Higher Dehydroepiandrosterone Sulfate Research Articles

High basal serum allopregnanolone levels in overweight girls

Several studies demonstrated that obese subjects have a hyperactive hypothalamic-pituitary-adrenal axis and that sex steroid hormones have been closely related to the regulation of adiposity, either through direct or indirect physiological mechanisms. Allopregnanolone (3alpha-hydroxy-5alpha-pregn-20-one; AP) is a circulating neuroactive steroid hormone involved in the modulation of behavioral functions, stress and neuroendocrine axis. The aim of our study was to evaluate basal serum AP levels in obese children. We studied 27 normal weight (NW) and 23 overweight (OW) girls. Gonadotropins and steroid hormones were assessed in all patients. Basal AP concentrations in OW girls were significantly higher than in NW controls (P=0.013). There was no difference found between the other gonadal and adrenal hormones. Considering the pubertal stage, we demonstrated that obese pubertal girls presented higher AP concentrations than prepubertal and pubertal NW ones (P=0.020), and higher dehydroepiandrosterone sulfate (DHEAS) levels with respect to prepubertal obese girls, and prepubertal and pubertal NW patients (P=0.025). AP and DHEAS were significantly directly related to weight (r=0.31 and r=0.54, respectively) and body mass index (r=0.29 and r=0.34, respectively). In pubertal OW girls, a significant positive correlation between AP and DHEAS (r=0.60), A (r=0.72) and luteinizing hormone (r=0.64) levels was demonstrated. The present study demonstrates that AP is hypersecreted in children and adolescent with OW involving DHEAS concentrations, too. Our data suggest a possible role of AP in the regulation of neuroendocrine axis related to obesity. We can also speculate that in OW girls, who could manifest emotional and behavioral problems, a part of higher levels of this neuroactive steroid might act as gamma-aminobutyric acid agonist producing anxiolytic-sedative effects.

Pubertal Development Predicts Resistance to Infection and Reinfection with Schistosoma japonicum

In communities where Schistosoma species are endemic, the prevalence and intensity of schistosomiasis is disproportionately high among children, compared with adults. This epidemiologic pattern is consistent with either the slow development of resistance or the requirement of host developmental changes for the expression of resistance. We enrolled 87 individuals aged 7-18 years who did not have Schistosoma japonicum infection and 641 individuals aged 7-30 years with S. japonicum infection, all of whom reside in 3 villages in Leyte, Philippines. At baseline, S. japonicum infection was assessed by Kato-Katz thick-smear stool examination, and the levels of the pubertal hormone dehydroepiandrosterone sulfate (DHEA-S) in serum were determined. Individuals with S. japonicum infection were treated with praziquantel, after which stool examination and DHEA-S level measurement were performed every 3 months for 18 months. In cross-sectional analyses, the intensity of infection among individuals with high DHEA-S levels was 43% lower (28 eggs per g, n = 243), compared with individuals with low DHEA-S levels (50 eggs per g, n = 242), even after adjusting for age, sex, and village (P = .01). Following praziquantel treatment, increased DHEA-S levels were associated with resistance to reinfection (P = .006). The intensity of reinfection among individuals with high DHEA-S levels was 42% lower, compared with individuals with low DHEA-S levels, even after adjusting for age, baseline intensity of S. japonicum infection, village, sex and water contact (P < .001). Increased DHEA-S levels in serum, a marker for adrenal development, is associated with reduced S. japonicum infection and reinfection, even after adjusting for age and, by proxy, cumulative exposure. These data suggest that an intrinsic property of host pubertal development mediates, in part, the resistance to infection observed in older individuals.

Prostate Cancer Risk: The Significance of Differences in Age Related Changes in Serum Conjugated and Unconjugated Steroid Hormone Concentrations Between Arab and Caucasian Men

