Increased Prevalence of Elevated DHEAS in PCOS Women with Non-Classic (B or C) Phenotypes: A Retrospective Analysis in Patients Aged 20 to 29 Years.

It is well known that a subgroup of women with PCOS present an excessive adrenal androgen production, generally associated with ovarian hyperandrogenism. In the past, it has been impossible to correlate adrenal hyperandrogenism to any clinical or hormonal pattern of PCOS. However, adrenal androgens are strictly dependent on age and their blood values reduce by 40% in patients moving from their twenties to thirties. Due to this, serum DHEAS values are strongly influenced by the age distribution of studied populations. To avoid this bias, in this study we retrospectively analyzed the clinical and hormonal data of PCOS women in their twenties (age between 20 and 29 years). Data of 648 young hyperandrogenic women with PCOS were evaluated. Serum DHEAS was increased in a third (33%) of studied patients and was associated with higher values of testosterone (T) and androstenedione (A). In each phenotype, patients with high DHEAS had higher values of T and A than patients with normal DHEAS of the same phenotype. Therefore, a DHEAS increase is generally part of a generalized higher androgen production in a subgroup of PCOS patients, independently of the finding of anovulatory or ovulatory cycles or of polycystic or normal ovaries. However, our study showed some important differences between PCOS phenotypes. A lower prevalence of increased DHEAS in A phenotype PCOS patients who generally have the highest androgen levels, versus non-classic (B or C) PCOS phenotypes, was observed. It was also found that patients with A phenotype PCOS present significantly lower BMI and serum insulin than patients with normal DHEAS of the same phenotype while, in patients with the B or C phenotype, the opposite occurs. We conclude that adrenal hyperandrogenism is more common in patients with non-classic (B and C) phenotypes of PCOS and is generally part of a generalized higher production of androgens in a subgroup of PCOS patients. However, other factors may increase the adrenal androgen production and influence the clinical expression of the syndrome. More studies in large, selected for age, populations of PCOS women with different phenotypes are needed.

The Immunoregulatory Actions of DHEA in Tuberculosis, A Tool for Therapeutic Intervention?

Dehydroepiandrosterone (DHEA) is an androgen synthesized by the adrenal cortex, which is an intermediary in the biosynthesis of sex hormones, such as testosterone and estradiol. DHEA mostly circulates as a conjugated ester, in the form of sulfate (DHEA-S). There exist several endogenous factors able to influence its synthesis, the most common ones being the corticotrophin-releasing hormone (CRH), adrenocorticotrophin (ACTH), growth factors, and proinflammatory cytokines, among others. Like other steroid hormones, DHEA, can alter the functioning of immune cells and therefore the course of diseases exhibiting an immune-inflammatory component, mostly from autoimmune or infectious nature. We herein review the role played by DHEA during a major infectious disease like tuberculosis (TB). Data recorded from TB patients, mouse models, or in vitro studies show that DHEA is likely to be implied in better disease control. This provides a stimulating background for carrying out clinical studies aimed at assessing the usefulness of DHEA as an adjuvant in TB patients.

Adrenal Androgen Predictive Effects on Clinical and Metabolic Abnormalities of Polycystic Ovary Syndrome.

OBJECTIVE: To examine the possible effects of adrenal prohormones in the prediction of clinical and metabolic abnormalities in women with polycystic ovary syndrome (PCOS). METHODS: The present study enrolled 299 normal cycling non-PCOS, 156 normoandrogenemic, and 474 hyperandrogenemic women with PCOS. Baseline characteristics were compared using a chi-squared test or analysis of variance (ANOVA) as appropriate. The roles of adrenal prohormones and their ratios with total testosterone in predicting co-occurring morbidities in women PCOS were evaluated using univariate and multivariate logistic regression analyses. RESULTS: Adrenal hyperandrogenism per dehydroepiandrosterone sulfate (DHEAS) levels were found in 32% of women with PCOS. In non-PCOS women, dehydroepiandrosterone (DHEA) and its sulfate had no predictive role concerning clinical, anthropometric, and metabolic parameters. In PCOS women, mainly in the hyperandrogenemic group, DHEA showed to be a significant predictor against most anthropometric-metabolic index abnormalities (odds ratio [OR] = 0.36-0.97; p < 0.05), and an increase in triglycerides (TG) levels (OR = 0.76; p = 0.006). Dehydroepiandrosterone sulfate presented a few predictive effects regarding PCOS-associated disorders. In controls, DHEAS predicted against the increase in estimated average glucose (OR= 0.38; p = 0.036). In the normoandrogenic group, it predicted against elevation in the waist/hip ratio (WHR) (OR= 0.59; p = 0.042), and in hyperandrogenemic PCOS women, it predicted against abnormality in the conicity index (CI) (OR = 0.31; p = 0.028). CONCLUSION: Dehydroepiandrosterone was shown to be a better predictor of abnormal anthropometric and biochemical parameters in women with PCOS than DHEAS. Thus, regarding adrenal prohormones, DHEA measurement, instead of DHEAS, should be preferred in PCOS management. The effects of androgen prohormones on the prediction of PCOS abnormalities are weak.

