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 gluconeogenesis. It moderates our immune system activity, assuring sufficient response to infection while preventing excessive reactions to the environment and our own tissues. Cortisol secretion has a strong diurnal pattern, levels are highest after awakening and decline throughout the day. Free cortisol levels vary ten-fold in a normal day and can increase several-fold under stress. ACTH and cortisol secretion are increased by stress, activity, eating, infection, inflammation and injury. Cortisol secretion is increased by many natural and artificial substances. The range and complexity of cortisol’s actions are apparent in the wide variety of physical and psychiatric problems caused by cortisol deficiency (CD). (See Table 1.) CD sufferers do not have the physical and mental/emotional stamina 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

Table 1. Symptoms of Cortisol DeficiencyFatigue— “adrenal fatigue” Depression, anxiety, irritabilityHeadaches: tension and migraine Myalgias and arthralgiasMuscle stiffness and weaknessCognitive dysfunction-“brain fog”Poor recovery from exertionInsomnia—frequent awakeningHot flashesPalpitations, tachyarrhythmiasNauseaDiarrhea, irritable bowel syndromeHypoglycemiaHypersensitivity to pain, light, noiseFood and environmental

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

appearance of hypocortisolemic symptoms with thyroid replacement exposes an underlying CD. Most “negative reactions” to thyroid replacement are due to undiagnosed CD. Hypothyroidism also masks the clinical evidence of CD, and vice versa. Classical hypothyroidism is seen in the presence of cortisol sufficiency and has many of the signs of cortisol excess: edematous appearance, 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 conditions, and beneficial responses to cortisol supplementation. (Table 2.) The majority of persons with lower cortisol levels in these studies do not have AI that could be diagnosed by current approaches. Their cortisol and DHEAS levels are not below the laboratory reference ranges. They simply have lower cortisol levels and/or effects than controls—a relative or partial CD. They do not have disease or damage affecting either the adrenal glands or the hypothalamic-pituitary (HP) system. These studies indicate that most persons with CD do not have AI. AI is in fact an archaic term. The adrenal glands are highly complex organs; so the diagnosis should reflect the precise biochemical problem that is found. The medulla 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 and the catecholamines. In central AI (insufficient ACTH production) only cortisol and DHEAS are

3

Table 2. Disorders related to Cortisol DeficiencySevere/Critical IllnessAutoimmune DiseaseAllergic disordersChronic Fatigue SyndromeFibromyalgia SyndromeDepressionPost-Traumatic Stress DisorderViolence/SuicideDrug addictionPremenstrual syndromesPost-partum disordersHyperemesis Gravidarum

Abbreviations:CD cortisol deficiencyCS cortisol supplementationAI adrenal insufficiencyACTH adrenocorticotrophic hormoneHP hypothalamic-pituitaryHPA hypothalamic-pituitary-adrenalHC hydrocortisone (cortisol)GC glucocorticoidDHEA(S) dehydroepiandrosterone(sulfate)

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 the local, intracellular generation of cortisol from cortisone by inhibiting 11-beta HSD-1.18 Estrogen supplementation reduces cortisol levels in postmenopausal women.19 This relative lack of cortisol effect allows the progression of inflammation,20,21 making women more susceptible to autoimmune disorders. This relative CD is a sufficient explanation for women’s greater tendency to suffer from fatigue, anxiety, depression, fibromyalgia, and various other disorders. (Table 3.) It explains why obsessive-compulsive symptoms in women are worse when estrogen levels are higher, after menarche and premenstrually, or when cortisol levels are lower postpartum.22 It explains why so many women are 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

Table 3. Female:Male RatiosNon-immune disorders: Fibromyalgia 8:1Multiple Chemical Sensitivity 8:1Chronic fatigue syndrome 4:1Depression 2:1Anxiety 3:2Autoimmune diseases:Sjögren’s syndrome 18:1Systemic Lupus Erythematosis 9:1Hashimoto's/Graves thyroiditis 5:1Rheumatoid arthritis 3:1Multiple Sclerosis 3:1Polymyalgia Rheumatica 2:1 Inflammatory Bowel Disease 1.3:1

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 long-acting 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 patients 63 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 dance-clubbing 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 recently-invented 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 HSD-2 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 the daytime and better in the evening, perhaps because cortisol levels are naturally lower during those hours. This marked variability is not seen with hypothyroidism or many other causes of fatigue. A patient’s response to exercise can provide clues. Some CD patients cannot do any physically-demanding tasks because they cannot recover afterwards. Others are able to raise their cortisol levels with exercise.177 They learn that they must exercise to feel well and become 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

Table 4. Other Clues for CD Variability over days, weeks, monthsWorsening of symptoms under stressFeels better in the eveningsWorsening of symptoms with thyroid, DHEA, or estradiol supplementationImprovement on glucocorticoids, SSRIs, amphetamines, some progestinsAutoimmune disease or antibodiesAllergic disordersNeeds to exercise to feel well

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 laboratory 183 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 20-200mcg/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 Cushing’s syndrome/disease.212,213,214 Saliva cortisol testing is also useful in conjunction with dexamethasone suppression testing215 and ACTH stimulation testing.216,217,218 Is it a practical means for assessing HPA function during and after glucocorticoid therapy;219 as useful as the AST.220,221 Saliva testing is now the gold standard for the assessment of

cortisol deficiency or excess. All major laboratories offer saliva cortisol testing. LabCorp 222 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

lower limits that are incompatible with health. (See Table 5.) This is due to the use of the classical 2 standard deviations from the mean method, applied to an unscreened population whose values are not normally-distributed but are skewed towards lower levels. ZRT Labs223 have attempted 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

Table 5: LabCorp’s LC/MS/MS Saliva Cortisol Ranges8 am: 0.02-0.60mcg/dLNoon: <0.01-0.33mcg/dL4 pm: 0.01-0.20mcg/dL

Table 6: ZRT’s Immunoassay: Classical vs. Diagnostic RangesMorning: 0-1.44 vs. 0.37-0.95mcg/dLNoon: 0-0.46 vs. 0.12-0.30mcg/dL Evening: 0-0.32 vs. 0.06-0.19mcg/dL Night: 0-0.21 vs. 0.04-0.10mcg/dL

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 own experience. I have patients collect samples on a non-working day (typically Sunday). The first saliva sample is collected 30mins after awakening. I have them withhold any SSRIs or amphetamines the day of the saliva collection and until after blood is drawn the 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

Table 7: Suggested LC/MS/MS Diagnostic Saliva Cortisol Ranges Post awakening: 0.25-0.60mcg/dLBefore lunch: 0.08-0.20mcg/dL

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

15

Methylprednisolone 5-7.5 0.5 18-40

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

16

followed by troughs within hours of ingestion, constituting a kind of pulse therapy. If the dose is 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 should be increased by at least 25%, and with fever by 100%. Endogenous cortisol secretion rates are much higher during and after surgery. Guidelines exist for HC dosing prior to and after surgical procedures. From the start of therapy, patients must have timely access to professional advice concerning their doses and symptoms. This task can be performed by e-mail or telephone contact with the physician or nurse or with trained counselors who themselves have CD.

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

17

Table 8. Challenges in Cortisol SupplementationShort-acting tablets, multiple dosesSuppression of cortisol production Emergency/accident coverageNeed for stress-dosing No test to determine proper doseSuppression of DHEA productionOvernight cortisol deficiency Reduction in aldosterone secretionWorsens hypothyroidism

known cortisol production rates and peak serum levels. However, such does are rarely sufficient 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 greater number of more smaller doses.252 The bioavailability of oral cortisol varies from 26 to 91%.253 By subcutaneous infusion, a person with AI typically needs 8–15mg/m2/day to restore normal diurnal salivary and serum cortisol levels; 30% higher than the endogenous production rate. The daily infusion dose a patient needs is about one-half of the clinically-adjusted oral dose.254

As the typical twice-daily oral doses must amount to more than twice the endogenous production, oral 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

18

Table 9. Signs, symptoms and tests of excess cortisol dosingFluid retentionExcessive weight gainFacial flushingPalpitationsCushingoid face, fat distributionNeuropsychological symptomsMuscle weakness, wastingHigh blood pressureInsulin resistance

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 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 moon-face, 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 TSH-normalizing 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

19

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.

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 of HC upon awakening to simulate the AM rise, and then lower doses as the day goes on. Often only two doses are needed, a large morning dose and a smaller afternoon dose. After an HC dose, serum levels peak at 1.2hrs on average, and back to baseline in around 6 hrs. Taking hydrocortisone after eating a meal delays and lowers the peak level and prolongs the serum elevation.267 (Figure 4.) A good strategy to take the AM dose on an empty stomach soon after awakening to increase cortisol 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

Table 10. Principles of HC TherapyStart with AM and afternoon doses Highest dose upon awakening, lower doses as day goes onAdd evening and/or bedtime doses only if necessaryFind the lowest effective daily doseRestore DHEAS to youthful levelsAdd fludrocortisone if indicatedMaintain thyroid/cortisol balance.Optimize sex hormone levels

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 suppression of DHEA is a thus a major cause of the deleterious effects of oral glucocorticoids, and DHEA supplementation is necessary to help prevent these effects.280 DHEA is also a neurosteroid; it protects hippocampal neurons from glucocorticoid-induced neurotoxicity,281 and is a non-competitive antagonist of the gamma-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 cells 288 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 and after menopause nearly 100%. After menopause, DHEA is the source of all estrogens. Therefore the loss of DHEA has a more profound effect upon women’s health. The postmenopausal ovary makes some DHEA: postmenopausal women with intact ovaries have 20% higher DHEAS levels than those without ovaries. This explains some of negative effects of oophorectomy.291 DHEA is important to the maintenance of female sexuality.292 Low DHEAS has been more closely correlated with decreased sexual function in menopausal women than low

testosterone.293,294 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 axillary and pubic hair

22

Table 12. Benefits of DHEA-DHEASMaintains bone massOpposes deleterious effects of cortisolReduces pain and inflammationImproves fertility and sexual function Improves insulin sensitivityReduces visceral fatInhibits platelet aggregationPrevents oxidation of LDL cholesterolImproves immune functionIncreases growth hormone secretion

Table 11. DHEA-DHEASMost abundant steroids in the bodyDHEAS and DHEA are interconvertibleAnabolic prohormone Anti-inflammatoryNeurosteroidLevels decline with age, stress, diseaseLower levels associated with mortality

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 IGF-1/IGFBP-3 levels.313,314,315 It increases IGF-1 levels and perceived physical and psychological well-being.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 pro-inflammatory 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 pro-inflammatory/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

27

1 Al-Aridi R, Abdelmannan D, Arafah BM. Biochemical Diagnosis of Adrenal Insufficiency: The added Value of

Dehydroepiandrosterone Sulfate (DHEA-S) Measurements. Endocr Pract. 2010 Dec 6:1-32. 2 Comtois R, Hébert J, Soucy JP. Increase in T3 levels during hypocorticism in patients with chronic secondary adrenocortical insufficiency. Acta Endocrinol (Copenh). 1992 Apr;126(4):319-24.3 De Nayer P, Dozin B, Vandeput Y, Bottazzo FC, Crabbe J. Altered interaction between triiodothyronine and its

nuclear receptors in absence of cortisol: a proposed mechanism for increased thyrotropin secretion in corticosteroid

deficiency states. Eur J Clin Invest. 1987 Apr;17(2):106-10.4 Hangaard J, Andersen M, Grodum E, Koldkjaer O, Hagen C. Pulsatile thyrotropin secretion in patients with

Addison's disease during variable glucocorticoid therapy.J Clin Endocrinol Metab. 1996 Jul;81(7):2502-7.5 Bános C, Takó J, Salamon F, Györgyi S, Czikkely R. Effect of ACTH-stimulated glucocorticoid hypersecretion on

the serum concentrations of thyroxine-binding globulin, thyroxine, triiodothyronine, reverse triiodothyronine and on

the TSH-response to TRH. Acta Med Acad Sci Hung. 1979;36(4):381-94.6 Iranmanesh A, Lizarralde G, Johnson ML, Veldhuis JD. Dynamics of 24-hour endogenous cortisol secretion and

clearance in primary hypothyroidism assessed before and after partial thyroid hormone replacement. J Clin

Endocrinol Metab. 1990 Jan;70(1):155-61.7 Nolan LA, Windle RJ, Wood SA, Kershaw YM, Lunness HR, Lightman SL, Ingram CD, Levy A. Chronic iodine deprivation attenuates stress-induced and diurnal variation in corticosterone secretion in female Wistar rats. J Neuroendocrinol. 2000 Dec;12(12):1149-59. 8 Purnell JQ, Brandon DD, Isabelle LM, Loriaux DL, Samuels MH. Association of 24-hour cortisol production rates,

cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult

men and women. J Clin Endocrinol Metab. 2004 Jan;89(1):281-7.9 Weykamp CW, Penders TJ, Schmidt NA, Borburgh AJ, van de Calseyde JF, Wolthers BJ. Steroid profile for urine:

reference values. Clin Chem. 1989 Dec;35(12):2281-4.10 Vierhapper H, Nowotny P, Waldhäusl W. Sex-specific differences in cortisol production rates in humans.

Metabolism. 1998 Aug;47(8):974-6.11 Roca CA, Schmidt PJ, Deuster PA, Danaceau MA, Altemus M, Putnam K, Chrousos GP, Nieman LK, Rubinow DR. Sex-

related differences in stimulated hypothalamic-pituitary-adrenal axis during induced gonadal suppression. J Clin

Endocrinol Metab. 2005 Jul;90(7):4224-31.12 Kudielka BM, Buske-Kirschbaum A, Hellhammer DH, Kirschbaum C. HPA axis responses to laboratory psychosocial

stress in healthy elderly adults, younger adults, and children: impact of age and gender. Psychoneuroendocrinology.