Factors responsible for the low incidence of clinical prostate cancer (3-8/100,000 men/year) in the Arab population remain unclear, but may be related to changes in steroid hormone metabolism. We compared the levels of serum conjugated and unconjugated steroids between Arab and Caucasian populations, to determine if these can provide a rational explanation for differences in incidence of prostate cancer between the two populations. Venous blood samples were obtained from 329 unselected apparently healthy indigenous Arab men (Kuwaitis and Omanis) aged 15-80 years. Samples were also obtained from similar Arab men with newly diagnosed prostate cancer or benign prostatic hyperplasia (BPH). The samples were taken between 8:00 am and 12:00 noon. Serum levels of total testosterone, (TT), sex hormone binding globulin (SHBG), free androgen index (FAI); adrenal C19-steroids, dehydroepiandrosterone sulphate (DHEAS) and androstenedione (ADT) were determined using Immulite kits (Diagnostic Systems Laboratories Inc, Webster Texas, USA). The results obtained in Arab men were compared with those reported for similarly aged Chinese, German and White USA men. In all four ethnic groups, median TT and FAI declined with age, while SHBG increased with age. However, the mean TT and SHBG was significantly lower (p < 0.01) and the FAI significantly higher in Arab men (p < 0.01) compared to German men only in 21-30 years age group. In the other age groups the levels of TT and SHBG were higher in the Germans but the differences were not statistically significant. In all the racial groups serum levels of DHEAS and ADT reached a peak by about 20 years of life, and then declined progressively. The mean DHEAS in American Caucasians aged 20-29 years was 11.4 micromol/l compared to 6.22 micromol/l in the Arabs (p < 0.001). The mean DHEAS in USA Caucasians aged 70-79 years was 2.5 micromol/l compared to 1.8 micromol/l (p < 0.03) in the Arabs. There was no significant difference in mean serum levels of DHEAS between German and USA men. Similarly, there was no significant difference in the level of the hormones between Arab and Chinese men. Arab men with newly diagnosed prostate cancer had high serum TT, SHBG and DHEAS compared to those without the disease. The mean TT and SHBG was significantly lower in Arab men compared to Caucasian men especially in early adulthood. Caucasians have significantly higher serum levels of the precursor androgens DHEAS and ADT especially in early adulthood compared to Arab men. These observations of low circulating androgens and their adrenal precursors in Arab men may partially account for the decreased risk for prostate cancer among Arab men.

Low serum dehydroepiandrosterone sulfate concentration is a predictor for deterioration of urinary albumin excretion in male patients with type 2 diabetes

We recently found that serum dehydroepiandrosterone sulfate (DHEA-S) concentration correlated inversely with the degree of urinary albumin excretion in a cross-sectional study. We therefore performed an observational study to investigate the relationship between serum DHEA-S concentrations and changes in urinary albumin excretion in male patients with type 2 diabetes to answer the question as to whether DHEA is a causal rather than simply coincidental intermediate linking urinary albumin excretion to cardiovascular disease (CVD). The relationship between serum DHEA-S concentration and changes in urinary albumin excretion was investigated in 207 consecutive male patients with type 2 diabetes. Baseline serum DHEA-S concentration and urinary albumin excretion were measured in 2003. After 12 months, urinary albumin excretion was measured and any changes in urinary albumin excretion were calculated. Patients were divided into tertiles according to DHEA-S concentration. Greater changes in urinary albumin excretion were seen in patients with low DHEA-S concentration (29.6 ± 7.6 mg/g creatinine) than in patients with high DHEA-S concentration (5.1 ± 3.6 mg/g creatinine, P = 0.0091). An inverse correlation was observed between serum DHEA-S concentration and changes in urinary albumin excretion ( r = −0.193, P = 0.0052). Multiple regression analysis demonstrated that HbA1c ( β = 0.241, P = 0.0009), and serum DHEA-S concentration ( β = −0.195, P = 0.0054) were independent determinants of changes in urinary albumin excretion. In conclusion, serum DHEA-S concentration was inversely correlated with changes in urinary albumin excretion, which may indicate causality in the increased CVD mortality in male patients with type 2 diabetes and low DHEA-S concentration.

CYP17 genotype predicts serum hormone levels among pre-menopausal women

CYP17, which encodes cytochrome P450c17alpha, mediates both steroid 17alpha-hydroxylase and 17,20-lyase activities, and is essential for the production of glucocorticoids and sex steroids. There is evidence that a common polymorphism in CYP17 (T27C) is associated with estrogen levels, making it a potential marker of disease risk. This is the first study to examine the relationship between CYP17 and estradiol (E2) using serum sampled exclusively from the early follicular phase of the menstrual cycle. We assessed the relationship between CYP17 and serum hormone levels, menstrual cycle length, bleed length, and age at menarche in 164 pre-menopausal women. Among women with body mass index (BMI) < or =25 kg/m2, those with the TC and CC genotypes had 19 and 42% higher E2 (P for trend 0.007) and 14 and 30% higher dehydroepiandrosterone sulphate respectively (P for trend 0.10) than women with the TT genotype. Androstenedione levels did not differ between genotypes. Among women with BMI >25 kg/m2, hormone levels did not differ by genotype. Women with the C allele were also more likely to have menstrual cycle lengths <27 days [odds ratio (OR) for TC=2.36, 95% confidence interval (CI)=1.24-4.52; OR for CC=5.59, 95% CI=1.53-20.43 compared to TT]. CYP17 genotype was not associated with menstrual bleed length or age at menarche. The CYP17 T27C polymorphism may be a marker of endocrine function.

