Metabolic clearance rate (MCR) of dehydroepiandrosterone sulfate (DS), its metabolism to dehydroepiandrosterone, androstenedione, testosterone, and dihydrotestosterone, and the effect of increased plasma DS concentration on DS MCR in normal women

The combined infusion of [3H]dehydroepiandrosterone sulfate [( 3H]DS) and [14C]estrone (E1) for 6 h in four normal women in the follicular phase of the cycle demonstrated values of 13.77 +/- 0.27 L/day (mean +/- SE) for the DS MCR (MCRDS) and 1343 +/- 206 L/day for MCRE1. The fraction of DS metabolized to dehydroepiandrosterone (D), [rho]DS-D, was 0.285 +/- 0.044, and the fraction of D arising from DS (delta D) was 0.318 +/- 0.096, determined using isotopic techniques. Raising the plasma DS concentration by 8.6 micrograms/mL (23 mumol/L) by infusing DS iv increased the MCRDS to 24.49 L/day in the first subject, and raising the plasma DS by 11.40 +/- 0.33 micrograms/mL (30.94 +/- 0.90 mumol/L) in the next three subjects raised the MCRDS to 35.7 +/- 1.3 L/day (P less than 0.01) without changing the MCRE1. The increase in MCRDS produced by increasing plasma DS makes it difficult to accurately measure the MCRDS in effect at the subject's endogenous plasma DS concentration by infusion of nonisotopic DS. Determination of the fractions of D, androstenedione (delta delta 4A), and testosterone (T) arising from DS using the increase in the plasma concentrations of these steroids produced by infusion of nonisotopic DS gave the following estimates: delta D = 0.262 +/- 0.042, delta delta 4A = 0.089 +/- 0.046, and delta T = 0.273 +/- 0.14.     

Circulating concentrations of dehydroepiandrosterone and dehydroepiandrosterone sulfate during puberty.

In order to quantitate the chronological change in circulating dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DS) levels during the period of sexual maturation, serum DHEA and DS concentration (3-5 PM) in 76 boys and 65 girls (ages 8 to 15) as well as in adult male and female subjects were measured by a specific and sensitive radioimmunoassay technique. Our data show a progressive and parallel increase in serum DHEA and DS concentrations in boys, and adult male levels were reached earlier for DHEA (age 13) than for DS (age 14). From age 8 to adult male, there was a 2.6-fold increase in DHEA (1.52 plus or minus 0.16 ng/ml to 3.91 lus or minus 0.34 ng/ml) and a 7.7-fold increase in DS (0.40 plus or minus 0.08 mug/ml to 3.09 plus or minus 0.36 mug/ml).The rise of DHEA and DS was not in a parallel fashion in girls; while DS rose progressively, DHEA showed an abrupt increase between 11 and 12 yr of age. Adult female range was reached by age 12 for DHEA and by age 15 for DS. From age 8 to adultfemale there was a 2.3-fold increase in DHEA (1.93 plus or minus 0.19 ng/ml to 4.49 plus or minus 0.76 ng/ml) and a 7.5-fold increase in DS (0.29 PLUS OR MINUS 0.05 MUg/ml to 2.17 plus or minus 0.34 mug/ml). The role of increased adrenal androgens inthe sexual development during early stages of puberty is discussed.     

Serum concentrations of dehydroepiandrosterone sulfate and leptin in obese patients with normal serum cholesterol

Normal (< 200 mg/dL) serum concentrations of cholesterol and a favorable ratio of cholesterol/high-density lipoprotein (HDL)-cholesterol are frequently seen in morbidly obese (body mass index [BMI] > 35 kg/m2) patients. Because it is unknown whether this subgroup is characterized by differences in other potential markers of cardiovascular disease, serum concentrations of dehydroepiandrosterone sulfate (DHEAS) and leptin were determined in 155 obese patients (BMI > 35 kg/m2, aged 20 to 50 years) with normal (n = 72) or with elevated (n = 83) total serum cholesterol. We found that seemingly negative marginal correlations between serum concentrations of DHEAS and cholesterol, as well as between DHEAS and the ratio cholesterol/HDL-cholesterol, were not any more apparent after correction for age, sex, and BMI. A negative correlation between serum leptin concentrations and the ratio cholesterol/HDL-cholesterol persisted after correction for age, sex, and BMI. In morbid obesity, there appears to be an association between serum concentrations of leptin and a more favorable lipid profile, whereas there is no direct interrelation between serum concentrations of cholesterol and DHEAS.     