2004 Jan;29(1):83-98.13 Takai N, Yamaguchi M, Aragaki T, Eto K, Uchihashi K, Nishikawa Y. Gender-specific differences in salivary biomarker

responses to acute psychological stress. Ann N Y Acad Sci. 2007 Mar;1098:510-5.

14 Van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma

cortisol. J Clin Endocrinol Metab. 1996 Jul;81(7):2468-73.15 Larsson CA, Gullberg B, Råstam L, Lindblad U. Salivary cortisol differs with age and sex and shows inverse associations with WHR in Swedish women: a cross-sectional study. BMC Endocr Disord. 2009 Jun 21;9:16. doi: 10.1186/1472-6823-9-16.

16 Mueller A, Binder H, Cupisti S, Hoffmann I, Beckmann MW, Dittrich R. Effects on the male endocrine system of long-term treatment with gonadotropin-releasing hormone agonists and estrogens in male-to-female transsexuals. Horm Metab Res. 2006 Mar;38(3):183-7.17 Gell JS, Oh J, Rainey WE, Carr BR. Effect of estradiol on DHEAS production in the human adrenocortical cell line,

H295R. J Soc Gynecol Investig. 1998 May-Jun;5(3):144-8.

18 Jamieson PM, Nyirenda MJ, Walker BR, Chapman KE, Seckl JR. Interactions between oestradiol and

glucocorticoid regulatory effects on liver-specific glucocorticoid-inducible genes: possible evidence for a role of

hepatic 11beta-hydroxysteroid dehydrogenase type 1. J Endocrinol. 1999 Jan;160(1):103-9.19 Kerdelhué B, Andrews MC, Zhao Y, Scholler R, Jones HW Jr. Short term changes in melatonin and cortisol serum

levels after a single administration of estrogen to menopausal women. Neuro Endocrinol Lett. 2006 Oct;27(5):659-

64.20 Cohen PG. Estradiol induced inhibition of 11beta-hydroxysteroid dehydrogenase 1: an explanation for the

postmenopausal hormone replacement therapy effects. Med Hypotheses. 2005;64(5):989-91.21 Ligeiro de Oliveira AP, Oliveira-Filho RM, da Silva ZL, Borelli P, Tavares de Lima W. Regulation of allergic lung

inflammation in rats: interaction between estradiol and corticosterone. Neuroimmunomodulation. 2004;11(1):20-

7.22 Guglielmi V, Vulink NC, Denys D, Wang Y, Samuels JF, Nestadt G. Obsessive-Compulsive Disorder and Female Reproductive Cycle Events: Results from the OCD and Reproduction Collaborative Study. Depress Anxiety. 2014 Jan 13. 23 Hellman L, Yoshida K, Zumoff B, Levin J, Kream J, Fukushima DK. The effect of medroxyprogesterone acetate on the pituitary-adrenal axis. J Clin Endocrinol Metab. 1976 May;42(5):912-7.24 Koubovec D, Ronacher K, Stubsrud E, Louw A, Hapgood JP. Synthetic progestins used in HRT have different glucocorticoid agonist properties. Mol Cell Endocrinol. 2005 Oct 20;242(1-2):23-32.

25 Leiba S, Kaufman H, Winkelsberg G, Bahary C. Transitory hypoadrenalism due to long-term treatment with

antiovulatory compounds. Isr J Med Sci. 1979 May;15(5):434-7.26 Lombardi I, Luisi S, Quirici B, Monteleone P, Bernardi F, Liut M, Casarosa E, Palumbo M, Petraglia F, Genazzani AR. Adrenal response to adrenocorticotropic hormone stimulation in patients with premenstrual syndrome. Gynecol Endocrinol. 2004 Feb;18(2):79-87

27 von Langen J, Fritzemeier KH, Diekmann S, Hillisch A. Molecular basis of the interaction specificity between the

human glucocorticoid receptor and its endogenous steroid ligand cortisol. Chembiochem. 2005 Jun;6(6):1110-8.

28 Ford JM. Experimental reversal of P-glycoprotein-mediated multidrug resistance by pharmacological chemosensitisers. Eur J Cancer. 1996 Jun;32A(6):991-1001.

29 Girdler SS, Pedersen CA, Straneva PA, Leserman J, Stanwyck CL, Benjamin S, Light KC. Dysregulation of

cardiovascular and neuroendocrine responses to stress in premenstrual dysphoric disorder. Psychiatry Res. 1998

Nov 16;81(2):163-78.30 Oda Y. [Influences of premenstrual syndrome on daily psychological states and salivary cortisol level]. Shinrigaku

Kenkyu. 2005 Dec;76(5):426-35.31 Odber J, Cawood EH, Bancroft J. Salivary cortisol in women with and without perimenstrual mood changes. J

Psychosom Res. 1998 Dec;45(6):557-68.32 Gunin AG, Mashin IN, Zakharov DA. Proliferation, mitosis orientation and morphogenetic changes in the uterus of

mice following chronic treatment with both estrogen and glucocorticoid hormones. J Endocrinol. 2001

Apr;169(1):23-31.33 Petrelluzzi KF, Garcia MC, Petta CA, Grassi-Kassisse DM, Spadari-Bratfisch RC. Salivary cortisol concentrations,

stress and quality of life in women with endometriosis and chronic pelvic pain. Stress. 2008;11(5):390-7.

34 Heim C, Ehlert U, Hanker JP, Hellhammer DH. Abuse-related posttraumatic stress disorder and alterations of the

hypothalamic-pituitary-adrenal axis in women with chronic pelvic pain. Psychosom Med. 1998 May-Jun;60(3):309-

18.35 Blackburn, ST, Maternal, Fetal, & Neonatal Physiology: A Clinical Perspective, Saunders, St. Louis, 2007, p. 67536 Jarnfelt-Samsioe A. Nausea and vomiting in pregnancy: a review.Obstet Gynecol Surv. 1987 Jul;42(7):422-7.37 Bondok RS, El Sharnouby NM, Eid HE, Abd Elmaksoud AM.Pulsed steroid therapy is an effective treatment for

intractable hyperemesis gravidarum. Crit Care Med. 2006 Nov;34(11):2781-3. 38 Nelson-Piercy C, Fayers P, de Swiet M. Randomised, double-blind, placebo-controlled trial of corticosteroids for the

treatment of hyperemesis gravidarum. BJOG. 2001 Jan;108(1):9-15.39 Allolio B, Hoffmann J, Linton EA, Winkelmann W, Kusche M, Schulte HM. Diurnal salivary cortisol patterns during

pregnancy and after delivery: relationship to plasma corticotrophin-releasing-hormone. Clin Endocrinol (Oxf). 1990

Aug;33(2):279-89.40 Kammerer M, Taylor A, Glover V. The HPA axis and perinatal depression: a hypothesis. Arch Womens Ment Health.

2006 Jul;9(4):187-96.41 Groer MW, Morgan K. Immune, health and endocrine characteristics of depressed postpartum mothers.

Psychoneuroendocrinology. 2007 Feb;32(2):133-9. 42 Kalantaridou SN, Makrigiannakis A, Zoumakis E, Chrousos GP. Stress and the female reproductive system. J Reprod

Immunol. 2004 Jun;62(1-2):61-8. 43 Mastorakos G, Ilias I. Maternal hypothalamic-pituitary-adrenal axis in pregnancy and the postpartum period.

Postpartum-related disorders. Ann N Y Acad Sci. 2000;900:95-106.44 Kapcala LP, Chautard T, Eskay RL. The protective role of the hypothalamic-pituitary-adrenal axis against lethality

produced by immune, infectious, and inflammatory stress. Ann N Y Acad Sci. 1995 Dec 29;771:419-37.45 Zimmerman JJ, Donaldson A, Barker RM, Meert KL, Harrison R, Carcillo JA, Anand KJ, Newth CJ, Berger J, Willson

DF, Jack R, Nicholson C, Dean JM; Real-time free cortisol quantification among critically ill children. Pediatr Crit Care

Med. 2011 Sep;12(5):525-31.46 Diederich S, Franzen NF, Bähr V, Oelkers W. Severe hyponatremia due to hypopituitarism with adrenal insufficiency:

report on 28 cases. Eur J Endocrinol. 2003 Jun;148(6):609-17.47 Gur A, Cevik R, Nas K, Colpan L, Sarac S. Cortisol and hypothalamic-pituitary-gonadal axis hormones in follicular-

phase women with fibromyalgia and chronic fatigue syndrome and effect of depressive symptoms on these

hormones. Arthritis Res Ther. 2004;6(3):R232-8. Epub 2004 Mar 15. 48 Jerjes WK, Cleare AJ, Wessely S, Wood PJ, Taylor NF. Diurnal patterns of salivary cortisol and cortisone output in

chronic fatigue syndrome. J Affect Disord. 2005 Aug;87(2-3):299-304.49 Strickland P, Morriss R, Wearden A, Deakin B. A comparison of salivary cortisol in chronic fatigue syndrome,

community depression and healthy controls. J Affect Disord. 1998 Jan;47(1-3):191-4.50 Jerjes WK, Peters TJ, Taylor NF, Wood PJ, Wessely S, Cleare AJ. Diurnal excretion of urinary cortisol, cortisone, and

cortisol metabolites in chronic fatigue syndrome. J Psychosom Res. 2006 Feb;60(2):145-53.51 Segal TY, Hindmarsh PC, Viner RM. Disturbed adrenal function in adolescents with chronic fatigue syndrome. J

Pediatr Endocrinol Metab. 2005 Mar;18(3):295-301.52 Scott LV, Salahuddin F, Cooney J, Svec F, Dinan TG. Differences in adrenal steroid profile in chronic fatigue

syndrome, in depression and in health. Affect Disord. 1999 Jul;54(1-2):129-337.

53 Kuratsune H, Yamaguti K, Sawada M, Kodate S, Machii T, Kanakura Y, Kitani T. Dehydroepiandrosterone sulfate

deficiency in chronic fatigue syndrome.Int J Mol Med. 1998 Jan;1(1):143-6.54 Greenfield JR, Samaras K. Evaluation of pituitary function in the fatigued patient: a review of 59 cases. Eur J

Endocrinol. 2006 Jan;154(1):147-57. 55 Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJ, Chrousos GP, Gold PW. Evidence for impaired

activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol

Metab. 1991 Dec;73(6):1224-34.56 Demitrack MA, Crofford LJ. Evidence for and pathophysiologic implications of hypothalamic-pituitary-adrenal axis

dysregulation in fibromyalgia and chronic fatigue syndrome. Ann N Y Acad Sci. 1998 May 1;840:684-97. 57 Di Giorgio A, Hudson M, Jerjes W, Cleare AJ. 24-hour pituitary and adrenal hormone profiles in chronic fatigue

syndrome. Psychosom Med. 2005 May-Jun;67(3):433-40.58 Jerjes WK, Taylor NF, Wood PJ, Cleare AJ. Enhanced feedback sensitivity to prednisolone in chronic fatigue

syndrome. Psychoneuroendocrinology. 2007 Feb;32(2):192-8. 59 Di Giorgio A, Hudson M, Jerjes W, Cleare AJ. 24-hour pituitary and adrenal hormone profiles in chronic fatigue

syndrome. Psychosom Med. 2005 May-Jun;67(3):433-40.60 Jerjes WK, Taylor NF, Wood PJ, Cleare AJ. Enhanced feedback sensitivity to prednisolone in chronic fatigue

syndrome. Psychoneuroendocrinology. 2007 Feb;32(2):192-8. 61 Rajeevan MS, Smith AK, Dimulescu I, Unger ER, Vernon SD, Heim C, Reeves WC. Glucocorticoid receptor

polymorphisms and haplotypes associated with chronic fatigue syndrome. Genes Brain Behav. 2006 Jun 162 Torpy DJ, Bachmann AW, Gartside M, Grice JE, Harris JM, Clifton P, Easteal S, Jackson RV, Whitworth JA. Association

between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism. Endocr

Res. 2004 Aug;30(3):417-29. 63 Cleare AJ, Heap E, Malhi GS, Wessely S, O'Keane V, Miell J. Low-dose hydrocortisone in chronic fatigue syndrome: a

randomised crossover trial. Lancet. 1999 Feb 6;353(9151):455-8.64 McKenzie R, O'Fallon A, Dale J, Demitrack M, Sharma G, Deloria M, Garcia-Borreguero D, Blackwelder W, Straus SE.

Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA. 1998 Sep

23-30;280(12):1061-6.65 Blockmans D, Persoons P, Van Houdenhove B, Lejeune M, Bobbaers H. Combination therapy with hydrocortisone

and fludrocortisone does not improve symptoms in chronic fatigue syndrome: a randomized, placebo-controlled,

double-blind, crossover study. Am J Med. 2003 Jun 15;114(9):736-41.66 McBeth J, Chiu YH, Silman AJ, Ray D, Morriss R, Dickens C, Gupta A, Macfarlane GJ. Hypothalamic-pituitary-adrenal

stress axis function and the relationship with chronic widespread pain and its antecedents. Arthritis Res Ther.

