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1.  Androstenediol Complements Estrogenic Bioactivity during the Menopausal Transition 
Menopause (New York, N.y.)  2012;19(6):650-657.
Objective
The perimenopausal increase in circulating dehydroepiandrosterone sulfate (DHEAS) levels during the menopausal transition (MT) is accompanied by other adrenal steroids that have the potential to alter the estrogen/androgen balance and explain the wide inter-woman range of estrogen-related symptoms experienced during the MT.
Methods
Annual serum samples from the Study of Women’s Health Across the Nation (SWAN), which had previously been analyzed for immunoreactive estradiol (E2), testosterone (T), DHEAS and sex hormone binding globulin (SHBG), were selected based on DHEAS concentration and analyzed for immunoreactive and bioactive estrogens and androgens, including immunoreactive androstenedione (Adione), dehydroepiandrosterone (DHEA) and 5-androstene-3β,17β-diol (androstenediol, Adiol).
Results
A two-fold increase in circulating Adione and T was found to rise in parallel with the rise in circulating DHEAS, while DHEA and Adiol concentrations rose seven to eightfold. Circulating Adiol, which has both androgenic and estrogenic biological activity, was significantly associated (p<0.02) with circulating estrogen bioactivity only when E2 concentrations were low and Adiol levels were high.
Conclusions
The wide range of circulating levels of Adiol and its contribution to total circulating estrogenicity during the MT is consistent with the observed inter-woman difference in symptoms at this time. Therefore, we conclude that Adiol contributes to circulating estrogenicity when E2 production falls at menopause and may contribute significantly to the endocrine changes experienced by midlife women.
doi:10.1097/gme.0b013e31823df577
PMCID: PMC3366061  PMID: 22415563
Androstenediol; estrogenicity; menopause; adrenal
2.  Dehydroepiandrosterone sulfate (DHEAS) levels reflect endogenous LH production and response to human chorionic gonadotropin (hCG) challenge in the older female macaque (Macaca fascicularis) 
Menopause (New York, N.Y.)  2013;20(3):329-335.
Hypothesis
We propose that the adrenal gland of an older higher primate female animal model will respond to a human chorionic gonadotropic (hCG) hormone challenge by secreting additional dehydroepiandrosterone sulfate (DHEAS). Such a response in surgically and chemically-castrated animals will provide proof-of-concept and a validated animal model for future studies to explore the rise of DHEAS during the menopausal transition of women.
Methods
Twenty four 18–26 y/o female cynomolgus monkeys were screened for ovarian function then either ovariectomized (n=4) or treated with a gonadotropic releasing hormone agonist (GnRHa) (n=20) to block ovarian steroid production. Following a recovery period from surgery or down-regulation, a single dose challenge (1,000 IU; IM) of human chorionic gonadotropin (hCG) was then administered in order to determine if LH/CG could accelerate circulating DHEAS production. Serum DHEAS, bioactive LH and urinary metabolites of ovarian sex steroids were monitored before, during and following these treatments.
Results
Circulating LH bioactivity and immunoreactive DHEAS concentrations were suppressed in all animals 14 days post administration of GnRHa. Urinary metabolites of estradiol and progesterone remained low following surgery or the flare reaction to GnRHa. Circulating DHEAS levels were increased following hCG administration and the increase in individual animals was proportional to the pre-treatment DHEAS baseline. Circulating DHEAS concentrations were positively correlated to endogenous LH bioactive concentrations prior to, and were increased by hCG challenge while no concomitant change was observed in ovarian steroid hormone excretion.
Conclusion
These data demonstrate a positive adrenal androgen response to LH/CG in older female higher primates and suggests a mechanism for the rise in adrenal androgen production during the menopausal transition in women. These results also illustrate that the nonhuman primate animal model can be effectively used to investigate this phenomenon.
doi:10.1097/GME.0b013e3182698f80
PMCID: PMC3546135  PMID: 23435031
DHEAS; menopause; adrenal androgens; LH/hCG
3.  Menopausal Transition Stage-Specific Changes in Circulating Adrenal Androgens 
Menopause (New York, N.y.)  2012;19(6):658-663.
Objective
It is now recognized that mean circulating DHEAS concentrations in most midlife women exhibit a positive inflection starting in the early perimenopause, continuing through the early post menopause and returning to early perimenopausal levels by late post menopause. This rise in mean DHEAS is accompanied by concomitant rises in testosterone (T), dehydroepiandrosteone (DHEA), androstenedione (Adione), and an equal rise androstenediol (Adiol). These observations suggest that there is a specific relationship between the circulating levels of steroids emanating from the adrenal, declining ovarian function and stages of the menopausal transition (MT). This study was designed to test the hypothesis that the menopausal stage-specific change in circulating DHEAS is associated with concomitant changes in the circulating pattern of adrenal steroids and that some of these adrenal androgens could influence the circulating estrogen/androgen balance.
Methods
Stored annual serum samples (n=120) were first selected to represent four longitudinal DS profiles of individual women in order to assess and compare changes in the adrenal contribution to circulating steroids.
Results
Changes in mean circulating DHEAS levels in midlife women during the MT is associated with changes in mean circulating Testosterone (T), androstendione (Adione), and androstenediol (Adiol). Mean Adione and T concentrations changed the least while mean DHEAS and Adiol changed the most.
Conclusion
Changes in circulating steroid hormone emanating from the adrenal during the menopausal transition may be more important than the decline of ovarian function in terms of altering the estrogen/androgen balance.
doi:10.1097/gme.0b013e31823fe274
PMCID: PMC3366025  PMID: 22415570
DHEAS; androstenediol; estrogen; estrogenicity; menopause; adrenal
4.  Modulation of Higher Primate Adrenal Androgen Secretion with Estradiol or Estradiol and Progesterone Intervention 
Menopause (New York, N.Y.)  2013;20(3):10.1097/GME.0b013e318273a070.
