Physiology and Clinical Relevance of Salivary Adrenal Steroids (Cortisol, DHEA & DHEAS) in Natural Medicine
Cortisol and The Stress Response
2019 John A. Catanzaro
The role of hormones in human physiology is complex and fascinating. The hormones are either secreted by a group of cells in a gland or by the whole gland. Since endocrine glands are ductless, the secreted hormones are carried to their target cells (organs) by blood plasma. The hormones affect or regulate either a particular organ, a group of organs, metabolic function(s), or every cell of the body. In this review, we attempt to explain hormones or prohormones viz., cortisol and dehydroepiandrosterone (DHEA), and its sulfate conjugate dehydro-epiandrosterone sulfate (DHEAS), with special emphasis on their assessment in saliva, and clinical relevance.
Adrenals are a pair of endocrine (duct-less) glands, which lie attached to the top of kidneys. Each gland is composed of two distinct zones, the larger outer cortex and the inner medulla. The adrenal cortex secretes cortico-steroids, which are broadly classified by their function as mineralocorticoids, glucocorticoids (cortisol), and androgens of interest are DHEA and DHEAS.
Assessment of Cortisol
Assessment of free cortisol, DHEA and DHEAS in saliva is an economical, convenient, noninvasive, and stress-free procedure. Saliva samples may be collected at home or workplace, which avoids the need of repeated visits to clinic/hospital, and costs involved. Free cortisol levels in saliva reflect the free plasma levels.( 53) In addition, total plasma cortisol measurements may be misleading, due to variations in the plasma cortisol-binding protein capacity resulting from drugs, pregnancy, congenital alterations or stress during veinipuncture.( 26, 77, 79) Salivary DHEAS levels correspond to about 0.1% of their concentration in blood plasma.( 53, 98)
Cortisol secretion in adrenocortex is regulated by ACTH (pituitary), which is counterregulated by CRF (hypothalamus). Cortisol, on the other hand, exerts a negative feedback on anterior pituitary (CRF) and on hypothalamus (ACTH). Also, there is a short loop negative feedback of CRF by ACTH in the hypothalamic-pituitary region. Cortisol levels are also regulated by other components viz., diurnal rhythm (sleep-wake rhythm or biological clock), neural stress signals, and/or pathological conditions that override the negative feedback mechanism(s) by cortisol.
Cortisol is a major glucocorticoid hormone synthesized in the cortex of adrenal glands. Cortisol production has been shown to be similar in both men and women, and differs siguificantly with age.( 59) Since cortisol is hydrophobic, most of the cortisol transported in blood is bound to proteins. The unbound or free cortisol is approximately 1–15% of the entire cortisol circulating in the plasma.( 31, 44, 81) The biological activity (glucocorticoid activity and negative inhibition of CRF and ACTH secretions) of cortisol in blood is the function of a small free fraction or unbound to serum proteins. Salivary cortisol accurately reflects the serum unbound cortisol levels throughout the physiological range.( 4, 52, 56, 77, 80, 93, 95, 96)
The circadian rhythm of cortisol is marked by a steep increase (peak) in the mornings and the levels gradually taper down to lowest circulatory levels by midnight. Episodic secretion of cortisol is due to intermittent transformation of cortisol from its precursors in the adrenal cortex by ACTH.( 49) The circadian rhythm of cortisol is set during infancy, and is regulated by the sleep-wake cycle. The neural signals maintain the circadian rhythm by controlling the cortisol negative feedback inhibition. An adrenergic regulation of circadian rhythm of cortisol is proposed based on the increase in ACTH and cortisol levels in response to administation of methoxamine (a-adrenergic receptor agonist), only in the mornings.( 78)
