A Clinical Approach to the Diagnosis and Treatment of ...



Fatigue, Pain, and Inflammation: The Clinical Diagnosis and Treatment of Cortisol Deficiency SummaryPartial cortisol deficiency is common, especially among women and is a frequent cause of fatigue, pain, depression, anxiety, headaches and cognitive dysfunction.Cortisol deficiency has a much larger role in many medical diseases and disorders than currently appreciated.The current approaches to the diagnosis and treatment of cortisol deficiency are ineffective.Saliva cortisol testing is the most accurate and sensitive way to assess cortisol status.The diagnosis and treatment of cortisol deficiency must be based upon clinical criteria.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.”The Cortisol ConnectionPrimary 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. 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 sensitivitiesCortisol 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.Cortisol-Thyroid InteractionThe 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.Abbreviations:CD cortisol deficiencyCS cortisol supplementationAI adrenal insufficiencyACTH adrenocorticotrophic hormoneHP hypothalamic-pituitaryHPA hypothalamic-pituitary-adrenalHC hydrocortisone (cortisol)GC glucocorticoidDHEA(S) dehydroepiandrosterone(sulfate)In CD, both TSH and T4-to-T3 conversion are increased, perhaps due to insufficient T3 action at its nuclear receptors. Sufficient cortisol is necessary for thyroid hormone action, but higher cortisol levels reduce TSH secretion and T4-to-T3 conversion. 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, cortisol levels eventually decline. Prolonged hypothyroidism can produce a relative central CD 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. The Spectrum of Cortisol DeficiencyTable 2. Disorders related to Cortisol DeficiencySevere/Critical IllnessAutoimmune DiseaseAllergic disordersChronic Fatigue SyndromeFibromyalgia SyndromeDepressionPost-Traumatic Stress DisorderViolence/SuicideDrug addictionPremenstrual syndromesPost-partum disordersHyperemesis GravidarumThe 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 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. The Female Problem with CortisolTable 3. Female:Male RatiosNon-immune disorders: Fibromyalgia 8:1Multiple Chemical Sensitivity 8:1Chronic fatigue syndrome 4:1Depression 2:1Anxiety 3:2Autoimmune diseases:Sj?gren’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 1.3:1The 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.,,,,,, However, one large study of saliva cortisol levels found higher levels in women than in men. Male-to-female estrogen therapy reduces serum cortisol levels by 50%. Estradiol reduces the adrenal production of cortisol by inhibiting 3-beta hydroxysteroid dehydrogenase (HSD), and reduces the local, intracellular generation of cortisol from cortisone by inhibiting 11-beta HSD-1. Estrogen supplementation reduces cortisol levels in postmenopausal women. This relative lack of cortisol effect allows the progression of inflammation,, 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. It explains why so many women are prescribed antidepressants that boost cortisol levels and progestins with glucocorticoid activity,, and the withdrawal syndromes that occur with stopping antidepressants and some oral contraceptives. The premenstrual syndrome and premenstrual dysphoric disorder are related to CD. Women with PMS have higher DHEAS levels compared to controls, and DHEA counteracts estradiol. Progesterone modulates cortisol actions in the body. Progesterone is a partial agonist at the cortisol receptor. 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.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.,, Sufficient cortisol antagonizes estrogen’s stimulatory effect on the endometrium; so with CD there is excessive endometrial proliferation that can lead to endometriosis. Endometriosis and pelvic pain have been related to CD.,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. Higher thyroid hormone levels produce a relative CD, and thus the morning nausea in the first trimester. Hyperemesis gravidarum, is associated with lower cortisol levels and is effectively treated with cortisol (hydrocortisone) supplementation., 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. 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 depression, and the increased incidence of autoimmune disorders in this period., Breastfeeding after pregnancy is efficacious in this regard as it suppresses ovarian function, keeping estradiol and progesterone levels low for months. Severe and Critical IllnessSeverely 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. A majority of critically-ill children have not just relatively inadequate, but actually low free cortisol levels indicative of CD. Severe hyponatremia is often due to CD and resolves with hydrocortisone therapy. 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.Chronic FatigueFatigue 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,,,, lower cortisol responses to low-dose ACTH stimulation testing, and lower DHEA and DHEAS levels., 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. The CD in CFS is usually due to HP dysfunction of unknown cause.,,, CFS sufferers have lower 24hr. and AM peak ACTH levels and enhanced feedback suppression of cortisol secretion with prednisolone. Single nucleotide polymorphisms have also been found in the glucocorticoid receptor gene and cortisol-binding-globulin (CBG) gene. Subphysiological doses of HC, 5mg or 10mg daily, reduce disability in CFS patients and replacement doses of 25 to 35mg/day produce significant improvements. Some studies show no benefit. 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.FibromyalgiaFibromyalgia 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,,,, lower expression of cortisol receptors and a higher incidence of cortisol receptor polymorphisms, lower peak cortisol responses to ACTH stimulation and insulin tolerance testing, a hyperreactive ACTH response to CRH, and glucocorticoid feedback resistance. 