Decreased dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) concentrations in plasma of Alzheimer's disease (AD) patients

DHEA is secreted by the adrenal cortex and is also a neurosteroid. Its sulfate (DHEAS) is the most abundant steroid in circulation. The levels of both are seen to decline in concentration with age. Evidence is available for altered levels of DHEA and DHEAS in AD but is limited to relatively few studies assessing small cohorts. This study assessed plasma DHEA and DHEAS levels in AD sufferers (n = 72) and compared them to age-matched controls (n = 72). Plasma DHEA concentrations were significantly lower in AD patients compared to control (4.24 ± 0.4 ng/ml for AD; 3.38 ± 0.3 ng/ml for control, p = 0.027, Mann-Whitney 1-tailed) and DHEA levels were significantly correlated to DHEAS levels in both control and AD conditions (Spearman's rho correlation coefficient = 0.635 in controls and 0.467 in AD, p ≤ 0.01). This study highlighted a measurable difference in DHEA and DHEAS concentrations in plasma from a large cohort of patients suffering from AD when compared to age-matched controls.     

Serum concentrations of dehydroepiandrosterone sulfate (DHEA-S) in oldest old Japanese women correlate with cognitive activity rather than activities of daily living

Background:   Dehydroepiandrosterone (DHEA) and its interconvertible sulfate ester, DHEA sulfate (DHEA-S), mainly produced by the adrenal glands, are progressively decreased with aging and are proven markers of longevity. Although serum level of DHEA (-S) has been shown to be decreased in dementing diseases, the issue remains controversial. We investigated the physiological significance of DHEA-S in oldest old Japanese women in respect of activities of daily living (ADL) or cognitive activities.
Methods:   Cross-sectional study of 50 women aged 90–103 years old. Serum concentrations of DHEA-S levels were measured by radioimmunoassay. ADL and cognitive activity were evaluated by the Bathel index and revised Hasegawa's dementia rating scale (HDS-R), respectively. Univariate or multivariate regression analyzes were used for statistics.
Results:   Of the 50 subjects, 80% exceeded the lowest level of the normal range for women in their forties. Serum concentrations of DHEA-S were significantly correlated with HDS-R but not with the Barthel index.
Conclusion:   Relatively higher levels of serum DHEA-S in oldest old women may reflect the longevity of this population and the levels might be associated with cognitive activity rather than ADL.     

Serum dehydroepiandrosterone sulfate concentrations in secondary adrenal insufficiency

Serum dehydroepiandrosterone sulfate (DHEA-S) concentrations were studied in 84 untreated patients with secondary adrenal insufficiency. Compared to values in normal subjects of corresponding age, DHEA-S levels were decreased in 80 patients. The decrease was unrelated to the cause of the secondary adrenal insufficiency or the serum PRL level. Serum cortisol concentrations, on the other hand, were low in 71 patients and low normal in the remaining 13. Serum DHEA-S levels were decreased in 11 of these 13 patients. The frequency of decreased serum DHEA-S levels in patients with secondary adrenal insufficiency was significantly higher than that of decreased cortisol levels. These results suggest that decreased serum DHEA-S levels reflect deficient ACTH secretion in secondary adrenal insufficiency and that simultaneous determination of serum DHEA-S and cortisol levels is useful in the diagnosis of this pathological state.     

Long-term longitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men.