Background
Circulating adrenal steroids rise during the menopausal transition (MT) in most mid-aged women and may contribute to differences in between-woman symptoms as well as ultimate health outcomes. However, the mechanism(s) for this shift in adrenal steroid production in mid-aged women is not known.
Objective
To determine if hormone replacement therapy (HT) for one year can modulate adrenal androgen production.
Method
Younger (9.8 +/− 0.4 y/o, n=20) and older (22.7+/−0.4 y/o, n=37) female laboratory macaques were ovariectomized (OVX), and then each group was treated with different regimens of HT for up to one year. Changes in adrenal histology and circulating adrenal androgens were monitored following estradiol treatment alone (E) or estrogen plus progesterone (E+P), and these changes were compare to the same measures in similar aged animals given vehicle (V).
Results
Zona reticularis (ZR) area and serum dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) were higher in younger compared to older V-treated animals (P< 0.02). Both E and E+P treatments decreased circulating DHEAS in the younger group (P<0.05). While E also decreased DHEAS in the older group, this was not statistically significant. In contrast, E+P treatment in the older group resulted in a rise in DHEAS over V, which was significantly higher than the results of E alone (p< 0.01). Circulating concentrations of DHEA exhibited similar trends but these changes did not reach statistical significance.
Conclusion
These data demonstrate that intervention with ovarian steroids can modulate adrenal androgen production in female higher primates and that both animal age and type of HT regimen determines the adrenal response.
doi:10.1097/GME.0b013e318273a070
PMCID: PMC3610787  PMID: 23435030
Adrenal; Steroids; Hormone Therapy; Replacement
5.  Circulating levels of monocyte chemoattractant protein-1 and interleukin-7 in women who have undergone bilateral salpingo-oophorectomy 
Purpose
The aim of the study reported here was to determine the effect of surgical menopause by bilateral salpingo-oophorectomy (BSO) on circulating levels of cytokines and chemokines related to the pathogenesis of atherosclerosis.
Patients and methods
A total of 110 women were recruited for this study from the outpatient clinic of our facility. We divided the women into three groups: 1) women with a regular menstrual cycle, 2) women in whom less than 5 years had passed since their BSO, and 3) women in whom 5 years or more had passed since their BSO. Concentrations of nine cytokines and chemokines in serum were measured.
Results
The serum monocyte chemoattractant protein-1 (MCP-1) level in women in whom less than 5 years had passed since their BSO was significantly higher than in women with a regular menstrual cycle (P<0.05). There were significant differences in serum interleukin (IL)-7 among the three groups (P=0.035). MCP-1 showed a significant positive correlation (r=0.320, P=0.008) with follicle-stimulating hormone in women with a regular menstrual cycle and in women in whom less than 5 years had passed since their BSO.
Conclusion
A hypoestrogenic state due to BSO induced changes in MCP-1 and IL-7 levels. MCP-1 level showed a significant increase in the early period after BSO, while IL-7 level showed a significant decrease in the late period after BSO.
doi:10.2147/JIR.S52728
PMCID: PMC3881980  PMID: 24399882
follicle-stimulating hormone; cytokines; chemokines; hypoestrogenism; surgical menopause
6.  EFFECT OF BILATERAL OOPHORECTOMY ON ADRENOCORTICAL FUNCTION IN WOMEN WITH POLYCYSTIC OVARY SYNDROME (PCOS) 
Fertility and sterility  2012;99(2):599-604.
Objective
To determine the impact of ovary-secreted products on adrenocortical function in women with PCOS by studying the adrenocortical response to acute adrenocorticotropic-stimulating hormone (ACTH) stimulation before and after bilateral oophorectomy.
Design
Prospective study.
Setting
Tertiary care medical center
Participants
Fourteen women with PCOS scheduled for bilateral oophorectomy for benign indications, on transdermal estradiol (E2) postoperatively.
Interventions
Physical exam, blood sampling before and after oophorectomy, measurement of hormone levels. Basal (Steroid0), maximum stimulated (Steroid60), and net increment (ΔSteroid) levels of androstenedione (A4), dehydroepiandrosterone (DHEA), and cortisol (F) before and after ACTH-1–24 stimulation were assessed.
Main Outcome Measures
Pre- and post-operative basal and ACTH(1–24)-stimulated hormonal levels.
Results
Total testosterone, free testosterone, and estrone levels decreased, and FSH levels increased significantly following oophorectomy. No significant differences in E2, DHEA sulfate (DHEAS) or sex hormone binding globulin levels were detected. Basal and ACTH-stimulated A4 levels decreased significantly following oophorectomy, and ΔA4 was significantly increased. No significant differences in DHEA0, DHEA60, or F0 levels were detected; F60 and ΔF levels tended to increase following oophorectomy, but the differencesdid not reach significance.
Conclusions
Ovarian factors do not appear to contribute significantly to the adrenocortical dysfunction of PCOS.
doi:10.1016/j.fertnstert.2012.10.016
PMCID: PMC3563739  PMID: 23122827
Polycystic ovary syndrome; adrenal androgen; oophorectomy
7.  Adrenal Androgens and the Menopausal Transition 
Synopsis
The concept that adrenal androgen production gradually declines with age has changed following the analysis of the longitudinal data collected in the Study of Women’s Health Across the Nation (SWAN). It is now recognized that four adrenal androgens (3-beta hydroxy-5-androsten-17-one or dehydroepiandrosterone--DHEA, its sulfate, dehydroepiandrosterone sulfate--DHEAS; androst-4-ene, 3,17-dione or androstenedione; and androst-5-ene-3-beta, 17-beta diol, also known as androstenediol or Adiol) rise during the menopausal transition in most women. Ethnic and individual differences in sex steroids are more apparent in circulating adrenal steroids than in either estradiol or cyclic ovarian steroid hormone profiles, particularly during the early and late perimenopause. Thus, adrenal steroid production may play a larger role in the occurrence of symptoms and the potential for healthier aging than previously recognized.
doi:10.1016/j.ogc.2011.06.001
PMCID: PMC3185242  PMID: 21961714
menopausal transition; androgens; adrenal
8.  Higher DHEA-S (Dehydroepiandrosterone Sulfate) Levels are Associated with Depressive Symptoms during the Menopausal Transition: Results from the PENN Ovarian Aging Study 
Archives of women's mental health  2011;14(5):375-382.