OBJETIVO: Examinar os possíveis efeitos dos pró-hormônios adrenais na predição de alterações clínicas e metabólicas em mulheres com síndrome dos ovários policísticos (SOP). MéTODOS: O presente estudo envolveu 299 mulheres com ciclos menstruais regulares e 630 mulheres com SOP, sendo 156 normoandrogenêmicas e 474 hiperandrogenêmicas. As variáveis incluídas como objeto do estudo foram comparadas entre os grupos usando o teste de qui-quadrado ou análise de variância (ANOVA, na sigla em inglês). Os impactos dos pró-hormônios adrenais e suas razões com a testosterona total na predição de comorbidades em mulheres com SOP foram determinados por regressão logística univariada e multivariada. RESULTADOS: Hiperandrogenismo adrenal foi encontrado em 32% das mulheres com SOP. Nos controles, a dehidroepiandrosterona e seu sulfato (DHEAS) não mostraram significância na predição das alterações clínicas, antropométricas e metabólicas. Em mulheres com SOP, principalmente no grupo de mulheres com hiperandrogenemia, a dehidroepiandrosterona (DHEA) mostrou ser um preditor significante da maioria das anormalidades nos índices antropométrico-metabólicos (odds ratio [OR] = 0,36­0,97; p < 0,05) e aumento nos níveis de triglicerídeos (TG) (OR = 0,76; p = 0,006). A DHEAS apresentou ter pouco valor na predição dos distúrbios associados à SOP; nas mulheres com androgênios elevados, restringiu-se à predição da elevação do índice de conicidade (IC) (OR = 0,31; p = 0,028). CONCLUSãO: A DHEA mostrou ser um melhor preditor na identificação das alterações dos parâmetros antropométricos e bioquímicos em mulheres com SOP do que o seu sulfato. Assim, em relação aos pró-hormônios adrenais, a dosagem de DHEA, em vez de DHEAS, parece ser mais útil no manejo da SOP. O papel dos pró-hormônios adrenais na predição de anormalidades antropométricas e metabólicas da SOP é limitado.

Steroid Sulfatase Stimulates Intracrine Androgen Synthesis and is a Therapeutic Target for Advanced Prostate Cancer.

PURPOSE: Most patients with prostate cancer receiving enzalutamide or abiraterone develop resistance. Clinical evidence indicates that serum levels of dehydroepiandrosterone sulfate (DHEAS) and biologically active DHEA remain in the high range despite antiandrogen treatment. The conversion of DHEAS into DHEA by steroid sulfatase (STS) may contribute to sustained intracrine androgen synthesis. Here, we determine the contribution of STS to treatment resistance and explore the potential of targeting STS to overcome resistance in prostate cancer. EXPERIMENTAL DESIGN: STS expression was examined in patients and cell lines. In vitro, STS activity and expression were modulated using STS-specific siRNA or novel STS inhibitors (STSi). Cell growth, colony formation, androgen production, and gene expression were examined. RNA-sequencing analysis was conducted on VCaP cells treated with STSi. Mice were treated with STSis with or without enzalutamide to determine their effects in vivo. RESULTS: STS is overexpressed in patients with castration-resistant prostate cancer (CRPC) and resistant cells. STS overexpression increases intracrine androgen synthesis, cell proliferation, and confers resistance to enzalutamide and abiraterone. Inhibition of STS using siRNA suppresses prostate cancer cell growth. Targeting STS activity using STSi inhibits STS activity, suppresses androgen receptor transcriptional activity, and reduces the growth of resistant C4-2B and VCaP prostate cancer cells. STSis significantly suppress resistant VCaP tumor growth, decrease serum PSA levels, and enhance enzalutamide treatment in vitro and in vivo. CONCLUSIONS: These studies suggest that STS drives intracrine androgen synthesis and prostate cancer proliferation. Targeting STS represents a therapeutic strategy to treat CRPC and improve second-generation antiandrogen therapy.

