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1.  Androstenediol Complements Estrogenic Bioactivity during the Menopausal Transition 
Menopause (New York, N.y.)  2012;19(6):650-657.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
PMCID: PMC3366025  PMID: 22415570
DHEAS; androstenediol; estrogen; estrogenicity; menopause; adrenal
4.  Factors Associated With Undergoing Bilateral Salpingo-Oophorectomy at the Time of Hysterectomy for Benign Conditions 
Obstetrics and gynecology  2009;113(6):1259-1267.
To identify possible factors associated with undergoing bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy among women with benign conditions.
This is a cross-sectional analysis using the 2005 Nationwide Inpatient Sample. Women 18 years or older who underwent hysterectomy with BSO or hysterectomy only for a noncancerous condition were included. We examined a broad range of factors associated with undergoing BSO in multivariable analyses.
Fifty-two percent of 461,321 hysterectomies included BSO, with a mean age of 49 years compared to 43 years in the hysterectomy only group (p<.001). The odds of BSO were two times higher in the Midwest and South, and 1.67 times higher in the West as compared to the Northeast (p<.001). Women who were uninsured or had Medicaid were more likely to undergo BSO compared to those with private insurance (OR 1.86, 95%CI 1.14–3.04 for “no charge/charity”, OR 1.21, 95% CI 1.08–1.35 for Medicaid) While BSO was more common among White women than African-American, Latina, and Asian women (p<0.001), lower income was associated with BSO among African-American and White women only, not among Asian and Latina women (P=.007 for test for interaction). BSO was 8 times as likely with a laparoscopic hysterectomy and 12 times as likely with an abdominal hysterectomy compared to a vaginal approach (p<.001). Women who had endometriosis, pelvic infection, or an ovarian cyst were more likely to undergo BSO (p<.001) compared to women who did not have these diagnoses.
There is significant nationwide variation in the practice of BSO. Age, route of hysterectomy, and diagnosis at surgery affect BSO rates. Nonclinical factors such as race/ethnicity, insurance status, income, and geographic location are also associated with BSO practice.
PMCID: PMC4670026  PMID: 19461420
5.  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.
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.
To determine if hormone replacement therapy (HT) for one year can modulate adrenal androgen production.
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).
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.
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.
PMCID: PMC3610787  PMID: 23435030
Adrenal; Steroids; Hormone Therapy; Replacement
6.  Circulating levels of monocyte chemoattractant protein-1 and interleukin-7 in women who have undergone bilateral salpingo-oophorectomy 
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.
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.
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.
PMCID: PMC3881980  PMID: 24399882
follicle-stimulating hormone; cytokines; chemokines; hypoestrogenism; surgical menopause
7.  Dehydroepiandrosterone Secretion in Healthy Older Men and Women: Effects of Testosterone and Growth Hormone Administration in Older Men 
Aging is associated with diminished gonadal steroid and GH/IGF-I axis activity; whether these changes contribute to the parallel declines of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) production is unknown, as are the effects of sex steroid and/or GH administration on DHEA and DHEAS production.
Our objective was to evaluate morning DHEAS concentrations and nocturnal DHEA secretory dynamics in healthy older men and women, before and after chronic administration of sex steroid(s) alone, GH alone, sex steroid(s) combined with GH, or placebo alone.
We compared nocturnal DHEA secretory dynamics (2000 h to 0800 h, sampling every 20 min, analyzed by multiparameter deconvolution and approximate entropy algorithms) in healthy older (65–88 yr) men (n = 68) and women (n = 36), both before and after 26 wk of administration of sex steroid(s) alone [testosterone (T) in men or estrogen/progesterone in women], GH alone, sex steroid(s) combined with GH, or placebo alone.
Morning concentrations of DHEAS were lower; nocturnal DHEA pulsatile production rate, burst frequency, and amplitude were higher; and half-life was shorter in women (P < 0.05). Nocturnal integrated DHEA concentrations, total production rate, and approximate entropy did not differ significantly by sex. Because of small treatment group sizes in women, only hormone intervention results in men are presented. In men, T and T plus GH administration significantly decreased nocturnal integrated DHEA but not morning DHEAS concentrations. GH alone exerted no significant effects on nocturnal DHEA secretion or morning DHEAS.
Spontaneous nocturnal DHEA secretion is sexually dimorphic in healthy older individuals, and T administration decreases nocturnal DHEA secretion in older men. The clinical significance of sex steroid modulation of DHEA secretion in older persons remains to be elucidated.