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. Many persons with FMS have cortisol, androgen, or growth hormone levels in the lower part of their reference ranges. FMS has also been related to insufficient thyroid hormone levels or effects.,, Patients with FMS or rheumatoid arthritis have a higher incidence of thyroid autoimmunity,, suggesting insufficient cortisol. Like many CFS patients, many FMS patients have low blood pressure and heart rate responses to tilt table testing. 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. Anxiety, Depression, and Anti-DepressantsIncreased 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. Low saliva cortisol levels combined with stressful life events are associated with subsequent psychopathology. Panic disorder patients show a striking lack of cortisol increase in response to stress. Peritraumatic cortisol elevation protects against the development of post-traumatic stress disorder (PTSD)., Persons with PTSD and those under chronic stress have lower cortisol levels than controls.,,,,, PTSD suffers have lower ACTH responses to metyrapone. Low-dose hydrocortisone (<20mg/day) reduces the cardinal symptoms of PTSD and improves brain metabolism and working memory. 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. 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. 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. Atypical depression is more common than major depression and has been frequently associated with low cortisol levels.,, There appears to be an exaggerated negative feedback regulation of the HPA axis. In treatment-resistant depression with fatigue and low-normal serum cortisol levels, prednisone (7.5mg/day) produces significant improvement. Asthma patients with depression have improved mood during prednisone bursts. Antidepressant medications have been repeatedly shown to enhance glucocorticoid signaling., They increase the access of cortisol to the brain and reduce CRH production. Desipramine, a older tricyclic antidepressant, increases cortisol levels in normals and in patients with atypical depression. 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. Sertraline, one of the newer selective serotonin reuptake inhibitors (SSRIs) increases both plasma cortisol and T3 levels in depressed patients and increases cortisol levels in controls. Paroxetine, citalopram, escitalopram and fluoxetine increase cortisol levels in controls.,,, 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. Drug AddictionThe 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 levels in both nicotine-naive and chronic smokers. Nicotine-withdrawal symptoms and the likelihood of relapse have been associated with lower cortisol levels. 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%.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, and this cortisol response is necessary for initiating and sustaining addiction. Ecstasy (MDMA) increases cortisol and DHEAS levels, most likely through serotonin-induced increases in ACTH. Cortisol levels rise by 800% when dance-clubbing on the drug whereas dance-clubbing alone has no effect. Marijuana stimulates ACTH and cortisol secretion acutely in human studies,,, 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., Abstinent alcoholics have lower cortisol levels than controls and lower ACTH and cortisol responses to insulin and CRH. The reduction in HPA reactivity in the abstinent state contributes to the likelihood of relapse; alcoholics may drink again to increase their cortisol secretion. Dextroamphetamine and related drugs (methamphetamine, Ritalin, Provigil, etc.) raise cortisol levels by a non-ACTH mechanism. Methamphetamine doubles cortisol levels in primates. Methamphetamine users have lower basal cortisol levels and when abstinent, have a reduced adrenocortical responsiveness to ACTH. In my experience, many persons with undiagnosed CD or hypothyroidism are often prescribed amphetamines to alleviate their fatigue and improve their cognitive dysfunction. Autoimmune DiseasePersons with active inflammation require higher cortisol levels/effects than healthy persons, but instead they usually have similar or lower cortisol levels; a relative CD. Significantly lower basal ACTH and cortisol levels are found in Sj?gren’s syndrome,, and patients with ankylosing spondylitis have inadequate responses to low-dose ACTH stimulation testing, indicating subclinical CD. Patients with untreated polymyalgia rheumatica have similar cortisol but lower DHEAS levels than controls and lower cortisol responses to low-dose ACTH stimulation testing. Low cortisol levels are found in systemic lupus erythematosis. Patients with rheumatoid arthritis (RA) also have inappropriately low cortisol levels, elevated IL-6 levels, and an inadequate cortisol response to surgical stress., Half of premenopausal women with RA have lower-quartile serum cortisol and DHEAS levels. RA patients have impaired cortisol secretion in the presence of intact ACTH secretion; probably secondary to the inflammatory disease process. Patients with active juvenile RA also have lower ACTH and cortisol levels. Tumor necrosis factor-alpha (TNF) inhibits CRF-stimulated ACTH production. 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. Long-term anti-TNF treatment increases cortisol levels relative to other adrenal hormones, increases ACTH secretion and normalizes adrenal androgen secretion. 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. Experts have argued that the benefits of low-dose GC treatment in RA and other autoimmune diseases outweigh the risks.,, 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.The Causes of Cortisol DeficiencyThe 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. 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.Cortisol is our primary stress-response hormone, and while moderate chronic stress, such as lower socioeconomic position, causes higher cortisol levels, severe chronic stress often causes lower cortisol levels.,, 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. Chronic excessive CRH production by the hypothalamus leads to downregulation of the pituitary ACTH response and glucocorticoid-receptor resistance.,, 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. 