Physiology of Cortisol
Cortisol promotes conservation of glucose to maintain the activity of glyconeogenic enzymes in the liver, and inhibits glucose utilization in the peripheral tissues. Cortisol promotes hepatic protein synthesis and gluconeogenesis, and stimulates release of fatty acids from adipose tissue by maintaining the synthesis of hormone sensitive lipase. Cortisol maintains tissue responsiveness to catecholamines, and stimulates a-adrenegic receptor function and receptors in vascular smooth muscle and nerve cells. Under physical, physiological and/or psychological stress, large amounts of cortisol are released to cope with the condition. Cortisol counterregulates the activity of insulin viz., lower blood glucose, higher glucose utilization in tissues, higher glycogen synthesis, lower gluconeo-genesis, lower release of fatty acids from adipose tissues, and higher protein sysnthesis.( 54) Controlled clinical studies confirmed the counterregulatory role of cortisol during hypoglycemia or insulin activity.( 21) Increased cortisol production was shown to be linked with obesity and is attributed to accelerated cortisol rates (shorter half life), with no significant difference in the integrity of circadian rhythm.( 62, 66) Higher cortisol levels can also suppress thyroid function leading to hypothyroidism and cause related illnesses.( 6, 29)
Cortisol is also antiinfiammatory, by down regulating phospholipase A2 activity and decreasing the permeability of capillary endothelium.( 9) Phospholipase A2 promotes the formation of arachidonic acid from phospholipids, which in turn is a precursor of the prostaglandins.( 54) Prostaglandins, and related compounds viz., thromboxanes, leukotrienes, are potent hormone-like substances, which help to stablize membrane integrity of secretory organelles.
Fluctuations and Stress
Diurnal fluctuations in the production of endogenous cortisol is correlated with the T lymphocyte proliferation in response to a challenge from tetanus toxoid (TT), especially in the mornings, where a steep increase in cortisol levels resulted in 38% reduction of T cell proliferation in vitro. T lymphocytes serve as regulatory and effector elements in all antigen specific responses, and also play a significant role in immune system by interacting with B cells, macrophages and antigen presenting cells.( 41) Glucocorticoids are anti-inflammatory, and highly immunosuppressive by down regulating the production of IL-2 and ginterferon.( 5, 35) Furthermore, a recent study found correlation between plasma cortisol levels, hydrocortisone-induced IgG secretion by human peripheral blood mononuclear cells and psychological profiles.( 47) Hypercortisolism in depression is also linked with immunosuppressive activity.( 58)
Stress can result in elevated cortisol levels and these levels are maintained for as long as the stressor is present, and during this time the negative feedback of cortisol is overridden. Prolonged stress causes increased secretion of glucocorticoids, a maladaptation of the adrenal cortex to stress, probably a result of adrenal cortical hypertrophy. In addition, stress-elevated cortisol levels could be a result of impaired corticosteroid receptors.( 43) Also, impairment of cortisol negative inhibition(s) with age could decrease the resiliency of HPA axis.( 87) Induced hypercortisolism in rats has shown damaged cells in the hippocampus (glucocorticoid receptors) that mediate cortisol-induced suppression of corticotrophin releasing hormone.( 86) The damage of the receptors may trigger further augmentation and higher cortisol levels.