The Early Dehydroepiandrosterone Sulfate Rise of Adrenarche and the Delay of Pubarche Indicate Primary Ovarian Failure in Turner Syndrome

Girls with Turner syndrome provide the first human model in which adrenal puberty (adrenarche) takes place without gonadal puberty. A wide range of serum dehydroepiandrosterone sulfate (DHEAS) concentrations has been observed, ranging from normal to very elevated. This study attempted to determine whether the course of adrenarche and pubarche is independent of ovarian function. A total of 867 serum DHEAS estimates were made over time in 111 girls with Turner syndrome. Puberty began spontaneously in 22 of these girls, whereas 45 had primary ovarian failure (POF). Serum DHEAS levels were compared with those of 322 healthy girls 3 to 17 years of age. POF was defined as a lack of spontaneous breast development and at least 1 follicle-stimulating hormone (FSH) level of 50 IU/L or higher before estrogen replacement therapy. Age-related serum concentrations of DHEAS were significantly higher in girls with Turner syndrome than in control girls from ages 7 to 17 years. Those with POF had significantly higher age-related levels than did girls experiencing spontaneous puberty at ages 9 to 15 years. Adrenarche occurred at a median age of 8.3 years in girls with POF, compared with 10.5 years for girls with spontaneous puberty and 11 years in normal girls. In both groups with Turner syndrome, mean DHEAS levels correlated closely with mean FSH and luteinizing hormone levels. Pubarche was delayed in girls with POF despite their high serum DHEAS levels. Puberty occurred more than 4.5 years after adrenarche, at a median age of 13 years, in girls with Turner syndrome, whereas in girls with spontaneous puberty, the interval was 1.4 years and the median age at pubarche was 11.9 years. These findings indicate that normally timed adrenarche depends on gonadal function. Normal pubarche represents the conversion of DHEAS to active androgens in the ovaries. Premature adrenarche and pubarche in an otherwise healthy girl may be the first clinical sign of functionally defective ovaries.

Stability of Adrenocortical Steroidogenesis over Time in Healthy Women and Women with Polycystic Ovary Syndrome

Adrenocortical secretion is up-regulated in women with polycystic ovary syndrome (PCOS), and absolute adrenal androgen (AA) excess is evident in approximately 25% of these patients. We hypothesized that AA biosynthesis is an inherited trait and that, as for other inherited traits, AA biosynthesis remains stable over time. To test this hypothesis, we prospectively studied 23 off-treatment PCOS patients and seven age- and body mass index-matched control women on two separate occasions 3-5 yr apart (45.0 +/- 19.0 months and 47.4 +/- 21.3 months, respectively; P > 0.05). All subjects underwent an acute adrenal stimulation using 0.25 mg ACTH-(1-24), and dehydroepiandrosterone (DHEA), androstenedione, and cortisol (F) were measured 0 and 60 min post ACTH; basal levels of total and free testosterone (T), SHBG, and DHEA sulfate (DHEA-S) were also assessed. Among PCOS patients, the mean DHEA-S levels during the repeat study were significantly lower when compared with the initial assessment (170 +/- 107 microg/dl vs. 134 +/- 79 microg/dl, respectively; P = 0.02). However, only patients with initial DHEA-S levels above the median (high DHEA-S) experienced a net decrease in the levels of this metabolite (252.5 +/- 99.2 microg/dl vs. 174.3 +/- 82.5 microg/dl; P = 0.001) over the time of the study; patients with initial DHEA-S levels in the lower half (low DHEA-S) did not experience a change in DHEA-S (94.6 +/- 28.9 microg/dl vs. 97.7 +/- 56.5 microg/dl; P = 0.85). In patients, the total T levels tended to be higher at the second study, although SHBG levels were also higher, resulting in unchanged free T levels over time. Among controls, no significant changes in basal androgens were observed over the time of the study. There were no significant differences in either the basal or ACTH-stimulated levels of DHEA, androstenedione, or F over the time of the study in either PCOS or control women. We conclude that the adrenocortical secretion of AAs or F in PCOS and control women remains stable over time, supporting the hypothesis that the adrenal response to ACTH may be an inherited trait. Alternatively, a decrease in DHEA-S levels over time was observed but only among PCOS patients whose initial levels of this metabolite were above the group median, suggesting that the activity of sulfotransferase in these patients may be up-regulated by factors other than those affecting adrenocortical biosynthesis and that such regulatory influences attenuate over time.

