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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.  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
3.  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
4.  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
5.  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
6.  Coordinated prophylactic surgical management for women with hereditary breast-ovarian cancer syndrome 
BMC Cancer  2008;8:101.
Background
Women with BRCA1 or BRCA2 mutations have a substantially increased risk of breast and ovarian cancer compared with the general population. Therefore, prophylactic mastectomy (PM) and bilateral salpingo-oophorectomy (BSO) have been proposed as risk-reduction strategies for BRCA1/2 mutation carriers. We aimed to assess the feasibility of coordinated PM and BSO in hereditary breast-ovarian cancer syndrome.
Methods
High risk women for breast and ovarian cancer who underwent coordinated PM and BSO were included in this study. Clinical characteristics and surgical and oncologic outcomes were retrospectively reviewed.
Results
Twelve patients underwent coordinated PM and BSO. Ten had history of previous breast cancer. Autologous breast reconstruction was performed in ten patients. The mean age at surgery was 43 (range 34–65). Mean operating time was 9.3 hours (range 3–16) with a mean postoperative hospitalization of 5.4 days (range 4–8). Intraoperatively, there were no major surgical complications. Postoperatively, one patient developed an abdominal wound dehiscence, another reoperation for flap congestion; one had umbilical superficial epidermolysis, and one patient developed aspiration pneumonia. At a mean follow-up of 84 months, 10 of patients were cancer-free. Although no patients developed a new primary cancer, two developed a distant recurrence.
Conclusion
Coordinated PM and BSO is a feasible procedure with acceptable morbidity in selected high-risk patients that desire to undergo surgery at one operative setting.
doi:10.1186/1471-2407-8-101
PMCID: PMC2362122  PMID: 18410690
7.  Oophorectomy as a Risk Factor for Coronary Heart Disease 
Objective
To examine the relationship between bilateral oophorectomy (BSO) and risk of coronary heart disease (CHD).
Study Design
We searched PubMed, EMBASE, meeting abstracts, and reference lists for studies that compared women with BSO at the time of hysterectomy to 1) women with hysterectomy and ovarian conservation, 2) naturally menopausal women, 3) premenopausal women or, 4) women with no history of hysterectomy or BSO but unreported menopausal status. The primary outcome was fatal or nonfatal CHD.
Results
We reviewed 1,956 citations. Seven observational studies met inclusion criteria. Heterogeneity among studies precluded formal meta-analysis. Four studies reported BSO increases risk for CHD but only in some subgroups of women or not in fully adjusted multivariate models. Three studies found no increased risk of CHD following BSO but these studies had significant limitations.
Conclusion
The existing evidence is inconclusive to determine the effect of BSO on risk of CHD.
doi:10.1016/j.ajog.2008.08.045
PMCID: PMC2770431  PMID: 19019330
oophorectomy; surgical menopause; coronary events
8.  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
9.  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
10.  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
11.  Ovarian carcinoma of low maligant potential treated at the Jewish General Hospital, Montreal, between 1973 and 1997 
Canadian Journal of Surgery  1999;42(4):253-257.
Objective
To review the epidemiologic and pathological characteristics and the management of ovarian cancer of low malignant potential (LMP) at a university teaching institution.
Data source
Hospital charts from 1973 to 1997.
Data extraction
The authors carried out a manual study of the individual hospital charts covering the study period.
Data synthesis
The findings of this review revealed that the mean age of the 30 women in the study was 48.7 years and was similar in the subgroups of women having serous (18) and mucinous (9) types. In those women for whom staging information was available, all had either stage I disease (12 serous, 7 mucinous) or stage III disease (4 serous, 1 mucinous). Treatment consisted of: total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) with or without omentectomy (OM); BSO, unilateral oophorectomy or ovarian cystectomy alone; or TAH, OM and left salpingo-oophorectomy in women with stage I tumours. All women with stage III tumours underwent TAH, BSO and OM. The recurrence rate was low. Only 1 of 22 stage I tumours but 3 of 5 stage III tumours recurred.
Conclusions
Appropriate postoperative treatment for women with this type of ovarian cancer should be conservative. However, the management of higher stage disease remains controversial.
PMCID: PMC3788992  PMID: 10459324
12.  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
13.  Dehydroepiandrosterone and age-related cognitive decline 
Age  2009;32(1):61-67.
