High Androgen Research Articles

Association of serum steroids with survival in metastatic hormone-sensitive prostate cancer.

The CHAARTED study showed that adding docetaxel (Doc) to androgen deprivation therapy (ADT) in men initiating treatment for metastatic hormone sensitive prostate cancer (mHSPC) prolongs survival, particularly in high-volume disease. Androgens drive both mHSPC and metastatic castration resistant prostate cancer (mCRPC). Lower nadir serum testosterone (T) concentrations are associated with better outcomes in men treated with ADT for biochemical relapse, while higher androgens at mCRPC are associated with better prognosis and increased benefit from abiraterone. We evaluated the association of serum steroids at 24 weeks with overall survival (OS) and time to CRPC (TTCRPC) in 588 men with available samples from the CHAARTED study. Steroid concentrations were measured using mass spectrometry. The median T concentration at 24 weeks was 8 ng/dl and did not differ in ADT alone vs ADT plus Doc arms. Achieving nadir T below 20ng/dl was not associated with OS or TTCRPC in either arm. In high volume disease, Doc conferred an OS and TTCRPC benefit regardless of steroid concentrations. In low volume disease, steroid concentrations in the lowest quartile at week 24 identified a subset of men with poor survival outcomes more like high volume disease, and in whom Doc was also associated with improved OS and TTCRPC. The known OS benefit of Doc in high volume mHSPC is not modified by serum steroid concentrations achieved on treatment. In low volume disease, steroid concentrations in the lowest quartile may identify a poor prognosis subset in whom Doc also confers OS benefit.

Postnatal Dysregulation of Androgens in Extremely Preterm Male Infants.

Neurodevelopmental impairments are common among survivors of extremely preterm birth, particularly in males. Hyperactivation of the hypothalamic-pituitary-gonadal (HPG) axis has been suggested as an underlying cause, but this has been poorly investigated. Establish levels and temporal changes in circulating androgens in extremely preterm infant males. Observational cohort study analyzing cord blood serum (n = 25) and postnatal plasma (n = 13) collected from day 0 until week 11 from infant males born at 22.8-27.9 weeks gestational age. Testosterone and dihydrotestosterone (DHT) were determined using gas chromatography mass spectrometry, sex hormone-binding globulin (SHBG) with an enzyme-linked immunosorbent assay, and follicle-stimulating hormone (FSH) and luteinizing hormone (LH) with the Luminex xMAP multiplex assay. Testosterone and DHT levels were higher on day 0 (median 4.27 and 0.30 ng/mL) than in cord blood (0.15 and 0.01 ng/mL) (P < .001 for both). Levels of the hormones then declined rapidly until day 5 (median 0.16 and 0.12 ng/mL), then remained relatively constant throughout the study period. Median levels of testosterone and DHT across the whole study period were approximately 6-fold higher than reported in utero levels. FSH and LH showed similar postnatal patterns as the androgens. SHBG steadily increased over time, and, as a result, the fraction of bioavailable testosterone declined with infant postnatal age. The HPG axis is activated immediately after birth in extremely preterm infant males, resulting in an androgen pulse occurring several months earlier than during a normal pregnancy. The long-term implications of high androgen exposure during a sensitive neurodevelopmental period warrant further studies.

7542 Androgen Receptor Oligomerization State Allows Cells to Exhibit Non-Linear Dose Responses to Androgens Resulting in Distinct Biological Outputs

Abstract Disclosure: R. Safi: None. S.E. Wardell: None. P. Watkinson: None. X. Qin: None. M. Lee: None. S. Park: None. T. Krebs: None. E. Dolan: None. T. Tsuji: None. S. Nayak: None. M. Khater: None. M. Newlin: None. M. Kirkland: None. Y. Xie: None. H. Long: None. E. Fink: None. S.W. Fanning: None. S. Runyon: None. M. Brown: None. S. Xu: None. K. Owzar: None. J.D. Norris: None. D.P. McDonnell: None. An unanswered fundamental question in androgen action is how cells recognize and respond in a non-linear fashion to different levels of androgens to elicit distinct biological outputs such as occurs in prostate cancer (PCa) cells. Indeed, most PCa express the androgen receptor (AR), and tumor growth and progression are facilitated by exceedingly low levels of systemic or intratumorally produced androgens. Paradoxically, high dose androgens have been used to treat patients with late-stage metastatic PCa. We have determined that androgen dose regulates the relative cellular abundance of AR monomers and dimers in cells and that the biological output of each oligomeric form of the receptor is different. Using in vitro systems that model exposure from castrate (low dose; LD) to eugonadal levels and above (high dose; HD) of androgens, we have determined that the global changes in gene expression are substantially different, with the changes induced by LD androgens (monomeric AR) being associated with cell proliferation, and HD androgens (dimeric AR) inducing a differentiated phenotype. A similar distinction in response to androgen levels was observed in vivo. Using a chemical biology strategy, we identified ligands which freeze AR in a monomeric form and demonstrate that these compounds faithfully recapitulate the LD biology exhibited by physiological AR agonists. Mechanistically, we determined that monomeric AR facilitates a non-genomic activation of the mTOR signaling pathway to drive proliferation, while the dimer suppresses c-MYC expression, inhibit proliferation, and drive a transcriptional program associated with a differentiated phenotype. These findings highlight the inherent liabilities in current approaches used to inhibit AR-action in prostate cancer and are instructive as to strategies that can be used to develop new therapeutics for this disease and other androgenopathies. Presentation: 6/3/2024