2005;7(5):R992-R1000. 67 Gur A, Cevik R, Nas K, Colpan L, Sarac S. Cortisol and hypothalamic-pituitary-gonadal axis hormones in follicular-

phase women with fibromyalgia and chronic fatigue syndrome and effect of depressive symptoms on these

hormones. Arthritis Res Ther. 2004;6(3):R232-8.68 Janssens KA, Oldehinkel AJ, Verhulst FC, Hunfeld JA, Ormel J, Rosmalen JG. Symptom-specific associations between

low cortisol responses and functional somatic symptoms: The TRAILS study.Psychoneuroendocrinology. 2011 Jul 29.

[Epub ahead of print]

69 Gur A, Cevik R, Sarac AJ, Colpan L, Em S. Hypothalamic-pituitary-gonadal axis and cortisol in young women with

primary fibromyalgia: the potential roles of depression, fatigue, and sleep disturbance in the occurrence of

hypocortisolism. Ann Rheum Dis. 2004 Nov;63(11):1504-6. 70 Macedo JA, Hesse J, Turner JD, Meyer J, Hellhammer DH, Muller CP. Glucocorticoid sensitivity in fibromyalgia

patients: decreased expression of corticosteroid receptors and glucocorticoid-induced leucine zipper.

Psychoneuroendocrinology. 2008 Jul;33(6):799-809. 71 Kirnap M, Colak R, Eser C, Ozsoy O, Tutus A, Kelestimur F. A comparison between low-dose (1 microg), standard-

dose (250 microg) ACTH stimulation tests and insulin tolerance test in the evaluation of hypothalamo-pituitary-

adrenal axis in primary fibromyalgia syndrome. Clin Endocrinol (Oxf). 2001 Oct;55(4):455-9.72 Griep EN, Boersma JW, Lentjes EG, Prins AP, van der Korst JK, de Kloet ER. Function of the hypothalamic-pituitary-

adrenal axis in patients with fibromyalgia and low back pain. J Rheumatol. 1998 Jul;25(7):1374-81.73 Neeck G, Crofford LJ. Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome. Rheum Dis Clin

North Am. 2000 Nov;26(4):989-1002.74 Geenen R, Jacobs JW, Bijlsma JW. Evaluation and management of endocrine dysfunction in fibromyalgia. Rheum

Dis Clin North Am. 2002 May;28(2):389-404.75 Lowe JC, Cullum ME, Graf LH Jr, Yellin J. Mutations in the c-erbA beta 1 gene: do they underlie euthyroid

fibromyalgia? Med Hypotheses. 1997 Feb;48(2):125-35.76 Lowe JC, Yellin J, Honeyman-Lowe G. Female fibromyalgia patients: lower resting metabolic rates than matched

healthy controls. Med Sci Monit. 2006 Jul;12(7):CR282-9.77 Neeck G, Riedel W. Thyroid function in patients with fibromyalgia syndrome. J Rheumatol. 1992 Jul;19(7):1120-2.78 Pamuk ON, Cakir N. The frequency of thyroid antibodies in fibromyalgia patients and their relationship with

symptoms. Clin Rheumatol. 2007 Jan;26(1):55-979 Ribeiro LS, Proietti FA. Interrelations between fibromyalgia, thyroid autoantibodies, and depression. J Rheumatol.

2004 Oct;31(10):2036-40.80 Bou-Holaigah I, Calkins H, Flynn JA, Tunin C, Chang HC, Kan JS, Rowe PC. Provocation of hypotension and pain

during upright tilt table testing in adults with fibromyalgia. Clinical and Experimental Rheumatology 1997; 15(3):

239-46.81 Soravia LM, Heinrichs M, Aerni A, Maroni C, Schelling G, Ehlert U, Roozendaal B, de Quervain DJ. Glucocorticoids

reduce phobic fear in humans. Proc Natl Acad Sci U S A. 2006 Apr 4;103(14):5585-90.82 Vinberg M, Miskowiak K, Kessing LV. Serotonin transporter genotype, salivary cortisol, neuroticism and life

events: Impact on subsequent psychopathology in healthy twins at high and low risk for affective disorder. Prog

Neuropsychopharmacol Biol Psychiatry. 2013 Oct 16;48C:193-198.83 Petrowski K, Herold U, Joraschky P, Wittchen HU, Kirschbaum C. A striking pattern of cortisol non-responsiveness to

psychosocial stress in patients with panic disorder with concurrent normal cortisol awakening responses.

Psychoneuroendocrinology. 2010 Apr;35(3):414-21. 84 Putman P, Hermans EJ, Koppeschaar H, van Schijndel A, van Honk A single administration of cortisol acutely

reduces preconscious attention for fear in anxious young men. J. Psychoneuroendocrinology. 2007 Aug;32(7):793-

802.85 Zorrilla EP, DeRubeis RJ, Redei E. High self-esteem, hardiness and affective stability are associated with higher basal

pituitary-adrenal hormone levels. Psychoneuroendocrinology. 1995;20(6):591-601

86 Heim C, Ehlert U, Hellhammer DH. The potential role of hypocortisolism in the pathophysiology of stress-related

bodily disorders. Psychoneuroendocrinology. 2000 Jan;25(1):1-35. 87 Yehuda R, Southwick SM, Nussbaum G, Wahby V, Giller EL Jr, Mason JW. Low urinary cortisol excretion in patients

with posttraumatic stress disorder. J Nerv Ment Dis. 1990 Jun;178(6):366-9. 88 Gill J, Vythilingam M, Page GG. Low cortisol, high DHEA, and high levels of stimulated TNF-alpha, and IL-6 in

women with PTSD. J Trauma Stress. 2008 Dec;21(6):530-9.89 Morris MC, Compas BE, Garber J., Relations among posttraumatic stress disorder, comorbid major depression, and

HPA function: a systematic review and meta-analysis. Clin Psychol Rev. 2012 un;32(4):301-15. 90 Bremner JD, Vythilingam M, Anderson G, Vermetten E, McGlashan T, Heninger G, Rasmusson A, Southwick SM,

Charney DS. Assessment of the hypothalamic-pituitary-adrenal axis over a 24-hour diurnal period and in response

to neuroendocrine challenges in women with and without childhood sexual abuse and posttraumatic stress

disorder. Biol Psychiatry. 2003 Oct 1;54(7):710-8.91 Kanter ED, Wilkinson CW, Radant AD, Petrie EC, Dobie DJ, McFall ME, Peskind ER, Raskind MA. Glucocorticoid

feedback sensitivity and adrenocortical responsiveness in posttraumatic stress disorder. Biol Psychiatry. 2001 Aug

15;50(4):238-45. 92 Neylan TC, Lenoci M, Maglione ML, Rosenlicht NZ, Metzler TJ, Otte C, Schoenfeld FB, Yehuda R, Marmar CR. Delta

sleep response to metyrapone in post-traumatic stress disorder. Neuropsychopharmacology. 2003 Sep;28(9):1666-

76.93 Aerni A, Traber R, Hock C, Roozendaal B, Schelling G, Papassotiropoulos A, Nitsch RM, Schnyder U, de Quervain DJ.

Low-dose cortisol for symptoms of posttraumatic stress disorder. Am J Psychiatry. 2004 Aug;161(8):1488-90.94 Yehuda R, Harvey PD, Golier JA, Newmark RE, Bowie CR, Wohltmann JJ, Grossman RA, Schmeidler J, Hazlett EA,

Buchsbaum MS. Changes in relative glucose metabolic rate following cortisol administration in aging veterans with

posttraumatic stress disorder: an FDG-PET neuroimaging study. J Neuropsychiatry Clin Neurosci. 2009

Spring;21(2):132-43.95 Derijk RH, de Kloet ER. Corticosteroid receptor polymorphisms: determinants of vulnerability and resilience. Eur J

Pharmacol. 2008 Apr 7;583(2-3):303-11.96 Pariante CM. The glucocorticoid receptor: part of the solution or part of the problem? J Psychopharmacol. 2006

Jul;20(4 Suppl):79-84.97 Ahrens T, Deuschle M, Krumm B, van der Pompe G, den Boer JA, Lederbogen F. Pituitary-Adrenal and Sympathetic

Nervous System Responses to Stress in Women Remitted From Recurrent Major Depression. Psychosom Med. 2008

May;70(4):461-7. 98 Stewart JW, Quitkin FM, McGrath PJ, Klein DF. Defining the boundaries of atypical depression: evidence from the

HPA axis supports course of illness distinctions. J Affect Disord. 2005 Jun;86(2-3):161-7.99 Rasgon NL, Kenna HA, Wong ML, Whybrow PC, Bauer M. Hypothalamic-pituitary-end organ function in women

with bipolar depression. Psychoneuroendocrinology. 2007 Apr;32(3):279-86. 100 Brouwer JP, Appelhof BC, Hoogendijk WJ, Huyser J, Endert E, Zuketto C, Schene AH,

Tijssen JG, Van Dyck R, Wiersinga WM, Fliers E Thyroid and adrenal axis in

major depression: a controlled study in outpatients. Eur J Endocrinol. 2005 Feb;152(2):185-91.101 Levitan RD, Vaccarino FJ, Brown GM, Kennedy SH. Low-dose dexamethasone challenge in women with atypical

major depression: pilot study. J Psychiatry Neurosci. 2002 Jan;27(1):47-51.

102 Bouwer C, Claassen J, Dinan TG, Nemeroff CB. Prednisone augmentation in treatment-resistant depression with

fatigue and hypocortisolaemia: a case series. Depress Anxiety. 2000;12(1):44-50.103 Brown ES, Suppes T, Khan DA, Carmody TJ 3rd. Mood changes during prednisone bursts in outpatients with

asthma. J Clin Psychopharmacol. 2002 Feb;22(1):55-61.104 Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the

pathophysiology of stress-related disorders. Am J Psychiatry. 2003 Sep;160(9):1554-65.105 Calfa G, Kademian S, Ceschin D, Vega G, Rabinovich GA, Volosin M. Characterization and functional significance

of glucocorticoid receptors in patients with major depression: modulation by antidepressant treatment.

Psychoneuroendocrinology. 2003 Jul;28(5):687-701.106 Pariante CM, Thomas SA, Lovestone S, Makoff A, Kerwin RW. Do antidepressants regulate how cortisol affects the

brain? Psychoneuroendocrinology. 2004 May;29(4):423-47.107 Torpy DJ, Grice JE, Hockings GI, Crosbie GV, Walters MM, Jackson RV. The effect of desipramine on basal and naloxone-stimulated cortisol secretion in humans: interaction of two drugs acting on noradrenergic control of adrenocorticotropin secretion. J Clin Endocrinol Metab. 1995 Mar;80(3):802-6.108 McGinn LK, Asnis GM, Rubinson E. Biological and clinical validation of atypical depression. Psychiatry Res. 1996

Mar 29;60(2-3):191-8.109 Kier A, Han J, Jacobson L. Chronic treatment with the monoamine oxidase inhibitor phenelzine increases

hypothalamic-pituitary-adrenocortical activity in male C57BL/6 mice: relevance to atypical depression.

Endocrinology. 2005 Mar;146(3):1338-47.110 Sagud M, Pivac N, Muck-Seler D, Jakovljevic M, Mihaljevic-Peles A, Korsic M. Effects of sertraline treatment on

plasma cortisol, prolactin and thyroid hormones in female depressed patients. Neuropsychobiology.

2002;45(3):139-43. 111 Ahrens T, Frankhauser P, Lederbogen F, Deuschle M. Effect of single-dose sertraline on the hypothalamus-pituitary-

adrenal system, autonomic nervous system, and platelet function. J Clin Psychopharmacol. 2007 Dec;27(6):602-6.112 Schlösser R, Wetzel H, Dörr H, Rossbach W, Hiemke C, Benkert O. Effects of subchronic paroxetine administration

on night-time endocrinological profiles in healthy male volunteers. Psychoneuroendocrinology. 2000

May;25(4):377-88.113 Hawken ER, Owen JA, Hudson RW, Delva NJ. Specific effects of escitalopram on neuroendocrine

response.Psychopharmacology (Berl). 2009 Nov;207(1):27-34. 114 Briscoe VJ, Ertl AC, Tate DB, Dawling S, Davis SN. Effects of a selective serotonin reuptake inhibitor, fluoxetine, on

counterregulatory responses to hypoglycemia in healthy individuals.Diabetes. 2008 Sep;57(9):2453-60. 115 Berardelli R, Margarito E, Ghiggia F, Picu A, Balbo M, Bonelli L, Giordano R, Karamouzis I, Bo M, Ghigo E,

Arvat E. Neuroendocrine effects of citalopram, a selective serotonin re-uptake inhibitor, during lifespan in humans. J

Endocrinol Invest. 2010 Oct;33(9):657-62. doi: 10.3275/6994. Epub 2010 Apr 22.116 Mendelson JH, Sholar MB, Goletiani N, Siegel AJ, Mello NK. Effects of low- and high-nicotine cigarette smoking on

mood states and the HPA axis in men. Neuropsychopharmacology. 2005 Sep;30(9):1751-63.117 Seyler LE Jr, Fertig J, Pomerleau O, Hunt D, Parker K. The effects of smoking on ACTH and cortisol secretion. Life Sci.

1984 Jan 2;34(1):57-65.118 Wilkins JN, Carlson HE, Van Vunakis H, Hill MA, Gritz E, Jarvik ME. Nicotine from cigarette smoking increases

circulating levels of cortisol, growth hormone, and prolactin in male chronic smokers. Psychopharmacology (Berl).

1982;78(4):305-8.

