Clinicopathological characteristics of adrenocortical carcinoma in the Kyushu-Okinawa area of Japan.

OBJECTIVE: Adrenocortical carcinoma is a rare condition, with limited comprehensive reports from Japan. This study aimed to review Japan's data on adrenocortical carcinoma by assessing information from 46 patients-with adrenocortical carcinoma across 10 Japanese university hospitals. METHODS: We conducted a retrospective multi-institutional analysis of the clinical characteristics of adrenocortical carcinoma in Japan. We evaluated data from 46 patients across 10 university hospitals over 10 years and analyzed the relationship between clinicopathological characteristics and overall survival. RESULTS: Five- and 10-year overall survival rates were 59% and 53%, respectively. Overall survival was significantly different among the tumor-node-metastasis system for adrenocortical carcinoma of the American Joint Committee on Cancer/International Union Against Cancer, with the worst prognosis in stage IV (p = 0.0044). In our cohort, neither the Weiss score nor the Ki-67 proliferation index correlated with overall survival. Adjuvant treatment did not yield improved overall survival, whereas resection of the primary tumor in stage IV disease was significantly associated with improved overall survival (p = 0.0262). Out of the cases evaluated for plasma hormones, plasma cortisol, aldosterone, testosterone, and DHEA-S levels were measured at 23%, 42%, 29%, and 62%, respectively, demonstrating higher levels than the upper normal limits. CONCLUSION: Patients with stage IV adrenocortical carcinoma had a poor prognosis; however, resection of the primary tumor in stage IV disease was associated with prolonged survival. The results of this study are expected to contribute to future treatment of adrenocortical carcinoma in Japan.

The effects of coenzyme Q10 supplementation on metabolic profiles and parameters of mental health in women with polycystic ovary syndrome.

OBJECTIVE: Evaluating the impact of coenzyme Q10 (CoQ10) supplementation on hormonal indices, mental health, and biomarkers of inflammatory responses and oxidative stress among female patients suffering from polycystic ovary syndrome (PCOS). METHODS: The present double-blinded, placebo-controlled randomized clinical trial consisted of 55 PCOS women (aged 18-40 years old), who were randomized into groups receiving 100 mg/day of CoQ10 (28 cases) or placebo (27 cases) for 12 weeks. RESULTS: The supplementation of CoQ10 decreased significantly the scores of Beck Depression Inventory (BDI) (p = .03) and Beck Anxiety Inventory (BAI) (p = .01) and high-sensitivity C-reactive protein (hs-CRP) level (p = .005) when comparing with the placebo group. Moreover, CoQ10 group exhibited a significant drop in total testosterone (p = .004), dehydroepiandrosterone sulfate (DHEAS) (p < .001), hirsutism (p = .002) and malondialdehyde (MDA) (p = .001) levels in the serum, and a significant rise in sex hormone-binding globulin (SHBG) (p < .001) and total antioxidant capacity (TAC) (p < .001) levels in the serum than the placebo group. CONCLUSIONS: 12-week supplementation of CoQ10 to PCOS women showed beneficial impact on BDI, BAI, hs-CRP, total testosterone, DHEAS, hirsutism, SHBG, TAC and MDA levels.

Pediatric adrenocortical tumors cohort characteristics and long-term follow-up at a single Argentinian tertiary center.

Pediatric adrenocortical tumors are rare and heterogeneous endocrine malignancies. OBJECTIVES: To report clinical, biochemical, and histological features, staging, and therapeutic interventions in a cohort of 28 patients treated at a single tertiary center. METHODS: A retrospective review of medical records of children with PACT (diagnosed before <18 years of age) followed between 1987-2018 at Hospital de Pediatría Garrahan, Buenos Aires, Argentina. RESULTS: Mean age at diagnosis was 4.6 years (range, 0.3-17.3 years) and median follow-up was 4.17 years (range, 0-12 years). Female to male ratio was 2.5:1. Signs and symptoms that prompted medical intervention were hormonal overproduction (57%), abdominal complaints (36%), and hypertensive encephalopathy (7%). In patients with clinically virilizing tumors (n=16) mean height standard deviation score (SDS) and bone age advance were significantly higher while body mass index (BMI) SDS was significantly lower than in those with clinical Cushing's (n=10) (p<0.05). Serum dehydroepiandrosterone sulfate (DHEAS) levels were significantly higher in stage IV than in stage I (p=0.03). Total adrenalectomy was performed in 26 patients. Eight patients (stage III-IV) received adjuvant chemotherapy. Five-year overall and disease-free survival were 100% for ST I-II, and 51% (95% CI 21-82) and 33% (95% CI 1.2-65) for ST III-IV, respectively (p=0.002). No statistical difference was found when comparing 2-year parameters with and without adjuvant chemotherapy. CONCLUSIONS: Height SDS and BMI SDS seem to mirror hormonal secretion in pediatric adrenocortical tumors. Higher DHEAS levels were found in patients with more advanced disease. Further large-scale studies are needed to validate a possible role for DHEAS as a biochemical marker of tumor stage and to draw robust conclusions on the use of adjuvant chemotherapy.

