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Milk was a source of important nutrients for humans and was especially important for children and adolescents. The modern dairy animal production pattern had contributed to residual sex steroid hormones in milk. When this milk was consumed by humans, these hormones entered the body leading to hormonal disruptions and potentially increasing the risk of various types of cancers. This article reviewed the presence of residual sex steroid hormones in milk, their potential risks on human health, and their possible association with the incidence of breast and prostate cancer. The potential linkage between dairy consumption and these cancers were described in detail. The hormones present in dairy products could affect the development and progression of these types of cancer. Sex steroid hormones could interact with different signaling pathways, influencing carcinogenic cascades that could eventually lead to tumorigenesis. Given these potential health risks, the article suggested appropriate consumption of dairy products. This included being mindful not just of the amount of dairy consumed, but also the types of dairy products selected. More scientific exploration was needed, but this review provided valuable insights for health-conscious consumers and contributed to the ongoing discussion on dietary guidelines and human health.

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Sex steroid hormones (SSH) are extremely versatile molecules with a myriad of physiological functions. Next to their well-known role in sexual development and reproduction, SSH play active roles in practically every tissue in the human body, including the oral cavity. It has long been demonstrated that periodontal tissues express SSH receptors and therefore are responsive to the presence of SSH. Interestingly, SSH not only interact with the periodontal tissues but also with other tissues in the oral cavity such as dental enamel, pulp, cementum, oral mucosa, and salivary glands. Questions concerning the possible physiological functions of these receptors and their role in maintenance of oral health, remain unanswered. The purpose of this scoping review was to gather and summarize all the available evidence on the role of SSH in physiological processes in the oral cavity in humans. Two comprehensive literature searches were performed. References were screened and selected based on title, abstract and full text according to our inclusion criteria. Both searches yielded 18,992 results of which 73 were included. Results were divided into four categories: (1) Periodontium; (2) Dental structure; (3) Mucosa; and (4) Salivary glands. The interaction of these tissues with progestagens, androgens and estrogens are summarized. Sex steroid hormones are an overlooked yet fundamental factor in oral homeostasis. They play important roles in the development and function of the periodontium, dental structure, mucosa and salivary glands. Dentists and healthcare providers should consider these hormonal factors when assessing and treating oral health conditions.

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PURPOSE OF REVIEW: Many synthetic endocrine-disrupting chemicals (EDCs) are ubiquitous in the environment and highly detected among pregnant people. These chemicals may disrupt maternal and/or fetal sex steroid hormones, which are critical to pregnancy maintenance and fetal development. Here, we review the epidemiological literature examining prenatal exposure to common synthetic EDCs in relation to maternal and fetal sex steroid hormones. RECENT FINDINGS: We performed a literature search using PubMed, SCOPUS, and Embase, ultimately identifying 29 articles for full review. Phenols, parabens, and persistent organic pollutants generally showed inverse associations with androgens, estrogens, and progesterone. Phthalates and per-and polyfluoroalkyl substances tended to be inversely associated with progesterone, while evidence regarding androgens and estrogens was mixed. Inconsistent, but noteworthy, differences by fetal sex and timing of exposure/outcome were observed. Overall, the literature suggests EDCs may disrupt maternal and fetal sex steroid activity, though findings are mixed. Given the pervasive, high-volume production of these synthetic chemicals and the critical functions sex steroid hormones play during gestation, additional research is warranted.

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Background: Sex steroid hormones, including testosterone and estradiol, play significant roles in various aspects of pulmonary health and diseases. However, although there were a few studies trying to link sex hormones with COPD, their effect remained limited due to small sample size and insufficient causal results. This study aims to investigate the association between sex hormones and chronic obstructive pulmonary disease (COPD) based on the National Health and Nutrition Examination Survey (NHANES) database and evaluate causality via a two-sample Mendelian randomization (MR). Methods: Data from NHANES 2013-2016 were enrolled for the cross-sectional study. The association between sex hormones and COPD was evaluated via multivariable logistic regression. Sex-stratified analysis, subgroup analyses and interaction tests were performed to further evaluate the correlation. For MR analysis, data were collected from genome-wide association studies and FinnGen datasets. The inverse-variance-weighted (IVW) approach, along with four other approaches, was applied in the analysis. Further sensitivity analysis was conducted to assess the existence of pleiotropy and heterogeneity. Results: 7,617 eligible participants were enrolled in the cross-sectional analysis. Negative associations were observed in both testosterone-COPD (OR 0.770, 95% CI 0.626, 0.948, p = 0.018) and estradiol-COPD (OR 0.794, 95% CI 0.688, 0.915, p = 0.005) relationships after covariate adjustments. However, the results from IVW-MR analysis showed that no causal relationship was observed in either the testosterone-COPD (OR 0.83, 95% CI 0.53, 1.29, p = 0.407) or estradiol-COPD (OR 0.74, 95% CI 0.23, 2.38, p = 0.616) relationship, which was also supported by the other four approaches (all p values > 0.05). Conclusion: Although a significant negative association was observed between sex hormones and COPD, the results of MR analysis did not support the causality of this relationship. Our study suggested that sex hormones may indirectly rather than directly affect the development of COPD via potential covariates, which warranted further investigations.