Adrenal and gonadal steroidogenesis in patients with ovarian polycystosis during buserelin test

Relationships between the secretion of gonadotropic hormones of the pituitary gland, the androgenic and glucocorticoidal functions of the adrenals and the steroidogenic function of the ovaries were studied in 21 patients with the ovarian polycystic syndrome (OPS) and in 7 healthy women in test with buserelin, a gonadotropin-releasing agonist. When stimulated with corti- sole, the secretion remained unchanged. Depending on the baseline level of dehydroepiandrosterone sulfate (DHAS), a change was found in the secretion of dehydroepiandrosterone (DHA) and its precursor 17-OH-pregnenolone. With the nor­mal baseline level of DHAS, the content of hormones increases while with its high level, their content does not change. The stimulation of gonadotropic secretion results in a higher disso­ciation in the secretion of luteinizing hormone (LH) and folli­cle-stimulating hormone (FSH) in patients with OPS, by in­creasing the LH/FSH ratio that is most significant in patients with the normal level of DHAS. Under stimulation, aromatase activity becomes higher in patients with high DHAS levels and remains unchanged in the other group of patients. The findings may lead to the conclusion that buserelin-induced stimulation of gonadotropic secretion may be accompanied by the activated synthesis of adrenal androgens in some patients with OPS. De­pending on the baseline androgenic activity of the adrenals, buserelin-induced stimulation of gonadotropic secretion is at­tended by a higher aromatase activity.

Relationships between hormonal status and cataract in french postmenopausal women: the POLA study.

Prevalence rate of cataract is higher in women than in men. Sex hormones have been hypothesized to be linked with this gender difference. Our aim is to study the relationships between hormonal status and cataract in postmenopausal women. The Pathologies Oculaires Liées à l'Age (POLA) study is a population-based study on age-related eye diseases and their risk factors, in 2584 residents of Sète (France). Cataract classification was based on a standardized lens examination, according to Lens Opacities Classification System III. Biological measurements were performed from fasting blood samples. We conducted a cross-sectional study in the female participants (n=1451) aged over 60 years. No association of hormone replacement therapy (HRT) with any type of cataract was found, but an increased risk of cataract surgery was observed in women with a long duration of hormone therapy >/=5 years) (multivariate-adjusted odds ratio (OR)=3.80; 95% CI: 1.45-9.94). Globally, the risk for cataract (any type) was not associated with a long duration of HRT use (OR=1.06; 95% CI: 0.64-1.74). After multivariate adjustment, oophorectomy was associated with a reduced risk of cataract (OR=0.60; 95% CI=0.38-0.94). In the multivariate model, no association was found between estradiol, total testosterone or sex-hormone-binding globulin and cataract. However, high levels of dehydroepiandrosterone sulfate (DHEAS) were associated with a reduced risk of cataract (OR=0.79; 95% CI: 0.63-0.99). HRT use was not associated with cataract. A reduced risk of cataract was found in oophorectomized women and in women with high DHEAS levels.

The effect of high dehydroepiandrosterone sulfate levels on tamoxifen blockade and breast cancer progression

Background We investigated the stimulatory potential of dehydroepiandrosterone sulfate (DHEA-S) on tamoxifen-treated cells and assessed its effect on cancer progression in the adjuvant setting. Methods Mean serial serum levels of sex hormones from 44 patients receiving tamoxifen were correlated with follow-up status. T-47D (ER+/PR+) and HCC1937 (ER−/PR−) breast cancer cells were pretreated with 100 μM anastrozole, with or without tamoxifen, and stimulated with 22.8 μM DHEA-S. Rapid colorimetric assays allowed calculation of growth percent change. Results Clinically, development of metastatic disease correlated only with ≥90 μg/dL DHEA-S ( P = 0.005). In vitro, T-47D cells stimulated with DHEA-S after anastrozole showed 35% increased growth. Addition of 0.01 nM tamoxifen demonstrated −7% inhibition. Increasing the DHEA-S/tamoxifen ratio reversed suppression to +25%. Conclusions DHEA-S ≥90 μg/dL is a risk factor for recurrence in the adjuvant setting. In vitro, although tamoxifen inhibits cell growth at high doses it can be circumvented by DHEA-S. These results indicate that DHEA-S contributes to tamoxifen resistance and disease progression.