Endogenous Circulating Sex Hormone Concentrations and Colon Cancer Risk in Postmenopausal Women: A Prospective Study and Meta-Analysis.

Background: Observational studies have consistently reported that postmenopausal hormone therapy use is associated with lower colon cancer risk, but epidemiologic studies examining the associations between circulating concentrations of endogenous estrogens and colorectal cancer have reported inconsistent results. Methods: We investigated the associations between circulating concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA), progesterone, and sex hormone-binding globulin (SHBG) with colon cancer risk in a nested case-control study of 1028 postmenopausal European women (512 colon cancer cases, 516 matched controls) who were noncurrent users of exogenous hormones at blood collection. Multivariable conditional logistic regression models were used to compute odds ratios and 95% confidence intervals to evaluate the association between circulating sex hormones and colon cancer risk. We also conducted a dose-response meta-analysis of prospective studies of circulating estrone and estradiol with colorectal, colon, and rectal cancer risk in postmenopausal women. All statistical tests were 2-sided. Results: In the multivariable model, a nonstatistically significantly positive relationship was found between circulating estrone and colon cancer risk (odds ratio per log2 1-unit increment = 1.17 [95% confidence interval = 1.00 to 1.38]; odds ratioquartile4-quartile1 = 1.33 [95% confidence interval = 0.89 to 1.97], P trend = .20). Circulating concentrations of estradiol, free estradiol, testosterone, free testosterone, androstenedione, DHEA, progesterone, and SHBG were not associated with colon cancer risk. In the dose-response meta-analysis, no clear evidence of associations were found between circulating estradiol and estrone concentrations with colorectal, colon, and rectal cancer risk. Conclusion: Our observational and meta-analysis results do not support an association between circulating concentrations of endogenous sex hormones and colon or rectal cancer in postmenopausal women.

A potential role for the adrenal gland in autism.

Androgens have been implicated in autism pathophysiology as recently, prenatal exposure to elevated androgens has been proposed as risk factor. However, published data on postnatal sex hormone levels in autistic children are controversial and the source of prenatal androgen exposure in autism remains unknown. Therefore, this study investigated postnatal sex hormone levels and dehydroepiandrosterone (DHEA) to shed light on a potential role for the adrenal gland in autism pathophysiology. A case-control study investigating estradiol (E2), DHEA, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels was conducted with 31 Saudi males with autism and 28 healthy, age-matched boys plasma. Moreover, correlation analysis with measured hormones and previously measured total testosterone (TT) and free testosterone (FT) in the same group of autism was conducted. DHEA was significantly higher (p < 0.05) in the autism group compared to controls. DHEA positively correlated with previously measured TT (r = + 0.79, p < 0.001) and FT (r = + 0.72, p < 0.001) levels in the same autism group. FSH levels were also significantly higher in the autism group than in the control group (p < 0.01). To the best of our knowledge, this is the first study to report a strong positive correlation between TT, FT and DHEA, suggesting an adrenal source for elevated androgen levels.

Correlations of androstenediol with reproductive hormones and cortisol according to stages during the menopausal transition in Japanese women.

Associations of androstenediol, which has both androgenic and estrogenic activities, with circulating reproductive hormones and stress hormone in women during the menopausal transition may be different depending on the menopausal stage. The aim of this study was to determine the changes in circulating androstenediol during the menopausal transition in Japanese women and the associations of androstenediol with estrogen, androgen and cortisol for each stage of the menopausal transition. We divided the 104 subjects into 6 stages by menstrual regularity and follicle-stimulating hormone level: mid reproductive stage, late reproductive stage, early menopausal transition, late menopausal transition, very early postmenopause and early postmenopause. Levels of dehydroepiandrosterone sulfate (DHEAS), estradiol, estrone, testosterone (T), free T, androstenedione and cortisol were measured. Serum androstenediol concentration was measured by using liquid chromatography mass spectrometry. There were no significant differences in androstenediol levels among the 6 stages. Levels of DHEA-S and testosterone showed significant and positive correlations with androstenediol in all stages. Estradiol levels showed negative correlations with androstenediol levels in the late menopausal transition and very early postmenopause (r=-0.452, p = 0.052 and r=-0.617, p = 0.006, respectively). Cortisol levels showed significant and positive correlations with androstenediol levels in the mid and late reproductive stages (r = 0.719, p = 0.003 and r = 0.808, p < 0.001, respectively).The associations of androstenediol with estradiol and cortisol were different depending on the stage of the menopausal transition. Androstenediol may play a compensatory role for estrogen deficiency from late menopausal transition to very early postmenopause.

