Low Androgen Levels Research Articles

Phosphorylation of HSP90 by protein kinase A is essential for the nuclear translocation of androgen receptor

The androgen receptor (AR) is often activated in prostate cancer patients undergoing androgen-ablative therapy because of the activation of cellular pathways that stimulate the AR despite low androgen levels. In many of these tumors, the cAMP-dependent protein kinase A (PKA) pathway is activated. Previous studies have shown that PKA can synergize with low levels of androgen to enhance androgen signaling and consequent cell proliferation, leading to castration-resistant prostate cancer. However, the mechanism by which PKA causes AR stimulation in the presence of low/no androgen is not established yet. Here, using immunofluorescence immunoblotting assays, co-immunoprecipitation, siRNA-mediated gene silencing, and reporter gene assays, we demonstrate that PKA activation is necessary for the phosphorylation of heat shock protein (HSP90) that binds to unliganded AR in the cytoplasm, restricting its entry into the nucleus. We also found that PKA-mediated phosphorylation of the Thr89 residue in HSP90 releases AR from HSP90, enabling AR binding to HSP27 and its migration into the nucleus. Substitution of the Thr89 in HSP90 prevented its phosphorylation by PKA and significantly reduced AR transactivation and cellular proliferation. We further observed that the transcription of AR target genes, such as prostate-specific antigen (PSA), is also lowered in the HSP90 Thr89 variant. These results suggest that using a small-molecule inhibitor against the HSP90 Thr89 residue in conjunction with existing androgen-ablative therapy may be more effective than androgen-ablative therapy alone in the treatment of prostate cancer patients.

Activation of cGMP/PKG/p65 signaling associated with PDE5-Is downregulates CCL5 secretion by CD8 + T cells in benign prostatic hyperplasia.

BackgroundBenign prostatic hyperplasia (BPH) is the most common urological disease in elderly men, but the underlying pathophysiological mechanisms are complex and not fully understood. Phosphodiesterase type 5 inhibitors (PDE5‐Is) used to treat BPH could upregulate the cyclic guanosine monophosphate (cGMP)‐dependent protein kinase G (PKG) signaling, which was shown to blunt inflammation in the prostate. Our previous findings indicate that CD8+ T cells promote the proliferation of BPH epithelial cells (BECs) in low androgen conditions through secretion of CCL5; however, the role of the cGMP/PKG pathway in the process is unclear.MethodsParaffin‐embedded tissues were used for expression quantity of CD8+ T cells, CCL5, cyclin D1, and PDE5 protein by immunohistology in prostate specimens which were/were not treated with finasteride 5 mg daily for at least 6 months before surgery. BPH‐1 cells were cocultured with or without CD8 + T cells or PDE5‐Is in low androgen conditions for 4 days. The conditioned media, BPH‐1 cells, and CD8 + T cells were harvested for the subsequent experiments. The quantitative polymerase chain reaction was used for assaying the level of messenger RNA expression of CCL5. CCL5 in the conditioned media was detected by the enzyme‐linked immunosorbent assay. The effect of PDE5‐Is on cocultured BPH‐1/CD8 + T‐cell proliferation was detected by the cell counting kit‐8. A high‐fat diet (HFD)‐induced prostatic hyperplasia rat model was used to investigate the effect of cGMP/PKG activation in CD8 + T cells in vivo.ResultsCD8+ T‐cell infiltration into human BPH tissues was positively correlated with the expression of CCL5, cyclin D1, and PDE5, whereas in an HFD‐induced prostatic hyperplasia rat model, the activation of the cGMP/PKG signaling by a PDE5‐I could suppress the CD8 + T‐cell infiltration and the CCL5 and cyclin D1 expression. Furthermore, the activation of the cGMP/PKG pathway inhibited CCL5 secretion by CD8 + T cells by downregulating nuclear factor‐κB p65 phosphorylation, which reduced the growth of BPH‐1 through CCL5/STAT5/CCND1 signaling.ConclusionsOur results indicate that the upregulation of the cGMP/PKG/p65 signaling reduces CCL5 secretion in CD8 + T cells, which in turn decreases the proliferation of BECs in low androgen conditions, suggesting that the combination of 5α reductase inhibitors lowering androgen levels and PDE5‐Is may be a novel, more effective treatment for BPH patients.

