II. Dehydroepiandrosterone Test DHEA and cortisol levels diverge in stress and disease states Avoid the inherent pitfalls of urinary steroid analysis Salivary steroids accurately reflect the tissue levels (for test details, please consult Test Specifications section p.34) Source and Origin Dehydroepiandrosterone (DHEA) is an adrenal steroid produced in abundant amounts. It has a plasma half-life of 25 minutes. More than 90% of DHEA is conjugated to sulfate to produce DHEAS prior to release into the circulation (1); DHEAS has about 60% of DHEA biological activity. The average daily production of DHEAS in men and women is 31 mg and 19 mg, respectively. The long half-life of DHEAS, 8-11 hours, is due to (2) its slow clearance by the liver and kidney (3). DHEA and DHEAS are enzymatically interconvertable with about 64 - 74% of DHEAS converted to DHEA (4). Both forms are in dynamic equilibrium with each other. Salivary DHEA(S)* is found in saliva at about 0.1% of its plasma concentration. Serum fluctuation in DHEA(S) concentrations are accurately and rapidly reflected in salivary levels (5). *DHEA(S) = Free Fractions of DHEA & DHEA(S) DHEA(S) Secretion Patterns Short term variation: Among the adrenal steroids, DHEAS shows the least fluctuation in serum concentration with a mean coefficient of variation of 12% within a 4 hour measurement span (6). Daily circadian variation: Variations in DHEAS over 24 hours exhibit a circadian rhythm in young adult individuals which disappears by the age of 70. The amplitude of variation is about 13% of the MESOR (7). MESOR is the mean estimated statistic of rhythm. Yearly or Circannual Variation: There seems to be a statistically significant seasonal increase in plasma concentration of DHEAS in autumn and winter (8). The mechanisms leading to seasonal variation of adrenal androgen rhythm are not elucidated yet.

Control of Secretion DHEA and DHEAS output is regulated by several mechanisms: Genetic factors Wang et al (9) compared DHEAS in normal British and Japanese women and reported lower plasma DHEAS in Japanese women. Familial effects were investigated in 26 families(10). When age was factored out a genetic component for variation of serum DHEA levels was found with an expression rate of 65%. ACTH Control While ACTH plays a permissive role in regulating DHEA & DHEAS, increasing evidence indicates the presence of other non ACTH regulatory components that modulate adrenal androgen secretion.This conclusion is apparent in many physiological and pathological situations in which divergence in cortisol and adrenal androgen occurs (11, 12, 13). Example 1 - Puberty: Pubertal augmentation of adrenal androgen output is not paralleled by ACTH changes (14). Example 2 - Aging: In normal aging humans, serum levels and secretion rates of cortisol show minimal changes. In contrast DHEA and DHEAS show age related (not age induced) progressive decrements amounting to an 80% reduction by the age of 75 (15). This reduction is a function of a cumulative stress effect. Example 3 - Cushing's disease: In a substantial percent of individuals suffering from excessive ACTH and hypercortisol, serum DHEAS levels are not higher than age-matched controls (16, 17). It is not clear why chronic ACTH output does not stimulate DHEA and DHEAS but significantly augments cortisol secretion.

Clinical Aspects and Correlates Conversion of DHEA(S ) to other hormones When DHEA(S) is given to healthy non-pregnant women it is rapidly converted to Estrogens (Estrone and Estradiol) (18)causing a 300% and 500% increase respectively. Testosterone levels also increase by 300 to 400%. Values progressively return to normal with time. Cortisol to DHEA(S) ratio Alzheimer's disease: Research (19) indicates that DHEAS levels in Alzheimer patients are 48% lower than age matched controls. These patients also show an elevated Cortisol / DHEAS ratio. Noteworthy, is the fact that elevations in Cortisol lead to hippocampal damage in animal studies (20), while DHEA intake is known to improve memory function in aging animals (21). Panic disorders: The Cortisol/DHEAS-S ratio in individuals with panic disorder is depressed by about 50% over the normal control (22). DHEA-S and Thyroid Disease Plasma concentrations of DHEA(S) are significantly decreased in women with primary hypothyroidism when compared with age matched euthyroid controls (23,24). In contrast, DHEAS in thyrotoxic individuals is increased. DHEA and bone metabolism DHEA and calcium absorption: There is some evidence that DHEA has a stimulatory effect on intestinal calcium absorption that may be mediated directly or indirectly via modulation of Vitamin D metabolism (25).