DHEAS and Differential Blood Counts as Indirect Signs of Glucocorticoid Excess in Adrenal Non-Producing Adenomas.

The majority of incidentally discovered adrenal tumors are later characterized as non-producing adrenocortical adenomas (NPA). We asked whether laboratory abnormalities in parameters that reflect glucocorticoid action can be found in patients with NPA despite their nature of being clinically unapparent. Since glucocorticoids are potent immunosuppressants we studied blood counts and differential blood counts along with corticotropin and dehydroepiandrostenedione sulfate (DHEAS) blood concentrations, as well as cortisol values before and after an overnight 1 mg dexamethasone suppression test. We compared the results of normal individuals, of patients with adrenal adenomas and normal hormone profiles and with subclinical autonomous glucocorticoid hypersecretion, as well as overt cortisol excess. We found that almost all indices of the blood counts were significantly different between the patients groups. In particular, patients with adrenal non-producing adenomas already showed signs of glucocorticoid excess, including relative lymphocytopenia, lowered DHEAS, and ACTH concentrations than control individuals. We also found that the extent of lymphocytopenia correlated with the concentrations of DHEAS and ACTH, and DHEAS correlated well with ACTH. We conclude that the basal ACTH and DHEAS values along with the differential blood counts give good information on the extent of glucocorticoid excess and that silent adrenal adenomas seem to oversecrete glucocorticoids at concentrations that already alter these parameters.

Diagnostic value of standard deviation score of log-transformed serum dehydroepiandrosterone sulfate in patients with hypothalamic-pituitary-adrenal axis insufficiency.

Serum dehydroepiandrosterone sulfate (DHEA-S) levels reflect the state of adrenocorticotropic hormone (ACTH) secretion. However, it is difficult to use serum DHEA-S to diagnose hypothalamic-pituitary-adrenal (HPA) axis insufficiency due to its non-normal and highly skewed distribution. In this study, we focused on HPA insufficiency caused by hypothalamic and/or pituitary dysfunction and evaluated the usefulness of the standard deviation score of log-transformed DHEA-S (ln DHEA-S SD score), which was calculated from the established age- and sex-specific reference values. We retrospectively reviewed the medical records of 94 patients suspected of having HPA insufficiency, in whom serum DHEA-S measurement and the rapid ACTH stimulation test were performed, and included 65 patients who met our criteria in this study. The ln DHEA-S SD scores were distributed more normally than measured DHEA-S levels and were significantly higher in patients with a peak cortisol level ≥18 µg/dL than in those below this value, suggesting that this score is a legitimate and strong indicator of adrenocortical function. The optimal cut-off value for impaired HPA function was -0.853, with a sensitivity of 70.3% and a specificity of 100%. Among the 37 patients whose peak cortisol levels were below 18 µg/dL, 11 patients with ln DHEA-S scores ≥-0.853 exhibited significantly higher basal ACTH and basal and peak cortisol levels than the 26 patients with scores <-0.853. Thus, this score plays a supportive role in evaluating HPA axis function, particularly in patients with borderline cortisol responses to ACTH.

Differential Effects of Various Androgens on Polycystic Ovary Syndrome.

The hyperandrogenism in polycystic ovary syndrome (PCOS) is associated with the risk for the future development of the cardiovascular disease. The objective of the study is to verify whether different androgens have the same harmful effect. This cross-sectional study enrolled 823 women with PCOS: 627 (76.2%) with biochemical hyperandrogenism and 196 (23.8%) with normal androgen levels. The role of individual androgen was evaluated using univariate and multivariate logistic regression. In normoandrogenemic PCOS (NA-PCOS), free androgen index (FAI) predicted significant abnormality in visceral adipose index (VAI, OR=9.2, p=0.002) and dehydroepiandrosterone (DHEA) predicted against alteration in ß-cell function (OR=0.5, p=0.007). In hyperandrogenemic PCOS (HA-PCOS), FAI predicted derangements in waist triglyceride index (WTI), VAI, and lipid accumulation product (LAP) (OR ranging from 1.6 to 5.8, p<0.05). DHEA weakly predicted against VAI (OR 0.7, p=0.018), dehydroepiandrosterone sulfate (DHEAS) tended to predict against the conicity index (OR=0.7, p=0.037). After multiple regression, FAI retained significant strength to predict various anthropometric and metabolic abnormalities (OR ranging from 1.1 to 3.0, p<0.01), DHEA was kept as a protector factor against WTI, LAP, and VAI (OR ranging from 0.6 to 0.9; p<0.01) and DHEAS against the conicity index (OR=0.5, p<0.001). In conclusion, the free androgen index was the most powerful predictor of anthropometric and metabolic abnormalities of polycystic ovary syndrome. Conversely, DHEA and DHEAS demonstrated protective effects against disorders in some markers of obesity and abnormal metabolism.