Genetic variants of SLCO1B7 are of relevance for the transport function of OATP1B3-1B7.

The family of Organic Anion Transporting Polypeptides are known to facilitate the transmembrane transport. OATP1B3-1B7 is a novel member of the OATP1B-subfamily, and is encoded by SLCO1B3-SLCO1B7 readthrough deriving from the genes SLCO1B3 and SLCO1B7 on chromosome 12. The resulting protein is expressed in the smooth endoplasmatic reticulum of hepatocytes, is functional, and transports dehydroepiandrosterone-sulfate (DHEAS). In the gene area encoding for the 1B7-part of the protein, there are coding polymorphisms. It was the aim of this study to test the frequency and the impact of these genetic variants on transport activity. The minor allele frequency (MAF) of the coding polymorphisms was determined in a cohort of 192 individuals. DHEAS transport function was determined by applying the vTF-7 based heterologous expression system using plasmids encoding for OATP1B3-1B7 or the respective variants. The genetic variants 641 T (MAF 0.021), 1073 G (MAF 0.169) and 1775 A (MAF 0.013) significantly reduced DHEAS accumulation in cells transfected with OATP1B3-1B7, albeit without significantly influencing expression of the transporter as determined by Western blot analysis and immunofluorescence after heterologous expression. Genotyping revealed complete linkage of the variants 884A, 1073 G and 1501C. Presence of the haplotype abolished the DHEAS-transport function of OATP1B3-1B7. Naturally and frequently occurring genetic variants located within the gene region of SLCO1B7 encoding for the 1B7-part of OATP1B3-1B7 influence the in vitro function of this member of the OATP1B-family. With their functional characterisation, we provide the basis for pharmacogenetic studies, which may help to understand the in vivo relevance of this transporter.

Levels of sex steroid hormones and their receptors in women with preeclampsia.

BACKGROUND: Pregnant women have high serum concentrations of sex steroid hormones, which are major regulators of paracrine and autocrine responses for many maternal and placental functions. The main purpose of this study was to compare patients with preeclampsia and patients with uncomplicated pregnancies in terms of serum steroid hormones (estradiol [E2], progesterone [P4], dehydroepiandrosterone sulfate [DHEAS], and testosterone [T]) throughout pregnancy and the levels of cord blood and placental steroid receptors during the third trimester. METHODS: Quantitative real-time reverse transcription PCR, western blotting, and immunohistochemistry were used to determine the levels of steroid hormones in the serum and cord blood and the placental levels of estrogen receptor-α (ERα), ERß, androgen receptor (AR), and progesterone receptor (PR). RESULTS: There were 45 women in the uncomplicated pregnancy group and 30 women in the preeclampsia group. Serum levels of T were greater and serum levels of E2 were reduced in the preeclampsia group, but the two groups had similar levels of P4 and DHEAS during the third trimester. Cord blood had a decreased level of DHEAS in the preeclampsia group, but the two groups had similar levels of P4, E2, and T. The two groups had similar placental mRNA levels of ERα, ERß, AR, and PR, but the preeclampsia group had a higher level of ERß protein and a lower level of ERα protein. Immunohistochemistry indicated that the preeclampsia group had a greater level of ERß in the nucleus and cytoplasm of syncytiotrophoblasts and stromal cells. CONCLUSIONS: Women with preeclampsia had lower levels of steroid hormones, estrogen, and ERα but higher levels of T and ERß. These molecules may have roles in the pathogenesis of preeclampsia.

Decreased levels of liver-expressed antimicrobial peptide-2 and ghrelin are related to insulin resistance in women with polycystic ovary syndrome.