Correlation between Second to Fourth Digit Ratio and Anthropometric Variables Indicative of Cardiovascular Disease

AbstractSecond to fourth digit ratio (2D:4D) is a sexually dimorphic biometric marker. Regarding indirect evidence, there have been several studies that link the waist-to-hip ratio (WHR) with the 2D:4D ratio. If the 2D:4D ratio is associated with testosterone and estrogen levels, it may be correlated with a risk of myocardial infarction (MI). The aim of the present study is to find out the correlation between anthropometric risk factors for cardiovascular disease and the 2D:4D ratio in 250 young females of the state of Haryana in Northern India. The present study was conducted on 250 females of the Haryana population aged between 17 and 35 years old. A series of 8 anthropometric measurements was obtained from the participants: height, weight, 2D:4D ratio, body mass index (BMI), waist circumference (WC), hip circumference (HC), neck circumference (NC), and WHR. The data was collected, tabulated and subjected to statistical computation using SPSS Statistics for Windows, Version 13.0 (SPSS Inc., Chicago, IL, USA). Strong positive associations between the NC and the WHR confirm that both measures are indicative of body fat. Also, a positive correlation between the 2D:4D ratio and the WHR suggests that low androgen levels in women are associated with a greater risk of obesity. Moreover, this result, as well as the positive correlation between 2D:4D ratios and NC, suggest that the digit ratio is indicative for being overweight in women and suggest a predisposition toward cardiovascular disease – however, these correlations of body measurements with digit ratios are not significant.

Abstract P5-04-16: Total estrogenic activity during neoadjuvant therapy with letrozole and exemestane – An intra-patient cross-over comparison using the AroER tri-screen

Abstract Background. Aromatase inhibitors (AIs), letrozole (Femarâ / Femaraâ) and exemestane (Aromasinâ), are widely used anti-hormonal drugs for breast cancer. Both compounds strongly reduce circulating estradiol levels in postmenopausal women. In the setting of metastatic breast cancer, these drugs may be used after another, causing new responses in selected patients by switching to the alternative drug after progressing on the first choice. This well-known ”lack of cross resistance” has been recognized for some time and is documented by several clinical trials. However, the precise explanation for this clinical observation is still unknown. The availability of mechanistic information may lead to an improved strategy against hormone-sensitive breast cancer. Patients and methods. NEO-LET-EXE was a neoadjuvant, randomized, open-label, intra-patient cross-over trial. Postmenopausal patients with estrogen receptor (ER) positive (>50%), HER-2 negative, locally advanced breast cancer were enrolled. Sequential blood samples (obtained at baseline, after 2 months and 4 months of treatment) were available from 29 patients. All patients were randomized to sequential treatment starting with either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d) for 2 months followed by another 2 months on the alternative compound. The total estrogenic activities in the collected blood samples were determined using AroER tri-screen assay developed by the Chen laboratory. The assay utilizes MCF-7aro ERE cells which contain both aromatase and ER. The samples were assayed in the presence as well as the absence of letrozole, to estimate relative contributions of estrogen and estrogen+androgen to the activities, respectively. Results. Using the highly sensitive AroER tri-screen assay, estrogenic activity were detected at three time points in all blood samples. Importantly, a significantly higher total estrogenic activity was found during therapy with exemestane compared to letrozole in 23 out of 26 patients. Only in three patients, the activity was higher during therapy with letrozole compared to exemestane. When letrozole was included in the assay, the estrogenic activities in most samples collected during exemestane treatment were further reduced, suggesting that low levels of androgen were present in samples from exemestane treatment. Four samples collected after exemestane treatment and three after letrozole treatment had higher activities than baseline samples when assay was carried out with letrozole. Discussion. Our results suggest the AroER tri-screen to be a very sensitive method to estimate the overall estrogen-mediated activity in human samples. Significant higher levels of estrogenic activity in human serum were observed during exemestane than those during letrozole treatment. Our observations, that additional letrozole could reduce further the estrogen activity in the exemestane-treated samples, demonstrate probably residual aromatase activity during therapy with exemestane alone.In addition to distinguish the effects of exemestane and letrozole, our results also demonstrate that the assay can also potentially detect the effects of estrogenic mimics. Citation Format: Bahrami N, Chang G, Kanaya N, Sauer T, Gravdehaug B, Chen S, Geisler J. Total estrogenic activity during neoadjuvant therapy with letrozole and exemestane – An intra-patient cross-over comparison using the AroER tri-screen [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-16.