6927 Metyrapone To Reset The Nocturnal Cortisol Rhythm In Mild Autonomous Cortisol Secretion (MACS) - Safety And Impact On Cardiometabolic Risk Factors

Abstract Disclosure: S. Berry: None. A. Iqbal: None. J.D. Newell-Price: Consulting Fee; Self; HRA Pharmaceuticals. M. Debono: Consulting Fee; Self; HRA Pharmaceuticals. Grant Recipient; Self; HRA Pharmaceuticals. Speaker; Self; HRA Pharmaceuticals. Background: MACS is associated with increased cardiometabolic risk including hypertension, type 2 diabetes and dyslipidemia. In MACS, serum and salivary cortisol and cortisone levels are significantly higher in the nocturnal period but follow the usual daytime pattern. Combined early and late evening dosing with the short-acting 11-beta hydroxylase inhibitor, metyrapone, has previously been shown to acutely ‘re-set’ this abnormal part of the cortisol curve to normal. We have now assessed the impact of long-term evening metyrapone on cardiometabolic dysfunction in MACS. Method: A retrospective, controlled, longitudinal study evaluated the safety and tolerability of nocturnal metyrapone and its impact on cardiometabolic risk factors. We included all patients (n=15) who were initiated on metyrapone treatment, 250mg-500mg at 6pm and 250mg at 10pm, for MACS at a tertiary endocrinology center between 2015 and 2022. Age and sex-matched controls were selected from patients with adrenal incidentalomas and non-suppressed serum cortisol following 1mg overnight dexamethasone suppression testing. Systolic blood pressure (SBP), diastolic blood pressure (DBP), weight, HbA1c and non-HDL cholesterol were assessed at baseline and after 6 months. Morning serum cortisol values were evaluated to check for adrenal axis over-suppression. Wilcoxon signed-rank test was used to compare pre/post-treatment, and Mann-Whitney U test was used to compare metyrapone group to controls. Results: Metyrapone was tolerated by 12/15 patients - two stopped due to diarrhea and one due to high androgens in a female. There were no occurrences of adrenal crises. The morning cortisol after metyrapone was 365 nmol/L (IQR 254-431nmol/L, n=13). ACTH increased from 4.5 pg/ml to 7.5 pg/ml (SE±2.15, n=12) after treatment. In the metyrapone group compared to controls, there were significant decreases in SBP (-26.4 SE±8.1mmHg, p=0.008, n=9) and DBP (-12.9 SE±5.5mmHg, p=0.024). Four patients in the control group had up-titration of antihypertensive medication between measurements compared to only one in the metyrapone group. The differences between groups in HbA1c, weight and non-HDL cholesterol were not statistically significant. However, the increase in HbA1c was less in the metyrapone group compared to the control group by 3.0 SE±4.5mmol/mol, as was the non-HDL cholesterol by 0.4 SE±0.33mmol/L (n=10). Conclusion: Evening metyrapone is associated with significant reductions in SBP and DBP in patients with MACS, without causing adrenal insufficiency and with preservation of normal morning serum cortisol. Monitoring 9am cortisol is important to avoid over-treatment. A larger, powered, prospective study is needed to definitively investigate the broader metabolic outcomes and assess the clinical utility of metyrapone in MACS. Presentation: 6/3/2024

High androgen level during controlled ovarian stimulation cycle impairs endometrial receptivity in PCOS patients