Dexamethasone suppression test versus selective ovarian and adrenal vein catheterization in identifying virilizing tumors in postmenopausal hyperandrogenism - a systematic review and meta-analysis.

OBJECTIVE: The diagnostic accuracy of tests in identifying virilizing tumors in postmenopausal hyperandrogenism is limited. This systematic review compares the dexamethasone suppression test against selective ovarian and adrenal vein sampling of androgens in distinguishing neoplastic from non-neoplastic causes of postmenopausal hyperandrogenism. METHODS: Diagnostic test accuracy studies on these index tests in postmenopausal women were selected based on pre-established criteria. The true positive, false positive, false negative, and true negative values were extracted and meta-analysis was conducted using the hierarchical summary receiver operator characteristics curve method. RESULTS: The summary sensitivity of the dexamethasone suppression test is 100% (95% CI 0-100%) and that for selective venous sampling is 100% (95% CI 0-100%). The summary specificity of the dexamethasone suppression test is 89.2% (95% CI 85.3-92.2%) and that for selective venous sampling is 100% (95% CI 0.3-100%). CONCLUSION: There is limited evidence for the use of dexamethasone suppression test or selective venous sampling in identifying virilizing tumors in postmenopausal hyperandrogenism.

Benefits of Airway Androgen Receptor Expression in Human Asthma.

Rationale: Androgens are potentially beneficial in asthma, but AR (androgen receptor) has not been studied in human airways.Objectives: To measure whether AR and its ligands are associated with human asthma outcomes.Methods: We compared the effects of AR expression on lung function, symptom scores, and fractional exhaled nitric oxide (FeNO) in adults enrolled in SARP (Severe Asthma Research Program). The impact of sex and of androgens on asthma outcomes was also evaluated in the SARP with validation studies in the Cleveland Clinic Health System and the NHANES (U.S. National Health and Nutrition Examination Survey).Measurements and Main Results: In SARP (n = 128), AR gene expression from bronchoscopic epithelial brushings was positively associated with both FEV1/FVC ratio (R2 = 0.135, P = 0.0002) and the total Asthma Quality of Life Questionnaire score (R2 = 0.056, P = 0.016) and was negatively associated with FeNO (R2 = 0.178, P = 9.8 × 10-6) and NOS2 (nitric oxide synthase gene) expression (R2 = 0.281, P = 1.2 × 10-10). In SARP (n = 1,659), the Cleveland Clinic Health System (n = 32,527), and the NHANES (n = 2,629), women had more asthma exacerbations and emergency department visits than men. The levels of the AR ligand precursor dehydroepiandrosterone sulfate correlated positively with the FEV1 in both women and men.Conclusions: Higher bronchial AR expression and higher androgen levels are associated with better lung function, fewer symptoms, and a lower FeNO in human asthma. The role of androgens should be considered in asthma management.

Comparison of the efficacy of different androgens measured by LC-MS/MS in representing hyperandrogenemia and an evaluation of adrenal-origin androgens with a dexamethasone suppression test in patients with PCOS.