Effect of low androgen levels on the sulphur dioxide signalling pathway in rat penile corpus cavernosum.

The aim of this study was to investigate the relationship between sulphur dioxide (SO2 ) signalling pathway and the changes in erectile function under low androgen levels. Thirty-six healthy male Sprague Dawley (SD) rats aged eight weeks were randomly divided into androgen replacement group, castration group and sham group. Rats in the androgen replacement group were subcutaneously injected with testosterone propionate at 3mg/kg every other day postcastration. The maximum intracavernous pressure/mean arterial pressure (ICPmax /MAP) and the relative content of SO2 in the penile corpus cavernosum were measured. The mRNA and protein expressions of aspartate aminotransferase (AAT1 and AAT2), cysteine oxidase (CDO), endothelial nitric oxide synthase (eNOS) and phosphorylation of endothelial nitric oxide synthase (P-eNOS) were detected. ICPmax /MAP, P-eNOS/eNOS and the level of SO2 decreased significantly in the castration group compared to the other groups (p<0.05). The expressions of mRNA and protein decreased significantly in the castration group compared to the androgen replacement group and the sham group (p<0.05), while there was no significant difference between the androgen replacement group and sham group. Low androgen levels can inhibit erectile function by downregulating the SO2 signalling pathway.

Adrenals Contribute to Growth of Castration-Resistant VCaP Prostate Cancer Xenografts

The role of adrenal androgens as drivers for castration-resistant prostate cancer (CRPC) growth in humans is generally accepted; however, the value of preclinical mouse models of CRPC is debatable, because mouse adrenals do not produce steroids activating the androgen receptor. In this study, we confirmed the expression of enzymes essential for de novo synthesis of androgens in mouse adrenals, with high intratissue concentration of progesterone (P4) and moderate levels of androgens, such as androstenedione, testosterone, and dihydrotestosterone, in the adrenal glands of both intact and orchectomized (ORX) mice. ORX alone had no effect on serum P4 concentration, whereas orchectomized and adrenalectomized (ORX+ADX) resulted in a significant decrease in serum P4 and in a further reduction in the low levels of serum androgens (androstenedione, testosterone, and dihydrotestosterone), measured by mass spectrometry. In line with this, the serum prostate-specific antigen and growth of VCaP xenografts in mice after ORX+ADX were markedly reduced compared with ORX alone, and the growth difference was not abolished by a glucocorticoid treatment. Moreover, ORX+ADX altered the androgen-dependent gene expression in the tumors, similar to that recently shown for the enzalutamide treatment. These data indicate that in contrast to the current view, and similar to humans, mouse adrenals synthesize significant amounts of steroids that contribute to the androgen receptor-dependent growth of CRPC.