In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.
doi:10.1007/s11357-009-9113-4
PMCID: PMC2829637  PMID: 19711196
Dehydroepiandrosterone; Cognitive decline; Intracrinology; Neurosteroidogenesis
14.  Dehydroepiandrosterone and age-related cognitive decline 
Age (Dordrecht, Netherlands)  2009;32(1):61-67.
In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.
doi:10.1007/s11357-009-9113-4
PMCID: PMC2829637  PMID: 19711196
Dehydroepiandrosterone; Cognitive decline; Intracrinology; Neurosteroidogenesis
15.  Plasma sex hormone concentrations and the risk of breast cancer in postmenopausal women: the Multiethnic Cohort Study 
Endocrine-related cancer  2010;17(1):125-134.
To add to the existing evidence, which comes mostly from within White populations, we conducted a nested case-control study within the Multiethnic Cohort to examine the association between circulating sex hormones and breast cancer risk among postmenopausal women. Of the women who had a plasma sample, 129 women developed breast cancer during follow-up. Two controls per case, matched on area (Hawaii, Los Angeles), ethnicity/race (Japanese American, White, Native Hawaiian, African American, Latina), birth year, date of blood draw and time fasting, were selected from the women who had not developed breast cancer. Levels of estradiol, estrone, androstenedione, dehydroepiandrosterone (DHEA) and testosterone were quantified with radioimmunoassay after organic extraction and Celite column chromatography separation. Estrone sulfate, dehydroepiandrosterone sulfate (DHEAS), and sex hormone binding globulin (SHBG) were quantified by direct immunoassays. As estimated with conditional logistic regression, the sex hormones were positively associated and SHBG was negatively associated with breast cancer risk. All associations, except those with DHEAS and testosterone showed a significant linear trend. The odds ratio associated with a doubling of estradiol was 2.29 (95% confidence interval (CI) 1.58–2.35) and the odds ratio associated with a doubling of testosterone was 1.35 (95% CI 0.98–1.82). The associations in Japanese American women, who constituted 54% of our sample, were similar or slightly qualitatively stronger than in those of other ethnicity/race. This study supports previous evidence of an association between sex hormones and breast cancer risk and suggests that the associations are similar in Japanese American women.
doi:10.1677/ERC-09-0211
PMCID: PMC2880171  PMID: 19903744
estrogens; androgens; blood; breast cancer; postmenopausal; nested case-control
16.  Dynamics of Adrenal Steroids Are Related to Variations in Th1 and Treg Populations during Mycobacterium tuberculosis Infection in HIV Positive Persons 
PLoS ONE  2012;7(3):e33061.
Tuberculosis (TB) remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA), its circulating form DHEA-suphate (DHEA-s) and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS), a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS.
doi:10.1371/journal.pone.0033061
PMCID: PMC3303789  PMID: 22431997
17.  Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study 
Lancet  2009;373(9658):125-136.
Summary
Background
Hysterectomy and bilateral salpingo-oophorectomy (BSO) is the standard surgery for stage I endometrial cancer. Systematic pelvic lymphadenectomy has been used to establish whether there is extra-uterine disease and as a therapeutic procedure; however, randomised trials need to be done to assess therapeutic efficacy. The ASTEC surgical trial investigated whether pelvic lymphadenectomy could improve survival of women with endometrial cancer.
Methods
From 85 centres in four countries, 1408 women with histologically proven endometrial carcinoma thought preoperatively to be confined to the corpus were randomly allocated by a minimisation method to standard surgery (hysterectomy and BSO, peritoneal washings, and palpation of para-aortic nodes; n=704) or standard surgery plus lymphadenectomy (n=704). The primary outcome measure was overall survival. To control for postsurgical treatment, women with early-stage disease at intermediate or high risk of recurrence were randomised (independent of lymph-node status) into the ASTEC radiotherapy trial. Analysis was by intention to treat. This study is registered, number ISRCTN 16571884.
Findings
After a median follow-up of 37 months (IQR 24–58), 191 women (88 standard surgery group, 103 lymphadenectomy group) had died, with a hazard ratio (HR) of 1·16 (95% CI 0·87–1·54; p=0·31) in favour of standard surgery and an absolute difference in 5-year overall survival of 1% (95% CI −4 to 6). 251 women died or had recurrent disease (107 standard surgery group, 144 lymphadenectomy group), with an HR of 1·35 (1·06–1·73; p=0·017) in favour of standard surgery and an absolute difference in 5-year recurrence-free survival of 6% (1–12). With adjustment for baseline characteristics and pathology details, the HR for overall survival was 1·04 (0·74–1·45; p=0·83) and for recurrence-free survival was 1·25 (0·93–1·66; p=0·14).