Background
The influence of sex hormones on mood during menopause has been the subject of ongoing investigation. Because dehydroepiandrosterone sulfate (DHEA-S) levels have been associated with several indicators of health outcomes associated with healthy aging, this PENN Ovarian Aging study (POAS) investigation was undertaken to determine the relationship between DHEA-S levels and both depressive symptoms and major depression during the transition through menopause. The original report revealed an unexpected positive correlation between DHEA sulfate (DHEA-S) levels and depressive symptoms in the cohort at baseline. To determine whether the positive association of DHEA-S levels and depression persists in a longitudinal analysis, the cohort was studied over 11 years.
Methods
Longitudinal cohort study with 11 assessments during an 11 year interval in Philadelphia, Pennsylvania. Participants: A randomly identified, population-based sample of 436 African American and Caucasian premenopausal women aged 35 to 47 years at enrollment. Outcome Measures: Center for Epidemiologic Studies Depression Scale score and standardized diagnosis of major depression.
Results
In a multivariable model, DHEA-S levels were positively associated with depressive symptoms, when adjusted for age, menopausal stage, race, smoking status and body mass index. There was no relationship between DHEA-S levels and a diagnosis of major depression.
Conclusions
DHEA-S levels were positively associated with depressive symptoms and not with major depression during the menopausal transition.
doi:10.1007/s00737-011-0231-5
PMCID: PMC3690802  PMID: 21773816
menopausal transition; dehydroepiandrosterone sulfate; depressive symptoms; major depression; longitudinal cohort
9.  Association of Adrenal Function and Disease Severity in Community-Acquired Pneumonia 
PLoS ONE  2014;9(6):e99518.
Introduction
Rapid and accurate risk stratification in patients with community-acquired pneumonia (CAP) is an unmet clinical need. Cortisol to dehydroepiandrosterone (DHEA) ratio was put forward as a prognostic marker in sepsis. We herein validated the prognostic value of the adrenal hormones DHEA, DHEA-Sulfate (DHEAS), cortisol/DHEA-, cortisol/DHEAS- and DHEA/DHEAS – ratios in patients with CAP.
Methods
We assessed severity of illness using the pneumonia severity index (PSI) and measured adrenal hormone concentrations in 179 serum samples of prospectively recruited patients hospitalized with CAP. We calculated spearman rank correlation, logistic regression analysis and Kaplan Meier curves to study associations of adrenal hormones and outcomes.
Results
There was a significant correlation between PSI score and total cortisol (r = 0.24, p = 0.001), DHEAS (r = −0.23, p = 0.002), cortisol/DHEA (r = 0.23, p = 0.003), cortisol/DHEAS (r = 0.32, p = <0.0001) and DHEA/DHEAS (r = 0.20, p = 0.009). In age and gender adjusted logistic regression analysis, cortisol (OR: 2.8, 95% CI: 1.48–5.28) and DHEA (OR: 2.62, 95% CI: 1.28–5.34), but not DHEAS and the different ratios were associated with all-cause mortality. The discriminatory accuracy of cortisol and DHEA in ROC analysis (area under the curve) was 0.74 and 0.61. In Kaplan Meier analysis, patients in the highest deciles of cortisol and DHEA (p = 0.005 and p = 0.015), and to a lesser extent of cortisol/DHEAS ratio (p = 0.081) had a higher risk of death.
Conclusion
Cortisol, DHEAS and their ratios correlate with CAP severity, and cortisol and DHEA predict mortality. Adrenal function in severe pneumonia may be an important factor for CAP outcomes.
doi:10.1371/journal.pone.0099518
PMCID: PMC4049821  PMID: 24910975
10.  Plasma Dehydroepiandrosterone and Risk of Myocardial Infarction in Women 
Clinical Chemistry  2008;54(7):1190-1196.
BACKGROUND
In this study we prospectively evaluated the relationships between plasma concentrations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) and subsequent myocardial infarction in women.
METHODS
Using case-control sampling, we selected participants from the Nurses’ Health Study cohort. Blood samples were collected from 1989 to 1990 when the women were 43 to 69 years old. During follow-up through June 1998, 239 women were diagnosed with myocardial infarction (fatal and nonfatal). We matched cases 1:2 by age, cigarette smoking status, fasting status, and month of blood collection and used conditional logistic regression to adjust for potential confounders, including anthropometric factors and dietary intake.
RESULTS
Baseline median (10th, 90th percentiles) concentrations of DHEA were 17.1 (4.3, 46.7) nmol/L among women who subsequently developed myocardial infarction and 16.6 (6.1, 37.9) among controls. The risk of myocardial infarction increased with plasma concentrations of DHEA and its sulfate. Women in the highest DHEA quartile had a rate ratio (RR) of 1.27 (95% CI 0.92–1.74, P for trend = 0.008) for myocardial infarction compared with those in the lowest quartile, after adjusting for covariates. The results did not vary significantly by menopausal status, postmenopausal estrogen therapy, fasting status, or age at time of blood collection. Similar relationships between concentrations of DHEA-S and risk were observed, with an RR of 1.58 (95% CI 1.13–2.21; P for trend = 0.06) for myocardial infarction in the highest vs lowest quartile.
CONCLUSIONS
We observed a modest positive relationship between plasma concentrations of DHEA and its sulfate and the risk of subsequent myocardial infarction among predominantly postmenopausal women.
doi:10.1373/clinchem.2007.099291
PMCID: PMC3400530  PMID: 18451313
11.  Hyposecretion of the adrenal androgen dehydroepiandrosterone sulfate and its relation to clinical variables in inflammatory arthritis 
Arthritis Research  2001;3(3):183-188.