Androgen receptor: what we know and what we expect in castration-resistant prostate cancer

Androgen deprivation therapy is an important therapy for prostate cancer (PCa) in aging men. Under the background of castration, it is inevitable that prostate cancer will develop into castration-resistant prostate cancer (CRPC), which has a high mortality rate, after 2-3years. Androgen receptor (AR) plays a key role in PCa development and is essential to CRPC. More recent research studies have reported that the development of CRPC is largely due to altered mechanisms related to AR, so it is important for us to understand the roles of AR and detailed AR-related mechanisms in CRPC. The multiple AR-related mechanisms promoting the development of CRPC are as follows: (1) enhanced transformation and increased synthesis of intratumoral androgen; (2) AR overexpression, which enables CRPC to be hypersensitive to low levels of androgen; (3) AR cofactors, which enhanced AR transactivation; (4) AR-spliced variants, which mediated downstream gene expression without androgen; (5) the interaction between the AR pathway and classic tumor-related pathways; and» (6) AR mutations, which reduced AR specificity and enhanced AR transcription.

Androgenic modulation of AR-Vs.

The importance of androgen receptor variants (AR-Vs) is recognized in prostate cancer. AR-Vs have been the focus of many studies. Expression of AR-Vs has been proposed as a biomarker for resistance to androgen deprivation therapy for metastatic disease. Herein, we show dynamic changes in AR-Vs expression in response to androgen modulation. The C4-2B cell line was exposed to low (10-13 M) and high (10-8 M) androgen (dihydrotestosterone, DHT) levels, with or without flutamide. mRNA and protein expression levels were assessed by qPCR and immunohistochemistry, respectively. We demonstrated that high levels of DHT downregulate AR-FL and AR-Vs. Even though AR-Vs did not present ligand-binding domain, thus were not capable of binding to DHT, they present dynamic changes under androgen treatment. Treatment with flutamide alone or in association with low levels of DHT stimulates growth of prostatic cells. Importantly, we provide evidence that AR-Vs respond differently to androgenic modulation. These findings have implications for a better understanding of the role of AR-Vs in prostate carcinogenesis.

Long-Lasting Androgen-Induced Cardiometabolic Effects in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, is characterized by androgen excess and ovarian dysfunction and presents with increased cardiometabolic risk factors such as obesity, insulin resistance, and elevated blood pressure (BP). We previously reported that administration of dihydrotestosterone (DHT) to female rats elicits cardiometabolic derangements similar to those found in women with PCOS. In this study, we tested the hypothesis that the DHT-mediated cardiometabolic derangements observed in PCOS are long lasting despite DHT withdrawal. Four-week-old female Sprague Dawley rats were treated with DHT (7.5 mg/90 days) or placebo for 6 months. DHT was discontinued (ex-DHT), and rats were followed for 6 additional months. After 6 months of DHT withdrawal, food intake, body weight, fat and lean mass, fasting plasma insulin, leptin, and adiponectin were elevated in ex-DHT rats. BP remained significantly elevated, and enalapril, an angiotensin-converting enzyme (ACE) inhibitor, normalized BP in ex-DHT rats. Expression of components of the intrarenal renin-angiotensin system was increased in ex-DHT rats. The cardiometabolic features found in ex-DHT rats were associated with lower plasma androgen levels but increased expression of renal and adipose tissue androgen receptors. In summary, androgen-induced cardiometabolic effects persisted after DHT withdrawal in a PCOS experimental model. Activation of intrarenal renin-angiotensin system plays a major role in the androgen-mediated increase in BP in ex-DHT. Upregulation of the renal and adipose tissue androgen receptor may explain the long-lasting effects of androgens. In clinical scenarios characterized by hyperandrogenemia in women, prompt normalization of androgen levels may be necessary to prevent their long-lasting cardiometabolic effects.

Finger Length Ratios of Identical Twins with Discordant Sexual Orientations.