Liver-expressed antimicrobial peptide 2 (LEAP-2) is a newly identified peptide hormone involved in glucose metabolism. It acts as a noncompetitive antagonist of ghrelin hormone's receptor. Polycystic ovary syndrome (PCOS) is a common metabolic and reproductive disease associated with insulin resistance. We aimed to compare circulating LEAP-2 levels in subjects with PCOS and controls. We also focused to determine whether there was a relationship between LEAP-2 and metabolic parameters in women with PCOS. We enrolled 64 subjects with PCOS and 64 age and body mass index (BMI)-matched controls into the current cross-sectional study. Circulating LEAP-2 and ghrelin levels were measured via ELISA method. Metabolic and hormonal parameters of the involved subjects were analyzed. We found that circulating LEAP-2 and ghrelin levels were decreased in women with PCOS as compared with controls. LEAP-2 showed a positively independent association with ghrelin while LEAP-2 exhibited an inverse association with insulin resistance, BMI, and free-androgen index (FAI). Additionally, subjects having the lowest tertile of LEAP-2 were in positive link of developing PCOS risk with respect to those subjects having the highest tertile of LEAP-2 levels. Decreased LEAP-2 levels were associated with a high possibility of having PCOS risk associated with insulin resistance.

The effect of probiotics, prebiotics, and synbiotics on hormonal and inflammatory indices in women with polycystic ovary syndrome: a systematic review and meta-analysis.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is among the most prevalent endocrine disorders in women and can lead to many other disorders and chronic diseases. Thus, early diagnosis and treatment of this syndrome is important. Using probiotics, prebiotics, and synbiotics supplementations to treat PCOS seems appropriate because of their useful effects and low complications. AIMS: To assess the effects of probiotics, prebiotics, and synbiotics on hormonal indices such as testosterone, dehydroepiandrosterone sulfate (DHEA-S), sex hormone binding globulin, Free Androgen Index (FAI), and inflammatory indices, such as high sensitive C reactive protein (hsCRP), malondialdehyde (MDA), total glutathione (GSH), nitric oxide (NO), and total antioxidant capacity (TAC) as the primary outcomes and the hirsutism score as the secondary outcome. METHODS: All published articles from the beginning until 10 November 2018 in English (Cochrane Library, Web of Sciences, Google Scholar, PubMed, Scopus, and ProQuest) and Persian (SID and Magiran) databases were searched. The effect of interventions on the outcomes was reported with a standard mean difference (SMD) and confidence interval of 95%. In case of high heterogeneity, the random effect model was used instead of the fixed effect model. The statistical heterogeneity of the included clinical trials was tested using the Chi square test and I2. RESULTS: Thirteen studies with 855 participants with PCOS(438 women in the intervention group and 417 women in the control group) were included in the meta-analysis. Results of the meta-analysis showed that the SHBG (SMD: 0.56; 95% CI 0.26-0.86; P = 0.0002) and NO (SMD: 0.38; 95% CI 0.09-0.68; P = 0.01) concentration increased significantly in the probiotics and synbiotics groups compared to the placebo group. FAI (SMD: - 0.58; 95% CI - 0.95 to - 0.21; P = 0.002) and MDA (SMD: - 0.76; 95% CI - 1.46 to - 0.05; P = 0.03) concentration in the probiotics and synbiotics groups reduced significantly compared to the placebo group. The results of meta-analyses on other hormonal and inflammatory indices such as testosterone, DHEAS, GSH, hsCRP, TAC, and hirsutism score showed that there were no significant differences between the intervention and control groups. CONCLUSION: Using synbiotics and probiotics in women with polycystic ovary syndrome improve hormonal (FAI, SHBG) and inflammatory (NO, MDA) indices in these patients.

Circulating Sex Hormone Levels and Risk of Esophageal Adenocarcinoma in a Prospective Study in Men.

OBJECTIVES: Sex hormones have been hypothesized to explain the strong male predominance in esophageal adenocarcinoma, but evidence is needed. This study examined how circulating sex hormone levels influence future risk of esophageal adenocarcinoma. METHODS: This case-control study was nested in a prospective Norwegian cohort (Janus Serum Bank Cohort), including 244 male patients with esophageal adenocarcinoma and 244 male age-matched control participants. Associations between prediagnostic circulating levels of 12 sex hormones and risk of esophageal adenocarcinoma were assessed using conditional logistic regression. In addition, a random-effect meta-analysis combined these data with a similar prospective study for 5 sex hormones. RESULTS: Decreased odds ratios (ORs) of esophageal adenocarcinoma were found comparing the highest with lowest quartiles of testosterone (OR = 0.44, 95% confidence interval [CI] 0.22-0.88), testosterone:estradiol ratio (OR = 0.37, 95% CI 0.19-0.72), and luteinizing hormone (OR = 0.50, 95% CI 0.30-0.98), after adjustment for tobacco smoking and physical activity. These associations were attenuated after further adjustment for body mass index (OR = 0.56, 95% CI 0.27-1.13 for testosterone; OR = 0.46, 95% CI 0.23-0.91 for testosterone:estradiol ratio; OR = 0.55, 95% CI 0.29-1.08 for luteinizing hormone). No associations were observed for sex hormone-binding globulin, dehydroepiandrosterone sulfate, follicle-stimulating hormone, prolactin, 17-OH progesterone, progesterone, androstenedione, or free testosterone index. The meta-analysis showed an inverse association between testosterone levels and risk of esophageal adenocarcinoma (pooled OR for the highest vs lowest quartile = 0.60, 95% CI 0.38-0.97), whereas no associations were identified for androstenedione, sex hormone-binding globulin, estradiol, or testosterone:estradiol ratio. DISCUSSION: Higher circulating testosterone levels may decrease the risk of esophageal adenocarcinoma in men.