PCOS is one of the most common endocrine disorders among women of reproductive age. While the mechanism involved is not yet fully characterized. Our study aims to examine the pregnancy outcomes of embryo transfers in women with PCOS after pretreatment, and to explore the possible effect of high androgen levels on endometrial receptivity. Retrospective cohort study was conducted to analyze pregnancy outcomes among 2714 infertile women with tubal factor and 452 PCOS women. Endometrium samples were collected from 6 controls and 6 PCOS patients to detect the expression of endometrial receptivity marks. The implantation rate, clinical and ongoing pregnancy rates and live birth rate in women with PCOS followed fresh embryo transfers were obviously decreased even after the pretreatment. Similar pregnancy outcomes were found in frozen-thawed embryo transfer cycles between women with or without PCOS. Strikingly, serum total testosterone (TT) levels on trigger day were significantly higher in PCOS women. Women with high TT levels presented significantly lower clinical and ongoing pregnancy rates, and the expression of insulin-like growth factor binding protein 1 (IGFBP-1), and leukemia inhibitory factor (LIF) in the endometria decreased significantly as well. High doses of testosterone significantly down-regulated the expression of IGFBP-1 and LIF in Ishikawa cells. Although endocrine abnormalities had been improved before the controlled ovarian stimulation (COS) cycle started, higher serum TT levels were detected on the trigger day of the COS cycle in PCOS patients, which may contribute to the decreased fresh embryo implantation by impairing endometrial receptivity.

Androgen-mediated maternal effects and trade-offs: postnatal hormone development, growth, and survivorship in wild meerkats.

Mammalian reproductive and somatic development is regulated by steroid hormones, growth hormone (GH), and insulin-like growth factor-1 (IGF-1). Based largely on information from humans, model organisms, and domesticated animals, testosterone (T) and the GH/IGF-1 system activate sexually differentiated development, promoting male-biased growth, often at a cost to health and survivorship. To test if augmented prenatal androgen exposure in females produces similar developmental patterns and trade-offs, we examine maternal effects in wild meerkats (Suricata suricatta), a non-model species in which adult females naturally, albeit differentially by status, express exceptionally high androgen concentrations, particularly during pregnancy. In this cooperative breeder, the early growth of daughters predicts future breeding status and reproductive success. We examine effects of normative and experimentally induced variation in maternal androgens on the ontogenetic patterns in offspring reproductive hormones (androstenedione, A4; T; estradiol, E2), IGF-1, growth from pup emergence at 1 month to puberty at 1 year, and survivorship. Specifically, we compare the male and female offspring of dominant control (DC or high-T), subordinate control (SC or lower-T), and dominant treated (DT or blocked-T) dams, the latter having experienced antiandrogen treatment in late gestation. Meerkat offspring showed sex differences in absolute T and IGF-1 concentrations, developmental rates of A4 and E2 expression, and survivorship - effects that were sometimes socially or environmentally modulated. Atypical for mammals were the early male bias in T that disappeared by puberty, the absence of sex differences in A4 and E2, and the female bias in IGF-1. Food availability was linked to steroid concentrations in females and to IGF-1, potentially growth, and survival in both sexes. Maternal treatment significantly affected rates of T, E2, and IGF-1 expression, and weight, with marginal effects on survivorship; offspring of DT dams showed peak IGF-1 concentrations and the best survivorship. Maternal effects thus impact offspring development in meerkats, with associated trade-offs: Whereas prenatal androgens modify postnatal reproductive and somatic physiology, benefits associated with enhanced competitiveness in DC lineages may have initial costs of reduced IGF-1, delay in weight gain, and decreased survivorship. These novel data further confirm the different evolutionary and mechanistic pathways to cooperative breeding and call for greater consideration of natural endocrine variation in both sexes.

Congenital Adrenal Hyperplasia: A Review of Current Knowledge and Future Directions