BACKGROUND: The aims of this study were to compare the efficacy of different androgens measured by liquid chromatography-mass spectrometry (LC-MS/MS) in representing hyperandrogenemia and to evaluate adrenal-origin androgens with a dexamethasone suppression test in patients with polycystic ovary syndrome (PCOS). METHODS: One hundred and two patients with PCOS and 41 healthy volunteers were recruited and total serum testosterone (TT), androstenedione (AD), dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) were measured by LC-MS/MS. ROC analysis was performed to compare the efficacy of different androgens in representing hyperandrogenemia. Dexamethasone suppression test was performed in 51 patients with PCOS and above indicators were measured after dexamethasone administration. The prediction efficacy of DHEA and DHEA-S at baseline in the dexamethasone suppression test was evaluated with ROC analysis. RESULTS: The AUCs of TT, AD, free androgen index (FAI) and DHEA-S in ROC analysis for representing hyperandrogenemia were 0.816, 0.842, 0.937 and 0.678, respectively. The optimal cutoff value of TT was 0.337 ng/ml, with a sensitivity of 72.0% and specificity of 82.93%. The optimal cutoff value for AD was 1.309 ng/ml, with a sensitivity of 81.0% and specificity of 73.17%. The optimal cutoff value of the FAI was 2.50, with a sensitivity of 87.0% and specificity of 92.68%. Alternatively, AD or FAI more than the optimal cutoff values as evidence of hyperandrogenemia had the highest sensitivity of 91.18%. The levels of cortisol, DHEA and DHEA-S were all suppressed to narrow ranges after dexamethasone administration. Nine and 8 of 51 patients with PCOS had significant decreases in TT and AD, respectively. DHEA can be used as a indicator for predicting significant decrease of TT in dexamethasone suppression test with cutoff value of 13.28 ng/ml. A total of 27.5% (14/51) of patients had DHEA-S excess, but only 1 of 9 patients who had a significant decrease in TT had elevated level of DHEA-S at baseline. CONCLUSIONS: AD measured by LC-MS/MS can represent hyperandrogenemia in PCOS patients and, combined with TT or FAI, can improve the screening efficiency of hyperandrogenemia. Seventeen percent of PCOS patients had adrenal-origin androgen dominance, with TT significantly decreasing after 2 days of dexamethasone administration. Adrenal-origin androgen dominance was not parallel with DHEA-S excess in patients with PCOS.

Menstrual dysfunction in polycystic ovary syndrome: association with dynamic state insulin resistance rather than hyperandrogenism.

OBJECTIVE: To examine the relation of menstrual cyclicity abnormalities to hyperandrogenism (HA) and dynamic state insulin resistance (IR) in oligo-ovulatory women with polycystic ovary syndrome (PCOS). DESIGN: Prospective cross-sectional study. SETTING: Tertiary-care academic center. PATIENT(S): Fifty-seven women with PCOS (1990 National Institutes of Health criteria) and 57 healthy control women matched by body mass index (BMI). INTERVENTION(S): Short insulin tolerance test (ITT). MAIN OUTCOME MEASURE(S): Menstrual cyclicity, sex hormone-binding globulin (SHBG), measures of HA (i.e., modified Ferriman-Gallwey score, total and free testosterone, dehydroepiandrosterone sulfate), and the rate constant for plasma glucose disappearance (kITT) derived from the short ITT. RESULT(S): Adjusting for age, BMI, and ethnicity, the mean androgen measures were higher and SHBG trended lower, kITT was lower, and the prevalence of IR was higher in PCOS than in controls, independent of menstrual cyclicity. The optimal cutoff point for IR was set at kITT value of 3.57%/minute or lower. Overall, 79% of the women with PCOS had IR. To control further for the effect of ethnicity, a subgroup of 46 non-Hispanic white PCOS participants were studied; those who exhibited amenorrhea (n = 15) or oligomenorrhea (n = 19) had or tended toward having a lower kITT and a higher prevalence of IR than the women with PCOS and oligo-ovulatory eumenorrhea (n = 12). The kITT trended lower and the prevalence of IR trended higher in women with PCOS and amenorrhea than those with oligomenorrhea. The measures of SHBG and HA were similar across the three menstrual groups. CONCLUSION(S): Oligo-ovulatory women with PCOS and overt oligo/amenorrhea have greater degrees of IR but not HA when compared with oligo-ovulatory eumenorrheic women with PCOS, suggesting that IR and hyperinsulinemia but not HA play a role in determining the degree of menstrual dysfunction, which can be used as a clinical marker for the degree of IR in oligo-ovulatory PCOS.

Effect of atorvastatin on testosterone levels.