Impact of adrenal hormones, reproductive aging, and major depression on memory circuitry decline in early midlife.

Dehydroepiandrosterone-sulfate (DHEAS) is an adrenal androgen that is, in part, aromatized to estradiol. It continues to be produced after menopause and provides estrogenicity after depletion of ovarian hormones. Estradiol depletion contributes to memory circuitry changes over menopause, including changes in hippocampal (HIPP) and dorsolateral- and ventrolateral-prefrontal cortex (DLPFC; VLPFC) function. Further, major depressive disorder (MDD) patients have, in general, lower levels of estradiol and lower DHEAS than healthy controls, thus potentially a higher risk of adverse menopausal outcomes. We investigated whether higher DHEAS levels after menopause is associated with better memory circuitry function, especially in women with MDD. 212 adults (ages 45-55, 50% women) underwent clinical and fMRI testing. Participants performed a working memory (WM) N-back task and an episodic memory verbal encoding (VE) task during fMRI scanning. DHEAS levels were significantly associated with memory circuitry function, specifically in MDD postmenopausal women. On the WM task, lower DHEAS levels were associated with increased HIPP activity. On the VE task, lower DHEAS levels were associated with decreased activity in the HIPP and VLPFC. In contrast, there was no association between DHEAS levels and memory circuitry function in MDD pre/perimenopausal women, men, and non-MDD participants regardless of sex and reproductive status. In fact, MDD postmenopausal women with higher levels of DHEAS were similar to MDD pre/perimenopausal women and men. Thus, memory circuitry deficits associated with MDD and a lower ability of the adrenal gland to produce DHEAS after menopause may contribute to a lower ability to maintain intact memory function with age.

Modern Management of Mild Autonomous Cortisol Secretion.

Incidentally discovered adrenal tumors are reported in ~ 5% of adults undergoing cross-sectional imaging. Mild autonomous cortisol secretion (MACS) from the adrenal mass is demonstrated in 5-48% of patients with adrenal tumors. The diagnosis of MACS represents a challenge due to limitations of the currently used diagnostic tests, differences in the definitions of the clinically relevant MACS, and heterogeneity in an individual's susceptibility to abnormal cortisol secretion from the adrenal mass. Patients with MACS present with increased risk of cardiovascular risk factors, cardiovascular events, metabolic bone disease, and mortality. Adrenalectomy improves or reverses MACS-associated comorbidities in selected patients. The current review will address diagnostic and management challenges in the care of patients with MACS, discuss data on emerging biomarkers, and suggest future directions in the field of MACS.

Association of prostate cancer SLCO gene expression with Gleason grade and alterations following androgen deprivation therapy.

BACKGROUND: SLCO-encoded transporters have been associated with progression to castration-resistant prostate cancer (CRPC) after initiation of androgen deprivation therapy (ADT). Although expressed at lower levels than in CRPC tissues, SLCO-encoded transporters may also play a role in response of primary prostate cancer (PCa) to ADT and biochemical recurrence. METHODS: We systematically explored expression of the 11 human SLCO genes in a large sample of untreated and ADT-treated normal prostate (NP) and primary PCa tissues, including tumors treated with neoadjuvant abiraterone. RESULTS: Transporters with the most recognized role in steroid uptake in PCa, including SLCO2B1 (DHEAS) and 1B3 (testosterone), were consistently detected in primary PCa. SLCO1B3 was nearly 5-fold higher in PCa vs NP with no difference in Gleason 3 vs 4 and no change with ADT. SLCO2B1 was detected at 3-fold lower levels in PCa than NP but was nearly 7-fold higher in Gleason 4 vs Gleason 3 and increased 3-fold following ADT (p < 0.05 for all). CONCLUSIONS: We observed clear differences in SLCO expression in PCa vs NP samples, in Gleason 4 vs Gleason 3 tumors, and in ADT-treated vs untreated tissues. These findings are hypothesis generating due to small sample size, but suggest that baseline and ADT-induced changes in PCa OATP expression may influence steroid uptake and response to ADT, as well as uptake and response to drugs such as abiraterone and docetaxel which are also subject to OATP-mediated transport and are now being routinely combined with ADT in the metastatic castration sensitive setting.