In an experimental study higher cortisol levels were recorded in patients under high stress and who stutter more than normal controls. It may be that patients who stutter perceive stress or daily hassles in a different manner than do patients who do not stutter.( 11) Patients with anorexia nervosa, who also exhibit high physical activity levels, exhibit increased cortisol levels in the mornings and throughout the day.( 28)
Stress Depression and Cortisol
Patients with endogenous depression (especially melancholia) show a hyperactive HPA axis activity manifested by an increased secretion of cortisol (hypercortisolism). Patients with endogenous depression show significantly higher morning and midnight( 31, 37) salivary cortisol levels, with disrupted circadian rhythm.( 33, 36, 85) Dexamethasone suppression test (DST) has been widely used to diagnose depression by registering the absence of cortisol suppressionion.( 16, 17, 60) A relationship between cortisol circadian rhythms and diurnal mood variations in depression or normal states of mind is suggested.( 97) Recurrence of stressful events or stressors attenuate cortisol hypersecretion.( 19) About 60.6% of chronic schizophrenia patients showed abnormal circadian rhythm of salivary cortisol, and 38.2% showed no response to dexamethasone administration.( 64)
A significant increase in the cortisol levels were reported at the onset of myocardial infarction and the levels substantially reduced within three days following the stress.( 25) Higher cortisol levels were recorded in patients with heart diseases.( 89)
During stressful conditions, excess of cortisol is produced by an accelerated conversion of progesterone, leading to deprivation of progesterone and estradiol, which play a key role in menstruation cycle. Alternatively, excess of testosterone, progesterone and estrogens could be secreted due to impaired feedback inhibition of cortisol. All of the above can lead to menstrual disorders. High cortisol levels were noted in women with exercise associated amenorrhea,( 45) and did not differ in women with hyperprolactinaemic amenorrhea.( 7) Salivary cortisol levels significantly increase during pregnancy and delivery, and later returned to normal levels. However, increased corticotrophin binding protein levels may tend to maintain normal free cortisol levels during pregnancy.( 1, 65)
Athletic Performance and Cortisol
Higher cortisol levels in athletes with exercise-related amenorrhea correlated with significantly low bone mineral density.( 45) Increased cortisol levels are associated with osteoporosis in oophorectomized women, and is linked to calcium malabsorption.( 61)
Controlled experiments on healthy male volunteers showed a direct correlation between high cortisol levels and high protein diet, and an inverse relationship with high carbohydrate diet.( 2) Higher cortisol levels were recorded in individuals involved in prolonged exhaustive exercise,( 91) and in trained runners following a marathon.( 72)
Sleep and Cortisol
Rapid eye movement (REM) sleep is associated with decreasing cortisol levels, indicating a diminished or absent secretory activity of the adrenals. Wakefulness and stage 1 sleep or slow wave sleep (SWS) were associated with increasing plasma cortisol concentrations, suggesting that the onset of SWS episodes may trigger the rise in plasma cortisol. In controlled experiments, cortisol infusion moderately increased the percentage of SWS and significantly decreased REM sleep.( 14, 15) Increased cortisol levels and lack of circadian rhythm was also recorded in cadets who had prolonged physical stress, and lack of sleep and food.( 73)
Nicotine and Cortisol
Habitual smokers showed an acute elevation of cortisol levels following cigarette smoking compared to nonsmokers. The difference in overall cortisol levels did not reflect profoundly on elevated baseline levels in smokers but rather an increase due to repeated cigarette smoking. Smokers showed lower cortisol levels when challenged by a psychological stress than by nonsmokers, probably due to lowered HPA response.( 51, 52)
Cushing’s Disease and Alzheimer’s
Patients suffering from Cushing’s syndrome show significantly higher levels of salivary cortisol at all times due to adrenocortical hypertrophy. Absence of a defined free cortisol circadian rhythm is also a characteristic of Cushing’s Syndrome.( 101) Patients with early Alzheimer’s disease showed no difference in their cortisol levels.( 67, 90)
Decreased Cortisol Levels
Patients with Addison’s Disease show pathologically low cortisol levels or acute adrenal insufficiency, especially absence of morning cortisol surge, and complete lack of a circadian rhythm.( 46) Cortisol deficiency results in anorexia, weight loss, weakness, apathy, hypotension, and inability to withstand stress.( 3)
Chronic Fatigue Syndrome
Chronic fatigue syndrome (CFS) is characterized by persistent or relapsing debilitating fatigue for at least 6 months in the absence of any definable diagnosis. CFS patients show low free cortisol levels or adrenal insufficiency. In CFS patients, the increased sensitivity of adrenocortex to ACTH does not correspond with the cortisol secretory capacity.( 22) Symptoms of patients suffering from CFS may include depression, hypotension, weight loss, and inability to endure stress. Cortisol deficiency also may lead to impaired counterregulation of the immune response, as evidenced by enhanced antibody titers to viral antigens in patients with CFS.( 44)
Literature survey also suggests an association between reduced cortisol output and chronic illness, autoimmune, and rheumatological diseases. Abnormalities were demonstrated in the HPA axis function of patients suffering from AIDS, which may be a factor in the progression of the disease. Glucocorticoid supplementation was found to be effective.( 103) Therefore, it is essential that underlying HPA axis deficits be addressed in clinical therapy.
Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone Sulfate (DHEAS)
Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are primarily produced and secreted from the zona reticularis of the adrenal cortex. DHEAS is the major steroid produced by the adrenals of the fetus. DHEA and DHEAS reach a maximum at about age 25, and then decline gradually to about 15–20% of its peak production by the age 75 and over.( 13, 84, 95) Quantitatively, DHEAS is the most abundant androgen in the circulation. In normal young adults, DHEAS circulates at a plasma concentration approximately 10 times that of cortisol.
Over 95% of the circulating DHEA is in sulfate form, DHEAS.( 8) The plasma half-life of DHEA is less than 30 minutes, and circulatory DHEAS help maintain DHEA levels at all times.( 82, 83) DHEAS is relatively unaffected by diurnal variation because of its long biological half-life (approximately 20 hours) and low rate of metabolic clearance, in contrast to DHEA, which has a high clearance rate and marked diurnal variation. Circulating levels of DHEAS are greater than 500 times that of DHEA. The conversion ratios for the conversion from DHEAS to DHEA in men and women are 0.006 and 0.004, respectively. The amount of DHEAS converted to DHEA in men and women are 73.4, 64.4%, respectively.( 10) Interracial differences were noted in DHEAS levels in blood circulation among normal Japanese and British women, DHEAS levels were lower in the former than latter.( 99)
Although abundant DHEAS levels are circulating in blood plasma, its physiological role is still unclear. DHEAS are metabolic intermediates in the pathway for synthesis of testosterone, estrone, and estradiol. DHEA and DHEAS have little native androgenic activity; however, they are metabolized in peripheral tissues to potent androgens such as testosterone and dihydrotestosterone. DHEAS affect lipogenesis, substrate cycling, peroxisome proliferation, mitochondrial respiration, protein synthesis, and thyroid hormone function.( 8)
DHEA levels show a circadian variation similar to that of cortisol. DHEAS levels show a less clear circadian or monthly (in women) variation probably due to low clearance, and also its formation by extra adrenal sulfonation. However, seasonal variations, such as higher plasma DHEAS levels were recorded during autumn-winter than in spring season.( 82, 23)
DHEA provided protection in rats subjected to acute sound stress, by inhibiting tryptophan hydroxylase enzyme activity.( 88) Recently, the use of DHEAS levels as a indicator of stress, aging, and age-related diseases viz., psychosomatic disorders, neurosis, depression, peptic ulcer, irritable bowel syndrome was reinforced.( 71) Significant reductions of DHEAS levels in urine of hypertensive individuals were noted. Although, the secretory rates of DHEA and DHEAS were 5 and 6 times higher, respectively, in hypertensive patients.( 24, 69) DHEA also has been shown to prevent dexamethasone induced hypertension in rats.( 13)
DHEA supplementation was shown to have an anti-obesity effect in laboratory animals, decreasing adipose tissue weights, hyperinsulinemia, and also affecting food intake.( 10, 18, 32) An oral administration of 1600 mg/day for four weeks to normal men resulted in 31% decrease in body fat.( 72) Oral administration of DHEA to young males also resulted in lower cholesterol and low density lipoprotein cholesterol (LDL-C) levels, without changes in other lipid parameters and glucose profile.( 68) On the contrary, some studies have shown that DHEA has no effect on obese men,( 8, 13, 94) nor on energy or protein metabolism in healthy males.( 100)
Measurement of DHEAS is primarily for the assessment of adrenal androgen production, because gonadal secretion is minimal. The clinical utility of the test is further enhanced by the lack of pulsatile secretion and the long plasma half-life of DHEAS.
