair. In persons with
low or borderline cortisol levels/effects, DHEA supplementation can produce hypocortisolemic
symptoms including fatigue, restlessness, heart palpitations, tachycardia, anxiety, body aches
and headache. The occurrence of these problems would require a lowering of the dose or
abandonment of DHEA supplementation.
How should one replace DHEA? DHEA is available over-the-counter in oral tablets and
capsules and in sublingual tablets. Compounding pharmacies can prepare topical creams or
vaginal suppositories. I believe that the best choice for most persons is a sublingual tablet taken
once or twice daily. The sublingual route assures some absorption of active DHEA directly into
the blood stream. Oral therapy is acceptable, but almost all of the DHEA is converted into
DHEAS by the liver. DHEAS and DHEA are interconvertible, but not easily so. The infusion of
DHEAS alone in men does not raise downstream androgen and estrogen levels as well as does
oral DHEA.382 Women appear to convert DHEAS to DHEA more readily.383 DHEA is very well
absorbed vaginally, and transvaginal/transdermal DHEA seems less likely to promote acne in
women than sublingual or oral DHEA. Local benefits can be obtained with DHEA. Intravaginal
DHEA reverses the atrophic changes of menopause without increasing serum estradiol levels
appreciably.384 Topical DHEA increases collagen synthesis and has other beneficial effects in the
skin.385
25
A serum DHEAS is the best measure of overall DHEA status with or without supplementation.
Its levels are much greater and more stable than DHEA. As with other hormones or medications,
a level drawn half-way between doses will give an acceptable estimate of the average level
throughout the day. For a person taking DHEA once-daily, a serum level should be done 12hrs
post-dose, and if twice daily, the test should be done at 6 hrs. post-dose.
What dose of DHEA is usually required? To restore youthful DHEAS levels of 200-280mcg/dl
for women and 400-500mcg/dl for men, older women require 5 to 50 mg and older men 15 to
100mg orally.386,387,388 Less is needed by the sublingual route. I start men on doses of 25mg
sublingually once daily and increase to twice daily if needed based upon testing. I start women
on 5 to 12.5mg daily and increase only if the dose is well tolerated and serum levels remain
suboptimal. Women are more prone to acne if they have had very low DHEAS levels for many
years, or if they have a history of acne. If women experience acne on low doses that do not
restore serum levels, I will either lower the dose and increase more slowly, or try vaginal
delivery. In such cases one can start with a very low dose, like 2.5mg daily, and increase only
every month or two. Usually, this tendency toward acne in susceptible women will diminish with
time as their bodies become re-accustomed to more youthful DHEAS levels.
26
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