Impact of Pubertal Maturation and Chronologic Age on Sex Steroids in Peripubertal Girls.

CONTEXT: There is a 4- to 5-year variation in age of breast maturation in girls. OBJECTIVE: To examine longitudinal changes in sex hormone values relative to chronologic age and time relative to breast maturation. SETTING AND DESIGN: Longitudinal observational study into which girls were recruited at 6 to 7 years of age and followed up every 6 months. MAIN OUTCOME MEASURES: Maturation status, chronologic age, race, and fasting blood specimen data were obtained. Hormones were analyzed at 6-month intervals between 2 years before and 1 year after breast maturation, using HPLC tandem mass spectroscopy. RESULTS: Estradiol and estrone levels correlated with chronologic age (R = 0.350 and 0.444, respectively); time was correlated relative to breast maturation (R = 0.222 and 0.323, respectively; all correlations, P < 0.0001). In generalized estimating equation (GEE) models, chronologic age and time relative to pubertal onset were significantly associated with serum estradiol, with similar results for estrone. Local estimated scatterplot smoothing for estradiol and estrone, by chronologic age, demonstrated differences between black and white girls, especially between 8.5 and 11 years of age, but not by race in time relative to breast maturation. Testosterone level was correlated to chronologic age (R = 0.362) and time relative to breast maturation (R = 0.259); in the GEE model, only chronologic age was significant. CONCLUSION: Chronologic age as well as time relative to onset of puberty provided unique information regarding estradiol and estrone concentrations in peripubertal girls. Serum estrogen concentrations should be evaluated with reference to chronologic age and race.

Central Precocious Puberty as a Presenting Sign of Nonclassical Congenital Adrenal Hyperplasia: Clinical Characteristics.

CONTEXT: Central precocious puberty (CPP) may be the first presentation of nonclassical congenital adrenal hyperplasia (NCCAH) in girls. Data on the prevalence and the clinical phenotype of CPP associated with NCCAH are sparse. OBJECTIVES: To study the clinical and laboratory characteristics that could differentiate idiopathic CPP from CPP associated with NCCAH and to determine the prevalence of NCCAH among girls with CPP. DESIGN: Case-control study. SETTING: Tertiary pediatric endocrinology institute. PARTICIPANTS AND METHODS: From 2008 to 2017, 147 girls who had undergone stimulation tests with gonadotropin-releasing hormone and ACTH were diagnosed with CPP; of these, seven (4.8%) were eventually diagnosed with NCCAH. These seven patients together with 30 girls who presented with CPP during 1984 to 2008 and were later diagnosed with NCCAH comprised the NCCAH group. Demographic, anthropometric, clinical, and laboratory data were compared between the NCCAH group and the 140 girls with idiopathic CPP (ICPP group). RESULTS: No between-group differences were found in height, weight, body mass index, bone age, and Tanner stage. Mean basal levels of androstenedione, dehydroepiandrosterone-sulphate, and 17-hydroxyprogesterone were significantly higher in the NCCAH group, although ranges overlapped between the groups, and stimulated cortisol level was higher in the ICPP group. CONCLUSION: NCCAH was found in 4.8% of girls presenting with true CPP over 10 years, and no single parameter could differentiate between the diagnoses. Thus, in girls with true CPP from populations in which NCCAH is prevalent, assessment of adrenal androgens is required, and ACTH test should be considered.

Adrenal androgens rescue prostatic dihydrotestosterone production and growth of prostate cancer cells after castration.