Interpretation
Our results show no evidence of benefit in terms of overall or recurrence-free survival for pelvic lymphadenectomy in women with early endometrial cancer. Pelvic lymphadenectomy cannot be recommended as routine procedure for therapeutic purposes outside of clinical trials.
Funding
Medical Research Council and National Cancer Research Network.
doi:10.1016/S0140-6736(08)61766-3
PMCID: PMC2646126  PMID: 19070889
18.  Pregnancy weight gain is not associated with maternal or mixed umbilical cord estrogen and androgen concentrations 
Cancer causes & control : CCC  2008;20(2):263-267.
The association of maternal weight gain with serum hormone concentrations was explored in 75 women who had healthy, singleton pregnancies. Estradiol, estriol, estrone, androstenedione, testosterone, dehydroepiandrosterone (DHEA) and DHEA sulfate concentrations were measured both in maternal and mixed umbilical cord serum to assess hormone levels in both the maternal and fetal circulation at delivery. Our data show no association of maternal or cord steroid hormone concentrations with pregnancy weight gain. Increased exposure to steroid hormones, especially estrogens, during pregnancy has been hypothesized to play a role in subsequent breast cancer risk for both mother and female offspring. Our results are not consistent with an effect of pregnancy weight gain being mediated by this pathway as reflected by hormone concentrations at the end of pregnancy.
doi:10.1007/s10552-008-9235-5
PMCID: PMC2631613  PMID: 18830676
Pregnancy; breast cancer; estrogens; androgens
19.  Clinical study investigating the role of lymphadenectomy, surgical castration and adjuvant hormonal treatment in endometrial stromal sarcoma 
British Journal of Cancer  2007;97(9):1194-1199.
The objective of this study is to assess the therapeutic importance of surgical castration, adjuvant hormonal treatment and lymphadenectomy in endometrial stromal sarcoma (ESS). A retrospective and multicentric search was performed. Clinicopathologic data were retrieved from cases that were confirmed to be ESS after central pathology review. The protocol was approved by the Ethical Committee. ESS was confirmed histopathologically in 34 women, but follow-up data were available in only 31 women. Surgical treatment (n=31) included hysterectomy with or without bilateral salpingo-oophorectomy (BSO) in 23 out of 31 (74%) and 8 out of 31 (26%) cases, respectively. Debulking surgery was performed in 6 out of 31 cases (19%). Stage distribution was as follows: 22 stage I, 4 stage III and 5 stage IV. Women with stage I disease recurred in 4 out of 22 (18%) cases. Among stage I women undergoing hormonal treatment with or without BSO, 3 out of 15 (20%) and 1 out of 7 (14%) relapsed, respectively. Among stages III–IV women receiving adjuvant hormonal treatment or not, 1 out of 5 (20%) and 3 out of 4 (75%) relapsed, respectively (differences=55.0%, 95% CI=−6.8–81.2%). Kaplan–Meier curves show comparable recurrence rates for stage I disease without adjuvant hormonal treatment when compared to stages III–IV disease treated with surgery and adjuvant hormonal treatment. Furthermore, women taking hormones at diagnosis have a better outcome when compared to women not taking hormonal treatment. Three out of 31 (9%) patients had a systematic lymphadenectomy whereas 3 out of 31 (9%) had a lymph node sampling. In one case, obvious nodal disease was encountered at presentation. Isolated retroperitoneal recurrence occurred in 1 out of 31 (3%) of all cases and in 1 out of 8 (13%) recurrences. This single woman later also developed lung and abdominal metastases. Leaving lymph nodes in situ does not appear to alter the clinical outcome of ESS. Although numbers are low, the retrospective data suggest that the need for surgical castration (BSO) in premenopausal women with early-stage disease should be discussed with the patient on an individual basis. The data support the current practice in some centres to administer adjuvant hormonal treatment.
doi:10.1038/sj.bjc.6603986
PMCID: PMC2360466  PMID: 17895898
endometrial; stromal; sarcoma; adenosarcoma; hormonal; lymphadenectomy
20.  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
21.  Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies 
British Journal of Cancer  2011;105(5):709-722.
Background:
Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood.
Methods:
Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies.
Results:
Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer.