Introduction: Congenital adrenal hyperplasia (CAH) is a group of diseases in which genetic defects occur that disturb the synthesis of cortisol. The most common variant of CAH (95%-99%) is caused by 21-hydroxylase deficiency as a result of mutations in the CYP21A2 gene and is one of the most common monogenic diseases. CAH is characterized by androgen overproduction along with variable degrees of cortisol and aldosterone deficiency. Age at diagnosis can provide some information about the underlying mutations, with those diagnosed at birth/early infancy being at greater risk of developing serious enzyme defects. Classic and non-classical forms of this disorder have been described in the literature. CAH diagnosis is based on the clinical presentation, hormonal panel, Adrenocorticotropic Hormone (ACTH) stimulation test, and genetic testing. The main goals of treatment for congenital adrenal hyperplasia are glucocorticoid/mineralcorticoid supplementation, control of high adrenal androgen levels, fertility control, genetic counseling, and optimization of patients’ quality of life. Purpose of the work: This study aims to review and characterize the clinical and pathophysiological aspects of congenital adrenal hyperplasia. Materials and methods: A comprehensive analysis of research papers available on PubMed, Google Scholar, Web of Science, Embase and Scopus was undertaken using the searchterms encompassing the following keywords: congenital adrenal hyperplasia, 21-hydroxylase deficiency, CYP21A2 Results: Congenital adrenal hyperplasia is a heterogeneous group of genetic disorders that can lead to serious and even fatal complications in the form of adrenal crisis. Therefore, screening tests and early diagnosis are crucial and can save the lives of newborns. Treatment should be individualized and allow patients to achieve normal growth, sexual development, fertility and a better quality of life.

Androgen receptor monomers and dimers regulate opposing biological processes in prostate cancer cells

Most prostate cancers express the androgen receptor (AR), and tumor growth and progression are facilitated by exceptionally low levels of systemic or intratumorally produced androgens. Thus, absolute inhibition of the androgen signaling axis remains the goal of current therapeutic approaches to treat prostate cancer (PCa). Paradoxically, high dose androgens also exhibit considerable efficacy as a treatment modality in patients with late-stage metastatic PCa. Here we show that low levels of androgens, functioning through an AR monomer, facilitate a non-genomic activation of the mTOR signaling pathway to drive proliferation. Conversely, high dose androgens facilitate the formation of AR dimers/oligomers to suppress c-MYC expression, inhibit proliferation and drive a transcriptional program associated with a differentiated phenotype. These findings highlight the inherent liabilities in current approaches used to inhibit AR action in PCa and are instructive as to strategies that can be used to develop new therapeutics for this disease and other androgenopathies.

Relationship between acne vulgaris and attention deficit hyperactivity disorder in adolescent: A cross-sectional study.

High androgen hormone exposure in intrauterine life is held to be responsible for the etiopathogenesis of both acne vulgaris (AV) and attention-deficit hyperactivity disorder (ADHD). In this study, we aimed to investigate the prevalence of ADHD in AV patients. Patients between the ages of 12 and 17, diagnosed with AV and a control group were included in the study. The Conners-Wells Adolescent Self-Report Scale-Long Form (CASS-L) was applied to both groups to determine the severity of the ADHD. Ninety-eight patients diagnosed with AV and 96 healthy controls participated in the study. All parameters of the CASS-L were found to be significantly higher in AV patients compared to the control group. In addition, with the severity of the Global Acne Grading System, a positive low level among conduct problems (r = 0.223), cognitive problems (r = 0.271), ADHD index (r = 0.238), inattention (r = 0.238), and a positive moderate level among hyperactivity (r = 0.349), hyperactivity-impulsivity (r = 0.414), and total score (r = 0.429). According to our results, patients diagnosed with AV were more prone to ADHD than the control group. Our study showed that adolescent patients diagnosed with AV were more prone to ADHD than people of similar age and gender without a diagnosis of AV. It should be noted that AV is not only a dermatological disease but may also be accompanied by psychiatric morbidities.

Enhancing the anticancer effect of androgen deprivation therapy by monocarboxylate transporter 1 inhibitor in prostate cancer cells.

Tumor initiation and progression necessitate a metabolic shift in cancer cells. Consequently, the progression of prostate cancer (PCa), a leading cause of cancer-related deaths in males globally, involves a shift from lipogenic to glycolytic metabolism. Androgen deprivation therapy (ADT) serves as the standard treatment for advanced-stage PCa. However, despite initial patient responses, castrate resistance emerges ultimately, necessitating novel therapeutic approaches. Therefore, in this study, we aimed to investigate the role of monocarboxylate transporters (MCTs) in PCa post-ADT and evaluate their potential as therapeutic targets. PCa cells (LNCaP and C4-2 cell line), which has high prostate-specific membrane antigen (PSMA) and androgen receptor (AR) expression among PCa cell lines, was used in this study. We assessed the expression of MCT1 in PCa cells subjected to ADT using charcoal-stripped bovine serum (CSS)-containing medium or enzalutamide (ENZ). Furthermore, we evaluated the synergistic anticancer effects of combined treatment with ENZ and SR13800, an MCT1 inhibitor. Short-term ADT led to a significant upregulation in folate hydrolase 1 (FOLH1) and solute carrier family 16 member 1 (SLC16A1) gene levels, with elevated PSMA and MCT1 protein levels. Long-term ADT induced notable changes in cell morphology with further upregulation of FOLH1/PSMA and SLC16A1/MCT1 levels. Treatment with ENZ, a nonsteroidal anti-androgen, also increased PSMA and MCT1 expression. However, combined therapy with ENZ and SR13800 led to reduced PSMA level, decreased cell viability, and suppressed expression of cancer stem cell markers and migration indicators. Additionally, analysis of human PCa tissues revealed a positive correlation between PSMA and MCT1 expression in tumor regions. Our results demonstrate that ADT led to a significant upregulation in MCT1 levels. However, the combination of ENZ and SR13800 demonstrated a promising synergistic anticancer effect, highlighting a potential therapeutic significance for patients with PCa undergoing ADT.