Adrenal androgens dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) are potential substrates for intracrine production of testosterone (T) and dihydrotestosterone (DHT), or directly to DHT, by prostate cancer (PCa) cells. Production of DHT from DHEAS and DHEA, and the role of steroid sulfatase (STS), were evaluated ex vivo using fresh human prostate tissue and in vitro using human PCa cell lines. STS was expressed in benign prostate tissue and PCa tissue. DHEAS at a physiological concentration was converted to DHT in prostate tissue and PCa cell lines, which was STS-dependent. DHEAS activation of androgen receptor (AR) and stimulation of PCa cell growth were STS-dependent. DHEA at a physiological concentration was not converted to DHT ex vivo and in vitro, but stimulated in vivo tumor growth of the human PCa cell line, VCaP, in castrated mice. The findings suggest that targeting metabolism of DHEAS and DHEA may enhance androgen deprivation therapy.

Dehydroepiandrosterone sulfate/free androgen index ratio predicts a favorable metabolic profile in patients with polycystic ovary syndrome.

Potential effect of hyperandrogenemia on metabolic disturbances in polycystic ovary syndrome (PCOS) has always been a matter of interest. We analyzed the records of 125 patients with PCOS and 54 age-matched healthy women. All participants underwent biochemical and hormonal assessment and a 75 g oral glucose tolerance test was performed. PCOS and control groups were comparable in terms of age. Dehydroepiandrosterone sulfate/free androgen index (DHEAS/FAI) ratio was negatively correlated with body mass index (BMI) (p < .001), fasting glucose (p = .02), area under the curve (AUC) of glucose (p = .03), AUC of insulin (p = .001), homeostasis model assessment-estimated insulin resistance (HOMA-IR) (p < .001), and triglycerides (TG) (p = .009), and positively correlated with insulin sensitivity index (ISI) (p < .001) and high-density lipoprotein cholesterol (HDL-C) (p < .001) among PCOS patients. In logistic regression analysis, higher DHEAS/FAI ratio levels were associated with lower risk of low HDL-C [RR(95%CI); 0.97(0.95-0.98); p < .001] as well as atherogenic dyslipidemia (TG/HDL-C) [RR(95%CI); 0.97(0.94-0.99); p = .035] even after adjustment for BMI in the PCOS group. Androgens, DHEAS and FAI act differently on metabolic parameters. Our results demonstrate that high DHEA-S/FAI ratio levels are associated with a more favorable metabolic profile.

Identification of zebrafish steroid sulfatase and comparative analysis of the enzymatic properties with human steroid sulfatase.

Steroid sulfatase (STS) plays an important role in the regulation of steroid hormones. Metabolism of steroid hormones in zebrafish has been investigated, but the action of steroid sulfatase remains unknown. In this study, a zebrafish sts was cloned, expressed, purified, and characterized in comparison with the orthologous human enzyme. Enzymatic assays demonstrated that similar to human STS, zebrafish Sts was most active in catalyzing the hydrolysis of estrone-sulfate and estradiol-sulfate, among five steroid sulfates tested as substrates. Kinetic analyses revealed that the Km values of zebrafish Sts and human STS differed with respective substrates, but the catalytic efficiency as reflected by the Vmax/Km appeared comparable, except for DHEA-sulfate with which zebrafish Sts appeared less efficient. While zebrafish Sts was catalytically active at 28 °C, the enzyme appeared more active at 37 °C and with similar Km values to those determined at 28 °C. Assays performed in the presence of different divalent cations showed that the activities of both zebrafish and human STSs were stimulated by Ca2+, Mg2+, and Mn2+, and inhibited by Zn+2 and Fe2+. EMATE and STX64, two known mammalian steroid sulafatase inhibitors, were shown to be capable of inhibiting the activity of zebrafish Sts. Collectively, the results obtained indicated that zebrafish Sts exhibited enzymatic characteristics comparable to the human STS, suggesting that the physiological function of STS may be conserved between zebrafish and humans.

Sex Hormones and Prolactin Levels and Their Association with Anti Cardiolipin Antibody in Patients with Systemic Lupus Erythematosus.