Increased Levels of DHEA
Excess DHEAS has been associated with several clinical conditions, including premature adronarche, congenital adrenal hyperplasia (CAH), adrenal carcinoma, and Cushing’s syndrome. Levels of DHEAS may be only mildly elevated in premature adronarche, thus differentiating this from more serious hyperandrogenic conditions. CAH is characterized by elevated DHEAS concentrations that are suppressible with dexamethasone. The adequacy of therapy in treating CAH may be assessed by following DHEAS levels. Adrenal hyperplasia in Cushing’s syndrome is often characterized by moderately elevated levels of DHEA, likewise suppressible by dexamethasone. Adrenal carcinomas are associated with very high levels of DHEAS; however, carcinoma-induced DHEAS excesses are not suppressible by dexamethasone. In contrast, adrenal adenomas are usually associated with low DHEAS values. In hirsute patients with elevated levels of only one circulating androgen, that analyte is usually DHEAS. Hirsutism may be caused by adrenal or ovarian hyperandrogen secretion. However, in some patients both the adrenals and the ovaries may contribute androgen. Significantly elevated levels of DHEAS almost invariably are associated with adrenal sites for androgenic activity, and are frequently indicative of adrenal tumor.
Decreased Levels of DHEA
Decreased levels of DHEAS have been noted in adrenal dysfunction, hypothyroidism, cardiovascular disease, prostate cancer, menstrual irregularities, osteoporosis, and in irnmunocompromised patients. The decline of DHEA levels with aging correlates with a general decline of cellmediated immunity and increased incidence of malignancies, suggesting immunomodulatory effects of DHEA.( 92)
SLE and DHEA
Systemic lupus erythematosus (SLE) is a classical organ non-specific autoimmune disorder, and is characterized by an aberrant immunoregulatory T cell function and B cell hyperactivity, both of which are associated with pathogenic autoantibody production. Deficient IL-2 activity is a well characterized abnormality of T lymphocytes from patients with SLE.( 92) Family studies of patients with SLE showed that IL-2 deficiency could result from genetic predisposition and precede rather than follow the onset of clinical symptoms.( 34) Serum levels of patients with SLE showed lower levels of DHEAS compared to normals, and supplementation of DHEA to in vitro cultures of T lymphocytes (CD4+) from patients with SLE can restore IL-2 production. It is possible that low serum concentrations of DHEA downregulate the ability of SLE T cells to secrete IL-2. Thus, deficient IL-2 production by T lymphocytes in patients at least, in part, attributed to the low serum levels of DHEA.( 40, 48, 92) DHEA stimulates IL-2 and interferon-ç production in T cells isolated from human donors.( 63) DHEA protects thymus gland from glucocorticoid-induced involution.( 57) T cells that can recognize foreign antigens and protect the body from infection are produced in thymus gland. IL-2 deficiency of T cells and lower serum DHEA levels has also been reported in patients with rheumatoid arthritis.( 20, 38, 39)
It appears that vegetarian diet promotes the production of androgens viz., DHEAS, testosterone, etc. A slight increase in the DHEA levels in volunteers fed with high carbohydrate diet was noted.( 2) A decrease in DHEA levels were recorded in South African men when switched from their customary vegetarian diet to cafeteriafed western diet.( 42)
DHEAS levels were significantly lower in patients with early or late Alzheimer’s Disease compared to normal controls and no correlation in serum cortisol levels with the disease were recorded, leading to an increase in the cortisol/DHEAS ratio.( 67, 90)
Imbalance in DHEAS/Cortisol Ratio or Maladaption of Adrenocortex Function
DHEAS/cortisol ratios were not significantly different among normal men and women.( 27) A reduction in DHEAS and an increase in cortisol synthesis may occur in the adrenal cortex due to mild to severe psycho-patho-physiological conditions, as a maladaptation to stress. These changes would result in a decrease in the DHEAS/cortisol ratio.( 74–76) Maladaptation in adrenocortex manifests by a shift in the pregnenolone metabolism away from both the mineralocorticoid and androgen pathways towards glucocorticoid pathway.( 75) A reduction in DHEAS levels to 1/3rd, and greater than 2-fold increase in cortisol levels were implicated in adult patients with thermal injuries, resulting in the decrease of DHEAS/cortisol ratio.( 76) A low DHEA/cortisol ratio was recorded in patients with surgical stress, such as patients in terminal gynecological malignancy treated with cytotoxic chemotherapy (stressors), and in depressed patients.( 27, 74) Low DHEA/cortisol ratios were also recorded in patients with anorexia nervosa.( 102) Alternatively, a significant increase in the DHEAS/cortisol ratio was recorded in patients with panic disorders.( 27)
The relation between DHEAS/Cortisol ratio and exercise is still unclear. One report suggests an increase in DHEAS levels during exercise,( 59) and another report contradicts any increases in DHEA levels due to endurance training exercises (Hersey, W.C., et al.1994).