Prevalence of endocrine disorders in 304 premenopausal women referred with oligomenorrhoea.

We aimed to evaluate 304 premenopausal women admitted to our clinic for oligomenorrhoea, and to screen for Cushing's syndrome (CS) in this population. The study included 304 premenopausal women referred to our clinic for oligomenorrhoea. Anthropometric measurements and Ferriman-Gallwey score were evaluated, and thyroid hormone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total testosterone, prolactin, dehydroepiandrosterone sulphate (DHEA-S), and 17-hydroxyprogesterone (17-OHP) levels were measured in all patients. If basal 17-OHP was > 2 ng/mL, we evaluated adrenocorticotropic hormone (ACTH)-stimulated 17-OHP levels. CS was screened by 1 mg-dexamethasone suppression test, and if the cortisol value was > 1.8 μg/dL, we performed additional confirmatory tests, and if necessary, pituitary magnetic resonance imaging (MRI) and inferior petrosal sinus sampling (IPSS) were performed. The most common cause of oligomenorrhoea was polycystic ovary syndrome (PCOS) that was detected in 81.57% of cases, followed by hyperprolactinemia at 7.23% and hypothalamic anovulation at 5.26%. The prevalence of premature ovarian failure (POF) was 1.6%, and non-classical congenital adrenal hyperplasia (NCAH) was 1.97%. CS was detected in 7 (2.30%) patients. All the patients with CS were found to have Cushing's disease (CD). Although 3 patients with CD had classical signs and symptoms, 4 had none. Patients with CD had similar total testosterone values to those in the PCOS and NCAH groups, but they had significantly higher DHEA-S compared to both groups (CD vs. PCOS, p = 0.001 and CD vs. NCAH, p = 0.030). We found higher prevalence of CS in patients with oligomenorrhoea even in the absence of clinical signs. Therefore, we suggest routine screening for CS during the evaluation of patients with oligomenorrhoea and/or PCOS. The likelihood of CS is greater in patients with high androgen, especially DHEA-S levels.

Relationship between Androgens and Vascular and Placental Function during Pre-eclampsia.

Hypertensive disorders of pregnancy (HDP) represent a substantial risk to maternal and fetal health. Emerging evidence suggests an association between testosterone and pre-eclampsia (PE), potentially mediated through androgen receptors (AR). Nevertheless, the mechanism driving this association is yet to be elucidated. On the other hand, reports of transgender men's pregnancies offer a limited and insightful opportunity to understand the role of high androgen levels in the development of HDP. In this sense, a literature review was performed from a little over 2 decades (1998-2022) to address the association of testosterone levels with the development of HDP. Furthermore, this review addresses the case of transgender men for the first time. The main in vitro outcomes reveal placenta samples with greater AR mRNA expression. Moreover, ex vivo studies show that testosterone-induced vasorelaxation impairment promotes hypertension. Epidemiological data point to greater testosterone levels in blood samples during PE. Studies with transgender men allow us to infer that exogenous testosterone administration can be considered a risk factor for PE and that the administration of testosterone does not affect fetal development. Overall, all studies analyzed suggested that high testosterone levels are associated with PE.