119 al'Absi M, Hatsukami D, Davis GL, Wittmers LE. Prospective examination of effects of smoking abstinence on

cortisol and withdrawal symptoms as predictors of early smoking relapse. Drug Alcohol Depend. 2004 Mar

8;73(3):267-78.120 Lovallo WR, Al'Absi M, Blick K, Whitsett TL, Wilson MF. Stress-like adrenocorticotropin responses to caffeine in

young healthy men. Pharmacol Biochem Behav. 1996 Nov;55(3):365-9. 121 Mello NK. Hormones, nicotine, and cocaine: clinical studies. Horm Behav. 2010 Jun;58(1):57-71.122 Goeders NE. The HPA axis and cocaine reinforcement. Psychoneuroendocrinology. 2002 Jan-Feb;27(1-2):13-33.123 Harris DS, Baggott M, Mendelson JH, Mendelson JE, Jones RT.Subjective and hormonal effects of 3,4-

methylenedioxymethamphetamine (MDMA) in humans.Psychopharmacology (Berl). 2002 Aug;162(4):396-405. 124 Parrott AC. Recreational Ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity. Pharmacol

Biochem Behav. 2002 Apr;71(4):837-44.125 Parrott AC, Lock J, Conner AC, Kissling C, Thome J. Dance clubbing on MDMA and during abstinence from

Ecstasy/MDMA: prospective neuroendocrine and psychobiological changes. Neuropsychobiology. 2008;57(4):165-

80.126 Cone EJ, Johnson RE, Moore JD, Roache JD. Acute effects of smoking marijuana on hormones, subjective effects

and performance in male human subjects. Pharmacol Biochem Behav. 1986 Jun;24(6):1749-54.127 Murphy LL, Muñoz RM, Adrian BA, Villanúa MA. Function of cannabinoid receptors in the neuroendocrine

regulation of hormone secretion. Neurobiol Dis. 1998 Dec;5(6 Pt B):432-46.128 Ranganathan M, Braley G, Pittman B, Cooper T, Perry E, Krystal J, D'Souza DC. The effects of cannabinoids on serum

cortisol and prolactin in humans. Psychopharmacology (Berl). 2009 May;203(4):737-44.129 Mendelson JH, Ogata M, Mello NK. Adrenal function and alcoholism. I. Serum cortisol. Psychosom Med. 1971

Mar-Apr;33(2):145-57.130 Gianoulakis C, Dai X, Brown T. Effect of chronic alcohol consumption on the activity of the hypothalamic-

pituitary-adrenal axis and pituitary beta-endorphin as a function of alcohol intake, age, and gender. Alcohol Clin Exp

Res. 2003 Mar;27(3):410-23.131 Adinoff B, Krebaum SR, Chandler PA, Ye W, Brown MB, Williams MJ. Dissection of hypothalamic-pituitary-adrenal

axis pathology in 1-month-abstinent alcohol-dependent men, part 1: adrenocortical and pituitary glucocorticoid

responsiveness. Alcohol Clin Exp Res. 2005 Apr;29(4):517-27.132 Costa A, Bono G, Martignoni E, Merlo P, Sances G, Nappi G. An assessment of hypothalamo-pituitary-adrenal axis

functioning in non-depressed, early abstinent alcoholics. Psychoneuroendocrinology. 1996 Apr;21(3):263-75.133 Junghanns K, Tietz U, Dibbelt L, Kuether M, Jurth R, Ehrenthal D, Blank S, Backhaus J. Attenuated salivary cortisol

secretion under cue exposure is associated with early relapse. Alcohol Alcohol. 2005 Jan-Feb;40(1):80-5.134 Jacobs D, Silverstone T, Rees L. The neuroendocrine response to oral dextroamphetamine in normal subjects.Int

Clin Psychopharmacol. 1989 Apr;4(2):135-47.135 Fehm HL, Holl R, Steiner K, Klein E, Voigt KH. Evidence for ACTH-unrelated mechanisms in the regulation of cortisol

secretion in man. Klin Wochenschr. 1984 Jan 2;62(1):19-24.136 Saito M, Yamaguchi T, Kawata T, Ito H, Kanai T, Terada M, Yokosuka M, Saito TR. Effects of methamphetamine

on cortisone concentration, NK cell activity and mitogen response of T-lymphocytes in female cynomolgus

monkeys. Exp Anim. 2006 Oct;55(5):477-81.

137 Carson DS, Bosanquet DP, Carter CS, Pournajafi-Nazarloo H, Blaszczynski A, McGregor IS. Preliminary evidence

for lowered basal cortisol in a naturalistic sample of methamphetamine polydrug users. Exp Clin Psychopharmacol.

2012 Dec;20(6):497-503.138 Li SX, Yan SY, Bao YP, Lian Z, Qu Z, Wu YP, Liu ZM. Depression and alterations in hypothalamic-pituitary-

adrenal and hypothalamic-pituitary-thyroid axis function in male abstinent methamphetamine abusers. Hum

Psychopharmacol. 2013 Sep;28(5):477-83.139 Cutolo M, Sulli A, Pizzorni C, Secchi ME, Soldano S, Seriolo B, Straub RH, Otsa K, Maestroni GJ. Circadian rhythms:

glucocorticoids and arthritis. Ann N Y Acad Sci. 2006 Jun;1069:289-99. 140 Johnson EO, Kostandi M, Moutsopoulos HM. Hypothalamic-pituitary-adrenal axis function in Sjögren's syndrome:

mechanisms of neuroendocrine and immune system homeostasis. Ann N Y Acad Sci. 2006 Nov;1088:41-51.141 Tzioufas AG, Tsonis J, Moutsopoulos HM. Neuroendocrine dysfunction in Sjogren's syndrome.

Neuroimmunomodulation. 2008;15(1):37-45. 142 Kebapcilar L, Bilgir O, Alacacioglu A, Yildiz Y, Taylan A, Gunaydin R, Yuksel A, Karaca B, Sari I. Impaired hypothalamo-

pituitary-adrenal axis in patients with ankylosing spondylitis. J Endocrinol Invest. 2010 Jan;33(1):42-7.143 Cutolo M, Straub RH, Foppiani L, Prete C, Pulsatelli L, Sulli A, Boiardi L, Macchioni P, Giusti M, Pizzorni C, Seriolo B,

Salvarani C. Adrenal gland hypofunction in active polymyalgia rheumatica. effect of glucocorticoid treatment on

adrenal hormones and interleukin 6. J Rheumatol. 2002 Apr;29(4):748-56.144 Demir H, Tanriverdi F, Ozogul N, Calis M, Kirnap M, Durak AC, Kelestimur F. Evaluation of the hypothalamic-

pituitary-adrenal axis in untreated patients with polymyalgia rheumatica and healthy controls. Scand J Rheumatol.

2006 May-Jun;35(3):217-23.145 Shah D, Kiran R, Wanchu A, Bhatnagar A. Relationship between T lymphocyte subsets and cortisol in systemic lupus

erythematosus. Kathmandu Univ Med J (KUMJ). 2009 Jul-Sep;7(27):213-9.146 Chikanza IC, Petrou P, Kingsley G, Chrousos G, Panayi GS. Defective hypothalamic response to immune and

inflammatory stimuli in patients with rheumatoid arthritis. Arthritis Rheum. 1992 Nov;35(11):1281-8.147 Mastorakos G, Ilias I. Relationship between interleukin-6 (IL-6) and hypothalamic-pituitary-adrenal axis hormones

in rheumatoid arthritis. Z Rheumatol. 2000;59 Suppl 2:II/75-9.148 Imrich R, Vigas M, Rovensky J, Aldag JC, Masi AT. Adrenal plasma steroid relations in glucocorticoid-naïve

premenopausal rheumatoid arthritis patients during insulin-induced hypoglycemia test compared to matched

normal control females. Endocr Regul. 2009 Apr;43(2):65-73.149 Gudbjornsson B, Skogseid B, Oberg K, Wide L, Hallgren R. Intact adrenocorticotropic hormone secretion but

impaired cortisol response in patients with active rheumatoid arthritis. Effect of glucocorticoids. J Rheumatol. 1996

Apr;23(4):596-602.150 Bilginer Y, Topaloglu R, Alikasifoglu A, Kara N, Besbas N, Ozen S, Bakkaloglu A. Low cortisol levels in active juvenile

idiopathic arthritis. Clin Rheumatol. 2010 Mar;29(3):309-14.151 Gaillard RC, Turnill D, Sappino P, Muller AF. Tumor necrosis factor alpha inhibits the hormonal response of the

pituitary gland to hypothalamic releasing factors. Endocrinology. 1990 Jul;127(1):101-6.152 Straub RH, Pongratz G, Cutolo M, Wijbrandts CA, Baeten D, Fleck M, Atzeni F, Grunke M, Kalden JR, Schölmerich J,

Lorenz HM, Tak PP, Sarzi-Puttini P.Increased cortisol relative to adrenocorticotropic hormone predicts improvement

during anti-tumor necrosis factor therapy in rheumatoid arthritis. Arthritis Rheum. 2008 Apr;58(4):976-84.

153 Atzeni F, Straub RH, Cutolo M, Sarzi-Puttini P. Psoriatic arthritis: clinical improvement and correlation with

hormone axes in etanercept-treated patients. Ann N Y Acad Sci. 2010 Apr;1193:176-8.154 Straub RH, Pongratz G, Schölmerich J, Kees F, Schaible TF, Antoni C, Kalden JR, Lorenz HM. Long-term anti-tumor

necrosis factor antibody therapy in rheumatoid arthritis patients sensitizes the pituitary gland and favors adrenal

androgen secretion. Arthritis Rheum. 2003 Jun;48(6):1504-12.155 Straub RH, Cutolo M. Involvement of the hypothalamic--pituitary--adrenal/gonadal axis and the peripheral nervous

system in rheumatoid arthritis: viewpoint based on a systemic pathogenetic role. Arthritis Rheum. 2001

Mar;44(3):493-507. 156 Bijlsma JW, van der Goes MC, Hoes JN, Jacobs JW, Buttgereit F, Kirwan Low-dose glucocorticoid therapy in

rheumatoid arthritis: an obligatory therapy. J. Ann N Y Acad Sci. 2010 Apr;1193:123-6.157 Da Silva JA, Jacobs JW, Bijlsma JW. Ann N Y Acad Sci. 2006 Jun;1069:275-88.158 Korczowska I, Olewicz-Gawlik A, Trefler J, Hrycaj P, Krzysztof Łacki J. Does low-dose and short-term glucocorticoids

treatment increase the risk of osteoporosis in rheumatoid arthritis female patients? Clin Rheumatol. 2008

May;27(5):565-72.159 Carlé A, Laurberg P, Pedersen IB, et al. Age Modifies the Pituitary TSH Response to Thyroid Failure. Thyroid

2007;17:139-44.160 Edwards AV, Jones CT. Autonomic control of adrenal function. J Anat. 1993 Oct;183 ( Pt 2):291-307.161 Li L, Power C, Kelly S, Kirschbaum C, Hertzman C. Life-time socio-economic position and cortisol patterns in mid-

life.Psychoneuroendocrinology. 2007 Aug;32(7):824-33. 162 Pruessner JC, Hellhammer DH, Kirschbaum C. Burnout, perceived stress, and cortisol responses to awakening.

Psychosom Med. 1999 Mar-Apr;61(2):197-204.163 Gunnar MR, Vazquez DM. Low cortisol and a flattening of expected daytime rhythm: potential indices of risk in

human development. Dev Psychopathol. 2001 Summer;13(3):515-38. 164 Zarkovic M, Stefanova E, Ciric J, Penezic Z, Kostic V, Sumarac-Dumanovic M, Macut D, Ivovic MS, Gligorovic PV.

Prolonged psychological stress suppresses cortisol secretion. Clin Endocrinol (Oxf). 2003 Dec;59(6):811-6.165 Yehuda R, Seckl J. Minireview: Stress-related psychiatric disorders with low cortisol levels: a metabolic hypothesis.

Endocrinology. 2011 Dec;152(12):4496-503.166 Cohen S, Janicki-Deverts D, Doyle WJ, Miller GE, Frank E, Rabin BS, Turner RB. Chronic stress, glucocorticoid

receptor resistance, inflammation, and disease risk. Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):5995-9.167 Heim C, Ehlert U, Hellhammer DH. The potential role of hypocortisolism in the pathophysiology of stress-related

bodily disorders. Psychoneuroendocrinology. 2000 Jan;25(1):1-35.168 Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the

pathophysiology of stress-related disorders. Am J Psychiatry. 2003 Sep;160(9):1554-65. 169 Gupta S, Aslakson E, Gurbaxani BM, Vernon SD. Inclusion of the glucocorticoid receptor in a hypothalamic pituitary

adrenal axis model reveals bistability. Theor Biol Med Model. 2007 Feb 14;4(1):8 170 Engeland WC. Functional innervation of the adrenal cortex by the splanchnic nerve. Horm Metab Res. 1998 Jun-

Jul;30(6-7):311-4.171 Buijs RM, Wortel J, Van Heerikhuize JJ, Feenstra MG, Ter Horst GJ, Romijn HJ, Kalsbeek A. Anatomical and

functional demonstration of a multisynaptic suprachiasmatic nucleus adrenal (cortex) pathway.Eur J Neurosci. 1999

May;11(5):1535-44.