Hypothalamic–pituitary–adrenal underactivity has been reported in rheumatoid arthritis (RA). This phenomenon has implications with regard to the pathogenesis and treatment of the disease. The present study was designed to evaluate the secretion of the adrenal androgen dehydroepiandrosterone sulfate (DHEAS) and its relation to clinical variables in RA, spondyloarthropathy (Spa), and undifferentiated inflammatory arthritis (UIA). Eighty-seven patients (38 with RA, 29 with Spa, and 20 with UIA) were studied, of whom 54 were women. Only 12 patients (14%) had taken glucocorticoids previously. Age-matched, healthy women (134) and men (149) served as controls. Fasting blood samples were taken for determination of the erythrocyte sedimentation rate (ESR), serum DHEAS and insulin, and plasma glucose. Insulin resistance was estimated by the homeostasis-model assessment (HOMAIR). DHEAS concentrations were significantly decreased in both women and men with inflammatory arthritis (IA) (P < 0.001). In 24 patients (28%), DHEAS levels were below the lower extreme ranges found for controls. Multiple intergroup comparisons revealed similarly decreased concentrations in each disease subset in both women and men. After the ESR, previous glucocorticoid usage, current treatment with nonsteroidal anti-inflammatory drugs, duration of disease and HOMAIR were controlled for, the differences in DHEAS levels between patients and controls were markedly attenuated in women (P = 0.050) and were no longer present in men (P = 0.133). We concluded that low DHEAS concentrations are commonly encountered in IA and, in women, this may not be fully explainable by disease-related parameters. The role of hypoadrenalism in the pathophysiology of IA deserves further elucidation. DHEA replacement may be indicated in many patients with IA, even in those not taking glucocorticoids.
PMCID: PMC30711  PMID: 11299059
Dehydroepiandrosterone sulfate; inflammatory arthritis
12.  BREAST DUCTAL LAVAGE FOR ASSESSMENT OF BREAST CANCER BIOMARKERS 
Hormones & cancer  2010;1(4):197-204.
Purpose
Lavage of the ductal systems of the breast provides fluid (DLF) containing hormones and products of hormone actions that may represent more accurately the composition of the breast than samples collected from blood or urine. The present study was undertaken to assess the presence of potential cancer biomarkers, their variation among individuals at high risk for breast cancer, and differences associated with menopause and tamoxifen treatment.
Methods
Seventy seven tamoxifen-eligible subjects with a 5-year breast cancer risk estimate (Gail > 1.6%)(N = 53) or recently diagnosed breast cancer (N = 24) were offered tamoxifen therapy; those not accepting tamoxifen were under observation only. After six months, all subjects underwent ductal lavage (DL) in an unaffected breast. Estradiol (E2), estrone sulfate, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulfate, progesterone, cathepsin D and epidermal growth factor (EGF) were measured in DLF by immunoassays. Data were expressed as the mass of analyte per mg of protein in DLF and normalized by natural log transformation.
Results
With the exception of DHEA, none of the analytes measured were significantly lower in postmenopausal women than in premenopausal women. The mean loge concentration difference in estradiol was 10.9%. Tamoxifen treatment for 6 months did not result in a significantly greater concentration of E2 or in any of the other analytes in DLF of pre- or postmenopausal women. The between-duct variance of the concentration of free steroids within the same breast averaged 51% less than that between subjects, and was similar to that of non-diffusible proteins.
Conclusions
The maintenance of estradiol concentrations in the breast after menopause demonstrates the importance of local biosynthesis. The fact that DLF E2 does not reflect the high serum concentrations of E2 during tamoxifen treatment indicates that breast concentrations of estradiol may be under feedback control. Unlike studies of low risk populations, progesterone concentrations were not significantly less in postmenopausal than in premenopausal women. The similarity in variance of free steroids and protein analytes between ducts of a breast indicates little transfer of steroids between lobules.
doi:10.1007/s12672-010-0021-y
PMCID: PMC3082955  PMID: 21533003
Breast; Cancer; Risk; Lavage; Hormones
13.  Preservation of androgen secretion during estrogen suppression with aminoglutethimide in the treatment of metastatic breast carcinoma. 
Journal of Clinical Investigation  1980;65(3):602-612.
We evaluated the comparative effects of aminoglutethimide (AG) on androgen and estrogen levels estrone ([E1], estradiol [E2], plasma dehydroepiandrosterone-sulfate [DHEA-S], testosterone [T], dihydrotestosterone [DHT], delta 4-androstenedione [delta 4-A]), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin in postmenopausal patients with breast cancer randomly allocated to either AG treatment or bilateral surgical adrenalectomy as a control group. In response to either treatment, the plasma levels of E1 fell 62-75% (P less than 0.001) and urine E1 85.7-88.7% (P less than 0.001) in all study days over a 12-wk period. Similarly, the concentrations of E2 in plasma and urine fell 40-72% without statistically significant differences between the two treatment modalities. The relatively weak androgen, DHEA-S, was reduced by 92% (877.3 +/- 184.6 to 71.8 +/- 14.5 ng/ml) at 12 wk in women treated with AG, but suppressed nearly 99% (1,151 +/- 262 to 5.8 +/- 3.3 ng/ml) in adrenalectomized women. At all time points after treatment, the DHEA-S levels were significantly higher in patients receiving AG. Plasma concentrations of the potent androgens, T and DHT, were also relatively preserved during AG treatment. T levels were never significantly reduced by AG, and DHT concentrations were decreased only at the 4th wk to a maximum of 20%. delta 4-A levels fell 56% in response to this drug only on the 12th wk of therapy (basal, 0.79 +/- 0.09 ng/ml; 12 wk, 0.35 +/- 0.07 ng/ml). In marked contrast, all androgens fell significantly at each time period in response to surgical adrenalectomy, with an 81% maximum suppression of T, 73% of DHT, and 97% of delta 4-A. In response to estrogen suppression, plasma levels of FSH, LH, and prolactin did not change significantly throughout the treatment period in either therapy group. To examine possible contributions of the postmenopausal ovary to hormone levels during therapy, data from surgically castrate and spontaneously menopausal women were evaluated separately. No significant differences between the two groups were observed for E1, E2, T, DHT, DHEA-S, delta 4-A, LH, FSH, and prolactin. We conclude that equivalent and highly significant estrogen suppression occurs with either AG or surgical adrenalectomy although androgen secretion is preserved during AG treatment but not after surgical adrenalectomy. The combined effects of estrogen deprivation associated with androgen preservation might be significant in the therapeutic action of AG in hormone-responsive neoplasms.