Relationship of Insulin Resistance and Overweight with Cortisol and Dehydroepiandrosterone-Sulfate Levels

Background Our objective was to assess the relationship of hormones such as cortisol and dehydroepiandrosterone-sulfate (DHEA-S) with insulin resistance and overweight. Methods We designed and conducted a cross-sectional, observational survey consisting of home visits within a previously defined area of Mexico City. The study included 303 apparently healthy volunteers from a middle-class socioeconomic urban community. We measured glucose, cholesterol, triglycerides, insulin, cortisol, and DHEA-S. Insulin resistance (IR) was defined as belonging to the first quartile of fasting glucose/insulin ratio (G/IR) distribution or fourth quartile of IR (HOMA). Overweight was defined as body mass index (BMI) ≥25 kg/m 2. Results To predict IR in women ≤35 years of age, principal component analysis (PCA) disclosed three components: 1) cholesterol, BMI, and diastolic blood pressure (DBP); 2) cholesterol, triglycerides, and cortisol, and 3) dehydroepiandrosterone-sulfate [DHEA-S]. Solely the latter (DHEA-S) was significantly associated with IR (odds ratio [OR] = 1.80, confidence interval 95% [CI 95%] 1.11–2.91, p = 0.015). For men ≤35 years of age, there were two components: 1) cholesterol, triglycerides, BMI, and DBP, and 2) DHEA-S, cholesterol, and cortisol. Component 1 was significantly associated with IR (OR = 5.65; CI 95% 1.62–19.65, p = 0.006). To predict overweight in women >35 years of age, there were three components, including 1) cholesterol and triglycerides, 2) cortisol, and 3) DHEA-S and G/IR. Component 2 was significantly associated with overweight (OR = 0.38, CI 95% 0.23–0.64, p = 0.000). Conclusions In women ≤35 years of age, high DHEA-S levels were associated with insulin resistance, which suggests that in young women DHEA-S exerts anti-estrogenic action, perhaps caused by its competitive binding with the estrogen receptor. Additionally, in women >35 years of age, low cortisol levels were associated with overweight. These associations were not identified for the male subgroup.

Monkey in the Middle

Beware, food-loving humans: Proof of calorie restriction's life-extending effects is approaching your species. A new study suggests that dieting rhesus monkeys live twice as long as normal and identifies three physiological changes shared between the primates and enduring humans. Calorie restriction is the only treatment that consistently prolongs the lives of numerous species, from yeast to mice. Whether the regime works in humans remains unclear, in part because a study that measures any intervention's effect on human life-span would be prohibitively expensive and time-consuming (see Walford et al. abstract and comments ). To circumvent that problem, scientists seek physiological parameters--or biomarkers--that provide surrogate measures of aging (see Miller Perspective ). Such biomarkers would likely maintain youthful concentrations in long-lived creatures. In the new work, gerontologist George Roth of the National Institute on Aging (NIA) in Baltimore, Maryland, and colleagues tested whether biomarkers of calorie-restricted monkeys also characterize long-lived humans. For 5 years, Roth's team has fed 30 rhesus monkeys 30% fewer calories than controls. Preliminary data add to previous evidence that calorie restriction works in primates: To date, 13% of the treated animals and 24% of the controls have perished. Although not statistically significant, the results suggest that calorie-restricted monkeys die at half the rate of normal animals. Roth's team previously showed that body temperatures and insulin concentrations of the calorie-restricted monkeys hover well below normal, consistent with observations of dieting mice and rats. For their age, the monkeys also harbor large amounts of dehydroepiandrosterone sulfate (DHEAS), a steroid hormone with an uncertain role in aging whose amounts decline with age. To investigate whether these biomarkers also correlate with longevity in people, the scientists analyzed data gathered as part of the Baltimore Longitudinal Study of Aging (BLSA), the world's longest running study of human aging. Among deceased human males, those who lived longer tended to have lower body temperatures and insulin concentrations and higher DHEAS concentrations. No one knows how calorie restriction works, but recent evidence suggests that it causes organisms to shift metabolic strategies (see "High-Octane Endurance--Yeast in the Metabolic Fast Lane Live Longer" ). The monkeys' low body temperatures mean that their metabolism is producing less heat than normal, so "a lower body temperature is a symptom of metabolic change," says Roth. In addition, reduced insulin concentrations could curb signaling pathways that normally trigger growth at the expense of longevity, he proposes. "This paper is a clever marriage of two NIA data sets [BLSA and rhesus] that advances the knowledge of aging in primates," says gerontologist Richard Weindruch of the University of Wisconsin, Madison. Next, says zoologist Steven Austad of the University of Idaho in Moscow, researchers will need to "determine whether these are general biomarkers or just a quirk of the data set." Numbers already available from studies similar to BLSA, but with fewer subjects, could answer the question quickly, he adds. If the results hold up, they could help scientists identify physiological changes that extend life. Gourmets shouldn't immediately renounce their Port Salut and profiteroles, but they might want to brace their bellies for the possibility. --Bijal P. Trivedi G. S. Roth, M. A. Lane, D. K. Ingram, J. A. Mattison, D. Elahi, J. D. Tobin, D. Muller, E. J. Metter, Biomarkers of caloric restriction may predict longevity in humans. Science 297 , 811 (2002). [Full Text]