PMCID: PMC4575787  PMID: 16926252
Fertility and sterility  2012;99(2):599-604.
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.
Prospective study.
Tertiary care medical center
Fourteen women with PCOS scheduled for bilateral oophorectomy for benign indications, on transdermal estradiol (E2) postoperatively.
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.
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.
Ovarian factors do not appear to contribute significantly to the adrenocortical dysfunction of PCOS.
PMCID: PMC3563739  PMID: 23122827
Polycystic ovary syndrome; adrenal androgen; oophorectomy
9.  Polymorphisms of estrogen metabolism-related genes ESR1, UGT2B17, and UGT1A1 are not associated with osteoporosis in surgically menopausal Japanese women 
Bilateral salpingo-oophorectomy (BSO) is a risk factor for osteoporosis. Previous studies have reported an association between genetic polymorphisms and the risk of developing osteoporosis. However, the relationship between osteoporosis and genetic polymorphisms in Japanese women treated with BSO is not well understood. To improve the quality of life for post-BSO patients, it is important to determine the genetic factors that influence their risk for osteoporosis. The aim of this study was to investigate the association between gene variations of estrogen metabolism-related genes and osteoporosis in surgically menopausal patients, which may improve their quality of life.
Material and methods
This study included 203 menopausal women treated with BSO because of gynecologic disorders. One hundred and twenty-six women with artificial (surgical) menopause, who had undergone BSO in the premenopausal period, were compared with 77 women with natural menopause, who had undergone BSO in the postmenopausal period. The women were tested for bone mineral density to diagnose osteoporosis. Polymorphisms of estrogen receptor 1 (ESR1) and UDP-glucuronosyl transferase (UGT) genes UGT2B17 and UGT1A1 were analyzed, and their association with bone mass and osteoporosis was statistically evaluated.
No significant association was found between osteoporosis and polymorphisms in ESR1, UGT2B17, or UGT1A1 in both groups, suggesting that BSO might be a more significant physiological factor in influencing bone mass density compared to genetic variations.
These results suggest that the ESR1, UGT2B17, and UGT1A1 polymorphisms are not genetic factors affecting osteoporosis in postmenopausal Japanese women.
PMCID: PMC4612551  PMID: 26528103
bilateral salpingo-oophorectomy; bone mineral density; gene polymorphism; menopause; osteoporosis
10.  Adrenal Androgens and the Menopausal Transition 
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.
PMCID: PMC3185242  PMID: 21961714
menopausal transition; androgens; adrenal
11.  Androgens, Bilateral Oophorectomy, and Cardiovascular Disease Mortality in Postmenopausal Women With and Without Diabetes: The Study of Osteoporotic Fractures 
Diabetes Care  2015;38(12):2301-2307.
Diabetes elevates cardiovascular disease (CVD) risk more markedly in women than in men. Because the high risk of CVD among women with type 2 diabetes (DM2) may be partly due to increased ovarian androgen production, we investigated whether a history of bilateral salpingo oophorectomy (BSO) is inversely associated with CVD mortality among women with DM2.
Data were obtained from 7,977 women (a random subset of 564 had measurements of sex-steroid hormones) enrolled in the Study of Osteoporotic Fractures (SOF), a community-based, multicenter study that monitored women aged ≥65 years for a mean of 15.1 years. Adjusted hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazards regression.
The average age at baseline was 71.5 years, with 6.3% and 18% of participants reporting a history of diabetes or BSO, respectively. In the subset of the SOF cohort with sex-steroid hormone measurements, those with DM2 had 43.6% significantly higher levels of free testosterone that were partly explained by age and adiposity, whereas total and free testosterone levels were lower in women with BSO than in those with intact ovaries. CVD mortality was elevated in women with DM2 without BSO (HR 1.95, 95% CI 1.62–2.35) as well as in women with DM2 and BSO (HR 2.56, 95% CI 1.79–3.65; P = 0.190 for interaction). Overall, BSO was not associated with CVD mortality (HR 1.05, 95% CI 0.89–1.23).
The association of diabetes with CVD was not reduced by BSO, suggesting that ovarian hyperandrogenemia may not be a primary mechanism to explain the high risk for CVD among women with DM2.