Exploring the Therapeutic Potential of Natural Products in Polycystic Ovarian Syndrome (PCOS): A Mini-Review of Lipid Profile, Blood Glucose, and Ovarian Histological Improvements.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women that is characterized by fluid-filled sacs in the ovaries and various symptoms, including high androgen levels, endometrial irregularities, and cysts. Although the main cause of PCOS remains unknown, it has been linked to genetic, endocrine, and metabolic factors, and there are several treatment options, including lifestyle modifications, medications, and surgery. Natural products such as medicinal plants and fruits are being explored as potential treatments for PCOS because of their bioactive compounds with pharmacological effects related to antioxidant, antimicrobial, anticancer, and antidiabetic properties. Some of these compounds improve insulin sensitivity, reduce inflammation, and enhance glucose metabolism, thereby benefiting patients with PCOS. This mini-review examined the effects of natural products on PCOS, including their effects on ovarian histological changes, blood glucose, sex hormones, and lipid profiles, based on animal and human studies. This study suggests that the use of natural products as complementary medicines can be a promising resource for the development of effective therapeutics for PCOS; however, further research is needed to fully understand their benefits.

Intra-ovarian inflammatory states and their associations with embryo quality in normal-BMI PCOS patients undergoing IVF treatment

BackgroundPolycystic ovary syndrome (PCOS) is the main cause of anovulatory infertility in women of reproductive age, and low-grade chronic inflammation plays a key role in the occurrence and development of PCOS. However, obesity, as a likely confounding factor, can affect the inflammatory state of PCOS patients.ObjectiveThe aim of this study was to comprehensively investigate intra-ovarian inflammatory states and their impact on embryo quality in PCOS patients with a normal BMI undergoing IVF treatment.MethodsDIA-mass spectrometry-based proteomics and bioinformatic analysis were combined to comprehensively profile the protein expression of granulosa cells (GCs) from 5 normal-BMI PCOS patients and 5 controls. Thirty-four cytokines were further systematically detected in follicular fluid (FF) from 32 age- and BMI-matched normal-BMI patients using Luminex liquid chip suspension technology. Next, the differentially expressed cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA) in 24 newly recruited subjects, and the relationship between these cytokines and embryo quality in PCOS patients was analysed. Finally, these cytokine levels were compared and evaluated in PCOS patients with different androgen levels.ResultsProteomic analysis showed that the suppression of substance metabolism and steroid biosynthesis, more interestingly, resulted in an enhanced immune and inflammatory response in the GCs of normal-BMI PCOS patients and prompted the involvement of cytokines in this process. Luminex analysis further showed that FF macrophage inflammatory protein-1 beta (MIP-1β) and stromal cell-derived factor-1 alpha (SDF-1α) levels were significantly increased in normal-BMI PCOS patients compared to controls (P = 0.005; P = 0.035, respectively), and the ELISA results were consistent with these findings. Besides, FF MIP-1β showed an inverse correlation with the number of D3 good-quality embryos and the good-quality blastocyst rate in patients with PCOS (P = 0.006; P = 0.003, respectively), which remained significant after correction for multiple comparisons. Moreover, SDF-1α levels had no relationship with embryo development in PCOS patients. Additionally, SDF-1α levels were significantly lower in PCOS patients with high androgen levels than in controls (P = 0.031).ConclusionsLocal ovarian inflammation was present in normal-BMI PCOS patients, affecting follicular development, and FF MIP-1β may be a potential biomarker associated with embryo quality in normal-BMI PCOS patients.Graphical abstract

Prenatal Exposure to Androgens and Gender Socialisation Effects on Children’s Academic Interests

Previous studies have documented gender differences in fields of study as well as interest in school subjects. Boys are on average more interested in mathematics, and girls show greater interest in languages. The extent to which these disparities are the result of biological or environment influences is still an open debate. On the one hand, brain organisation theory suggests that physiological and behavioural differences may be linked to prenatal hormone levels. On the other hand, sociological and psychological perspectives highlight the importance of gender socialisation. This paper combines biological, psychological, and sociological perspectives to examine the emergence of gendered academic interests in children.The study draws on data from 9‑year-old children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Our results suggest that for both boys and girls, medium to high compared with low prenatal exposure to circulating maternal testosterone might increase children’s interests in mathematics relative to English, although results vary depending on how prenatal testosterone exposure is measured. As the distributions of prenatal androgen exposure and the relationships with maths versus English interests are very similar for boys and girls, prenatal androgen exposure does not contribute to explaining gender differences in academic interests. However, we find some evidence that the relationship with parental gender socialisation varies by prenatal androgen exposure. A more gender-equal parental division of domestic work is more strongly associated with less gendered academic interests for girls with low prenatal androgen exposure and for boys with medium to high androgen exposure.