PMCID: PMC371401  PMID: 6986409
14.  In rats, oral oleoyl-DHEA is rapidly hydrolysed and converted to DHEA-sulphate 
BMC Pharmacology  2007;7:4.
Background
Dehydroepiandrosterone (DHEA) released by adrenal glands may be converted to androgens and estrogens mainly in the gonadal, adipose, mammary, hepatic and nervous tissue. DHEA is also a key neurosteroid and has antiglucocorticoid activity. DHEA has been used for the treatment of a number of diseases, including obesity; its pharmacological effects depend on large oral doses, which effect rapidly wanes in part because of its short half-life in plasma. Since steroid hormone esters circulate for longer periods, we have studied here whether the administration of DHEA oleoyl ester may extend its pharmacologic availability by keeping high circulating levels.
Results
Tritium-labelled oleoyl-DHEA was given to Wistar male and female rats by gastric tube. The kinetics of appearance of the label in plasma was unrelated to sex; the pattern being largely coincident with the levels of DHEA-sulfate only in females, and after 2 h undistinguishable from the results obtained using labelled DHEA gavages; in the short term, practically no lipophilic DHEA label was found in plasma. After 24 h only a small fraction of the label remained in the rat organs, with a different sex-related distribution pattern coincident for oleoyl- and free- DHEA gavages. The rapid conversion of oleoyl-DHEA into circulating DHEA-sulfate was investigated using stomach, liver and intestine homogenates; which hydrolysed oleoyl-DHEA optimally near pH 8. Duodenum and ileum contained the highest esterase activities. Pure hog pancreas cholesterol-esterase broke down oleoyl-DHEA at rates similar to those of oleoyl-cholesterol. The intestinal and liver esterases were differently activated by taurocholate and showed different pH-activity patterns than cholesterol esterase, suggesting that oleoyl-DHEA can be hydrolysed by a number of esterases in the lumen (e.g. cholesterol-esterase), in the intestinal wall and the liver.
Conclusion
The esterase activities found may condition the pharmacological availability (and depot effect) of orally administered steroid hormone fatty acid esters such as oleoyl-DHEA. The oral administration of oleoyl-DHEA in order to extend DHEA plasma availability has not been proved effective, since the ester is rapidly hydrolysed, probably in the intestine itself, and mainly converted to DHEA-sulfate at least in females.
doi:10.1186/1471-2210-7-4
PMCID: PMC1831771  PMID: 17346356
15.  Low Circulating Levels of Dehydroepiandrosterone in Histologically Advanced Nonalcoholic Fatty Liver Disease 
Hepatology (Baltimore, Md.)  2008;47(2):484-492.
The biological basis of variability in histological progression of nonalcoholic fatty liver disease (NAFLD) is unknown. Dehydroepiandrosterone(DHEA) is the most abundant steroid hormone and has been shown to influence sensitivity to oxidative stress, insulin sensitivity, and expression of peroxisome proliferator-activated receptor alpha and procollagen messenger RNA. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of DHEA. Serum samples were obtained prospectively at the time of liver biopsy in 439 patients with NAFLD (78 in an initial and 361 in validation cohorts) and in controls with cholestatic liver disease (n = 44). NAFLD was characterized as mild [simple steatosis or nonalcoholic steatohepatitis (NASH) with fibrosis stage 0–2] or advanced (NASH with fibrosis stage 3–4). Serum levels of sulfated DHEA (DHEA-S) were measured by enzyme-linked immunosorbent assay. Patients with advanced NAFLD had lower plasma levels of DHEA-S than patients with mild NAFLD in both the initial (0.25 ± 0.07 versus 1.1 ± 0.09 µg/mL, P < 0.001) and validation cohorts (0.47 ± 0.06 versus 0.99 ± 0.04 µg/mL, P < 0.001). A “dose effect” of decreasing DHEA-S and incremental fibrosis stage was observed with a mean DHEA-S of 1.03 ± 0.05, 0.96 ± 0.07, 0.83 ± 0.11, 0.66 ± 0.11, and 0.35 ± 0.06 µg/mL for fibrosis stages 0, 1, 2, 3, and 4, respectively. All patients in both cohorts in the advanced NAFLD group had low DHEA-S levels, with the majority in the hypoadrenal range. The association between DHEA-S and severity of NAFLD persisted after adjusting for age. A relationship between disease/fibrosis severity and DHEA-S levels was not seen in patients with cholestatic liver diseases.
Conclusion
More advanced NAFLD, as indicated by the presence of NASH with advanced fibrosis stage, is strongly associated with low circulating DHEA-S. These data provide novel evidence for relative DHEA-S deficiency in patients with histologically advanced NASH.
doi:10.1002/hep.22063
PMCID: PMC2906146  PMID: 18220286
16.  Lower Serum DHEAS levels are associated with a higher degree of physical disability and depressive symptoms in middle-aged to older African American women 
Maturitas  2007;57(4):347-360.
Background
Changes in androgen levels and associations with chronic disease, physical and neuropsychological function and disability in women over the middle to later years of life are not well understood and have not been extensively studied in African-American women.
Aims
The present cross-sectional analysis reports such levels and associations in community dwelling, African American women aged 49 – 65 years from St. Louis, Missouri.