Therapeutic Dosing of DHEA and Cortisol
Caution must be exercised when administering DHEA. At present, DHEA administration seems to be quite safe, however, there is not enough scientific literature to validate its use over the long term. The commonly used dosage levels range from 0.5 to 500 mg per day, with no clear standards yet developed to determine the optimal dose. DHEA itself is not water soluble and tissue levels of the drug tend to fluctuate. Clinicians have reported that uptake of the drug varies among individuals. The average recommendation is to begin therapy at the lowest dosage and titrate while monitoring serum levels. The same applies in weaning the patient off of the drug. Divided doses of DHEA at various time intervals is recommended. A single oral dose (500 mg) of DHEA to 10 healthy young men resulted in a significant increase in rapid eye movement (REM) sleep period. Since REM sleep is implicated in memory storage, there is a potential for clinical usefulness of DHEA in age-related dementia.( 30, 43) Recent preclinical research suggests that DHEA supplements may prevent neuronal damage in DHEA deficient patients.( 12)
The dosage range for cortisol is 20–150 mg in divided doses per day with careful monitoring of serum levels. Lower dosages are more effective in cases of HPA axis disturbance or adrenal fatigue. Higher dosages are recommended in autoimmune and rheumatological diseases. Extreme caution must be taken when administering glucocorticoids in patients with diabetes mellitus. The endocrine system responds to small corrections, however, administration of higher amounts of substances may be necessary. The clinician must always keep homeostasis in mind when administering any therapy. Baseline and therapeutic levels of DHEA and Cortisol should be obtained to appropriately monitor therapy.
Treatment Design for HPA Axis Stress Secretory Patterns
In cases of HPA Axis disturbance it is necessary to consider stress reduction and effective stress management by counseling, regular exercise, sufficient sleep, and adequate glycemic control. When treating conditions that manifest hyper/hypo-cortisol secretion patterns it is essential to identify possible underlying stressors. Factors that contribute to hyper/hypo-cortisol secretion patterns are: 1) stress and/or trauma; 2) food and enviromental allergies; 3) impaired mucosal immune defense (bowel and other mucosal surfaces); 4) chronic immune dysfunction; 5) increased antigenic stress on the liver; 6) psychoemotional factors and 7) tumor or associated malignancy.
Determining underlying stressors is of extreme importance in developing a treatment design. Treatment protocol can include the use of adaptogenic botanicals (Eleutherococcus and Panax ginseng), other botanicals like Kava, Valerian, Hypericum, Ginkgo, and Coleus. Vitamin, mineral and amino acid therapies have demonstrated favorable results (B complex, B12 and folate (IM), Vit C, E, manganese, magnesium, etc.). Carotenoids, proanthocyanadins and biofiavonoids are useful in cases of allergy and inflammation. Antioxidants can reduce the total oxidative burden when they are given in proper dosages and routes of administration (glutathione, SOD, CoQ10). Hormonal therapies can be useful in resynchronizing feedback mechanisms. For example, melatonin is known in the research literature for its resynchronizing effects on cortisol,( 104) and DHEA therapy has been shown to be useful in cases of stress, depression, anxiety, and allergy. Homeopathy can address vitality and constitutional deficits. Relaxation techniques like deep breathing, relaxing baths, therapeutic massage, light therapy, music therapy, prayer and/or meditation, can all greatly improve hypercortisol stress patterns. Dietary factors should always be taken into consideration with patients suffering from asthma and multiple sensitivities.
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Townsend Letter for Doctors & Patients.
By Rama K. Velicheti; John A. Catanzaro and Raymond M. Suen
John A. Catanzaro