172 Apostolova G, Schweizer RA, Balazs Z, Kostadinova RM, Odermatt A. Dehydroepiandrosterone inhibits the

amplification of glucocorticoid action in adipose tissue. Am J Physiol Endocrinol Metab. 2005 May;288(5):E957-64.173 Muller C, Hennebert O, Morfin R.J The native anti-glucocorticoid paradigm. Steroid Biochem Mol Biol. 2006

Jul;100(1-3):95-105.174 Stewart PM. Eur J Endocrinol. Tissue-specific Cushing's syndrome, 11beta-hydroxysteroid dehydrogenases and the

redefinition of corticosteroid hormone action. 2003 Sep;149(3):163-8.175

Andrioli M, Pecori Giraldi F, Cavagnini F. Isolated corticotrophin deficiency. Pituitary. 2006;9(4):289-95.176 Bleicken B, Hahner S, Ventz M, Quinkler M. Delayed diagnosis of adrenal insufficiency is common: a cross-

sectional study in 216 patients. Am J Med Sci. 2010 Jun;339(6):525-31.177 Garde AH, Persson R, Hansen AM, Osterberg K, Orbæk P, Eek F, Karlson B. Effects of lifestyle factors on

concentrations of salivary cortisol in healthy individuals.Scand J Clin Lab Invest. 2008 Nov 4:1-9.178 Kasperlik-Załuska AA, Czarnocka B, Czech W, et al. Secondary adrenal insufficiency associated with autoimmune

disorders: a report of twenty-five cases. Clin Endocrinol (Oxf) 1998;49:779-83.179 Terzidis K, Panoutsopoulos A, Mantzou A, et al. Lower early morning plasma cortisol levels are associated with

thyroid autoimmunity in the elderly. Eur J Endocrinol. 2010;162:307-13. 180 Greenfield JR, Samaras K. Evaluation of pituitary function in the fatigued patient: a review of 59 cases. Eur J

Endocrinol 2006;154:147-57.181 Koubovec D, Ronacher K, Stubsrud E, Louw A, Hapgood JP. Synthetic progestins used in HRT have different

glucocorticoid agonist properties. Mol Cell Endocrinol. 2005 Oct 20;242(1-2):23-32.182 Weibel L, Follenius M, Spiegel K, Ehrhart J, Brandenberger G. Comparative effect of night and daytime sleep on the

24-hour cortisol secretory profile. Sleep. 1995 Sep;18(7):549-56183 http://www.utrc2.org/sites/default/files/pubs/Impact-of-Mode-%26-Mode-Transfer-on-Commuter-Stress-

Montclair-Connection.pdf184 Garde AH, Persson R, Hansen AM, Osterberg K, Orbæk P, Eek F, Karlson B. Effects of lifestyle factors on

concentrations of salivary cortisol in healthy individuals.Scand J Clin Lab Invest. 2008 Nov 4:1-9.185 Weibel L, Follenius M, Spiegel K, Ehrhart J, Brandenberger G. Comparative effect of night and daytime sleep on the

24-hour cortisol secretory profile. Sleep. 1995 Sep;18(7):549-56186 Leproult R, Colecchia EF, L'Hermite-Baleriaux M, Van Cauter E. Transition from dim to bright light in the morning

induces an immediate elevation of cortisol levels. J Clin Endocrinol Metab. 2001 Jan;86(1):151-7. 187 Reimondo G, Pituitary. 2008;11(2):147-54., Streeten DH, J Clin Endocrinol Metab. 1996 Jan;81(1):285-90. 188 Greenfield JR, Samaras K. Evaluation of pituitary function in the fatigued patient: a review of 59 cases. Eur J

Endocrinol. 2006 Jan;154(1):147-57. 189 Al-Aridi R, Abdelmannan D, Arafah BM. Biochemical Diagnosis of Adrenal Insufficiency: The added Value of

Dehydroepiandrosterone Sulfate (DHEA-S) Measurements. Endocr Pract. 2010 Dec 6:1-32. 190 Streeten DH, Anderson GH Jr, Bonaventura MM. The potential for serious consequences from misinterpreting

normal responses to the rapid adrenocorticotropin test. J Clin Endocrinol Metab. 1996 Jan;81(1):285-90. 191 Oki K, Yamane K, Yoneda M, Nojima H, Watanabe H, Kohno N. A Case of Addison's Disease Confirmed with Low

Dose Cosyntropin Stimulation Test. Endocr J. 2007 Dec;54(5):765-9. 192 Thaler LM, Blevins LS Jr. The low dose (1-microg) adrenocorticotropin stimulation test in the evaluation of patients

with suspected central adrenal insufficiency. J Clin Endocrinol Metab. 1998 Aug;83(8):2726-9.

193 Kazlauskaite R, Evans AT, Villabona CV, Abdu TA, Ambrosi B, Atkinson AB, Choi CH, Clayton RN, Courtney CH,

Gonc EN, Maghnie M, Rose SR, Soule SG, Tordjman K; Consortium for Evaluation of Corticotropin Test in

Hypothalamic-Pituitary Adrenal Insufficiency. Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency:

a metaanalysis. J Clin Endocrinol Metab. 2008 Nov;93(11):4245-53.194 Reimondo G, Bovio S, Allasino B, Terzolo M, Angeli A. Secondary hypoadrenalism. Pituitary. 2008;11(2):147-54.195 Kamrath C, Boehles H. The low-dose ACTH test does not identify mild insufficiency of the hypothalamnic-pituitary-

adrenal axis in children with inadequate stress response. J Pediatr Endocrinol Metab. 2010 Nov;23(11):1097-104.196 Soule S, Van Zyl Smit C, Parolis G, Attenborough S, Peter D, Kinvig S, Kinvig T, Coetzer E. The low dose ACTH

stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary

hypoadrenalism.Clin Endocrinol (Oxf). 2000 Aug;53(2):221-7.197 Odeniyi IA, Fasanmade OA, Ajala MO, Ohwovoriole AE. Comparison of low dose and standard dose

adrenocorticotropin stimulation tests in healthy Nigerians. Afr J Med Med Sci. 2010 Jun;39(2):113-8.198 Giordano R, Pellegrino M, Oleandri S, Baldi M, Balbo M, Laureti S, Falorni A, Ghigo E, Arvat E. Adrenal sensitivity to

adrenocorticotropin 1-24 is reduced in patients with autoimmune polyglandular syndrome. J Clin Endocrinol

Metab. 2004 Feb;89(2):675-80.199 Ammari F, Issa BG, Millward E, Scanion MF. A comparison between short ACTH and insulin stress tests for assessing

hypothalamo-pituitary-adrenal function. Clin Endocrinol (Oxf). 1996 Apr;44(4):473-6.200 Kamrath C, Boehles H. The low-dose ACTH test does not identify mild insufficiency of the hypothalamnic-pituitary-

adrenal axis in children with inadequate stress response. J Pediatr Endocrinol Metab. 2010 Nov;23(11):1097-104.201 Yamaji T, Ishibashi M, Takaku F, Itabashi A, Katayama S, Ishii J. Serum dehydroepiandrosterone sulfate

concentrations in secondary adrenal insufficiency. J Clin Endocrinol Metab. 1987 Sep;65(3):448-51.202 Al-Aridi R, Abdelmannan D, Arafah BM. Biochemical Diagnosis of Adrenal Insufficiency: The added Value of

Dehydroepiandrosterone Sulfate (DHEA-S) Measurements. Endocr Pract. 2010 Dec 6:1-32. 203 Arafah BM, Nishiyama FJ, Tlaygeh H, Hejal R. Measurement of salivary cortisol concentration in the assessment of

adrenal function in critically ill subjects: a surrogate marker of the circulating free cortisol. J Clin Endocrinol Metab.

2007 Aug;92(8):2965-71. 204 Laudat MH, Cerdas S, Fournier C, Guiban D, Guilhaume B, Luton JP. Salivary cortisol measurement: a practical

approach to assess pituitary-adrenal function. J Clin Endocrinol Metab. 1988 Feb;66(2):343-8.205 Gozansky WS, Lynn JS, Laudenslager ML, Kohrt WM. Salivary cortisol determined by enzyme immunoassay is

preferable to serum total cortisol for assessment of dynamic hypothalamic--pituitary--adrenal axis activity. Clin

Endocrinol (Oxf). 2005 Sep;63(3):336-41.206 Vining RF, McGinley RA, Maksvytis JJ, Ho KY. Salivary cortisol: a better measure of adrenal cortical function than

serum cortisol. Ann Clin Biochem. 1983 Nov;20 (Pt 6):329-35.207 Gozansky WS, Lynn JS, Laudenslager ML, Kohrt WM. Salivary cortisol determined by enzyme immunoassay is

preferable to serum total cortisol for assessment of dynamic hypothalamic--pituitary--adrenal axis activity. Clin

Endocrinol (Oxf). 2005 Sep;63(3):336-41.208 Vining RF, McGinley RA, Maksvytis JJ, Ho KY. Salivary cortisol: a better measure of adrenal cortical function than

serum cortisol. Ann Clin Biochem. 1983 Nov;20 (Pt 6):329-35.209 Umeda T, Hiramatsu R, Iwaoka T, Shimada T, Miura F, Sato T. Use of saliva for monitoring unbound free cortisol

levels in serum. Clin Chim Acta. 1981 Mar 5;110(2-3):245-53.

210 Dorn LD, Lucke JF, Loucks TL, Berga SL. Salivary cortisol reflects serum cortisol: analysis of circadian profiles. Ann

Clin Biochem. 2007 May;44(Pt 3):281-4.211 Løvås K, Husebye ES. [Salivary cortisol in adrenal diseases] Tidsskr Nor Laegeforen. 2007 Mar 15;127(6):730-2.212 Doi M, Sekizawa N, Tani Y, Tsuchiya K, Kouyama R, Tateno T, Izumiyama H, Yoshimoto T, Hirata Y. Late-night Salivary

Cortisol as a Screening Test for the Diagnosis of Cushing's Syndrome in Japan. Endocr J. 2008 Jan 17.213 Putignano P, Toja P, Dubini A, Pecori Giraldi F, Corsello SM, Cavagnini F. Midnight salivary cortisol versus urinary

free and midnight serum cortisol as screening tests for Cushing's syndrome. J Clin Endocrinol Metab. 2003

Sep;88(9):4153-7.214 Raff H, Raff JL, Findling JW. Late-night salivary cortisol as a screening test for Cushing's syndrome. J Clin Endocrinol

Metab. 1998 Aug;83(8):2681-6.215 Cardoso EM, Arregger AL, Tumilasci OR, Contreras LN. Diagnostic value of salivary cortisol in Cushing's syndrome.

Clin Endocrinol (Oxf). 2008 Aug 15;999 (999A). 216 Contreras LN, Arregger AL, Persi GG, Gonzalez NS, Cardoso EM. A new less-invasive and more informative low-

dose ACTH test: salivary steroids in response to intramuscular corticotrophin. Clin Endocrinol (Oxf). 2004

Dec;61(6):675-82.217 Marcus-Perlman Y, Tordjman K, Greenman Y, Limor R, Shenkerman G, Osher E, Stern N. Low-dose ACTH (1 microg)

salivary test: a potential alternative to the classical blood test.Clin Endocrinol (Oxf). 2006 Feb;64(2):215-8. 218 Cetinkaya S, Ozon A, Yordam N. Diagnostic value of salivary cortisol in children with abnormal adrenal cortex

functions. Horm Res. 2007;67(6):301-6. 219 Jollin L, Thomasson R, Le Panse B, Baillot A, Vibarel-Rebot N, Lecoq AM, Amiot V, De Ceaurriz J, Collomp K. Saliva

DHEA and cortisol responses following short-term corticosteroid intake. Eur J Clin Invest. 2010 Feb;40(2):183-6. 220 Patel RS, Shaw SR, McIntyre HE, McGarry GW, Wallace AM. Morning salivary cortisol versus short Synacthen test as

a test of adrenal suppression. Ann Clin Biochem. 2004 Sep;41(Pt 5):408-10.221 Patel RS, Wallace AM, Hinnie J, McGarry GW. Preliminary results of a pilot study investigating the potential of

salivary cortisol measurements to detect occult adrenal suppression secondary to steroid nose drops. Clin

Otolaryngol Allied Sci. 2001 Jun;26(3):231-4.222 https://www.labcorp.com223 http://www.zrtlab.com/224 http://www.zrtlab.com/component/docman/doc_download/145-reference-range-determination?Itemid= pages 23-25225 Patel RS, Shaw SR, Macintyre H, McGarry GW, Wallace AM. Production of gender-specific morning salivary cortisol

reference intervals using internationally accepted procedures. Clin Chem Lab Med. 2004;42(12):1424-9.

(Conversion factor for cortisol pmol/L to mcg/dL: 27.6)226 Marcus-Perlman Y, Tordjman K, Greenman Y, Limor R, Shenkerman G, Osher E, Stern N. Low-dose ACTH (1 microg)

salivary test: a potential alternative to the classical blood test.Clin Endocrinol (Oxf). 2006 Feb;64(2):215-8. 227 Restituto P, Galofré JC, Gil MJ, Mugueta C, Santos S, Monreal JI, Varo N. Advantage of salivary cortisol

measurements in the diagnosis of glucocorticoid related disorders. Clin Biochem. 2008 Jun;41(9):688-92. 228 Deutschbein T, Unger N, Mann K, Petersenn S. Diagnosis of Secondary Adrenal Insufficiency: Unstimulated Early

Morning Cortisol in Saliva and Serum in Comparison with the Insulin Tolerance Test. Horm Metab Res 2009

Nov;41(11):834-9.