Conclusion:
Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.
doi:10.1038/bjc.2011.254
PMCID: PMC3188939  PMID: 21772329
breast cancer; hormones; oestrogens; androgens; sex hormone-binding globulin
22.  Dysregulation of Neurosteroids in Obsessive Compulsive Disorder 
Journal of psychiatric research  2008;43(4):442-445.
Alterations in hormone concentrations, including adrenocorticotropin, corticotropin releasing hormone, and cortisol have been reported in patients with obsessive compulsive disorder (OCD). Dehydroepiandrosterone (DHEA) and its sulfated metabolite, DHEA-S, have not been assessed in patients with OCD. We report 24-hour serum DHEA, DHEA-S, and cortisol concentrations in a young man with OCD and 15 healthy young men. Circadian patterns of DHEA and cortisol were markedly different in the subject with OCD than in the control subjects. DHEA and DHEA-S concentrations were substantially higher in the OCD subject than in the control subjects. In contrast, cortisol concentrations were similar in the OCD subject and the control subjects. Future clinical studies are needed to evaluate the significance of DHEA and DHEA-S in OCD.
doi:10.1016/j.jpsychires.2008.04.007
PMCID: PMC2654381  PMID: 18514738
23.  Advantages of nerve-sparing intrastromal total abdominal hysterectomy 
Video abstract
Video
Background
The purpose of the prospective study was to evaluate the effect of the nerve-sparing intrastromal abdominal hysterectomy bilateral salpingo-oophorectomy (ISTAH-BSO) on intraoperative, and postoperative complications namely blood loss and length of hospital stay.
Methods
Forty female patients were allocated by a block randomization method into a study group and a control group. The study group consisted of 20 patients who underwent ISTAH-BSO over a 2-year period. The control group included 20 patients who underwent conventional hysterectomy by the same surgeon during the same time frame. Both groups were followed for outcomes of interest, which included length of hospital stay, blood loss, and surgical complications. The participants in both groups were as similar as possible with respect to all known or unknown factors that might affect the study outcome.
Results
Postoperative hemoglobin levels were higher in the study group (blood loss 1.0 g/dL versus 1.4 g/dL in control group). Average hospital stay was significantly shorter in the study group (2.7 days versus 3.15 days in the control group, P = 0.028). No significant complications such as urinary fistula, vaginal vault prolapse, blood transfusion, or postoperative infections were identified in the study group.
Conclusion
The nerve-sparing ISTAH-BSO procedure described in this study has the potential to reduce length of hospital stay after abdominal hysterectomy by reducing blood loss and postoperative complications. Follow-up observations suggest that urinary function and sexual satisfaction are also preserved. Since this research, 175 cases have been performed, with an average of 5 years of follow-up. The outcomes of these cases have been reported as similar.
doi:10.2147/IJWH.S39631
PMCID: PMC3556916  PMID: 23378786
cervical cancer; support system; nerve sparing; complications; blood loss; hospital stay
24.  Non-closure of peritoneum after abdominal hysterectomy for uterine carcinoma does not increase late intestinal radiation morbidity 
Background/Aim
To evaluate whether non-closure of the visceral peritoneum after total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) in patients with uterine corpus carcinoma influences the volume of the small intestine within the irradiated volume during adjuvant radiotherapy or late radiation intestinal toxicity.
Materials and methods
A total of 152 patients after TAH + BSO with adjuvant pelvic radiotherapy were studied. The state of peritonealization was retrospectively evaluated based on surgical protocols. The volume of irradiated bowels was calculated by CT-based delineation in a radiotherapy planning system. The influence of visceral peritonealization upon the volume of the small intestine within the irradiated volume and consequent late morbidity was analyzed.
Results
Visceral peritonealization was not performed in 70 (46%) of 152 studied patients. The state of peritonealization did not affect the volume of the irradiated small intestine (p = 0.14). Mean volume of bowels irradiated in patients with peritonealization was 488 cm3 (range 200–840 cm3, median 469 cm3); mean volume of bowels irradiated in patients without peritonealization was 456 cm3 (range 254–869 cm3, median 428 cm3). We did not prove any significant difference between both arms. Nor did we observe any influence of non-peritonealization upon late intestinal morbidity (p = 0.34).
Conclusion
Non-closure of the visceral peritoneum after hysterectomy for uterine corpus carcinoma does not increase the volume of the small intestine within the irradiated volume, with no consequent intestinal morbidity enhancement.
doi:10.1016/j.rpor.2011.10.007
PMCID: PMC3863157  PMID: 24376992
Peritonealization; Hysterectomy; Intestine; Radiotherapy
25.  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

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