Osteoporosis and adrenal androgens A large number of studies relating adrenal steroids to osteoporotic bone loss support the concept that postmenopausal bone loss is a multifactorial problem that includes: ·Decreased androstenedione and DHEA production coupled with decrease conversion to testosterone ·Decreased estrone production with reduced conversion to estradiol ·Decreased progesterone production ·Increased cortisol production The overall effect of these changes appears to be decreased bone formation and increased bone resorption leading to net bone loss. DHEAS and cardiovascular disease Myocardial infarcts: DHEA and DHEAS levels were significantly elevated in men who had survived infarcts at least 6 months earlier, when compared to age matched controls. However, men with at least 50% coronary occlusion on angiography (with no infarcts) had normal DHEA and DHEAS values (26). Further evidence (46) indicates that DHEAS levels are a marker for underlying protective effects, or that DHEAS [or its metabolite(s)] is a protective substance in itself. Hypertension and DHEAS: Urinary DHEAS i.e. excretion rates were significantly decreased by 85 - 95% below controls in clinically hypertensive patients. (27, 28). Further investigation revealed that circulating DHEAS levels were not different in hypertensive individuals when compared to their age matched control. Reduced production and clearance account for low urinary levels. Note: Urinary DHEAS determinations have inherent limitations of interpretation in hypertensive individuals.

Obesity and Adrenal steroids Cortisol: The cortisol secretion rate is increased in obese individuals coupled to accelerated clearance rate. The circulating and urine free cortisol, however, remain unchanged (29) with increased adrenal sensitivity to circulating ACTH. DHEA and DHEAS: Production rates of DHEA and DHEAS are increased in obese patients (30). However circulating DHEA and DHEAS levels remain unchanged due to an accelerated metabolic clearance rate (MCR). Note: Interpreting urinary steroid fractions in obese individuals has many inherent pitfalls. Diet and adrenal steroids Vegetarian diets and varying ratios of dietary saturated to unsaturated fats have no significant effects on DHEA and DHEAS, however, decreases in androstenedione, estrone and estradiol have been reported (31). High carbohydrate diets are associated with increase testosterone and decreased cortisol levels when compared with high protein diets (32). DHEA and immune function Animal research indicates that DHEA has a direct stimulating effect on T-lymphocytes in-vivo and in-vitro, by enhancing IL-2 production which is pivotal in cell mediated immune responses. Additionally, DHEA can overcome the immunosuppressive effect of cortisol on T-lymphocytes. Cortisol is known to depress IL-2 production (33).

Therapeutic Aspects Effect on lipid metabolism Clinical studies have shown that oral DHEA intake over variable durations of time can lower total serum cholesterol by an average of 18% (34), while other authors have examined DHEA effect on total and LDL serum cholesterol (35). Effect on weight loss Oral administration of DHEA 1600 mg/day (non micronized), for one month to healthy males caused a 31% reduction in body fat content with no overall weight loss. (No dietary or exercise pattern changes were allowed). This indicated a corresponding increase in muscle weight (35). Stress and Adrenal Androgens Effect of exercise Acute exercise including running, swimming, football, etc., causes an increase in serum concentrations of cortisol, DHEA, & DHEAS in both men and women (36-39). In contrast, marathon runners, 1100 Km for 20 days, show no change in DHEAS and a return to normal cortisol levels after 24 or 40 week training program (40-42). Psychological stress Stressful events defined by their cortisol stimulating effect, include anticipating death of family member or surgery, hospital admission, public speaking, mental performance testing and residence relocation in the elderly (43), which have a depressing effect on DHEA.

Dehydroepiandrosterone Test (continued) Chronic stress and adrenal steroids Divergence of steroid production: Studies on chronically ill individuals have shown a divergence in the cortisol and DHEA and DHEAS levels (Figure 1- to be added). The DHEAS to cortisol ratio shows a 77% reduction due to chronic stress of illness (44). Figure 1 illustrates the divergence in cortisol and DHEAS production in severe stress caused by burns (45). Mechanism of divergence: The divergence in cortisol and DHEAS serum levels is postulated to be due to the following: 1.Biochemical diversion of pregnenolone and progesterone, the precursors for both cortisol and adrenal androgens, into the cortisol pathway. This "precursor steal" causes a net reduction in DHEA and DHEAS output (44). (See Figure 2 on next page) 2.A defect in ACTH stimulated DHEA and DHEAS output. Chronically stressed individuals show a normal increment of cortisol but a 57% reduction in DHEA levels following ACTH stimulus(44). Additional page of graphics- to be added


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