Elevated dehydroepiandrosterone sulfate levels as the reproductive phenotype in the brothers of women with polycystic ovary syndrome.

There is an inherited susceptibility to polycystic ovary syndrome (PCOS). Some investigators have suggested that premature male-pattern balding is a male phenotype in PCOS families, but this remains controversial. We recently reported evidence for an autosomal monogenic abnormality in ovarian and adrenal steroidogenesis in the sisters of women with PCOS. We performed this study to determine whether we could identify a clinical or biochemical phenotype in the brothers of women with PCOS. One hundred nineteen brothers of 87 unrelated women with PCOS and 68 weight- and ethnicity-comparable unrelated control men were examined and had fasting blood samples obtained. The odds of balding (Hamilton score > or = V) did not differ in the brothers of PCOS women compared with control men. Brothers of women with PCOS had significantly elevated dehydroepiandrosterone sulfate (DHEAS) levels [brothers 3035 +/- 1132 ng/ml (mean +/- SD) vs. control men 2494 +/- 1172 ng/ml; P < 0.05]. There was a significant positive linear relationship between DHEAS levels in PCOS probands and their brothers (r = 0.35; P = 0.001). There was no significant bimodal distribution in DHEAS levels, and there were no significant differences in other parameters in brothers of PCOS women with high DHEAS levels compared with those with low DHEAS levels. There is familial clustering of elevated DHEAS levels in the brothers of women with PCOS, suggesting that this is a genetic trait. This might reflect the same underlying defect in steroidogenesis that we found in the sisters of women with PCOS. Balding was not increased in the brothers of women with PCOS. We conclude that there is a biochemical reproductive endocrine phenotype in men in PCOS families.

Prospective measurements of dehydroepiandrosterone sulfate in a cohort of elderly subjects: relationship to gender, subjective health, smoking habits, and 10-year mortality.

The decrease with age of the adrenal-secreted dehydroepiandrosterone sulfate (DHEAS) in serum has suggested that it may be causally related to longevity. For the PAQUID [People (Personnes) Aged (Agées) About What (Quid, in Latin)] cohort of elderly subjects, we have previously reported higher DHEAS in men than in women, a decrease with age and, among men, a negative correlation between the DHEAS level and mortality at 2 and 4 years. Here, with an 8-year followup in 290 subjects, we show a global decrease of 2.3% per year for men and 3.9% per year for women. However, in approximately 30% of cases, there was an increase of DHEAS. We observed no relationship between the evolution of DHEAS level and functional, psychological, and mental status, possibly because of selection by death. In women, no association was found between mortality and DHEAS level. In men, the relative risk (RR) of death was higher for the lowest levels of DHEAS (RR = 1.9, P = 0.007), with RR = 6.5, P = 0.003 for those under 70 years old, a result indicating heterogeneity of the population. There was an effect of subjective health on mortality that disappeared after adjustment of DHEAS levels, suggesting its relation with these DHEAS levels. Death RR was much higher in smokers with a low DHEAS level than in nonsmokers with high DHEAS (RR = 6.7, P = 0.001). We submit that the involvement of DHEAS is possibly different according to gender, that association between low DHEAS level and mortality only for men under 70 years old possibly reflects heterogeneity of the population, and that DHEAS level is a reliable predictor of death in male smokers.

Human resistance to Plasmodium falciparum increases during puberty and is predicted by dehydroepiandrosterone sulfate levels.