Dehydroepiandrosterone sulfate (DS) was measured by direct tritium RIA in longitudinal plasma specimens from 97 normal healthy male participants in the Baltimore Longitudinal Study of Aging. Fasting blood was collected at regular visits (approximately 1.5 yr apart) over an average 13 yr of adulthood (cumulative age range: 32-83 yr). DS was measured in 3-4 widely spaced specimens from each subject. A decline in DS was found in 65 (67%) subjects, 13 subjects (13%) showed no change, and increases were found in the 19 remaining subjects during the study period. A plot of individual data points revealed the same pattern we had obtained previously from a cross-sectional study of a different normal male population. A plot of DS values vs. age among subjects whose DS increased during the study also revealed an age-related decline. Thus, the longitudinal decrease in circulating DS, long inferred from cross-sectional data, is confirmed for normal men in the present study. A more detailed study of every specimen collected during the study period from 12 of the Baltimore Longitudinal Study of Aging subjects (4 whose values tended to be low, 4 whose values tended to be high, and 4 whose values were near the mean) failed to reveal any patterns of variation that could be correlated with changes in life circumstances, health status, or any other discernible factors. Hence, the wide variability seen in DS among individuals within normal populations remains unexplained.     

Long term effects of a first pregnancy on serum concentrations of dehydroepiandrosterone sulfate and dehydroepiandrosterone

A previous paper in this journal reported that first pregnancy was followed by a marked decrease in dehydro-epiandrosterone sulfate (DHAS) and dehydroepiandrosterone (DHA) levels. We report here confirmatory observations from cross-sectional measurements in 460 women. In premenopausal subjects (n = 306), the mean DHAS level was 21% lower (P = 0.005) and the mean DHA level was 32% lower (P less than 0.001) in parous than in nulliparous women. Neither DHAS nor DHA was related to parity in postmenopausal women (n = 154).     

Serum concentration of dehydroepiandrosterone sulfate and testosterone in women with severe atopic eczema/dermatitis syndrome.

BACKGROUND: Although a growing body of evidence indicates that androgens modulate immune response and certain alterations in sex hormone metabolism and balance are thought to predispose an individual to immune-mediated diseases, few studies have investigated the role of androgens in atopic eczema/dermatitis syndrome (AEDS). OBJECTIVE: We evaluated serum concentration of dehydroepiandrosterone sulfate (DHEA-S) and total testosterone in women with severe AEDS to characterize the hormonal milieu of such patients. METHODS: Serum concentrations of DHEA-S and total testosterone in 13 female patients with severe AEDS were compared with concentrations in weight- and age-matched healthy controls. Measurement was by electrical chemiluminescence immunoassay. RESULTS: There were no significant differences in serum concentrations of DHEA-S or testosterone between the 2 groups. We found no correlation between serum concentrations of DHEA-S and total immunoglobulin E. CONCLUSION:This small study suggests there may be no abnormalities in peripheral blood concentrations of DHEAS-S and total testosterone in women with severe AEDS.     

Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood

In a cross-sectional study, serum dehydroepiandrosterone sulfate (DS) concentrations were measured in 981 men and 481 women, aged 11-89, yr. The resulting data were asymetrically distributed and were normalized by logarithmic transformation and analyzed by 5-yr age grouping (e.g. 15-19 yr, 20-24 yr, etc.). The DS concentration peaked at age 20-24 yr in men (logarithmic mean, 3470 ng/ml) and at age 15-19 yr in women (log mean, 2470 ng/ml). Mean values then declined steadily in both sexes (log mean at greater than 70 yr of age, 670 ng/ml in men and 450 ng/ml in women) and were significantly higher in men than women at ages from 20-69 yr. Analysis of 517 randomly selected sera (from women) which had been stored frozen for 10-15 yr gave results indistinguishable from values obtained from fresh specimens. In a supplementary study, a longitudinal analysis of weekly specimens from 4 normal men, aged 36-59 yr, revealed individual variability (mean coefficient of variation, 19%) and failed to demonstrate any monthly, seasonal, or annual rhythmicity. Based on the above analyses, a table of normal serum DS ranges for adult men and women is presented for use as a clinical reference.     