PMCID: PMC4657615  PMID: 26459275
12.  Novel dehydroepiandrosterone troche supplementation improves the serum androgen profile of women undergoing in vitro fertilization 
Dehydroepiandrosterone (DHEA) is the most abundant steroid hormone in the circulation and has potent multifunctional activity. Epidemiological evidence suggests that levels of serum DHEA decrease with advancing age, and this has been associated with onset or progression of various age-related ailments, including cognitive decline and dementia, cardiovascular disease, and obesity. Consequently, these findings have sparked intense research interest in DHEA supplementation as an “antiaging” therapy. Currently, DHEA is being used by 25% of in vitro fertilization (IVF) clinicians as an adjuvant in assisted reproductive programs, yet the therapeutic benefit of DHEA is unclear. Here, we examined the use of novel DHEA-containing oral troches in patients undertaking IVF and investigated the impact of these troches on their serum androgen profile. This retrospective study determined the androgen profile of 31 IVF patients before (baseline) and after DHEA supplementation (with DHEA). Baseline serum measurements of testosterone (total and free), DHEA sulfate (DHEAS), sex hormone-binding globulin (SHBG), and androstenedione were made before and after supplementation. Each patient received DHEA troches containing 25 mg of micronized DHEA, and troches were administered sublingually twice daily for a period of no greater than 4 months. Adjuvant treatment with DHEA boosted the serum concentration of a number of androgen-related analytes, including total and free testosterone, androstenedione, and DHEAS, while serum SHBG remained unchanged. Supplementation also significantly increased the free-androgen index in IVF patients. Interestingly, the increase in serum analyte concentration following DHEA supplementation was found to be dependent on body mass index (BMI), but not individual age. Patients with the lowest BMI (<20.0 kg/m2) tended to have lower testosterone and DHEAS, but higher SHBG and androstenedione levels in comparison with other BMI groups postsupplementation. However, patients in the highest BMI group (>30.0 kg/m2) tended to have lower androgen responses following DHEA supplementation, but these were not statistically different from the corresponding baseline level. This method of DHEA administration results in a similar enhancement of testosterone, DHEAS, and androstenedione levels in comparison with other methods of administration. Furthermore, we showed that BMI significantly influences DHEA uptake and metabolism, and that BMI should be carefully considered during dosage calculation to ensure a significant and robust androgen-profile boost.
PMCID: PMC4607057  PMID: 26487801
androstenedione; testosterone; sex hormone-binding globulin; IVF; oral troches; drug delivery
13.  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.
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.
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.
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.
DHEA-S levels were positively associated with depressive symptoms and not with major depression during the menopausal transition.
PMCID: PMC3690802  PMID: 21773816
menopausal transition; dehydroepiandrosterone sulfate; depressive symptoms; major depression; longitudinal cohort
14.  Association of Adrenal Function and Disease Severity in Community-Acquired Pneumonia 
PLoS ONE  2014;9(6):e99518.
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.
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.
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.
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.
PMCID: PMC4049821  PMID: 24910975
15.  Plasma Dehydroepiandrosterone and Risk of Myocardial Infarction in Women 
Clinical Chemistry  2008;54(7):1190-1196.
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.
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.
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.
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.
PMCID: PMC3400530  PMID: 18451313
16.  The Relationship Between Bilateral Oophorectomy and Plasma Hormone Levels in Postmenopausal Women 
Hormones & cancer  2014;6(1):54-63.
Oophorectomy prior to natural menopause reduces breast cancer risk. We evaluated whether timing of oophorectomy (during premenopause vs. postmenopause) or hysterectomy was associated with hormone levels, specifically estradiol, estrone, estrone sulfate, testosterone, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), and prolactin, using data from the Nurses’ Health Study.
We included 2,251 postmenopausal women not using hormones who provided blood samples in 1989–1990 and/or 2000–2002, and who were controls in various nested case-control studies. We used multivariate linear mixed effects models to assess geometric mean hormone levels by surgery status.
Bilateral oophorectomy was associated with 25% lower testosterone levels vs. women with natural menopause (20.8 vs. 15.5 ng/dL)(P<0.0001) with no effect of timing of surgery (P=0.80). SHBG levels were lower among women with a premenopausal oophorectomy (52.2 nmol/L) vs. those with natural menopause (58.1 nmol/L) or a postmenopausal oophorectomy (62.0 nmol/L)(P = 0.02). There was no significant association of oophorectomy with estradiol, estrone, estrone sulfate, DHEAS, or prolactin levels (P ≥ 0.23). A simple hysterectomy was associated with a significant 8% lower testosterone (P=0.03) and 14% lower DHEAS (P=0.02) levels compared to women with natural menopause, but not with other hormone levels.