Methods
A home-based physical examination and a health status questionnaire were administered to randomly sampled women. Body composition (DEXA), lower limb and hand-grip muscle strength, physical and neuropsychological function and disability levels were assessed. Blood was drawn and assayed for total testosterone (T), sex hormone-binding globulin (SHBG), dehydroepiandrosterone-sulfate (DHEAS), oestradiol (E2), adiponectin, leptin, triglycerides, glucose, C-reactive protein (CRP) and cytokine receptors (sIL2r, sIL6r, sTNFr1 & sTNFr2). Multiple linear regression modelling was used to identify the best predictors of testosterone, DHEAS and Free Androgen Index (T/SHBG).
Results
Seventy-four percent of women were menopausal and a quarter of these were taking oestrogen therapy. DHEAS and E2 declined between the ages of 49 and 65 years, whereas total T, SHBG and FAI remained stable. Total T and DHEAS levels were strongly correlated. In this population sample there were no independent associations of either total T or FAI with indicators of functional limitations, disability or clinically relevant depressive symptoms. Unlike total T and FAI, lower DHEAS levels was independently associated with both higher IADL scores (indicating a higher degree of physical disability) and higher CESD scores (indicating a higher degree of clinically relevant depressive symptoms).
Conclusion
There is an age-related decline in serum DHEAS in African-American women. Lower DHEAS levels appear to be associated with a higher degree of physical disability and depressive symptoms in this population.
doi:10.1016/j.maturitas.2007.03.003
PMCID: PMC2041800  PMID: 17451893
17.  Effect of dehydroepiandrosterone supplementation on bone mineral density, bone markers, and body composition in older adults 
Summary
We present results of a randomized, placebo-controlled trial to examine the effect of 50 mg daily oral DHEA supplementation for one year on bone mineral density (BMD), bone metabolism and body composition in 225 healthy adults aged 55 to 85 years.
Introduction
Dehydroepiandrosterone (DHEA) levels decline dramatically with age, concurrent with the onset of osteoporosis, suggesting a role for DHEA supplementation in preventing age-related bone loss.
Methods
We conducted a randomized, placebo-controlled trial to examine the effect of 50 mg daily oral DHEA supplementation for one year on bone mineral density (BMD), bone metabolism and body composition in 225 healthy adults aged 55 to 85 years.
Results
DHEA treatment increased serum DHEA and DHEA sulfate levels to concentrations seen in young adults. Testosterone, estradiol and insulin-like growth factor (IGF-1) levels increased in women (all p<0.001), but not men, receiving DHEA. Serum C-terminal telopeptide of type-1 collagen levels decreased in women (p=0.03), but not men, whereas bone-specific alkaline phosphatase levels were not significantly altered in either sex. After 12 months, there was a positive effect of DHEA on lumbar spine BMD in women (p=0.03), but no effect was observed for hip, femoral neck or total body BMD, and no significant changes were observed at any site among men. Body composition was not affected by DHEA treatment in either sex.
Conclusion
Among older healthy adults, daily administration of 50 mg of DHEA has a modest and selective beneficial effect on BMD and bone resorption in women, but provides no bone benefit for men.
doi:10.1007/s00198-007-0520-z
PMCID: PMC2435090  PMID: 18084691
Body composition; Bone metabolism; Bone mineral density (BMD); Dehydroepiandrosterone (DHEA) levels; Placebo-controlled trial; Testosterone
18.  Low dehydroepiandrosterone sulphate is associated with increased risk of ischemic stroke among women 
Stroke; a journal of cerebral circulation  2013;44(7):10.1161/STROKEAHA.111.000485.
Background and Purpose
Previous research suggests greater risk of coronary heart disease with lower levels of the adrenal steroid dehydroepiandrosterone sulfate (DHEAS). No studies have examined the association between DHEAS and risk for ischemic stroke. DHEAS may influence ischemic stroke risk through atherosclerotic related mechanisms (endothelial function and smooth muscle cell proliferation) or insulin resistance.
Methods
Between 1989-1990, 32,826 women without prior stroke in the Nurses’ Health Study, an observational cohort, provided blood samples and were followed for cardiovascular events. Among this sample, using a nested-case control design, 461 ischemic strokes confirmed by medical records through 2006. Cases were matched to controls free of stroke at the time of the index case and by age, ancestry, menopausal status, postmenopausal hormone use, smoking status and date of sample collection. Multivariable conditional logistic regression was utilized.
Results
Median DHEAS levels did not differ between cases (median=58.7) and controls (median=66.0; p-value=0.10). Conditional on matching factors, the lowest DHEAS quartile exhibited a relative risk (RR) of 1.30 for ischemic stroke (95% confidence interval [CI]: 0.88-1.94), compared with the highest quartile and marginally unchanged when adjusted for confounders (RR=1.33; 95%CI: 0.87-2.02). When modeled as a binary variable dichotomized at the lowest quartile, women with low DHEAS (≤the lowest quartile) had a significantly increased multivariable adjusted risk of ischemic stroke compared to those with higher levels (RR=1.41; 95%CI: 1.03-1.92).
Conclusions
Lower DHEAS levels were associated with a greater risk of ischemic stroke, even after adjustment for potential confounders. These novel observations warrant confirmation in other populations.
doi:10.1161/STROKEAHA.111.000485
PMCID: PMC3811081  PMID: 23704104
Ischemic stroke; dehydroepiandrosterone sulphate
19.  Dehydroepiandrosterone Sulfate (DHEAS) Stimulates the First Step in the Biosynthesis of Steroid Hormones 
PLoS ONE  2014;9(2):e89727.