BACKGROUND: Statins are one of the most prescribed classes of drugs worldwide. Atorvastatin, the most prescribed statin, is currently used to treat conditions such as hypercholesterolaemia and dyslipidaemia. By reducing the level of cholesterol, which is the precursor of the steroidogenesis pathway, atorvastatin may cause a reduction in levels of testosterone and other androgens. Testosterone and other androgens play important roles in biological functions. A potential reduction in androgen levels, caused by atorvastatin might cause negative effects in most settings. In contrast, in the setting of polycystic ovary syndrome (PCOS), reducing excessive levels of androgens with atorvastatin could be beneficial. OBJECTIVES: Primary objective To quantify the magnitude of the effect of atorvastatin on total testosterone in both males and females, compared to placebo or no treatment. Secondary objectives To quantify the magnitude of the effects of atorvastatin on free testosterone, sex hormone binding globin (SHBG), androstenedione, dehydroepiandrosterone sulphate (DHEAS) concentrations, free androgen index (FAI), and withdrawal due to adverse effects (WDAEs) in both males and females, compared to placebo or no treatment. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to 9 November 2020: the Cochrane Hypertension Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; ;two international trials registries, and the websites of the US Food and Drug Administration, the European Patent Office and the Pfizer pharmaceutical corporation. These searches had no language restrictions. We also contacted authors of relevant articles regarding further published and unpublished work. SELECTION CRITERIA: RCTs of daily atorvastatin for at least three weeks, compared with placebo or no treatment, and assessing change in testosterone levels in males or females. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the citations, extracted the data and assessed the risk of bias of the included studies. We used the mean difference (MD) with associated 95% confidence intervals (CI) to report the effect size of continuous outcomes,and the risk ratio (RR) to report effect sizes of the sole dichotomous outcome (WDAEs). We used a fixed-effect meta-analytic model to combine effect estimates across studies, and risk ratio to report effect size of the dichotomous outcomes. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included six RCTs involving 265 participants who completed the study and their data was reported. Participants in two of the studies were male with normal lipid profile or mild dyslipidaemia (N = 140); the mean age of participants was 68 years. Participants in four of the studies were female with PCOS (N = 125); the mean age of participants was 32 years. We found no significant difference in testosterone levels in males between atorvastatin and placebo, MD -0.20 nmol/L (95% CI -0.77 to 0.37). In females, atorvastatin may reduce total testosterone by -0.27 nmol/L (95% CI -0.50 to -0.04), FAI by -2.59 nmol/L (95% CI -3.62 to -1.57), androstenedione by -1.37 nmol/L (95% CI -2.26 to -0.49), and DHEAS by -0.63 µmol/l (95% CI -1.12 to -0.15). Furthermore, compared to placebo, atorvastatin increased SHBG concentrations in females by 3.11 nmol/L (95% CI 0.23 to 5.99). We identified no studies in healthy females (i.e. females with normal testosterone levels) or children (under age 18). Importantly, no study reported on free testosterone levels. AUTHORS' CONCLUSIONS: We found no significant difference between atorvastatin and placebo on the levels of total testosterone in males. In females with PCOS, atorvastatin lowered the total testosterone, FAI, androstenedione, and DHEAS. The certainty of evidence ranged from low to very low for both comparisons. More RCTs studying the effect of atorvastatin on testosterone are needed.

The effect of synbiotic on glycemic profile and sex hormones in overweight and obese breast cancer survivors following a weight-loss diet: A randomized, triple-blind, controlled trial.

BACKGROUND: The investigation was designed to assess the effects of synbiotic supplementation on glycemic profile, insulin-like growth factor-1 (IGF-1) and sex hormones in overweight and obese postmenopausal breast cancer survivors (BCSs) who had hormone-receptor-positive breast cancer. METHODS: This randomized, triple-blind, placebo-controlled trial was conducted on 76 overweight and obese BCSs aged 57.43 (5.82) years. All participants were given a specified low calorie diet and were randomly assigned into two groups to intake 109 CFU/day of synbiotic supplement (n = 38) or placebo (n = 38) for 8 weeks. Body composition, physical activity, glycemic profile, IGF-1, estradiol, testosterone and dehydroepiandrosterone sulfate (DHEA-S) were measured at baseline and after 8 weeks. RESULTS: A significant reduction in serum insulin (median change (Q1, Q3) from baseline of -1.05 (-2.36, 0.32) µIU/mL; P = 0.006) and insulin resistance (HOMA-IR) (mean change (SD) from baseline of -4.0 (0.9); P = 0.007) were seen over the 8 weeks in the synbiotic group. However, no significant changes were observed in serum insulin, fasting plasma glucose, HbA1c, HOMA-IR, IGF-1, estradiol, testosterone, DHEA-S and sex hormone binding globulin between-groups at the end of the intervention. CONCLUSIONS: Overall, as the 8-week synbiotic consumption compared with placebo had insignificant-reducing effects on glycemic profile, IGF-1 and sex hormones among overweight and obese postmenopausal BCSs, synbiotics may exert considerable beneficial consequences, which need to be further assessed in future clinical trials. TRIAL REGISTRATION: IRCT, IRCT2015090223861N1. Registered 02 February 2017, http://www.irct.ir: IRCT2015090223861N1.