Diagnostic role and prognostic impact of PSAP immunohistochemistry: A tissue microarray study on 31,358 cancer tissues from 127 different tumor types

Abstract Introduction/Objective Prostatic specific acid phosphatase (PSAP) protein is produced in prostate epithelial cells and it is used as an immunohistochemical marker for prostate cancer. However, studies have reported PSAP expression to occur in various other tumor entities as well. Methods/Case Report Prostatic specific acid phosphatase (PSAP) protein is produced in prostate epithelial cells and it is used as an immunohistochemical marker for prostate cancer. However, studies have reported PSAP expression to occur in various other tumor entities as well. Results (if a Case Study enter NA) In prostate cancer, PSAP staining was seen in 100% of Gleason 3 + 3, 95.5% Gleason 4 + 4, 93.8% recurrent prostate cancer under androgen deprivation therapy, 91.0% Gleason 5 + 5 and 31.2% small cell neuroendocrine prostate cancer. Reduced PSAP staining was strongly linked to high pT stage, high Gleason grade, lymph node metastasis, early PSA-recurrence (p&amp;lt;0.0001 each),high androgen receptor expression and TMPRSS2:ERG fusions. In multivariate analyses, low PSAP expression was able to predict PSA recurrence independent of pre- and postoperative prognostic markers in ERG negative cancers. In extra-prostatic cancers, PSAP immunostaining was only seen in 3 of 94 (3.2%) neuroendocrine tumors of the pancreas and in 1 of 129 (0.8%) diffuse type gastric adenocarcinomas. Conclusion A positive PSAP immunostaining is highly specific for prostate cancer and reduced PSAP expression is associated with an aggressive prostate cancer phenotype. The independent association of reduced PSAP expression with poor prognosis in ERG negative prostate cancer makes PSAP measurement a candidate marker for prognostic multiparameter panels for prostate cancer.

Causal pathways linking polycystic ovary syndrome to distinct breast cancer subtypes through mediator factors: a multivariable mendelian randomization analysis

Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by ovarian cysts, high androgen levels, and irregular menstruation. The causality between PCOS and breast cancer (BC) has been widely discussed as they share a significant intersection in clinical manifestations. Previous epidemiological studies have not provided consistent conclusions in association between PCOS and BC, while mendelian randomization (MR) analyses have confirmed the causality between PCOS and estrogen receptor-positive breast cancer (ER + BC), but among a series of clinical manifestations resulting from PCOS, which related traits mediate the causal effect remains unknown. In this study, we conducted multivariable mendelian randomization (MVMR) analysis to explore the potential mediator variables in the mechanism linking PCOS to distinct subtypes of BC, and calculated the mediating effects proportion. We analyzed 13 PCOS-related traits and found that age at menopause may mediate PCOS-induced ER + BC (with -4.82% proportion) with a weak protective effect through the repair of DNA double-strand breaks by homologous recombination. This study helps to better comprehend the shared mechanisms contributing to the development of both PCOS and BC, and to screen high-risk populations for BC and take appropriate preventive measures.

Diagnostic Role and Prognostic Impact of PSAP Immunohistochemistry: A Tissue Microarray Study on 31,358 Cancer Tissues.

Prostate-specific acid phosphatase (PSAP) is a marker for prostate cancer. To assess the specificity and prognostic impact of PSAP, 14,137 samples from 127 different tumor (sub)types, 17,747 prostate cancers, and 76 different normal tissue types were analyzed via immunohistochemistry in a tissue microarray format. In normal tissues, PSAP staining was limited to the prostate epithelial cells. In prostate cancers, PSAP was seen in 100% of Gleason 3 + 3, 95.5% of Gleason 4 + 4, 93.8% of recurrent cancer under androgen deprivation therapy, 91.0% of Gleason 5 + 5, and 31.2% of small cell neuroendocrine cancer. In non-prostatic tumors, PSAP immunostaining was only found in 3.2% of pancreatic neuroendocrine tumors and in 0.8% of diffuse-type gastric adenocarcinomas. In prostate cancer, reduced PSAP staining was strongly linked to an advanced pT stage, a high classical and quantitative Gleason score, lymph node metastasis, high pre-operative PSA levels, early PSA recurrence (p < 0.0001 each), high androgen receptor expression, and TMPRSS2:ERG fusions. A low level of PSAP expression was linked to PSA recurrence independent of pre- and postoperative prognostic markers in ERG-negative cancers. Positive PSAP immunostaining is highly specific for prostate cancer. Reduced PSAP expression is associated with aggressive prostate cancers. These findings make PSAP a candidate marker for prognostic multiparameter panels in ERG-negative prostate cancers.