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. The suprachiasmatic nucleus in the brain affect the adrenal cortex’s sensitivity to ACTH via innervation. 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., 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, 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 marked symptoms of CD and a beneficial response to cortisol supplementation do not have low saliva and serum cortisol levels.The Diagnosis of Cortisol DeficiencyThe 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. 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. 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. 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 wellBesides 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. 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, thyroid antibodies,, 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 activity and can ameliorate CD. A history of improvement in the patient’s hypocortisolemic symptoms on SSRIs, amphetamines or 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. The AM Serum Cortisol TestThe 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. 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 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. No matter what time of day, awakening is associated with a significant increase in cortisol levels. The transition to bright light increases cortisol levels by 50%, no matter what time of day. 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. 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. More than half of patients with hypocortisolemic symptoms and an AM cortisol level <14.5mcg/dL can have AI. Some have argued that one should pursue the diagnosis in symptomatic patients with a level <12mcg/dL. ACTH Stimulation TestingGiven 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 AI and incomplete Addison’s Disease. Given its lack of sensitivity, some experts recommend that the AST be performed with only 1mcg. This low-dose AST test (LAST) is more sensitive, although technically challenging. However, a normal response to a LAST also does not rule out recent or partial central AI. It fails to detect mild AI in children. 50% of symptomatic persons who passed a LAST failed an overnight metyrapone challenge test. The 1mcg dose is still superphysiological, producing the same 30 min. cortisol levels in adults as 250mcg. 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. Since so many patients, even with known AI, have normal AST results, some experts assert that the ITT should remain the standard dynamic test.,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.Serum DHEAS LevelDHEAS 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., 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. Saliva CortisolTable 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/dL11pm: <0.01-0.09mcg/dLBefore lunch: 0.08 to 0.2Before dinner: 0.04 to 0.13Before bedtime: 0.02 to 0.07The 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.,,, Salivary cortisol levels best represent the free, biologically active, free fraction of cortisol in the serum.,, and correlate very well with serum cortisol concentrations throughout the 24hr period. Saliva testing can be used to screen for CD and a late-night saliva cortisol is a valuable screening tool for Cushing’s syndrome/disease.,, Saliva cortisol testing is also useful in conjunction with dexamethasone suppression testing and ACTH stimulation testing.,, Is it a practical means for assessing HPA function during and after glucocorticoid therapy; as useful as the AST., Saliva testing is now the gold standard for the assessment of cortisol deficiency or excess. All major laboratories offer saliva cortisol testing. LabCorp provides saliva collection kits with instructions and labels to indicate the time of each sample. 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 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 Labs 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, 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). 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. AM saliva cortisol levels in Addison’s Disease were 0.15mcg/dL, vs. 0.67mcg/dL in controls. 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.A single AM saliva test is still insensitive, 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.Table 7: Suggested LC/MS/MS Diagnostic Saliva Cortisol Ranges Post awakening: 0.25-0.60mcg/dLBefore lunch: 0.08-0.20mcg/dLBefore dinner: 0.04-0.13mcg/dLBefore bedtime: 0.02-0.07mcg/dLA 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.,, 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. Physiological vs. Pharmacologic Glucocorticoid TherapySufficient 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 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 DexamethasoneFigure 2. Arrows mark the significant structural alterations of commonly prescribed glucocorticoids. (Images from Wikipedia)Table 8. Relative potencies of various glucocorticoidsNameGlucocorticoid potencyMineralocorticoid potencyDuration of action (half-life in hours)Cortisol (hydrocortisone)118Prednisone3.5-50.816-36Methylprednisolone5-7.50.518-40Dexamethasone25-80036-54Fludrocortisone 1520024The 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. The prednisolone:HC ratio for growth suppression in children is 15:1. Methylprednisolone is said to be 5 times more potent than HC, but in this ratio it causes insulin levels to rise twice as high, and causes a much greater reduction in the phagocytic and bacteriocidal activities of human granulocytes than does HC. 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. 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. Since dexamethasone does not easily cross the blood-brain barrier and can deplete the brain of cortisol-effect. 