A proposed marker of prenatal androgen exposure is the ratio of the index finger to ring finger (2D:4D). Within each sex, this ratio may be lower for those who were exposed to higher levels of androgens and become attracted to women, as compared to those who were exposed to lower levels of androgens and become attracted to men. We examined these patterns in identical twins with discordant sexual orientations. Because these twins are genetically identical, differences in prenatal androgen exposure, as reflected in their different finger length ratios, might contribute to their discordance. For 18 female twin pairs, non-straight (bisexual or lesbian) twins had significantly lower, or more masculinized, 2D:4D ratios than their straight co-twins, but only in the left hand. For 14 male pairs, non-straight twins had, contrary to our prediction, more masculinized finger length ratios than straight co-twins, but this difference was not significant. A reanalysis of present and previous data (Hall & Love, 2003; Hiraishi, Sasaki, Shikishima, & Ando, 2012) suggested that these patterns were robust. Furthermore, males had more masculinized 2D:4D ratios than females. This sex difference did not vary by sexual orientation.

Abstract 3740: Functional cross-talk between nuclear receptor LRH-1 and androgen receptor signalling in prostate cancer

Abstract Liver Receptor Homolog 1 (LRH-1, NR5A2) is an orphan nuclear receptor that is over-expressed in cancers in tissues such as the breast, colon and pancreas. In prostate cancer, LRH-1 is reported as a potent transcription factor to facilitate the formation of CRPC (castration-resistant prostate cancer cells) which is resistant to androgen deprivation therapy (ADT). However, it is still elusive how LRH-1 responses to ADT and facilitates the growth of CRPC. After deprivation of androgen in mouse prostate cancer xenograft model, LRH-1 mRNA was upregulated dramatically at a very low androgen level. After CRPC formation, LRH-1 mRNA was downregulated when androgen level recovered. KLK3/PSA is an important downstream target of activated AR (Androgen receptor), whose expression level at 4 days after castration is downregulated, while upregulated after relapse. Since PSA level/AR signaling activity showed an opposite expression pattern to LRH-1, we hypothesized that LRH-1 was suppressed by androgen in a negative-feedback manner. With androgen treatment of an androgen-sensitive prostate cancer cell line LNCaP, LRH-1 was downregulated in both dose- and time-dependent manner, while PSA shows an opposite expression pattern. And knocking down of AR blocked the suppression of androgen on LRH-1, indicating that androgen suppresses LRH-1 through AR. Furthermore, AR antagonist Enzalutamide can block the binding of androgen to AR thus upregulate LRH-1. According to ChIP-seq data, AR binds to the promoter and enhancer of LRH-1,and the binding intensity increased with androgen treatment. Through ChIP-qPCR, several binding sites of AR on LRH-1 promoter and enhancer were validated. The transcription activity of luciferase reporter with these AR binding sites was also suppressed by treatment of androgen. In the future work, to find out the epigenetics modifiers in the AR complexes when suppressing LRH-1 will be critical for the understanding of the detailed mechanism. Citation Format: Wenxing You, Yuliang Wang, Leung Chan. Functional cross-talk between nuclear receptor LRH-1 and androgen receptor signalling in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3740.

711 Is free testosterone good or evil for lower urinary tract symptoms? : analysis of a Japanese community-based study

Age-related testosterone deficiency may adversely affect the functions of multiple organ systems. Although it causes various clinical symptoms such as low libido, erectile dysfunction, depressed mood, decreased vitality and so on, the relationship between the low androgen level and lower urinary tract symptoms (LUTS) is not clear. We evaluated the relationship between androgen decline and LUTS based on data from a cross-sectional community-based study on LUTS suggestive of benign prostatic hyperplasia (BPH) in Japanese men. In 2007, we conducted a cross-sectional community-based study on BPH/LUTS in aged men in Shimamaki-mura, Hokkaido, Japan. We investigated the International Prostate Symptom Score (IPSS) and measured the prostate volume and free testosterone level. A total of 91 of the 135 participants were eligible for this study. Associations between the free testosterone level and the IPSS and prostate volume were assessed by Spearman’s rank correlation. The median age of the participants was 69 years (range: 53-93). The median IPSS, prostate volume and free testosterone levels were 8 (range: 0-27), 24.5ml (range: 8.7-76.9) and 4.3pg/ml (0.6-9.0), respectively. Free testosterone was significantly and negatively correlated with the storage IPSS subscore (r=-0.239, p <0.05) and the frequency of nocturia (r=-0.280, p <0.05). A low level of free testosterone was also associated with large prostate volume (r=-0.210, p <0.05).