Digit Ratio (2D:4D; Right-Left 2D:4D) and Multiple Phenotypes for Same-Sex Attraction: The BBC Internet Study Revisited

Same-sex attraction may be linked to low prenatal androgen (in men) and high prenatal androgen (in women). Digit ratio (2D:4D) is thought to be a negative correlate of prenatal androgen and right-left 2D:4D (Dr-l) to reflect lateralized differences in sensitivity to prenatal androgen. Lower 2D:4D has been reported for lesbians compared to heterosexuals, but links to high 2D:4D in gay men are less clear. The largest study thus far (the BBC Internet study) found no significant difference between the 2D:4D of lesbians and heterosexual women but a higher 2D:4D in gay men compared to heterosexual men. Here we consider the possibility that low and high prenatal androgen is associated with same-sex attraction in men (n = 108,779) and women (n = 87,742), resulting in more than two phenotypes. We examined the associations between 2D:4D, Dr-l, and same-sex attraction scores in the BBC Internet study. In contrast to the earlier report, which considered sexual orientation in categories, there were positive linear associations in men (right and left 2D:4D, but not Dr-l) and negative linear associations in women (right 2D:4D and Dr-l, but not left 2D:4D). There were no curvilinear relationships for right and left 2D:4D. However, Dr-l showed a U-shaped association with same-sex attraction in men. Thus, (1) high prenatal androgen may be implicated in female homosexuality, while both low and high prenatal androgen may be implicated in male homosexuality, and (2) large side differences in sensitivity to androgen may be associated with elevated same-sex attraction in men.

OR15-01 Overweight/Obese Pubertal Girls Have Higher Androgen Levels - Can Metabolomics Tell Us Why?

Abstract Disclosure: M. Calvert: None. S. Molsberry: None. A.K. Jarmusch: None. K.E. Overdahl: None. N. Shaw: None. Introduction: The Body Weight and Puberty Study (BWPS) was a 4-year longitudinal study of 90 healthy pubertal, pre-menarchal girls consisting of dual-energy x-ray absorptiometry to calculate total body fat (TBF), Tanner staging, breast ultrasound, and hormone tests. We observed that with time, girls with higher TBF demonstrated higher serum total and free testosterone and androstenedione levels. The cause of this association is unknown but is hypothesized to relate to greater insulin resistance. Methods: To investigate the association between higher androgens and higher TBF in late pubertal girls, we conducted an untargeted metabolomics study using our BWPS collection of 158 blood and 178 urine samples. Samples were run on an ultra-high performance liquid chromatograph (Vanquish, Thermo Scientific) coupled to a high-resolution mass spectrometer (Orbitrap Fusion Tribrid, Thermo Scientific) and analyzed in positive and negative ionization modes. We investigated the association between TBF or BMI Z-score and metabolites and the association between metabolites and serum androgen levels. All associations were examined cross-sectionally and lagged by one visit using linear generalized estimating equation models, adjusting for breast morphological stage and age at baseline, race, and time between visits. Benjamini-Hochberg false discovery rate (FDR) adjusted p-values were calculated to account for multiple testing. RaMP DB (Relational database of Metabolomic Pathways) was used to conduct enriched pathway analyses among metabolites nominally associated with body composition or hormone levels. Results: 70 participants (aged 10.9 ± 1.39 SD years; 60% White, 24% Black, 16% Other; 63% normal weight, 37% overweight/obese) contributed an average of 2.39 blood and 2.54 urine samples over the course of 1.15 ± 0.47 SD years of follow-up. While few metabolites were significantly associated with body composition or androgen levels after strict multiple testing correction, RaMP DB enriched pathway analyses identified several pathways linking TBF and androgen levels: 1) in lagged analyses of urinary metabolites, overall amino acid metabolism, arginine and proline metabolism, and the urea cycle linked TBF with androstenedione; 2) in cross-sectional analyses of serum metabolites, bile acid synthesis and metabolism, VEGF or extra-nuclear estrogen signaling (related to the metabolite, sphingosine-1-phosphate), and tryptophan metabolism linked TBF with androstenedione. Conclusions: Metabolomic analyses of samples from pubertal girls did not uncover signatures of insulin resistance (e.g., branched chain amino acids or C3- and C5-acyclcarnitines) to explain the association between higher androgens and TBF. Instead, we identified potential novel signaling pathways that may involve amino acid, bile acid, or sphingosine-1-phosphate action at the ovary and/or adrenal gland. Presentation: Friday, June 16, 2023