229 Raff H. Utility of Salivary Cortisol Measurements in Cushing's Syndrome and Adrenal Insufficiency. J Clin Endocrinol

Metab. 2009 Oct;94(10):3647-55.230 Koefoed P, Brahm J. The permeability of the human red cell membrane to steroid sex hormones. Biochim Biophys

Acta. 1994 Oct 12;1195(1):55-62.231 Vimpeli T, Tinkanen H, Huhtala H, Ronnberg L, Kujansuu E. Salivary and serum progesterone concentrations during

two luteal support regimens used in in vitro fertilization treatment. Fertil Steril. 2001 Oct;76(4):847-8.232 Hermann AC, Nafziger AN, Victory J, Kulawy R, Rocci ML Jr, Bertino JS Jr. Over-the-counter progesterone cream

produces significant drug exposure compared to a food and drug administration-approved oral progesterone

product. J Clin Pharmacol 2005;45:614-619233 Jodar E, Valdepenas MP, Martinez G, Jara A, Hawkins F. Long-term follow-up of bone mineral density in Addison's

disease. Clin Endocrinol (Oxf). 2003 May;58(5):617-20.234 Punthakee Z, Legault L, Polychronakos C. Prednisolone in the treatment of adrenal insufficiency: a re-evaluation of

relative potency. J Pediatr. 2003 Sep;143(3):402-5. 235 Bruno A, Carucci P, Cassader M, Cavallo-Perin P, Gruden G, Olivetti C, Pagano G. Serum glucose, insulin and C-

peptide response to oral glucose after intravenous administration of hydrocortisone and methylprednisolone in

man. Eur J Clin Pharmacol. 1994;46(5):411-5.236 Baltch AL, Hammer MC, Smith RP, Bishop MB, Sutphen NT, Egy MA, Michelsen PB. Comparison of the effect of

three adrenal corticosteroids on human granulocyte function against Pseudomonas aeruginosa. J Trauma. 1986

Jun;26(6):525-33.237 Suliman AM, Freaney R, Smith TP, McBrinn Y, Murray B, McKenna TJ. The impact of different glucocorticoid

replacement schedules on bone turnover and insulin sensitivity in patients with adrenal insufficiency. Clin

Endocrinol (Oxf). 2003 Sep;59(3):380-7. 238 Plihal W, Krug R, Pietrowsky R, Fehm HL, Born J. Corticosteroid receptor mediated effects on mood in humans.

Psychoneuroendocrinology. 1996 Aug;21(6):515-23.239 De Kloet ER, Vreugdenhil E, Oitzl MS, Joëls M. Brain corticosteroid receptor balance in health and disease. Endocr

Rev. 1998 Jun;19(3):269-301.240 http://www.duocort.com/241 http://www.diurnal.co.uk/242 Holtorf, K. Diagnosis and Treatment of Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysfunction in Patients with

Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM), J Chron Fatig Synd, 2008, (14)3:1-14.243 Hiroi N, Ichijo T, Ueshiba H, Miyachi Y. Intranasal administration of adrenocorticotropin-(1-24) stimulates

adrenocortical hormone secretion. J Clin Endocrinol Metab. 2002 Apr;87(4):1750-3.244 Hahner S, Loeffler M, Fassnacht M, Weismann D, Koschker AC, Quinkler M, Decker O, Arlt W, Allolio

B. Impaired subjective health status in 256 patients with adrenal insufficiency on standard therapy based on cross-sectional analysis. J Clin Endocrinol Metab. 2007 Oct;92(10):3912-22.

245 Løvås K, Loge JH, Husebye ES. Subjective health status in Norwegian patients with Addison's disease. Clin Endocrinol (Oxf). 2002 May;56(5):581-8.

246 Bergthorsdottir R, Leonsson-Zachrisson M, Odén A, Johannsson G. Premature mortality in patients with Addison's

disease: a population-based study. J Clin Endocrinol Metab. 2006 Dec;91(12):4849-53.247 Erichsen MM, Løvås K, Fougner KJ, Svartberg J, Hauge ER, Bollerslev J, Berg JP, Mella B, Husebye ES. Normal

overall mortality rate in Addison's disease, but young patients are at risk of premature death.

Eur J Endocrinol. 2009 Feb;160(2):233-7.248 Mills JL, Schonberger LB, Wysowski DK, Brown P, Durako SJ, Cox C, Kong F, Fradkin JE. Long-term mortality in

the United States cohort of pituitary-derived growth hormone recipients. J Pediatr. 2004 Apr;144(4):430-6.249 Groves RW, Toms GC, Houghton BJ & Monson JP. Corticosteroid replacement therapy: twice or thrice daily?

Journal of the Royal Society of Medicine 1988 81 514–516.250 Linder BL, Esteban NV, Yergey AL, Winterer JC, Loriaux DL, Cassorla F. Cortisol production rate in childhood and

adolescence. J Pediatr. 1990 Dec;117(6):892-6.251 Kraan GP, Dullaart RP, Pratt JJ, Wolthers BG, Drayer NM, De Bruin R. The daily cortisol production reinvestigated

in healthy men. The serum and urinary cortisol production rates are not significantly different. J Clin Endocrinol

Metab. 1998 Apr;83(4):1247-52.252 Bliesener N, Steckelbroeck S, Redel L, Klingmuller D. Dose distribution in hydrocortisone replacement therapy has a

significant influence on urine free cortisol excretion. Exp Clin Endocrinol Diabetes. 2003 Oct;111(7):443-6.253 Heazelwood VJ, Galligan JP, Cannell GR, Bochner F, Mortimer RH. Plasma cortisol delivery from oral cortisol and cortisone acetate: relative bioavailability. Br J Clin Pharmacol. 1984 Jan;17(1):55-9.

254 Løvås K, Husebye ES. Continuous subcutaneous hydrocortisone infusion in Addison's disease. Eur J Endocrinol.

2007 Jul;157(1):109-12.255 Jefferies, W.K. Safe Uses of Cortisol256 Larsen et al., Williams Textbook of Endocrinology, 10th edition, Elsevier, Philadelphia, 2003, p. 531.257 McConnell EM, Bell PM, Ennis C, Hadden DR, McCance DR, Sheridan B, Atkinson AB. Effects of low-dose oral

hydrocortisone replacement versus short-term reproduction of physiological serum cortisol concentrations on

insulin action in adult-onset hypopituitarism. Clin Endocrinol (Oxf). 2002 Feb;56(2):195-201.258 McConnell EM, Bell PM, Hadden DR, McCance DR, Sheridan B, Atkinson AB. Prevalence of diabetes and impaired

glucose tolerance in adult hypopituitarism on low dose oral hydrocortisone replacement therapy. Clin Endocrinol

(Oxf). 2001 May;54(5):593-9.259 Mah PM, Jenkins RC, Rostami-Hodjegan A, Newell-Price J, Doane A, Ibbotson V, Tucker GT, Ross RJ. Weight-

related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency.

Clin Endocrinol (Oxf). 2004 Sep;61(3):367-75.260 Purnell JQ, Brandon DD, Isabelle LM, Loriaux DL, Samuels MH. Association of 24-hour cortisol production rates,

cortisol-binding globulin, and plasma-free cortisol levels with body composition, leptin levels, and aging in adult

men and women. J Clin Endocrinol Metab. 2004 Jan;89(1):281-7.261 Lamberts SW. The glucocorticoid insensitivity syndrome. Horm Res. 1996;45 Suppl 1:2-4. 262 Ebrecht M, Buske-Kirschbaum A, Hellhammer D, Kern S, Rohleder N, Walker B, Kirschbaum C. Tissue specificity of

glucocorticoid sensitivity in healthy adults. J Clin Endocrinol Metab. 2000 Oct;85(10):3733-9.263 Løvås K, Husebye ES. Continuous subcutaneous hydrocortisone infusion in Addison's disease. Eur J Endocrinol.

2007 Jul;157(1):109-12.264 Bryan SM, Honour JW, Hindmarsh PC. Management of altered hydrocortisone pharmacokinetics in a boy with

congenital adrenal hyperplasia using a continuous subcutaneous hydrocortisone infusion. J Clin Endocrinol Metab.

2009 Sep;94(9):3477-80.265 Tschöp M, Lahner H, Feldmeier H, Grasberger H, Morrison KM, Janssen OE, Attanasio AF, Strasburger CJ. Effects of

growth hormone replacement therapy on levels of cortisol and cortisol-binding globulin in hypopituitary adults. Eur

J Endocrinol. 2000 Dec;143(6):769-73.266 McGuire JS Jr, Tomkins GM. The effects of thyroxin administration on the enzymic reduction of delta 4-3-

ketosteroids. J Biol Chem. 1959 Apr;234(4):791-4.267 Barbhaiya RH, Welling PG. Influence of food on the absorption of hydrocortisone from the gastrointestinal tract.

Drug Nutr Interact. 1982;1(2):103-12.268 Charmandari E, Johnston A, Brook CG, Hindmarsh PC. Bioavailability of oral hydrocortisone in patients with

congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Endocrinol. 2001 Apr;169(1):65-70.269 Barbetta L, Dall'Asta C, Re T, Libe R, Costa E, Ambrosi B. J Comparison of different regimens of glucocorticoid

replacement therapy in patients with hypoadrenalism. Endocrinol Invest. 2005 Jul-Aug;28(7):632-7. 270 Mah PM, Jenkins RC, Rostami-Hodjegan A, Newell-Price J, Doane A, Ibbotson V, Tucker GT, Ross RJ. Weight-related

dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clin

Endocrinol (Oxf). 2004 Sep;61(3):367-75.271 Løvås K, Husebye ES. Continuous subcutaneous hydrocortisone infusion in Addison's disease. Eur J Endocrinol.

2007 Jul;157(1):109-12.272 Oksnes M, Björnsdottir S, Isaksson M, Methlie P, Carlsen S, Nilsen RM, Broman JE, Triebner K, Kämpe O, Hulting

AL, Bensing S, Husebye ES, Løvås K. Continuous subcutaneous hydrocortisone infusion versus oral hydrocortisone replacement for treatment of Addison's disease: A randomized clinical trial.J Clin Endocrinol Metab. 2014 Feb 11273 Cizza G, Rother KI. Cortisol binding globulin: more than just a carrier? J Clin Endocrinol Metab. 2012

Jan;97(1):77-80.274 Torpy DJ, Ho JT. Corticosteroid-binding globulin gene polymorphisms: clinical implications and links to idiopathic

chronic fatigue disorders. Clin Endocrinol (Oxf). 2007 Aug;67(2):161-7.275 Friel PN, Alexander T, Wright JV. Suppression of adrenal function by low-dose prednisone: assessment with 24-hour

urinary steroid hormone profiles--a review of five cases. Altern Med Rev. 2006 Mar;11(1):40-6.276 Genazzani AR, Pluchino N, Begliuomini S, Stomati M, Bernardi F, Pieri M, Casarosa E, Palumbo M, Genazzani AD,

Luisi M. Long-term low-dose oral administration of dehydroepiandrosterone modulates adrenal response to

adrenocorticotropic hormone in early and late postmenopausal women. Gynecol Endocrinol. 2006 Nov;22(11):627-

35.277 Kroboth PD, Amico JA, Stone RA, Folan M, Frye RF, Kroboth FJ, Bigos KL, Fabian TJ, Linares AM, Pollock BG, Hakala

C. Influence of DHEA administration on 24-hour cortisol concentrations. J Clin Psychopharmacol. 2003

Feb;23(1):96-9.278 Pluchino N, Ninni F, Stomati M, Freschi L, Casarosa E, Valentino V, Luisi S, Genazzani AD, Potì E, Genazzani AR. One-

year therapy with 10mg/day DHEA alone or in combination with HRT in postmenopausal women: effects on

hormonal milieu. Maturitas. 2008 Apr 20;59(4):293303.279 Rabijewski M, Zgliczynski W. [Positive effects of DHEA therapy on insulin resistance and lipids in men with

angiographically verified coronary heart disease - preliminary study.] Endokrynol Pol. 2005;56(6):904-910. 280 Robinzon B, Cutolo M. Should dehydroepiandrosterone replacement therapy be provided with glucocorticoids?

Rheumatology (Oxford). 1999 Jun;38(6):488-95.

281 Kimonides VG, Spillantini MG, Sofroniew MV Fawcett JW Herbert J. Dehydroepiandrosterone antagonizes the

neurotoxic effects of corticosterone and translocation of stress-activated protein kinase 3 in hippocampal primary

cultures. Neuroscience 1999 Mar;89(2):429-36.282 Carta MG, Bhat KM, Preti A. GABAergic neuroactive steroids: a new frontier in bipolar disorders? Behav Brain

Funct. 2012 Dec 19;8:61.283 Twede V, Tartaglia AL, Covey DF, Bamber BA: The neurosteroids dehydroepiandrosterone sulfate and

pregnenolone sulfate inhibit the UNC-49 GABA receptor through a common set of residues. Mol Pharmacol 2007,

72(5):1322–9.284 Larsen, PR, Williams Textbook of Endocrinology, 10th Ed., Saunders, Philadelphia, 2003.285 Roberts KD, Vandewiele RL, Lieberman S. The conversion in vivo of dehydroisoandrosterone sulfate to

androsterone and etiocholanolone glucuronidates. J Biol Chem. 1961 Aug;236:2213-5.286 Labrie F. Adrenal androgens and intracrinology. Semin Reprod Med. 2004 Nov;22(4):299-309.287 Labrie F, Luu-The V, Bélanger A, Lin SX, Simard J, Pelletier G, Labrie C. Is dehydroepiandrosterone a hormone? J

Endocrinol. 2005 Nov;187(2):169-96.288 Liu D, Dillon JS.J Dehydroepiandrosterone activates endothelial cell nitric-oxide synthase by a specific plasma

membrane receptor coupled to Galpha(i2,3). Biol Chem. 2002 Jun 14;277(24):21379-88.289 Meikle AW, Dorchuck RW, Araneo BA, Stringham JD, Evans TG, Spruance SL, Daynes RA. The presence of a

dehydroepiandrosterone-specific receptor binding complex in murine T cells. J Steroid Biochem Mol Biol. 1992

May;42(3-4):293-304.290 Arlt W, Justl HG, Callies F, Reincke M, Hübler D, Oettel M, Ernst M, Schulte HM, Allolio B. Oral

dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to

androgens and estrogens in young healthy females after dexamethasone suppression. J Clin Endocrinol Metab.