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),, 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.) Cortisol SupplementationEvery 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. CS, given at the lowest dose that provides sufficient clinical benefit, and combined with DHEA replacement, is both safe and effective. In CD, CS improves mood, energy, mental function, muscle function, and sleep. It reduces pain, anxiety, and inflammation. CS is both more effective and more safe than the many drugs used to treat the signs and symptoms of CD or the inflammation associated with CD. CS may be the only treatment needed for many allergic and autoimmune disorders. Clinical success is more certain when the saliva cortisol and serum DHEAS levels are clearly low, but is probable in symptomatic persons with normal levels. Cortisol is, however, the most difficult hormone to replace for many reasons. In the United States only short-acting HC tablets are available; 2 to 4 doses are required each day and there are marked swings in serum levels and hormone effects. It is impossible to mimic the diurnal pattern, let alone the dynamic nature of cortisol production. There are unphysiological peaks followed by troughs within hours of ingestion, constituting a kind of pulse therapy. If the dose is too low, the unnatural peak can still over-suppress the dysfunctional HP system, leaving levels too low when the dose wears off. 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 hypothyroidismAs 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, 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.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., Treated patients have a higher rate of premature death from cardiovascular, malignant and infectious causes. Chilren and patients under 40 have a higher risk of death from adrenal insufficiency itself,, suggesting inadequate treatment. Some experts today recommend very low doses, like 10mg in the AM, 5mg in the PM, based on known cortisol production rates and peak serum levels. However, such does are rarely sufficient in my clinical experience. Clinicians who adjust the dose by symptoms typically prescribe 30 to 40mg on average. Table 9. Signs, symptoms and tests of excess cortisol dosingFluid retentionExcessive weight gainFacial flushingPalpitationsCushingoid face, fat distributionNeuropsychological symptomsMuscle weakness, wastingHigh blood pressureInsulin resistanceHow much cortisol does the body actually make each day? The mean cortisol production rate in children is estimated to be 6.8mg/m2/day and in young men 9-11mg/m2/day. 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. The bioavailability of oral cortisol varies from 26 to 91%. 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. 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, 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. In hypopituitary adults, 20mg of HC daily (15mg+5mg) does not increase endogenous glucose production or insulin resistance compare to a physiological HC infusion., 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.). 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). Hereditary abnormalities in the glucocorticoid receptor gene make 6.6% of the normal population relatively hypersensitive to glucocorticoids and 2.3% are relatively resistant. Interindividual variations in GC sensitivity can be tissue-specific in healthy subjects. 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. A young male with CAD required 33mg per day by infusion (equiv. to 66mg orally) to normalize ACTH levels and adrenal androgen production. 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. 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. The liver’s intracellular T3 comes primarily from the circulation, and oral T3 therapy produces highly superphysiological T3 levels in the portal circulation during absorption, and superphysiological serum levels for several hours. This overstimulation increases the rates of many hepatic processes including cortisol metabolism. Persons receiving both DHEA and T4/T3 thyroid replacement therapy will require higher HC doses than seen in any existing studies. Cortisol Dosing StrategiesTable 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 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. (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, so smaller doses then produce greater effect. Postponing the second dose until dinner will usually cause an afternoon nadir. 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. Figure 4. Mean serum cortisol concentrations following a fixed dose of 10 mg hydrocortisone, in fasting and fed states.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., Troubleshooting Cortisol SupplementationA 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.,Fear of Adrenal SuppressionMany 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. 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. 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,,, explaining why persons with CD cannot tolerate DHEA. DHEA improves insulin sensitivity 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. DHEA is also a neurosteroid; it protects hippocampal neurons from glucocorticoid-induced neurotoxicity, and is a non-competitive antagonist of the gamma-aminobutyric (GABA) receptor.. Table 11. DHEA-DHEASMost abundant steroids in the bodyDHEAS and DHEA are interconvertibleAnabolic prohormone Anti-inflammatoryNeurosteroidLevels decline with age, stress, diseaseLower levels associated with mortalityThe adrenal glands secrete large amounts of and DHEA and DHEAS, estimated at 4mg and 7-15mg/day respectively. 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. 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. The study of this process has been called “intracrinology.” DHEA is has been considered to be a prohomone only, but DHEA receptors have been found on endothelial cells and T-cells. 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 secretionAdrenal DHEA(S) is the source of the majority of androgens in females. 