Serum dehydroepiandrosterone sulfate and adverse health outcomes in older men and women

Low serum dehydroepiandrosterone sulfate (DHEAS) is common in older persons with poor health. The geriatric syndrome of physical frailty is associated with a higher risk of developing fatal and nonfatal health outcomes. However, the association of DHEAS with frailty is uncertain. This study investigated the association of serum DHEAS with frailty and its related adverse outcomes in 416 men and 504 women aged ≥65 years from an Italian prospective population-based cohort study. At baseline, frailty status was defined according to the physical phenotype, and serum DHEAS was measured in a fasting venous blood sample. After 4 years, subjects were reassessed for incident frailty and occurrence of nonfatal frailty-related outcomes (hospital admission, nursing home placement, disability, falls, and fractures). All-cause mortality after 8 years was also recorded. Incident frailty was inversely associated with baseline log-transformed DHEAS in men (odds ratio [OR]=0.35, 95% confidence interval [CI] 0.14-0.88, p=0.026) but not in women. Independent of baseline frailty status, women in the lowest DHEAS quartile compared to the upper three quartiles had a higher risk of hospital admission (OR=0.44, 95% CI 0.21-0.91, p=0.027) and nursing home placement (OR=0.27, 95% CI 0.08-0.95, p=0.041). Baseline log-transformed serum DHEAS was also inversely associated with mortality risk, but limited to women with concurrent frailty (hazard ratio [HR]=0.27, 95% CI 0.11-0.68, p=0.005) or preexisting major diseases (HR=0.57, 95% CI 0.33-0.98, p=0.041). These findings suggest that DHEAS is associated with incident frailty in older men and with fatal and nonfatal frailty-related adverse outcomes in older women.     

Hyperinsulinaemia and decreased plasma levels of dehydroepiandrosterone sulfate in premenopausal women with coronary heart disease

Abstract. Objectives. The purpose of the study was to establish plasma levels of insulin, ovarian sex hormones and dehydroepiandrosterone sulfate (DHEA-S) and to evaluate their correlations with lipids in premenopausal women with angiographically demonstrated coronary stenosis. Design. Differences in plasma levels of insulin, ovarian sex hormones, DHEA-S and lipids between groups were compared by analysis of variance. Setting. From January 1993 until December 1993 patients were diagnosed in the Outpatient Clinic of the Department of Endocrinology Medical Centre for Postgraduate Education, Warsaw. Subjects. Premenopausal women with normal oral glucose tolerance test (OGTT) results, with and without coronary stenosis were studied: 21 women after acute myocardial infarction with angiographically demonstrated coronary stenosis (women with CHD), and 14 women with chest pain, a positive exercise test without significant changes of coronary arteries on coronarography (women with normal coronarography, NC). The control group consisted of nine, healthy women with no risk factors for CHD. Main outcome measures. In premenopausal women with CHD, the decreased plasma level of DHEA-S and hyperinsulinaemia were anticipated. Results. In women with CHD, the plasma levels of DHEA-S (926.5 ± 83 ng mL^?1) were significantly lower than those in women with NC (1375.7 ± 181 ng mL^?1) and in healthy controls (1984 ± 127 ng mL^?1), P < 0.02 and P < 0.001, respectively. The fasting insulin and insulin response to an OGTT in women with CHD and with NC was higher than in healthy subjects. A significant decrease of high-density lipoprotein (HDL) cholesterol, HDL-2 cholesterol and apolipoprotein A-I, and an increase of total cholesterol, low-density lipoprotein cholesterol C and apolipoprotein B levels in women with CHD compared to healthy controls were observed. A negative correlation between fasting insulin and the plasma levels of DHEA-S was established. Conclusion. In premenopausal women, hyperinsulinaemia and decreased DHEA-S levels may contribute to the development of coronary atherosclerosis.     

Serum concentrations of estradiol and dehydroepiandrosterone sulfate and soy product intake in relation to psychologic well-being in peri- and postmenopausal Japanese women