Although limited by small numbers, our findings suggest no differential influence of timing of surgery on sex hormone levels. The reduction in testosterone levels women with oophorectomy or hysterectomy suggests a possible role of this hormone in postmenopausal breast cancer development.
PMCID: PMC4496792  PMID: 25523946
sex hormones; oophorectomy; hysterectomy; breast cancer; postmenopausal
17.  Ovarian Cancer Rates After Hysterectomy With and Without Salpingo-oophorectomy 
Obstetrics and gynecology  2014;123(1):65-72.
To estimate ovarian and peritoneal cancer rates after hysterectomy with and without salpingo-oophorectomy for benign conditions.
All patients after hysterectomy for benign disease from 1988–2006 in Kaiser Permanente Northern California, an integrated health organization. Incidence rates per 100,000 person-years were calculated.
Of 56,692 patients, the majority (54%) underwent hysterectomy with bilateral salpingo-oophorectomy (BSO); 7% had hysterectomy with unilateral salpingo-oophorectomy, and 39% had hysterectomy alone. There were 40 ovarian and eight peritoneal cancers diagnosed during follow-up. Median age at ovarian and peritoneal cancer diagnosis was 50 and 64 years, respectively. Age-standardized rates (per 100,000 person-years) of ovarian or peritoneal cancer were 26.7 (95%CI=16–37.5) for those with hysterectomy alone, 22.8 (95%CI=0.0–46.8) for hysterectomy and unilateral salpingo-oophorectomy, and 3.9 (95%CI=1.5–6.4) for hysterectomy and BSO. Rates of ovarian cancer were 26.2 (95%CI=15.5–37) for those with hysterectomy alone, 17.5 (95%CI=0.0–39.1) for hysterectomy and unilateral salpingo-oophorectomy, and 1.7 (95%CI=0.4–3) for those with hysterectomy and BSO. Compared to women undergoing hysterectomy alone, those also receiving an unilateral salpingo-oophorectomy had a hazard ratio (HR) for ovarian cancer of 0.58 (95%CI=0.18–1.9); those undergoing BSO had a HR of 0.12 (95%CI=0.05–0.28).
The removal of both ovaries decreases incidence of ovarian and peritoneal cancers. Removal of one ovary might also decrease the incidence of ovarian cancer but warrants further investigation.
PMCID: PMC4624417  PMID: 24463665
18.  In Vivo and In Vitro Evidences of Dehydroepiandrosterone Protective Role on the Cardiovascular System 
Dehydroepiandrosterone (DHEA) and its sulfate ester, Dehydroepiandrosterone Sulfate (DHEA-S) have been considered as putative anti-aging hormones for many years. Indeed, while DHEAS is the most abundant circulating hormone, its concentration is markedly decreased upon aging and early epidemiologic trials have revealed a strong inverse correlation between the hormone concentrations and the occurrence of several dysfunctions frequently encountered in the elderly. Naturally, hormonal supplementation has been rapidly suggested to prevent DHEA (S) deficiency and therefore, age-related development of these pathologies, using the same strategy as estrogen replacement therapy proposed in postmenopausal women.
Evidence Acquisition:
All references were searched using PubMed and the following strategy: our initial selection included all articles in English and we sorted them with the following keywords: “DHEA or DHEA-S” and “heart or vascular or endothelium or cardiovascular disease”. The search was limited to neither the publication date nor specific journals. The final selection was made according to the relevance of the article content with the aims of the review. According to these criteria, fewer than 10% of the articles retrieved at the first step were discarded.
In this short review, we have focused on the cardiovascular action of DHEA. We started by analyzing evidences in favor of a strong inverse association between DHEA (S) levels and the cardiovascular risk as demonstrated in multiple observational epidemiologic studies for several decades. Then we discussed the different trials aimed at supplementing DHEA (S), both in animals and human, for preventing cardiovascular diseases and we analyzed the possible reasons for the discrepancy observed among the results of some studies. Finally, we presented putative molecular mechanisms of action for DHEA (S), demonstrated in vitro in different models of vascular and cardiac cells, highlighting the complexity of the involved signaling pathways.
The identification of the beneficial cardiovascular effects of DHEA (S) and a better understanding of the involved mechanisms should be helpful to develop new strategies or pharmacologic approaches for many lethal diseases in Western countries.