Heterogeneity of Endocrinologic and Metabolic Parameters in Reproductive Age Polycystic Ovary Syndrome (PCOS) Women Concerning the Severity of Hyperandrogenemia-A New Insight on Syndrome Pathogenesis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, anovulation, infertility, obesity, and insulin resistance, which results in increased concentrations of testosterone (T), which disturbs follicular growth and ovulation. This study aimed to assess PCOS women's clinical, endocrinological, and metabolic parameters concerning hyperandrogenism severity. RESULTS: 314 women (mean age 27.3 ± 4.6; mean body mass index (BMI) 25.7 ± 5.6) with PCOS, were divided into terciles according to T concentrations: <0.64 ng/mL (group 1), 0.64 to 0.84 ng/mL (Group 2) and >0.84 ng/mL (group 3). The mean concentration of T in all women was 0.59 ng/mL and correlated negatively with the number of menstrual cycles per year (MPY) (r = -0.36; p < 0.0001) and positively with Ferriman-Gallway score (FG) (r = 0.33; p < 0.0001), luteinizing hormone (LH) (r = 0.19; p < 0.0001) and dehydroepiandrosterone sulfate (DHEAS) (r = 0.52; p < 0.0001). Positive correlation between BMI and hirsutism (r = 0.16; p < 0.0001), total cholesterol (TC) (r = 0.18; p < 0.0001), low-density lipoprotein (LDL) (r = 0.29; p < 0.0001), and triglycerides (TG) (r = 0.40; p < 0.0001) was demonstrated. The division into subgroups confirmed the lowest MPY, highest LH, and hirsutism in group 3. BMI, insulin sensitivity indices, and lipid profile parameters were not different between the three T subgroups. CONCLUSIONS: We found no correlation between testosterone levels and insulin sensitivity or dyslipidemia in women with PCOS. Metabolic abnormalities may contribute more significantly than hyperandrogenemia to PCOS development.

In utero and peripubertal metals exposure in relation to reproductive hormones and sexual maturation and progression among boys in Mexico City.

BACKGROUND: Endocrine disrupting chemicals (EDCs) such as metals have been reported to alter circulating reproductive hormone concentrations and pubertal development in animals. However, the relationship has rarely been investigated among humans, with the exception of heavy metals, such as Pb and Cd. Our aim was to investigate measures of in utero and peripubertal metal exposure in relation to reproductive hormone concentrations and sexual maturation and progression among boys from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohorts. METHODS: Our analysis included 118 pregnant women and their male children from the ELEMENT study. Essential and non-essential metals were measured in urine collected from the mothers during the third trimester of pregnancy and their male children at 8-14 years. Reproductive hormone concentrations [serum testosterone, estradiol, dehydroepiandrosterone sulfate (DHEA-S), inhibin B, and sex hormone-binding globulin (SHBG)] were measured in blood samples from the children at 8-14 years. We also assessed Tanner stages for sexual maturation (genital, pubic hair development, and testicular volume), at two time points (8-14, 10-18 years). We used linear regression to independently examine urinary metal concentrations in relation to each peripubertal reproductive hormones adjusting for child age and BMI. Generalized estimation equations (GEEs) were used to evaluate the association of in utero and peripubertal metal exposures with sexual maturation and progression during follow-up based on Tanner staging and testicular volume. RESULTS: In utero and prepubertal concentrations of some urinary metals were associated with increased concentrations of peripubertal reproductive hormones, especially non-essential metal(loid)s As and Cd (in utero), and Ba (peripubertal) as well as essential metal Mo (in utero) in association with testosterone. More advanced pubic hair developmental stage and higher testicular volume at the early teen visit was observed for boys with higher non-essential metal concentrations, including in utero Al and peripubertal Ba, and essential metal Zn concentration (peripubertal). These metals were also associated with slower pubertal progression between the two visits. CONCLUSION: These findings suggest that male reproductive development may be associated with both essential and non-essential metal exposure during in utero and peripubertal windows.

Correlation Between Fecal Metabolomics and Gut Microbiota in Obesity and Polycystic Ovary Syndrome.