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. DHEA is important to the maintenance of female sexuality. Low DHEAS has been more closely correlated with decreased sexual function in menopausal women than low testosterone., Females with AI and low DHEAS levels lose axillary and pubic hair, have dry skin and low libido. In women with hypopituitarism, oral DHEA restores axillary and pubic hair growth, sexual relations, alertness, stamina and initiative.,, DHEA may play a role in preventing breast cancer. DHEA in Adrenal DisordersPersons 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. 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. In women with hypercortisolism, the best predictor of vertebral fracture is not the cortisol level, but the cortisol-to-DHEAS ratio. In AI patients, DHEA supplementation in lowers cholesterol levels and increases insulin sensitivity. It enhances self-esteem and improves mood and energy. DHEA and AgingThere 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.,,,, The zona reticularis of the adrenal cortex atrophies with aging; the cause is unknown. 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.” A person’s DHEAS level serve as a general indicator of aging and health status. Lower DHEAS has been correlated with the risk of death in both sexes. 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.,, It increases IGF-1 levels and perceived physical and psychological well-being.,, In elderly women, DHEA supplementation improves bone mass, libido, and skin quality,, and reduces visceral fat and insulin levels. DHEA supplementation lowers leptin and C-reactive protein levels. DHEA supplementation has a salutary effect on the immune system, increasing natural killer cell population and cytotoxicity., It improves cognitive function and activities of daily living scores in women with dementia. 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. DHEA in Cardiovascular DiseasePeople who are given glucocorticoids for long periods have 2.5 times the risk of cardiovascular disease. 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, independent of lipid levels. Lower DHEAS levels are found in men with a history of a premature myocardial infarction and in postmenopausal women with coronary artery disease. Lower DHEAS levels are associated with vascular disease in grafted blood vessels. Elevated insulin levels reduce the production of DHEA and increase its elimination; this may contribute to the negative effects of hyperinsulemia including atherogenesis.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., DHEAS is associated with improved flow-mediated dilation, suggesting a protective effect on the endothelium. DHEA protects vascular endothelial cells from apoptosis while also inhibiting their excess growth. The loss of DHEA contributes to the pro-clotting diathesis of aging. DHEA retards platelet aggregation and lowers fibrinogen levels. It inhibits vascular smooth muscle cell proliferation and enhances large and small vessel endothelial cell function, apparently via a DHEA-specific receptor. DHEA decreases the levels of plasminogen activator inhibitor type 1 (PAI-1). 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.DHEA in PsychiatryLow 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. Lower DHEAS levels are associated with depression in abstinent alcoholics, with autism, and with relapse in cocaine addiction. Anorexic women have low DHEAS levels and DHEA supplementation improves weight gain, bone density, IGF-1 levels, and psychological parameters. DHEA supplementation is an effective treatment for major and minor depression, depression in AIDS patients, and schizophrenia, especially in women., DHEA supplementation improves mood and memory in young men. DHEA in RheumatologyIn 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. 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. 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. DHEA supplementation reduces IL-6 levels. In SLE, DHEA supplementation reduces IL-10 levels by 70%. DHEA downregulates several pro-inflammatory/resorptive cytokines In human osteoblastic cells. 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. In SLE, DHEA supplementation reduces the signs and symptoms of the disease and allows a reduction GC dose., It improves mental well-being and sexuality. Bone density: The Importance of DHEA and Sex SteroidsCortisol 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 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., Adult women have a significant decrease in bone mineral density (BMD) with just a 12-week course of physiological CS. DHEA helps maintain and build bone mass both by its anti-cortisol effects and its ability to increase levels of estradiol testosterone, and IGF-1. In men with inflammatory bowel disease low BMD was correlated to low DHEAS levels, not to testosterone levels. DHEA protects against osteoporosis by being converted into estrogens by aromatase activity, and by raising IGF-I and reducing osteolytic IL-6. Women with osteoporosis have much lower DHEAS levels than those with normal BMD. Long-term DHEA supplementation in post-menopausal women can increase BMD by 3.6%. DHEA supplementation in menopauses has the additional benefits of alleviating menopausal symptoms without thickening the uterine lining. 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. Women with systemic lupus erythematosis (SLE) receiving GC therapy gain bone mass when DHEA is added. Women on long-term GC therapy also gain bone density with estrogen and estrogen/progestin therapy., 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. The treatment of growth hormone deficiency increases BMD, most markedly in men and in women who also receive sex hormone replacement. Adding growth hormone to estrogen therapy in postmenopausal women increases BMD by up to 14% in 18 months. Principles of DHEA SupplementationDue 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. Women appear to convert DHEAS to DHEA more readily. 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. Topical DHEA increases collagen synthesis and has other beneficial effects in the skin.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.,, 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. ................
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