1998 Jun;83(6):1928-34.291 Labrie F, Martel C, Balser J. Wide distribution of the serum dehydroepiandrosterone and sex steroid levels in

postmenopausal women: role of the ovary? Menopause. 2010 Jul 28. [Epub ahead of print]292 Spark RF. Dehydroepiandrosterone: a springboard hormone for female sexuality. Fertil Steril. 2002 Apr;77 Suppl

4:S19-25.293 Gracia CR, Freeman EW, Sammel MD, Lin H, Mogul M. Hormones and sexuality during transition to menopause.

Obstet Gynecol. 2007 Apr;109(4):831-40.294 Basson R, Brotto LA, Petkau AJ, Labrie F. Role of androgens in women's sexual dysfunction. Menopause. 2010 Sep-

Oct;17(5):962-71.295 Johannsson G, Burman P, Wirén L, Engström BE, Nilsson AG, Ottosson M, Jonsson B, Bengtsson BA, Karlsson FA.

Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen-deficient women: a placebo-

controlled trial. J Clin Endocrinol Metab. 2002 May;87(5):2046-52.296 Binder G, Weber S, Ehrismann M, Zaiser N, Meisner C, Ranke MB, Maier L, Wudy SA, Hartmann MF, Heinrich U,

Bettendorf M, Doerr HG, Pfaeffle RW, Keller E; and the South German Working Group for Pediatric Endocrinology.

Effects of dehydroepiandrosterone therapy on pubic hair growth and psychological well-being in adolescent girls

and young women with central adrenal insufficiency: a double-blind, randomized, placebo-controlled phase III trial.

J Clin Endocrinol Metab. 2009 Apr;94(4):1182-90.

297 Arlt W, Callies F, Allolio B. DHEA replacement in women with adrenal insufficiency--pharmacokinetics,

bioconversion and clinical effects on well-being, sexuality and cognition. Endocr Res. 2000 Nov;26(4):505-11.298 Labrie F. Dehydroepiandrosterone, androgens and the mammary gland. Gynecol Endocrinol. 2006 Mar;22(3):118-

30.299 Reisch N, Hahner S, Bleicken B, Flade L, Gil FP, Loeffler M, Ventz M, Hinz A, Beuschlein F, Allolio B, Reincke M,

Quinkler M. Quality of life is less impaired in adults with congenital adrenal hyperplasia due to 21-hydroxylase

deficiency than in patients with primary adrenal insufficiency. Clin Endocrinol (Oxf). 2010 Nov 2. doi:

10.1111/j.1365-2265.2010.03920.x. 300 Minetto M, Reimondo G, Osella G, Ventura M, Angeli A, Terzolo M. Bone loss is more severe in primary adrenal

than in pituitary-dependent Cushing's syndrome. Osteoporos Int. 2004 Nov;15(11):855-61. 301 Tauchmanovà L, Pivonello R, De Martino MC, Rusciano A, De Leo M, Ruosi C, Mainolfi C, Lombardi G, Salvatore M,

Colao A. Effects of sex steroids on bone in women with subclinical or overt endogenous hypercortisolism. Eur J

Endocrinol. 2007 Sep;157(3):359-66.302 Dhatariya K, Bigelow ML, Nair KS. Effect of dehydroepiandrosterone replacement on insulin sensitivity and lipids in

hypoadrenal women. Diabetes. 2005 Mar;54(3):765-9.303 Hunt PJ, Gurnell EM, Huppert FA, Richards C, Prevost AT, Wass JA, Herbert J, Chatterjee VK. Improvement in mood

and fatigue after dehydroepiandrosterone replacement in Addison's disease in a randomized, double blind trial.

Clin Endocrinol Metab. 2000 Dec;85(12):4650-6.304 Labrie F, Belanger A, Cusan L, Gomez J-L, Candas B. Marked decline in serum concentrations of adrenal C19 sex

steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab. 1997;82:2396-

2402.305 Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone

sulfate concentrations throughout adulthood. J Clin Endocrinol Metab. 1984;59:551-555.306 Orentreich N, Brind JL, Bogelman JH, Andres R, Baldwin H. Long-term longitudinal measurements of plasma

dehydroepiandrosterone sulfate in normal men. J Clin Endocrinol Metab. 1992;75:1002-1004.307 Sulcova J, Hill M, Starka L. Age and sex related differences in serum levels of unconjugated

dehydroepiandrosterone and its sulphate in normal subjects. J Endocrinol.1997;154:57-62.308 Zumoff B, Walter L, Rosenfeld RS, Strain JJ, Degen K, Strain GW, Levin J, Fukushima D. Subnormal plasma adrenal

androgen levels in men with uremia. J Clin Endocrinol Metab. 1980;51:801-805.309 Dharia S, Parker CR Jr. Adrenal androgens and aging. Semin Reprod Med. 2004 Nov;22(4):361-8. 310 Valenti G. Adrenopause: an imbalance between dehydroepiandrosterone (DHEA) and cortisol secretion. J

Endocrinol Invest. 2002;25(10 Suppl):29-35. 311 Ravaglia G, Forti P, Maioli F, Sacchetti L, Nativio V, Scali CR, Mariani E, Zanardi V, Stefanini A, Macini PL.

Dehydroepiandrosterone-sulfate serum levels and common age-related diseases: results from a cross-sectional

Italian study of a general elderly population. Exp Gerontol. 2002 May;37(5):701-12.312 Glei DA, Goldman N. Dehydroepiandrosterone Sulfate (DHEAS) and Risk for Mortality Among Older Taiwanese. Ann

Epidemiol. 2006 Jul;16(7):510-5.313 Casson PR, Faquin LC, Stentz FB, Straughn AB, Andersen RN, Abraham GE, Buster JE. Replacement of

dehydroepiandrosterone enhances T-lymphocyte insulin binding in postmenopausal women. Fertil Steril. 1995

May;63(5):1027-31.

314 Casson PR, Santoro N, Elkind-Hirsch K, Carson SA, Hornsby PJ, Abraham G, Buster JE. Postmenopausal

dehydroepiandrosterone administration increases free insulin-like growth factor-I and decreases high-density

lipoprotein: a six-month trial. Fertil Steril. 1998 Jul;70(1):107-10. 315 Lasco A, Frisina N, Morabito N, Gaudio A, Morini E, Trifiletti A, Basile G, Nicita-Mauro V, Cucinotta D. Metabolic

effects of dehydroepiandrosterone replacement therapy in postmenopausal women. Eur J Endocrinol. 2001

Oct;145(4):457-61. 316 Morales AJ, Nolan JJ, Nelson JC, Yen SS. Effects of replacement dose of dehydroepiandrosterone in men and

women of advancing age. J Clin Endocrinol Metab. 1994 Jun;78(6):1360-7. 317 Genazzani AR, Inglese S, Lombardi I, Pieri M, Bernardi F, Genazzani AD, Rovati L, Luisi M. Long-term low-dose

dehydroepiandrosterone replacement therapy in aging males with partial androgen deficiency. Aging Male. 2004

Jun;7(2):133-43.318 Morales AJ, Haubrich RH, Hwang JY, Asakura H, Yen SS. The effect of six months treatment with a 100 mg daily

dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-

advanced men and women. Clin Endocrinol (Oxf). 1998 Oct;49(4):421-32.319 Baulieu EE, Thomas G, Legrain S, Lahlou N, Roger M, Debuire B, Faucounau V, Girard L, Hervy MP, Latour F, Leaud

MC, Mokrane A, Pitti-Ferrandi H, Trivalle C, de Lacharriere O, Nouveau S, Rakoto-Arison B, Souberbielle JC, Raison J,

Le Bouc Y, Raynaud A, Girerd X, Forette F. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution

of the DHEAge Study to a sociobiomedical issue. Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4279-84.320 Hackbert L, Heiman JR. Acute dehydroepiandrosterone (DHEA) effects on sexual arousal in postmenopausal

women. J Womens Health Gend Based Med. 2002 Mar;11(2):155-62. 321 Villareal DT, Holloszy JO. Effect of DHEA on abdominal fat and insulin action in elderly women and men: a

randomized controlled trial. JAMA. 2004 Nov 10;292(18):2243-8.322 Yamada Y, Sekihara H, Omura M, Yanase T, Takayanagi R, Mune T, Yasuda K, Ishizuka T, Ueshiba H, Miyachi Y,

Iwasaki T, Nakajima A, Nawata H. Changes in serum sex hormone profiles after short-term low-dose administration

of dehydroepiandrosterone (DHEA) to young and elderly persons. Endocr J. 2007 Feb;54(1):153-62.323 Casson, P et al (1993) "Oral dehydroepiandrosterone in physiologic doses modulates immune function in

postmenopausal women" Am J. Obstet Gynecol 169: 1536-39.324 Solerte SB, Fioravanti M, Vignati G, Giustina A, Cravello L, Ferrari E. Dehydroepiandrosterone sulfate enhances

natural killer cell cytotoxicity in humans via locally generated immunoreactive insulin-like growth factor I. J Clin

Endocrinol Metab 1999 Sep; 84(9):3260-7.325 Yamada S, Akishita M, Fukai S, Ogawa S, Yamaguchi K, Matsuyama J, Kozaki K, Toba K, Ouchi Y. Effects of

dehydroepiandrosterone supplementation on cognitive function and activities of daily living in older women with

mild to moderate cognitive impairment. Geriatr Gerontol Int. 2010 May 17. 326 Stomati M, Rubino S, Spinetti A, Parrini D, Luisi S, Casarosa E, Petraglia F, Genazzani AR. Endocrine, neuroendocrine

and behavioral effects of oral dehydroepiandrosterone sulfate supplementation in postmenopausal women.

Gynecol Endocrinol. 1999 Feb;13(1):15-25.327 Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent

cardiovascular disease. Ann Intern Med. 2004 Nov 16;141(10):764-70.328 Barrett-Connor E, Khaw KT Yen SS. A prospective study of dehydroepiandrosterone sulfate, mortality, and

cardiovascular disease. N Eng J Med 1986 Dec;315:1519-24.

329 Feldman FA, Johannes CB, Araujo AB, Mohr BA, Longcope C, McKinlay JB. Low dehydroepiandrosterone and

ischemic heart disease in middle-aged men: prospective results from the Massachusetts Male Aging Study. Am J

Epidemiol, 2001;153(1):79-89.330 Mitchell LE, Sprecher DL, Borecki IB, Rice T, Laskarzewski PM, Rao DC. Evidence for an association between

dehydroepiandrosterone sulfate and nonfatal, premature myocardial infarction in males. Circulation. 1994

Jan;89(1):89-93.331 Sablik Z, Samborska-Sablik A, Goch JH. [Concentrations of adrenal steroids and sex hormones in postmenopausal

women suffering from coronary artery disease] Pol Merkur Lekarski. 2008 Oct;25(148):326-9.332 Herrington DM. Section of Cardiology, Bowman Gray School of Medicine, Winston-Salem, North Carolina 27157,

USA. Ann N Y Acad Sci 1995 Dec 29;774:271-80333 Nestler JE, Clore JN, Blackard WG. Dehydroepiandrosterone: the "missing link" between hyperinsulinemia and

atherosclerosis? FASEB J. 1992 Sep;6(12):3073-5.334 Lavallée B, Provost PR, Roy R, Gauthier MC, Bélanger A. Dehydroepiandrosterone-fatty acid esters in human

plasma: formation, transport and delivery to steroid target tissues. J Endocrinol. 1996 Sep;150 Suppl:S119-24.335 Khalil A, Fortin JP, LeHoux JG, Fulop T Age-related decrease of dehydroepiandrosterone concentrations in low

density lipoproteins and its role in the susceptibility of low density lipoproteins to lipid peroxidation. J Lipid Res

2000;41:1552-61.336 Akishita M, Hashimoto M, Ohike Y, Ogawa S, Iijima K, Eto M, Ouchi Y. Association of plasma

dehydroepiandrosterone-sulfate levels with endothelial function in postmenopausal women with coronary risk

factors. Hypertens Res. 2008 Jan;31(1):69-74.337 Liu D, Si H, Reynolds KA, Zhen W, Jia Z, Dillon JS. Dehydroepiandrosterone protects vascular endothelial cells

against apoptosis through a Galphai protein-dependent activation of phosphatidylinositol 3-kinase/Akt and

regulation of antiapoptotic Bcl-2 expression.Endocrinology. 2007 Jul;148(7):3068-76.338 Hinson JP, Khan M. Dehydroepiandrosterone sulphate (DHEAS) inhibits growth of human vascular endothelial cells.

Endocr Res. 2004 Nov;30(4):667-71.339 Jesse RL, Loesser K, Eich DM, Qian YZ, Hess ML, Nestler JE. Department of Medicine, Medical College of

Virginia/Virginia Commonwealth University, Richmond 23298, USA. Ann N Y Acad Sci 1995 Dec 29;774:281-90340 Rabijewski M, Zgliczyński W. [Dehydroepiandrosterone therapy in men with angiographically verified coronary

heart disease: the effects on plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and

fibrinogen plasma concentrations] Endokrynol Pol. 2007 May-Jun;58(3):213-9.341 Williams MR, Ling S, Dawood T, Hashimura K, Dai A, Li H, Liu JP, Funder JW, Sudhir K, Komesaroff PA.