PMCID: PMC4389253  PMID: 25926854
Dehydroepiandrosterone; Endothelium; Myocytes, Cardiac; Cardiovascular System; Disease; Steroids
19.  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
Hormones & cancer  2010;1(4):197-204.
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.
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.
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.
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.
PMCID: PMC3082955  PMID: 21533003
Breast; Cancer; Risk; Lavage; Hormones
21.  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
22.  In rats, oral oleoyl-DHEA is rapidly hydrolysed and converted to DHEA-sulphate 
BMC Pharmacology  2007;7:4.
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.
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.
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.
PMCID: PMC1831771  PMID: 17346356
23.  Ovarian adrenal interactions during the menopausal transition 
Minerva ginecologica  2013;65(6):641-651.
Observations over the past decade using longitudinal data reveal a gender-specific shift in adrenal steroid production. This shift is represented by an increase in the circulating concentrations of delta 5 steroids in 85% of all women and is initiated only after the menopausal transition has begun. While the associated rise in the major adrenal androgen, dehydroepiandrosterone sulfate (DHEAS), is modest, the parallel rises in dehydroepiandrosteone (DHEA) and androstenediol (Adiol) are much more robust. These increases in circulating steroid concentrations are qualitatively similar on average between ethnicities but quantitatively different between individual women. Both circulating testosterone (T) and androstenedione (Adione) also rise concomitantly but modestly by comparison. This phenomenon presents a new and provocative aspect to the endocrine foundations of the menopausal transition and may provide important clues to understanding the fundamentals of mid-aged women's healthy aging, particularly an explanation for the wide diversity in phenotypes observed during the MT as well as their different responses to hormone replacement therapies. Experimental studies using the nonhuman primate animal model show an acute adrenal response to human chorionic gonadotropin (hCG) challenge as well as the presence of luteinizing hormone receptors (LHR) in their adrenal cortices. These experimental results support the concept that LHRs are recruited to the adrenal cortices of mid-aged women that subsequently function to respond to increasing circulating LH to shunt pregnenolone metabolites towards the delta 5 pathway. Future investigations are required to determine the relationship of these changes in adrenal function to symptoms and health outcomes of mid-aged women.
PMCID: PMC4417336  PMID: 24346252
Adrenal glands; Menopause; Gonadal steroid hormones
24.  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.
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.
PMCID: PMC2906146  PMID: 18220286
25.  PAPSS2 Deficiency Causes Androgen Excess via Impaired DHEA Sulfation—In Vitro and in Vivo Studies in a Family Harboring Two Novel PAPSS2 Mutations 
PAPSS2 (PAPS synthase 2) provides the universal sulfate donor PAPS (3′-phospho-adenosine-5′-phosphosulfate) to all human sulfotransferases, including SULT2A1, responsible for sulfation of the crucial androgen precursor dehydroepiandrosterone (DHEA). Impaired DHEA sulfation is thought to increase the conversion of DHEA toward active androgens, a proposition supported by the previous report of a girl with inactivating PAPSS2 mutations who presented with low serum DHEA sulfate and androgen excess, clinically manifesting with premature pubarche and early-onset polycystic ovary syndrome.
Patients and Methods:
We investigated a family harboring two novel PAPSS2 mutations, including two compound heterozygous brothers presenting with disproportionate short stature, low serum DHEA sulfate, but normal serum androgens. Patients and parents underwent a DHEA challenge test comprising frequent blood sampling and urine collection before and after 100 mg DHEA orally, with subsequent analysis of DHEA sulfation and androgen metabolism by mass spectrometry. The functional impact of the mutations was investigated in silico and in vitro.
We identified a novel PAPSS2 frameshift mutation, c.1371del, p.W462Cfs*3, resulting in complete disruption, and a novel missense mutation, c.809G>A, p.G270D, causing partial disruption of DHEA sulfation. Both patients and their mother, who was heterozygous for p.W462Cfs*3, showed increased 5α-reductase activity at baseline and significantly increased production of active androgens after DHEA intake. The mother had a history of oligomenorrhea and chronic anovulation that required clomiphene for ovulation induction.
We provide direct in vivo evidence for the significant functional impact of mutant PAPSS2 on DHEA sulfation and androgen activation. Heterozygosity for PAPSS2 mutations can be associated with a phenotype resembling polycystic ovary syndrome.
PMCID: PMC4399300  PMID: 25594860

Results 1-25 (1679885)