Effect of low androgen levels on IKca and SKca3 channels in rat penile corpus cavernosum.

We investigated whether low androgen levels affected erectile function by regulating the expressions of intermediate-conductance Ca2+ -activated K+ channel (IKca) and small-conductance Ca2+ -activated K+ channel 3 (SKca3) in corpus cavernous of rats. Thirty-six healthy male SD rats were randomly divided into the 4-week control group, 4-week castration group, 4-week androgen replacement after castration group, 8-week control group, 8-week castration group and 8-week androgen replacement after castration group, respectively. The rats in the androgen replacement groups were subcutaneously injected with testosterone (3mg/kg) every other day after castration. After 4 and 8weeks, maximum intracavernous pressure/mean arterial pressure (ICPmax /MAP) was measured. Expressions of IKca, SKca3, endothelial nitric oxide synthase (eNOS) and P-eNOS in penile corpus cavernosum were detected. ICPmax /MAP decreased significantly in the castration groups as compared to the control groups and the androgen replacement groups (p<0.01). mRNA expressions of IKca and SKca3 decreased significantly in the castration groups as compared to the control groups and androgen replacement groups (p<0.01). Protein expressions of eNOS, P-eNOS, IKca and SKca3 in the castration groups were significantly reduced as compared to the control groups and androgen replacement groups (p<0.01). Under low androgen levels, ICPmax /MAP can be reduced by down-regulating the expressions of SKca3 and IKca, inhibiting P-eNOS/eNOS and reducing eNOS bioactivity.

Prevalence of low androgen levels among middle and old age men attending Outpatient Clinics

Introduction: Tiredness is a common symptom of hypogonadism, which can be profound, but there are many medical practitioners who do not include the assessment of testosterone levels in the clinical workup of this symptom. Although male hypogonadism is an established clinical condition, which can be treated, many men experiencing it are undiagnosed.Aim:The aim was to assess the prevalence of low androgen level among middle and old age men in a cohort of patients attending Kasr Elaini hospital outpatient clinics.Patients and Methods: A total of 265 male patients older than 40 years attending the outpatient clinics in different specialty were included. All included men were subjected to full history taking and complete general and local examinations. All participants were interviewed personally face to face using Arabic generic version of full aging male scale (AMS) questionnaire. Venous blood samples were withdrawn between 8 and 10 a.m. after a 12-h overnight fast for measurements of total and free testosterone levels.Results: The mean total testosterone level was 4.0 ± 2.6 ng/ml, ranging from 0.4 to 16.4 ng/ml. The mean free testosterone level was 6.9 ± 2.4 pg/ml, with range between 1.4 and 18.5 pg/ml. Low androgen level was founded in 19.2% of the participants based on total testosterone and in 36.2% when adding the participants with low free testosterone levels. AMS score showed statistically significant difference between age groups (P<0.001). Age is negatively correlated with total and free testosterone levels (r=-0.226 and -0.242, respectively), but the correlation is weak. Total testosterone level shows strong positive correlation with free testosterone level and weak negative correlation with AMS score (r=0.732 and -0.240, respectively).Conclusion: The prevalence of hypogonadism among middle and old age males seeking medical consultation in different specialties may be high.

Prevalence and treatment of central hypogonadism and hypoandrogenism in women with hypopituitarism.