Objective: This study aimed to explore the relationship between the fecal metabolites and gut microbiota in obese patients with PCOS and provide a new strategy to elucidate the pathological mechanism of obesity and PCOS. Methods: The fecal samples of obese patients with PCOS (n = 18) and obese women without PCOS (n = 15) were analyzed by 16S rRNA gene sequencing and untargeted metabolomics. The peripheral venous blood of all subjects was collected to detect serum sex hormones. The association among fecal metabolites, gut microbiota, and serum sex hormones was analyzed with the R language. Results: A total of 122 named differential fecal metabolites and 18 enrichment KEGG pathways were obtained between the groups. Seven fecal metabolites can be used as characteristic metabolites, including DHEA sulfate. The richness and diversity of gut microbiota in the obese PCOS group were lower than those in the control group. Lachnoclostridium, Fusobacterium, Coprococcus_2, and Tyzzerela 4 were the characteristic genera of the obese patients with PCOS. Serum T level significantly and positively correlated with the abundance of fecal DHEA sulfate (p < 0.05), and serum DHEAS level significantly and negatively correlated with the abundance of fecal teasterone (p < 0.05). Conclusion: Specific fecal metabolites may be used as characteristic metabolites for obese patients with PCOS. The closely relationship among gut microbiota, fecal metabolites, and serum sex hormones may play a role in the related changes caused by hyperandrogenemia.

Analytical bias of automated immunoassays for six serum steroid hormones assessed by LC-MS/MS.

INTRODUCTION: There is a growing amount of evidence showing the significant analytical bias of steroid hormone immunoassays, but large number of available immunoassays makes conduction of a single comprehensive study of this issue hardly feasible. Aim of this study was to assess the analytical bias of six heterogeneous immunoassays for serum aldosterone, cortisol, dehydroepiandrosterone sulphate (DHEAS), testosterone, 17-hydroxyprogesterone (OHP) and progesterone using the liquid chromatography coupled to the tandem mass spectrometry (LC-MS/MS). MATERIALS AND METHODS: This method comparison study included 49 serum samples. Testosterone, DHEAS, progesterone and cortisol immunoassays were performed on the Abbott Architect i2000SR or Alinity i analysers (Abbott Diagnostics, Chicago, USA). DiaSorin's Liaison (DiaSorin, Saluggia, Italy) and DIAsource's ETI-Max 3000 analysers (DIAsource ImmunoAssays, Louvain-La-Neuve, Belgium) were chosen for aldosterone and OHP immunoassay testing, respectively. All immunoassays were evaluated against the LC-MS/MS assay relying on the commercial kit (Chromsystems, Gräfelfing, Germany) and LCMS-8050 analyser (Shimadzu, Kyoto, Japan). Analytical biases were calculated and method comparison was conducted using weighted Deming regression analysis. RESULTS: Depending on the analyte and specific immunoassay, mean relative biases ranged from -31 to + 137%. Except for the cortisol, immunoassays were positively biased. For none of the selected steroids slope and intercept 95% confidence intervals simultaneously contained 0 and 1, respectively. CONCLUSIONS: Evaluated immunoassays failed to satisfy requirements for methods' comparability and produced significant analytical biases in respect to the LC-MS/MS assay, especially at low concentrations.

Menstrual Pattern, Reproductive Hormones, and Transabdominal 3D Ultrasound in 317 Adolescent Girls.

CONTEXT: The knowledge of normal variation of reproductive hormones, internal genitalia imaging, and the prevalence of gynecological disorders in adolescent girls is limited. OBJECTIVE: The study aimed to describe reproductive parameters in postmenarchal girls from the general population including the frequency of oligomenorrhea, polycystic ovary syndrome, and use of hormonal contraception. DESIGN: The Copenhagen Mother-Child Cohort is a population-based longitudinal birth cohort of 1210 girls born between 1997 and 2002. SETTING: University hospital. PARTICIPANTS: A total of 317 girls were included, with a median age of 16.1 years and time since menarche of 2.9 years. MAIN OUTCOME MEASURE(S): Tanner stage, height, weight, age at menarche, menstrual cycle length and regularity, ovarian/uterine volume, and number of follicles were recorded. Serum concentrations of FSH, LH, anti-Müllerian hormone (AMH), inhibin B, estradiol, testosterone, SHBG, androstenedione, dehydroepiandrosterone sulfate, 17-OH-progesterone, and IGF-1 were measured. RESULTS: Twenty girls (6.3%) had oligomenorrhea and differed significantly in serum androgens and AMH, age at and time since menarche from girls with regular cycles. Twenty-seven girls were classified with PCOS (8.5%) and had significantly higher 17-OH-progesterone, estradiol, AMH, LH, and age at menarche than the reference group. Girls on oral contraception had significantly higher serum SHBG concentrations and lower serum concentrations of all hormones except AMH and IGF-1. Ovarian follicles 2 to 29.9 mm correlated positively with serum AMH (P < 0.0001). CONCLUSIONS: Most 16-year-old girls had regular menstrual cycles, normal reproductive hormones, and uterine and ovarian ultrasound. Serum AMH reflected ovarian follicle count and may be a useful biomarker of ovarian reserve.