Dehydroepiandrosterone sulfate (DHEAS) is the most abundant circulating steroid in human, with the highest concentrations between age 20 and 30, but displaying a significant decrease with age. Many beneficial functions are ascribed to DHEAS. Nevertheless, long-term studies are very scarce concerning the intake of DHEAS over several years, and molecular investigations on DHEAS action are missing so far. In this study, the role of DHEAS on the first and rate-limiting step of steroid hormone biosynthesis was analyzed in a reconstituted in vitro system, consisting of purified CYP11A1, adrenodoxin and adrenodoxin reductase. DHEAS enhances the conversion of cholesterol by 26%. Detailed analyses of the mechanism of DHEAS action revealed increased binding affinity of cholesterol to CYP11A1 and enforced interaction with the electron transfer partner, adrenodoxin. Difference spectroscopy showed Kd-values of 40±2.7 µM and 24.8±0.5 µM for CYP11A1 and cholesterol without and with addition of DHEAS, respectively. To determine the Kd-value for CYP11A1 and adrenodoxin, surface plasmon resonance measurements were performed, demonstrating a Kd-value of 3.0±0.35 nM (with cholesterol) and of 2.4±0.05 nM when cholesterol and DHEAS were added. Kinetic experiments showed a lower Km and a higher kcat value for CYP11A1 in the presence of DHEAS leading to an increase of the catalytic efficiency by 75%. These findings indicate that DHEAS affects steroid hormone biosynthesis on a molecular level resulting in an increased formation of pregnenolone.
doi:10.1371/journal.pone.0089727
PMCID: PMC3931814  PMID: 24586990
20.  Administration of Dehydroepiandrosterone (DHEA) Enhances Visual-Spatial Performance in Post-Menopausal Women 
Behavioral neuroscience  2011;125(5):742-752.
The current paper examines the effect of administering Dehydroepiandrosterone (DHEA) on visual-spatial performance in post-menopausal women (N=24, ages 55-80). The concurrent reduction of serum DHEA levels and visual-spatial performance in this population, coupled with the documented effects of DHEA’s androgenic metabolites on visual-spatial performance, suggest that DHEA administration may enhance visual-spatial performance. The current experiment used a double-blind placebo-controlled crossover design in which 50 mg of oral DHEA was administered daily in the drug condition to explore this hypothesis. Performance on the Mental Rotation, Subject-Ordered Pointing, Fragmented Picture Identification, Perceptual Identification, Same-Different Judgment, and Visual Search tasks and serum levels of DHEA, DHEAS, testosterone, estrone and cortisol were measured in the DHEA and placebo conditions. In contrast to prior experiments using the current methodology that did not demonstrate effects of DHEA administration on episodic and short-term memory tasks, the current experiment demonstrated large beneficial effects of DHEA administration on Mental Rotation, Subject-Ordered Pointing, Fragmented Picture Identification, Perceptual Identification and Same-Different Judgment. Moreover, DHEA administration enhanced serum levels of DHEA, DHEAS, testosterone and estrone, and regression analyses demonstrated that levels of DHEA and its metabolites were positively related to cognitive performance on the visual-spatial tasks in the DHEA condition
doi:10.1037/a0025151
PMCID: PMC3715689  PMID: 21942436
Dehydroepiadrosterone (DHEA); post-menopausal women; cognition; visual-spatial tasks; androgens
21.  Nipple aspiration and ductal lavage in women with a germline BRCA1 or BRCA2 mutation 
Breast Cancer Research  2005;7(6):R1122-R1131.
Introduction
The aim of this study was to collect serial samples of nipple aspirate (NA) and ductal lavage (DL) fluid from women with germline BRCA1/2 mutations in order to create a biorepository for use in identifying biomarkers of breast cancer risk.
Methods
Between March 2003 and February 2005, 52 women with germline BRCA1 or BRCA2 mutations (median age 43 years, range 27 to 65 years) were scheduled for six-monthly NA, DL and venesection. DL was attempted for all NA fluid-yielding (FY) and any non-FY ducts that could be located at each visit.
Results
Twenty-seven (52%) women were postmenopausal, predominantly (19/27) from risk reducing bilateral salpingo-oophorectomy (BSO). FY ducts were identified in 60% of all women, 76% of premenopausal women versus 44% of postmenopausal (P = 0.026). Eighty-five percent of women had successful DL. Success was most likely in women with FY ducts (FY 94% versus non-FY 71% (P = 0.049). DL samples were more likely to be cellular if collected from FY ducts (FY 68% versus non-FY 43%; P = 0.037). Total cell counts were associated with FY status (FY median cell count 30,996, range 0 to >1,000,000 versus non-FY median cell count 0, range 0 to 173,577; P = 0.002). Four women (8%) had ducts with severe atypia with or without additional ducts with mild epithelial atypia; seven others had ducts with mild atypia alone (11/52 (21%) in total). Median total cell count was greater from ducts with atypia (105,870, range 1920 to >1,000,000) than those with no atypia (174, 0 to >1,000,000; P ≤ 0.001).
Conclusion
It is feasible to collect serial NA and DL samples from women at high genetic risk of breast cancer, and we are creating a unique, prospective collection of ductal samples that have the potential to be used for discovery of biomarkers of breast cancer risk and evaluate the ongoing effects of risk reducing BSO. DL cellular atypia was not predictive of a current breast cancer and longer follow up is needed to determine whether atypia is an additional marker of future breast cancer risk in this population already at high genetic risk of breast cancer.
doi:10.1186/bcr1348
PMCID: PMC1410769  PMID: 16457692
22.  Surveillance of women at high risk for hereditary ovarian cancer is inefficient 
British Journal of Cancer  2006;94(6):814-819.
To determine the effectiveness of annual gynaecological screening (pelvic examination, transvaginal ultrasound, and CA-125), a prospective cohort study of women at high risk for hereditary ovarian cancer was conducted. Women were offered DNA analysis followed by either annual screening or prophylactic bilateral salpingo-oophorectomy (BSO). Study population consisted of 512 high-risk women (median follow-up 2.07 years, range 0–9.4 years): 265 women (52%) had a BRCA mutation. Persisting abnormalities indicated diagnostic surgery in 24 women resulting in one primary ovarian cancer FIGO stage IIIc was found. The effectiveness of screening was studied by calculating the probability of finding ovarian cancers in the BRCA-1 and BRCA-2 carrier group and comparing this to the identified number of ovarian cancers. The number of ovarian cancer patients found at surveillance was in accordance with the predicted number of ovarian cancers. A total number of 169 women underwent prophylactic BSO: one ovarian cancer stage IIb was found. In conclusion, the surveillance programme for hereditary ovarian cancer does identify patients with ovarian cancer but is very inefficient considering the high number of surveillance visits and the advanced stage of ovarian cancer in the identified patient. For prevention of advanced stage ovarian cancer, prophylactic BSO from age 35–40 years is a more efficient alternative.