Dehydroepiandrosterone inhibits human vascular smooth muscle cell proliferation independent of ARs and ERs.J

Clin Endocrinol Metab. 2002 Jan;87(1):176-81.342 Kawano H, Yasue H, Kitagawa A, Hirai N, Yoshida T, Soejima H, Miyamoto S, Nakano M, Ogawa H.

Dehydroepiandrosterone supplementation improves endothelial function and insulin sensitivity in men. J Clin

Endocrinol Metab. 2003 Jul;88(7):3190-5.343 Martina V, Benso A, Gigliardi VR, Masha A, Origlia C, Granata R, Ghigo E. Short-term dehydroepiandrosterone

treatment increases platelet cGMP production in elderly male subjects. Clin Endocrinol (Oxf). 2006 Mar;64(3):260-

4.

344 Morgan CA 3rd, Southwick S, Hazlett G, Rasmusson A, Hoyt G, Zimolo Z, Charney D. Relationships among plasma

dehydroepiandrosterone sulfate and cortisol levels, symptoms of dissociation, and objective performance in

humans exposed to acute stress. Arch Gen Psychiatry. 2004 Aug;61(8):819-25.345 Heinz A, Weingartner H, George D, Hommer D, Wolkowitz OM, Linnoila Psychiatry Res 1999 Dec 20;89(2):97-

106346 Strous RD, Golubchik P, Maayan R, Mozes T, Tuati-Werner D, Weizman A, Spivak B. Lowered DHEA-S plasma

levels in adult individuals with autistic disorder. Eur Neuropsychopharmacol. 2005 May;15(3):305-9.347 Wilkins JN, Majewska MD, Van Gorp W, Li SH, Hinken C, Plotkin D, Setoda D. DHEAS and POMS measures identify

cocaine dependence treatment outcome. Psychoneuroendocrinology. 2005 Jan;30(1):18-28348 Gordon CM, Grace E, Emans SJ, Feldman HA, Goodman E, Becker KA, Rosen CJ, Gundberg CM, LeBoff MS. Effects

of oral dehydroepiandrosterone on bone density in young women with anorexia nervosa: a randomized trial. J Clin

Endocrinol Metab. 2002 Nov;87(11):4935-41.349 Schmidt PJ, Daly RC, Bloch M, Smith MJ, Danaceau MA, St Clair LS, Murphy JH, Haq N, Rubinow DR.

Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch Gen Psychiatry. 2005

Feb;62(2):154-62.350 Rabkin JG, McElhiney MC, Rabkin R, McGrath PJ, Ferrando SJ. Placebo-controlled trial of dehydroepiandrosterone

(DHEA) for treatment of nonmajor depression in patients with HIV/AIDS. Am J Psychiatry. 2006 Jan;163(1):59-66.351 Strous RD, Maayan R, Lapidus R, Stryjer R, Lustig M, Kotler M, Weizman A. Dehydroepiandrosterone augmentation

in the management of negative, depressive, and anxiety symptoms in schizophrenia. Arch Gen Psychiatry. 2003

Feb;60(2):133-41.352 Strous RD. Dehydroepiandrosterone (DHEA) augmentation in the management of schizophrenia symptomatology.

Essent Psychopharmacol. 2005;6(3):141-7.353 Alhaj HA, Massey AE, McAllister-Williams RH. Effects of DHEA administration on episodic memory, cortisol and

mood in healthy young men: a double-blind, placebo-controlled study. Psychopharmacology (Berl). 2005 Oct 18;:1-

11 354 Straub RH, Scholmerich J, Zietz B. Replacement therapy with DHEA plus corticosteroids in patients with chronic

inflammatory diseases--substitutes of adrenal and sex hormones. Z Rheumatol 2000;59 Suppl 2:II/108-18.355 Straub RH, Konecna L, Hrach S, Rothe G, Kreutz M, Scholmerich J, Falk W, Lang B Serum dehydroepiandrosterone

(DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion

from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence. J

Clin Endocrinol Metab 1998 Jun;83(6):2012- 7.356 Ferrucci L, Harris TB, Guralnik JM, Tracy R post-dose; P, Corti MC, Cohen HJ, Penninx B, Pahor M, Wallace R, Havlik

RJ. Serum IL-6 level and the development of disability in older persons. J Am Geriatr Soc 1999 Jun;47(6):639-46. 357 Daynes RA, Araneo BA, Ershler WB, Maloney C, Li GZ, Ryu SY. Altered regulation of IL-6 production with normal

aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative. J

Immunol 1993 Jun 15;150(12):5219-30.358 Chang DM, Chu SJ, Chen HC, Kuo SY, Lai JH. Dehydroepiandrosterone suppresses interleukin 10 synthesis in women

with systemic lupus erythematosus. Ann Rheum Dis. 2004 Dec;63(12):1623-6.359 Harding G, Mak YT, Evans B, Cheung J, MacDonald D, Hampson G. The effects of dexamethasone and

dehydroepiandrosterone (DHEA) on cytokines and receptor expression in a human osteoblastic cell line: potential

steroid-sparing role for DHEA. Cytokine. 2006 Oct;36(1-2):57-68. 360 Brignardello E, Runzo C, Aragno M, Catalano MG, Cassader M, Perin PC, Boccuzzi G. Dehydroepiandrosterone

administration counteracts oxidative imbalance and advanced glycation end product formation in type 2 diabetic

patients. Diabetes Care. 2007 Nov;30(11):2922-7. 361 Petri MA, Lahita RG, Van Vollenhoven RF, Merrill JT, Schiff M, Ginzler EM, Strand V, Kunz A, Gorelick KJ, Schwartz

KE; GL601 Study Group. Effects of prasterone on corticosteroid requirements of women with systemic lupus

erythematosus: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2002 Jul;46(7):1820-9.362 van Vollenhoven RF, Morabito LM, Engleman EG, McGuire JL. Treatment of systemic lupus erythematosus with

dehydroepiandrosterone: 50 patients treated up to 12 months. J Rheumatol 1998 Feb;25(2):285-9.363 Nordmark G, Bengtsson C, Larsson A, Karlsson FA, Sturfelt G, Rönnblom L. Effects of dehydroepiandrosterone

supplement on health-related quality of life in glucocorticoid treated female patients with systemic lupus

erythematosus. Autoimmunity. 2005 Nov;38(7):531-40.364 Florkowski CM, Holmes SJ, Elliot JR, Donald RA, Espiner EA. Bone mineral density is reduced in female but not male

subjects with Addison's disease. N Z Med J. 1994 Feb 23;107(972):52-3.365 Valero MA, Leon M, Ruiz Valdepeñas MP, Larrodera L, Lopez MB, Papapietro K, Jara A, Hawkins F. Bone density and

turnover in Addison's disease: effect of glucocorticoid treatment. Bone Miner. 1994 Jul;26(1):9-17.366 McKenzie R, Reynolds JC, O'Fallon A, Dale J, Deloria M, Blackwelder W, Straus SE. Decreased bone mineral density

during low dose glucocorticoid administration in a randomized, placebo controlled trial. J Rheumatol. 2000

Sep;27(9):2222-6.367 Jankowski CM, Gozansky WS, Kittelson JM, Van Pelt RE, Schwartz RS, Kohrt WM. Increases in bone mineral

density in response to oral dehydroepiandrosterone replacement in older adults appear to be mediated by serum

estrogens. J Clin Endocrinol Metab. 2008 Dec;93(12):4767-73.368 Weiss EP, Shah K, Fontana L, Lambert CP, Holloszy JO, Villareal DT. Dehydroepiandrosterone replacement therapy in

older adults: 1- and 2-y effects on bone. Am J Clin Nutr. 2009 May;89(5):1459-67. 369 Szathmári M, Vásárhelyi B, Treszl A, Tulassay T, Tulassay Z. Association of dehydroepiandrosterone sulfate and

testosterone deficiency with bone turnover in men with inflammatory bowel disease.Int J Colorectal Dis. 2002

Mar;17(2):63-6.370 Adachi M, Takayanagi R. Role of androgens and DHEA in bone metabolism Clin Calcium. 2006 Jan;16(1):61-6. 371 Haden ST, Glowacki J, Hurwitz S, Rosen C, LeBoff MS. Effects of age on serum dehydroepiandrosterone sulfate, IGF-

I, and IL-6 levels in women. Calcif Tissue Int 2000 Jun;66(6):414-8.372 Osmanagaoglu MA, Okumus B, Osmanagaoglu T, Bozkaya H. The relationship between serum

dehydroepiandrosterone sulfate concentration and bone mineral density, lipids, and hormone replacement therapy

in premenopausal and postmenopausal women. J Womens Health (Larchmt). 2004 Nov;13(9):993-9.373 Weiss EP, Shah K, Fontana L, Lambert CP, Holloszy JO, Villareal DT. Dehydroepiandrosterone replacement therapy in

older adults: 1- and 2-y effects on bone. Am J Clin Nutr. 2009 May;89(5):1459-67.374 Stomati M, Monteleone P, Casarosa E, Quirici B, Puccetti S, Bernardi F, Genazzani AD, Rovati L, Luisi M, Genazzani

AR. Six-month oral dehydroepiandrosterone supplementation in early and late postmenopause. Gynecol

Endocrinol. 2000 Oct;14(5):342-63.375 Tauchmanovà L, Pivonello R, De Martino MC, Rusciano A, De Leo M, Ruosi C, Mainolfi C, Lombardi G,

Salvatore M, Colao A. Effects of sex steroids on bone in women with subclinical or overt endogenous

hypercortisolism. Eur J Endocrinol. 2007 Sep;157(3):359-66.376 Mease PJ, Ginzler EM, Gluck OS, Schiff M, Goldman A, Greenwald M, Cohen S, Egan R, Quarles BJ, Schwartz

KE. Effects of prasterone on bone mineral density in women with systemic lupus erythematosus receiving chronic

glucocorticoid therapy. J Rheumatol. 2005 Apr;32(4):616-21.377 Lukert BP, Johnson BE, Robinson RG. Estrogen and progesterone replacement therapy reduces glucocorticoid-

induced bone loss. J Bone Miner Res. 1992 Sep;7(9):1063-9.378 Hall GM, Daniels M, Doyle DV, Spector TD. Effect of hormone replacement therapy on bone mass in rheumatoid

arthritis patients treated with and without steroids. Arthritis Rheum. 1994 Oct;37(10):1499-505. 379 Buckley LM, Leib ES, Cartularo KS, Vacek PM, Cooper SM. Calcium and vitamin D3 supplementation prevents bone

loss in the spine secondary to low-dose corticosteroids in patients with rheumatoid arthritis. A randomized, double-

blind, placebo-controlled trial. Ann Intern Med. 1996 Dec 15;125(12):961-8.380 Gotherstrom G, Bengtsson BA, Bosaeus I, Johannsson G, Svensson J. Ten-year GH replacement increases bone

mineral density in hypopituitary patients with adult onset GH deficiency. Eur J Endocrinol. 2007 Jan;156(1):55-64.381 Landin-Wilhelmsen K, Nilsson A, Bosaeus I, Bengtsson BA. Growth hormone increases bone mineral content in

postmenopausal osteoporosis: a randomized placebo-controlled trial. J Bone Miner Res. 2003 Mar;18(3):393-405. 382 Hammer F, Subtil S, Lux P, Maser-Gluth C, Stewart PM, Allolio B, Arlt W. No evidence for hepatic conversion of

dehydroepiandrosterone (DHEA) sulfate to DHEA: in vivo and in vitro studies. J Clin Endocrinol Metab. 2005

Jun;90(6):3600-5. 383 Legrain S, Massien C, Lahlou N, Roger M, Debuire B, Diquet B, Chatellier G, Azizi M, Faucounau V, Porchet H,

Forette F, Baulieu EE. Dehydroepiandrosterone replacement administration: pharmacokinetic and

pharmacodynamic studies in healthy elderly subjects. J Clin Endocrinol Metab. 2000 Sep;85(9):3208-17.384 Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Moreau M, Dubé R,

Côté I, Labrie C, Lavoie L, Bérubé R, Bélanger P, Berger L, Gilbert L, Martel C, Balser J. Serum steroid levels

during 12-week intravaginal dehydroepiandrosterone administration. Menopause. 2009 Sep-Oct;16(5):897-906.385 Shin MH, Rhie GE, Park CH, Kim KH, Cho KH, Eun HC, Chung JH. Modulation of collagen metabolism by the topical

application of dehydroepiandrosterone to human skin. J Invest Dermatol. 2005 Feb;124(2):315-23.386 Rommler A. Adrenopause and dehydroepiandrosterone: pharmacological therapy versus replacement therapy

Gynakol Geburtshilfliche Rundsch. 2003 Apr;43(2):79-90. [GERMAN}387 Legrain S, Massien C, Lahlou N, Roger M, Debuire B, Diquet B, Chatellier G, Azizi M, Faucounau V, Porchet H,

Forette F, Baulieu EE. Dehydroepiandrosterone replacement administration: pharmacokinetic and

pharmacodynamic studies in healthy elderly subjects. J Clin Endocrinol Metab. 2000 Sep;85(9):3208-17. 388 Callies F, Arlt W, Siekmann L, Hubler D, Bidlingmaier F, Allolio B. Influence of oral dehydroepiandrosterone (DHEA)

on urinary steroid metabolites in males and females. Steroids. 2000 Feb;65(2):98-102.