Immunity to Plasmodium falciparum develops slowly in areas of endemicity, and this is often ascribed to poorly immunogenic or highly variant parasite antigens. However, among populations newly exposed to malaria, adults acquire immunity more rapidly than children. We examined the relationship between pubertal development and resistance to P. falciparum. During two transmission seasons in western Kenya, we treated the same cohort of young males to eradicate P. falciparum and then obtained blood smears each week for 4 months. We determined pubertal development by Tanner staging and by levels of dehydroepiandrosterone sulfate (DHEAS) and testosterone in plasma. In multivariate and age-stratified analyses, we examined the effect of pubertal development on resistance to malaria. In both seasons (n = 248 and 144 volunteers, respectively), older males were less susceptible than younger males. Age-related decreases in the frequency and density of parasitemia were greatest during puberty (15- to 20-year-olds). DHEAS and testosterone were significant independent predictors of resistance to P. falciparum parasitemia, even after accounting for the effect of age. Fifteen- to 20-year-old males with high DHEAS levels had a 72% lower mean parasite density (P<0.01) than individuals with low DHEAS levels. Similarly, 21- to 35-year-old males with high DHEAS levels had a 92% lower mean parasite density (P<0.001) and 48% lower frequency of parasitemia (P<0.05) than individuals with low DHEAS levels. These data suggest that the long period needed to attain full immunity could be explained as a consequence of host development rather than as the requirement to recognize variant or poorly immunogenic parasite antigens.

Adrenal hyperandrogenism in adolescent girls with a history of low birthweight and precocious pubarche.

Girls with precocious pubarche (PP) are at increased risk for ovarian dysfunction, hyperinsulinism and dyslipidaemia in adolescence, in particular when PP is preceded by reduced fetal growth. However, it is not known whether PP girls still have adrenal hyperandrogenism after puberty and if so, which fraction of PP girls develops so-called functional adrenal hyperandrogenism (FAH), an entity characterized by ACTH-dependent 17-ketosteroid excess. Data were longitudinally collected from 47 girls with PP: at birth (weight for gestational age), at diagnosis of PP (age 6.7+/- 1.1 years) and in adolescence (age 15.0+/-1.9 years). Serum dehydroepiandrosterone sulphate (DHEAS) and androstenedione were measured at PP diagnosis, as well as the 17-hydroxyprogesterone (17-OHP) response to ACTH; postpubertal evaluation included assessment of adrenal and ovarian function, and of insulin responses to a glucose load. PP girls were considered to have FAH in adolescence if both DHEA and androstenedione responses to ACTH were excessive (> 1500 ng/dl and > 350 ng/dl, respectively). At diagnosis of PP, girls had high DHEAS and androstenedione levels, as well as high 17-OHP responses to ACTH. In adolescence, PP girls had a normal BMI, presented with mild hirsutism and had high baseline and post-ACTH concentrations of most adrenal androgens, low SHBG levels and tended to have hyperinsulinemia and to present biological signs of ovarian hyperandrogenism. More than a third of the PP cohort developed FAH in adolescence. Neither baseline DHEAS, androstenedione, nor post-ACTH 17-OHP values at diagnosis of PP predicted the development of FAH in adolescence. In PP girls, only a low weight at birth was found to be significantly associated with subsequent FAH. These longitudinal findings in girls with PP point to the possibility of an endocrine sequence of prenatal onset: low weight at birth, PP in childhood and adrenal hyperandrogenism in adolescence. The pathophysiological mechanisms underpinning this newly recognized sequence remain to be identified.

Endogenous androgens and carotid intimal-medial thickness in women.

The influence of endogenous androgens on atherosclerotic disease in women is unknown. In this study involving 101 pre- and post-menopausal females, we evaluated the relationship between serum androgen levels and both carotid artery intimal-medial thickness (IMT) and major cardiovascular risk factors. In addition to evaluation of blood pressure, body mass index, and waist-to-hip ratio, serum dehydroepiandrosterone sulfate (DHEA-S), androstenedione (A), total testosterone (TTS), free testosterone (FTS), insulin, cholesterol (total and high density lipoproteins), triglycerides, and glucose were measured. All women underwent carotid ultrasonography. Spearman correlation coefficients showed that serum DHEA-S and A levels were negatively related (P < 0.03-0.0004) to several IMT measures. Higher tertiles of DHEA-S, A, and FTS corresponded to significantly lower measures of carotid thickness. DHEA-S, and all androgens were inversely related to age (P < 0.03 or less), showing no unfavorable association with major cardiovascular risk factors. In contrast, serum DHEA-S was negatively associated with WHR (P < 0.02), while A was negatively associated with body mass index (P < 0.02). Stepwise multiple regression analysis indicated that A and FTS showed an inverse association with IMT measures (P < 0.05-0.001). In conclusion, our data indicate that in women serum DHEA-S and androgens decline with age and that normal hormonal levels are not associated with major cardiovascular risk factors. They also show that higher DHEA-S and androgen concentrations are related to lower carotid wall thickness; for A this association is independent of cardiovascular risk factors. Our results suggest that, in the physiological range, DHEA-S and androgens in women are correlated with lower risk of carotid artery atherosclerosis.