Pathogenesis of systemic lupus erythematosus (SLE) is complex and multi-factorial. Among various suggested mechanisms for the disease, the hormonal theory has been considered as one of the most important mechanisms. Recently, the association of sex hormones with manifestations of antiphospholipid antibody syndrome (APLS) has been hypothesized. The aim of present study was to assess the serum levels of anticardiolipin antibody (ACA), sex hormones and prolactin in SLE female patients and their association with the disease. This study comprised 40 SLE female patients and 41 healthy age-matched female subjects. For all patients and controls, the serum levels of ACA (IgG and IgM), estradiol, testosterone, progesterone, dehydroepiandrosterone sulfate (DHEA-S) and prolactin were measured by ELISA method. Our study revealed that serum levels of testosterone, DHEA-S and progesterone were significantly lower in SLE patients than control (p<0.001). However, serum levels of estradiol and prolactin were significantly higher in SLE patients compared to controls (p<0.001). There was a significant difference between mild and moderate severity patients group for ACA positivity (95% CI 13.67-41.3; p=0.03). Also, SLE patients with positive ACA showed significantly lower (p<0.001) serum levels of testosterone, DHEA-S and progesterone and significantly higher (p<0.001) estradiol and prolactin serum levels compared to negative ACA patients. The results of our study indicated that expression and metabolism of sex hormones and prolactin are different in female SLE patients compared to healthy subjects. It seems, change in serum levels of these hormones is related to higher SLE disease activity, increased thrombotic risks and increased renal involvement.

Tribulus terrestris Protects against Male Reproductive Damage Induced by Cyclophosphamide in Mice.

Tribulus terrestris (TT) has been considered as a potential stimulator of testosterone production, which has been related with steroidal saponins prevailing in this plant. Cyclophosphamide (CP) is the most commonly used anticancer and immunosuppressant drug, which causes several toxic effects, especially on the reproductive system. Patients who need to use CP therapy exhibit reduced fertility or infertility, which impacts both physically and emotionally on the decision to use this drug, especially among young men. We hypothesized that the treatment with TT dry extract would protect the male reproductive system against CP toxicity. Mice received dry extract of TT (11 mg/kg) or vehicle by gavage for 14 days. Saline or CP was injected intraperitoneally at a single dose (100 mg/kg) on the 14th day. Animals were euthanized 24 h after CP administration, and testes and epididymis were removed for biochemical and histopathological analysis and sperm evaluation. The dry extract of TT was evaluated by HPLC analysis and demonstrated the presence of protodioscin (1.48%, w/w). CP exposure increased lipid peroxidation, reactive species, and protein carbonylation and altered antioxidant enzymes (SOD, CAT, GPx, GST, and GR). Moreover, acute exposure to CP caused a reduction on 17 ß-HSD activity, which may be related to the reduction in serum testosterone levels, histopathological changes observed in the testes, and the quality of the semen. The present study highlighted the role of TT dry extract to ameliorate the alterations induced by CP administration in mice testes, probably due to the presence of protodioscin.

Hormonal and metabolic aspects of acne vulgaris in women with polycystic ovary syndrome.

OBJECTIVE: Acne vulgaris in women can indicate a systemic disease, such as polycystic ovary syndrome (PCOS), which is associated with hormonal and metabolic disorders. The aim of this study was to investigate the influence of hormonal and metabolic disorders on acne vulgaris in women with PCOS. PATIENTS AND METHODS: The study included 110 women with PCOS. Women were divided according to their androstenedione concentration: within reference range (n=66) or higher (n=44). All patients were between 17-36 years old. Acne was graded according to the US FDA scale for a five-category global system (acne global severity scale). Hirsutism was defined using a modified Ferriman-Gallwey method. Fasting plasma glucose, insulin, luteinizing hormone, follicle-stimulating hormone, 17α-hydroxyprogesterone, 17-beta-estradiol, sex hormone-binding globulin and androgen (androstenedione, total testosterone, free testosterone, dehydroepiandrosterone sulfate) were assessed, as were prolactin and cortisol concentrations. Thyrotropin and free thyroxine concentrations were also measured. The free androgen index (FAI) and homeostatic model assessment-insulin resistance (HOMA-IR) index were calculated. RESULTS: The average age and rating on the hirsutism scale were similar in both analyzed groups. A higher percentage of severe acne was observed in the group of women with an androstenedione concentration within reference range than in the group with the higher concentration. Meanwhile, the severity of acne in the group of PCOS women with the higher androstenedione concentration was correlated with higher concentrations of total testosterone, free testosterone, dehydroepiandrosterone sulfate, and cortisol. Increased glucose concentration was also proportional to the severity of acne. We did not observe a statistically significant correlation between the severity of acne and the androstenedione concentration. In the group of PCOS women as a whole, the severity of acne was correlated only with higher dehydroepiandrosterone sulfate concentration; other androgens did not affect the severity. CONCLUSIONS: The acne global severity scale in PCOS women is associated with higher concentrations of total testosterone, free testosterone, dehydroepiandrosterone sulfate, and FAI value. Higher concentrations of androstenedione did not affect acne severity.