The effect of steroid hormones, such as estrogen and dehydroepiandrosterone (DHEA) on psychologic well-being of women has been suggested. Dietary estrogen may also affect psychologic status. We examined the cross-sectional relationships of serum concentrations of estradiol (E2) and DHEA sulfate (DHEAS) and dietary intake of soy products to psychologic status measured using the Center for Epidemiologic Studies Depression Scale (CES-D) and General Health Questionnaire (GHQ)-12 scales in 86 peri- and postmenopausal Japanese women. Intake of soy products and other dietary components was estimated from a validated semiquantitative food frequency questionnaire. A fasting blood sample was obtained from each woman to measure serum concentrations of E2 and DHEAS. Serum DHEAS was significantly inversely correlated with CES-D scale (r = -.22, P = .04) and GHQ-12 scale (r = -.27, P = .01). Soy product intake was significantly inversely correlated with CES-D scale (r = -.22, P = .04). Neither serum E2 concentration nor the ratio of serum E2 to sex hormone-binding globulin (SHBG) was associated with any of the psychologic measurements. These data suggest a possibility that endogenous DHEA sulfate and dietary soy may modulate psychologic well-being of peri- and postmenopausal women.     

Oral dehydroepiandrosterone (DHEA) replacement therapy in women with Addison's disease

OBJECTIVE: Patients with primary adrenocortical failure (Addison's disease) have abnormally low levels of DHEA and androgens relative to age. To define a suitable dose, the effect of oral dehydroepiandrosterone (DHEA) replacement therapy in women with Addison's disease (n = 9) was evaluated. DESIGN AND MEASUREMENTS: DHEA was administered as a daily oral dose of either 50 mg (n = 5) or 200 mg (n = 4). Blood sampling and measurements of insulin sensitivity (as measured with euglycemic insulin clamp technique) and body composition (as measured by dual energy X-ray absorptiometry) were performed before and during DHEA treatment and at a 3-month follow up. RESULTS: DHEA and DHEA(S) levels were restored to normal in those patients receiving 50 mg whereas DHEA(S) level was slightly above the normal reference value in those receiving 200 mg. Circulating levels of androgens (androstenedione, testosterone and testosterone/SHBG ratio) were normalized in all patients. A slight rise in IGF-1 levels was seen in both groups as was a decrease in the levels of low and high density lipoproteins. No effect on blood glucose levels or insulin sensitivity was seen and no change of body composition was observed. No serious side-effects were seen, but some of the patients experienced increased apocrine sweat secretion (n = 7), itchy scalp (n = 2) and acne (n = 7), all of which were reversed when DHEA was discontinued. CONCLUSION: A daily replacement dose of 50 mg of DHEA results in near physiological levels of DHEA, DHEA(S) androstenedione and testosterone in women with Addison's disease, without severe side-effects.     

Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock

CONTEXT: Dehydroepiandrosterone (DHEA) replacement in sepsis has been advocated because of the sepsis-associated decrease in serum DHEA sulfate (DHEAS). However, experimental sepsis in rodents leads to down-regulation of DHEA sulfotransferase, which inactivates DHEA to DHEAS, theoretically resulting in higher DHEA levels. OBJECTIVE: The objective of the study was to test whether serum DHEA and DHEAS are dissociated in septic shock and to determine their association with circulating cortisol in the context of severity of disease and mortality. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study consisting of 181 patients with septic shock, 31 patients with acute trauma, and 60 healthy controls. MAIN OUTCOME MEASURES: Serum cortisol, DHEA, and DHEAS were measured before and 60 min after ACTH stimulation. RESULTS: Serum cortisol was increased and DHEAS was decreased in both septic shock and trauma patients (all P < 0.001). However, compared with healthy controls, DHEA was significantly increased in sepsis but decreased after trauma (all P < 0.001). In sepsis, neither cortisol nor DHEA increased significantly after ACTH. Most severely ill patients had higher cortisol (P = 0.069) and lower DHEA (P = 0.076) and a significantly higher cortisol to DHEA ratio (P = 0.004). Similarly, the cortisol to DHEA ratio was significantly increased in nonsurvivors of septic shock (P = 0.026), whereas survivors did not differ from controls (P = 0.322). CONCLUSIONS: The observed dissociation of DHEA and DHEAS in septic shock contradicts the previous concept of sepsis-associated DHEA deficiency. Increased DHEA levels may maintain the balance between glucocorticoid- and DHEA-mediated immune and vascular effects. However, most severe disease and mortality is associated with an increased cortisol to DHEA ratio, which may represent a novel prognostic marker in septic shock.