Women with hypopituitarism have increased morbidity and mortality, and hypogonadism has been suggested to be a contributing mechanism. The purpose of this study was to investigate the prevalence of central hypogonadism and hypoandrogenism in women with hypopituitarism at a single Swedish center. All consecutive women (n = 184) who commenced growth hormone (GH) replacement therapy at Sahlgrenska University Hospital in Gothenburg between 1995 and 2015 were included. In accordance with the Endocrine Society Clinical Practice Guidelines, strict criteria, based on menstrual history combined with laboratory measurements, were used to define central hypogonadism. Hypoandrogenism was defined as subnormal levels of dehydroepiandrosterone sulfate and/or androstenedione. Central hypogonadism was present in 78% of the women, in 75% of those ≤ 52years and in 82% of those > 52years of age. Hypoandrogenism was found in 61% of all the women and in 92% of those with adrenocorticotropic hormone (ACTH) deficiency. The estrogen substitution rate in hypogonadal women ≤ 52years was lower than the hormonal substitution rate in the other pituitary hormone axes (74% versus 100%, P < 0.001). The use of estrogen substitution tended to decrease between 2000 and 2016. Few women received androgen treatment. In this first study of hypogonadism in women with hypopituitarism, using stringent diagnostic criteria for hypogonadism, the prevalence of central hypogonadism and low androgen levels was high and estrogen substitution was insufficient. Further studies are needed to elucidate the importance of hypogonadism and insufficient sex steroid replacement for the increased morbidity in hypopituitary women.

The human fetal adrenal produces cortisol but no detectable aldosterone throughout the second trimester

BackgroundHuman fetal adrenal glands are highly active and, with the placenta, regulate circulating progesterone, estrogen and corticosteroids in the fetus. At birth the adrenals are essential for neonate salt retention through secretion of aldosterone, while adequate glucocorticoids are required to prevent adrenal insufficiency. The objective of this study was to carry out the first comprehensive analysis of adrenal steroid levels and steroidogenic enzyme expression in normal second trimester human fetuses.MethodsThis was an observational study of steroids, messenger RNA transcripts and proteins in adrenals from up to 109 second trimester fetuses (11 weeks to 21 weeks) at the Universities of Aberdeen and Glasgow. The study design was balanced to show effects of maternal smoking.ResultsConcentrations of 19 intra-adrenal steroids were quantified using liquid chromatography and mass spectrometry. Pregnenolone was the most abundant steroid while levels of 17α-hydroxyprogesterone, dehydroepiandrosterone sulphate (DHEAS) and progesterone were also high. Cortisol was present in all adrenals, but aldosterone was undetected and Δ4 androgens were low/undetected. CYP17A1, CYP21A2 and CYP11A1 were all highly expressed and the proteins localized to the adrenal fetal zone. There was low-level expression of HSD3B and CYP11B2, with HSD3B located mainly in the definitive zone. Maternal smoking altered fetal plasma adrenocorticotropic hormone (ACTH) (P = 0.052) and intra-adrenal progesterone, 17α-hydroxyprogesterone and 16α-hydroxyprogesterone, but not plasma or intra-adrenal cortisol, or intra-adrenal DHEAS. Fetal adrenal GATA6 and NR5A1 were increased by maternal smoking.ConclusionsThe human fetal adrenal gland produces cortisol but very low levels of Δ4 androgens and no detectable aldosterone throughout the second trimester. The presence of cortisol in fetal adrenals suggests that adrenal regulation of circulating fetal ACTH remains a factor in development of congenital adrenal hyperplasia during the second trimester, while a relative lack of aldosterone explains the salt-wasting disorders frequently seen in extreme pre-term neonates. Finally, maternal smoking may alter fetal adrenal sensitivity to ACTH, which could have knock-on effects on post-natal health.

Assessing the links among environmental contaminants, endocrinology, and parasites to understand amphibian declines in montane regions of Costa Rica.