doi:10.1038/sj.bjc.6603015
PMCID: PMC2361371  PMID: 16495917
BRCA; surveillance; ovarian cancer; prophylactic surgery; hereditary cancer
23.  The Association of Plasma Androgen Levels with Breast, Ovarian, and Endometrial Cancer Risk Factors Among Postmenopausal Women 
Although androgens may play an etiologic role in breast, ovarian, and endometrial cancers, little is known about factors that influence circulating androgen levels. We conducted a cross-sectional analysis among 646 postmenopausal women in the Nurses' Health Study to examine associations between adult risk factors for cancer, including the Rosner/Colditz breast cancer risk score, and plasma levels of testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEAS). All analyses were adjusted for age, laboratory batch, and other cancer risk factors. Free testosterone levels were 79% higher among women with a BMI of ≥30 vs. <22 kg/m2 (p-trend<0.01) and 25% higher among women with a waist circumference of >89 vs. ≤ 74 cm (p-trend=0.02). Consuming >30 grams of alcohol a day vs. none was associated with a 31% increase in DHEA and 59% increase in DHEAS levels (p-trend=0.01 and <0.01, respectively). Smokers of ≥25 cigarettes per day had 35% higher androstenedione and 44% higher testosterone levels than never smokers (p-value, F-test=0.03 and 0.01, respectively). No significant associations were observed for height or time since menopause with any androgen. Testosterone and free testosterone levels were approximately 30% lower among women with a hysterectomy vs. without (both p-values<0.01). Overall breast cancer risk was not associated with any of the androgens. Thus, several risk factors, including body size, alcohol intake, smoking, and hysterectomy, were related to androgen levels among postmenopausal women, while others, including height and time since menopause, were not. Future studies are needed to clarify further which lifestyle factors modulate androgen levels.
doi:10.1002/ijc.24709
PMCID: PMC2875384  PMID: 19569181
androgens; endogenous hormones; cancer risk factors; epidemiology
24.  The Protective Effect of Dehydroepiandrosterone on Ovarian Tissues After Torsion-Detorsion Injury: A Stereological and Histopathological Study 
Objective
Ovarian torsion is a rare problem in pre-pubescent girls that must be included in the differential diagnosis of patients with abdominal or pelvic pain. Current advice for treatment to support ovary preservation considers the macroscopic appearance of the ovary, but this is not a reliable indicator of the degree of injury in cases of ovarian torsion. The aim of this study was to determine the effects of dehydroepiandrosterone (DHEA) treatment on the rat ovary after torsion-detorsion injury using a histopathological approach and stereological methods.
Materials and Methods
Fifteen adult female Sprague Dawley rats were divided into three groups: sham operated (Control; n=5), torsion-detorsion with saline (Saline; n = 5), and torsion-detorsion with DHEA (DHEA; n = 5). Rats in the sham-operated group underwent a surgical procedure similar to the other groups, but the adnexa were not torsioned. The DHEA group was injected intraperitoneally 3 hours before detorsion and saline was administered to the saline group. After 24 h of adnexal detorsion, the rats in all groups were sacrificed and the adnexa were removed. The volume of ovarian stroma and edema were estimated using the Cavalieri Principle and were applied to serial paraffin sections. Ovary sections were also evaluated histopathologically.
Results
The volume of ovarian edema was 35.4% lower in the saline group compared to the control group (p> 0.05). The volume of ovarian edema increased by 73.4% in the DHEA group (p<0.05). In the experimental groups, stromal volume was 41.0% higher in the saline group and 52% higher in the DHEA group in comparison to the control group. Statistically significant differences were found when comparing the volume of both ovarian edema and stroma between experimental groups (Detorsion/Saline group – Detorsion/DHEA group; p< 0.01). Histopathologically, mononuclear cell infiltration and vascular dilatation, perivascular edema and common necrotic changes were obvious in the torsion-detorsion damaged ovary. These changes were partially ameliorated by DHEA treatment.
Conclusions
The present study shows that administration of DHEA has beneficial effects in the prevention of ischemia-reperfusion injuries of the ovaries.
PMCID: PMC4261661  PMID: 25610059
Ovarian torsion; DHEA; Stereology; Cavalieri Principle; Histopathology
25.  Virilizing Leydig-Sertoli Cell Ovarian Tumor Associated with Endometrioid Carcinoma of the Endometrium in a Postmenopausal Patient: Case Report and General Considerations 
Introduction
Sertoli-Leydig cell tumors (SLCTs) are rare tumors mostly occurring in young women. Here we report an unusual case of a SLCT with simultaneous occurrence of endometrioid adenocarcinoma of the endometrium in a woman in menopause.
Case report
A 67-year-old woman presented with progressive signs of virilization. Blood tests showed increased levels of testosterone, delta-4-androstenedione, and dehydroepiandrosterone (DHEA). DHEA-sulphate, 17β-estradiol, estrone, and sex-hormone binding globulin serum levels were within the normal range. Magnetic resonance imaging revealed a solid mass of 2.7 × 2.9 cm in the right ovary set against the background of the uterus. The patient underwent bilateral salpingo-oophoretomy with hysterectomy. The mass in the right ovary was a differentiated SLCT. Incidentally, the endometrium revealed an endometrioid adenocacinoma. Following surgical treatment the plasma androgens dropped to normal levels, and signs and symptoms of virilization improved.
Conclusion
SLCT should be suspected in postmenopausal women who present rapid progressive androgen excess symptoms with hyperandrogenemia.
doi:10.4137/CCRep.S10555
PMCID: PMC3489072  PMID: 23133317
ovarian cancer; hyperandrogenism; virilization; Sertoli-Leydig tumor; endometrial cancer

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