Decrease in the expression of the 3beta-hydroxysteroid dehydrogenase gene in human adrenal tissue during prepuberty and early puberty: implications for the mechanism of adrenarche.

Adrenarche is the increase of adrenal androgen secretion, mainly dehydroepiandrosterone and dehydroepiandrosterone sulfate, that occurs during prepuberty in higher primates. This event takes place at about 6-8 y of age in humans. It had been postulated that adrenarche might reflect an increase in the 17,20 lyase:17OH-ase activity ratio of microsomal cytochrome P450c17. However, studies to demonstrate this mechanism have been unsuccessful. Because it has been described that virilizing adrenocortical carcinomas have high dehydroepiandrosterone sulfate secretion and low 3beta-hydroxysteroid dehydrogenase (3betaHSD) activity, in this study we evaluated the possible existence of maturative changes of the level of 3betaHSD type II mRNA in 11 normal prepubertal and early pubertal human adrenals. Adrenal glands from subjects aged 0.1 to 13 y were obtained from organ donors, patients undergoing resection of the kidney for renal neoplasms or necropsies with less than 6 h of postmortem time. The expression of 3betaHSD type II gene was studied by dot blot in all samples and by relative reverse transcriptase (RT)-PCR in nine samples. The size of the transcripts was evaluated by Northern blot. Hybridization was performed using labeled human 3betaHSD cDNA probes. The uniformity of loading was tested using labeled human beta actine cDNA. The relative intensities of hybridization signals were quantified by scanning densitometry. The expected bands after relative RT-PCR were eluted, and radioactivity was measured in a scintillation counter. For the analysis of the results, subjects were divided into two groups as a function of age: group 1, less than 8 y (n = 6; range 0.1-2.48 y) and group 2, equal or older than 8 y (n = 5; range 8-13 y). 3BetaHSD type II mRNA expression, analyzed by dot blot and relative RT-PCR, was significantly higher (p < 0.05) in group 1 (median and range 4.99, 0.50-8.00 and 16.3, 13.5-40.0 arbitrary units, respectively) than in group 2 (0.15, 0.12-0.75 and 5.66, 3.18-13.0, respectively). In conclusion, we have shown a decrease of the expression 3betaHSD type II gene as a function of age in prepubertal and early pubertal normal human adrenal tissue. This maturative change might be involved in the mechanism of human adrenarche.

Dehydroepiandrosterone Sulfate (DHEA-S) and Psychiatric and Laboratory Measures of Frailty in a Residential Care Population

Previous reports have found low levels of dehydroepiandrosterone sulfate (DHEA-S) in association with frailty in elderly patients. The mechanisms underlying these associations are not known. Therefore, psychiatric symptoms and disorders that are common in frail elderly patients were correlated with DHEA-S levels in a convenience sample selected from a nursing home population. Low DHEA-S levels were associated with high degrees of self-rated disability and insomnia. In women, low DHEA-S levels were also associated with increased numbers of pain sites. However, cognitive impairment was associated with higher DHEA-S levels in women. Thus, in frail elderly patients, there are contradictory relationships between DHEA-S and neuropsychiatric measures of frailty (cognitive impairment, disability, insomnia, and number of pain sites), and there may also be gender differences in these relationships.

Specificity improvement of a recombinant anti-testosterone Fab fragment by CDRIII mutagenesis and phage display selection.

The monoclonal antibodies so far developed by hybridoma technology have not had high enough specificity or affinity to distinguish the closely related steroid hormones in routine clinical assays. We have employed random mutagenesis and phage display approaches to improve the specificity of one anti-testosterone monoclonal antibody (3-C4F5). The affinity of the antibody is 0.3 x 10(9) M(-1) and the cross-reactivities with most of the related steroids are low. However, the antibody cross-reacts about 1% with dehydroepiandrosterone sulfate (DHEAS) and owing to the high DHEAS serum concentration this is about 1000-fold too high for clinical immunoassays. The complementarity-determining regions (CDRs) of the heavy and light chains, which were predicted by molecular modelling to be in close contact with the testosterone (TES) ligand, were randomized and mutant Fab libraries were cloned into a phagemid vector. Binders were selected by a competitive panning procedure. By combining the identified light and heavy chain CDRIII mutations the TES affinity was preserved at the wild-type level but DHEAS cross-reactivity was decreased to 0.03%. An important finding was that by the competitive panning procedure the overall binding specificity of the 3-C4F5 antibody was refined, since the cross-reactivities to related steroids were also significantly decreased in the combined mutant.