Amphibians inhabiting montane riparian zones in the Neotropics are particularly vulnerable to decline, but the reasons are poorly understood. Because environmental contaminants, endocrine disruption, and pathogens often figure prominently in amphibian declines it is imperative that we understand how these factors are potentially interrelated to affect montane populations. One possibility is that increased precipitation associated with global warming promotes the deposition of contaminants in montane regions. Increased exposure to contaminants, in turn, potentially elicits chronic elevations in circulating stress hormones that could contribute to montane population declines by compromising resistance to pathogens and/or production of sex steroids regulating reproduction. Here, we test this hypothesis by examining contaminant levels, stress and sex steroid levels, and nematode abundances in male drab treefrogs, Smilisca sordida, from lowland and montane populations in Costa Rica. We found no evidence that montane populations were more likely to possess contaminants (i.e., organochlorine, organophosphate and carbamate pesticides or benzidine and chlorophenoxy herbicides) than lowland populations. We also found no evidence of elevational differences in circulating levels of the stress hormone corticosterone, estradiol or progesterone. However, montane populations possessed lower androgen levels, hosted more nematode species, and had higher nematode abundances than lowland populations. Although these results suggested that nematodes contributed to lower androgens in montane populations, we were unable to detect a significant inverse relationship between nematode abundance and androgen level. Our results suggest that montane populations of this species are not at greater risk of exposure to contaminants or chronic stress, but implicate nematodes and compromised sex steroid levels as potential threats to montane populations.

Genitourinary syndrome of menopause - is the problem solved? State of the art 2018.

Vulvovaginal atrophy accompanied by lower urinary tract dysfunction related to low levels of estrogen and androgens is labeled as genitourinary syndrome of menopause (GSM). Although this condition affects most postmenopausal women worldwide, it seems to be underdiagnosed and undertreated. Women should be properly advised to choose an adequate treatment modality to improve their quality of life, sexual relationships and social activity. The aim of this article to is increase knowledge of GSM. The current treatment options, both hormonal and non-hormonal, are reviewed. Topical estrogen therapy still remains the gold standard, but the demand for individually tailored therapy is growing. New treatment modalities are continuously included in clinical practice. They should consider the whole personality of a woman as well as cultural and social factors. Further studies on GSM and on the effectiveness of various treatment options are necessary to achieve this purpose.

Diagnostic value of histopathological examination results obtained during screening of patients with diagnosed atypical hyperplasia.

Vulvovaginal atrophy accompanied by lower urinary tract dysfunction related to low levels of estrogen and androgens is labeled as genitourinary syndrome of menopause (GSM). Although this condition affects most postmenopausal women worldwide, it seems to be underdiagnosed and undertreated. Women should be properly advised to choose an adequate treatment modality to improve their quality of life, sexual relationships and social activity. The aim of this article is to increase knowledge of GSM. The current treatment options, both hormonal and non-hormonal, are reviewed. Topical estrogen therapy still remains the gold standard, but the demand for individually tailored therapy is growing. New treatment modalities are continuously included in clinical practice. They should consider the whole personality of a woman as well as cultural and social factors. Further studies on GSM and on the effectiveness of various treatment options are necessary to achieve this purpose.

Neuroanatomical and molecular correlates of cognitive and behavioural outcomes in hypogonadal males.

Robust epidemiological, clinical and laboratory evidence supports emerging roles for the sex steroids in such domains as neurodevelopment, behaviour, learning and cognition. Regions of the mammalian brain that are involved in cognitive development and memory do not only express the classical nuclear androgen receptor, but also the non-genomic membrane receptor, which is a G protein-coupled receptor that mediates some rapid effects of the androgens on neurogenesis and synaptic plasticity. Under physiological conditions, hippocampal neurons do express the enzyme aromatase, and therefore actively aromatize testosterone to oestradiol. Although glial expression of the aromatase enzyme is minimal, increased expression following injury suggests a role for sex steroids in neuroprotection. It is therefore plausible to deduce that low levels of circulating androgens in males would perturb neuronal functions in relation to cognition and memory, as well as neural repair following injury. The present review is an overview of some roles of the sex steroids on cognitive function in males, and the neuroanatomical and molecular underpinnings of some behavioural and cognitive deficits characteristic of such genetic disorders noted for low androgen levels, including Klinefelter syndrome, Bardet-Biedl syndrome, Kallman syndrome and Prader-Willi syndrome. Recent literature in relation to some behavioural and cognitive changes secondary to surgical and pharmacological castration are also appraised.