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Aging involves complex biological changes that affect disease susceptibility and aging trajectories. Although females typically live longer than males, they have a higher susceptibility to diseases like Alzheimer's, speculated to be influenced by menopause, and reduced ovarian hormone production. Understanding sex-specific differences is crucial for personalized medical interventions and gender equality in health. Our study aims to elucidate sex differences in regional cerebellar structure and connectivity during normal aging by investigating both structural and functional connectivity variations, with a focus on investigating these differences in the context of sex-steroid hormones. The study included 138 participants (mean age = 57(13.3) years, age range = 35-86 years, 54% women). The cohort was divided into three groups: 38 early middle-aged individuals (EMA) (mean age = 41(4.7) years), 48 late middle-aged individuals (LMA) (mean age = 58(4) years), and 42 older adults (OA) (mean age = 72(6.3) years). All participants underwent MRI scans, and saliva samples were collected for sex-steroid hormone quantification (17ß-estradiol (E), progesterone (P), and testosterone (T)). We found less connectivity in females between Lobule I-IV and the cuneus, and greater connectivity in females between Crus I, Crus II, and the precuneus with increased age. Higher 17ß-estradiol levels were linked to greater connectivity in Crus I and Crus II cerebellar subregions. Analyzing all participants together, testosterone was associated with both higher and lower connectivity in Lobule I-IV and Crus I, respectively, while higher progesterone levels were linked to lower connectivity in females. Structural differences were observed, with EMA males having larger volumes compared to LMA and OA groups, particularly in the right I-IV, right Crus I, right V, and right VI. EMA females showed higher volumes in the right lobules V and VI. These results highlight the significant role of sex hormones in modulating cerebellar connectivity and structure across adulthood, emphasizing the need to consider sex and hormonal status in neuroimaging studies to better understand age-related cognitive decline and neurological disorders.

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The primary mechanism of traumatic spinal cord injury (SCI) comprises the initial mechanical trauma due to the transmission of energy to the spinal cord, subsequent deformity, and persistent compression. The secondary mechanism of injury, which involves structures that remained undamaged after the initial trauma, triggers alterations in microvascular perfusion, the liberation of free radicals and neurotransmitters, lipid peroxidation, alteration in ionic concentrations, and the consequent cell death by necrosis and apoptosis. Research in the treatment of SCI has sought to develop early therapeutic interventions that mitigate the effects of these pathophysiological mechanisms. Clinical and experimental evidence has demonstrated the therapeutic benefits of sex-steroid hormone administration after traumatic brain injury and SCI. The administration of estradiol, progesterone, and testosterone has been associated with neuroprotective effects, better neurological recovery, and decreased mortality after SCI. This review evaluated evidence supporting hormone-related neuroprotection over SCI and the possible underlying mechanisms in animal models. As neuroprotection has been associated with signaling pathways, the effects of these hormones are observed on astrocytes and microglia, modulating the inflammatory response, cerebral blood flow, and metabolism, mediating glutamate excitotoxicity, and their antioxidant effects. Based on the current evidence, it is essential to analyze the benefit of sex steroid hormone therapy in the clinical management of patients with SCI.

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BACKGROUND: The sex steroid hormones fluctuate during the menstrual cycle, which affects the strength and postural stability of females and leads to injuries and risk of falls. These hormones may be modulated by exercise to impact the overall health of females. OBJECTIVE: To determine the effects of exercise on sex steroid hormones in eumenorrheic females. METHODS: This review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA) guidelines in Lahore, Pakistan. The full-length articles were searched using these databases/search engines (PubMed, Web of Science and Google Scholar, Sci-Hub). Randomized controlled trials along with single group experimental studies were also included. All types of exercises were compared with no exercise in the control group. The Cochrane Risk of Bias assessment tool assessed and screened the articles. The data were then analyzed. The primary outcomes were the levels of estrogen, progesterone and testosterone. RESULTS: Eleven studies were included (5 randomized controlled trials and 6 quasi-experimental studies). The effects of exercise on free estradiol concentration and serum progesterone level were not significant [p = 0.37 (SMD = 0.33, 95% CI = 0.14 to 0.74, I2 = 0%) and p = 0.84 (S.D= -0.65, C.I= -6.92 to 5.62, I2 = 94%)] respectively, whereas, the effects on testosterone levels were significant [p value < 0.00001 (M.D = 0.89, 95% C.I= -2.16 to 3.95, I2 = 94%)]. CONCLUSION: A blinded randomized controlled trial should be conducted in which a structured approach should be followed by women along with warm-ups, cool down and rest intervals. TRIAL REGISTRATION NUMBER: The systematic review was registered prospectively on PROSPERO with registration number CRD42023473767.

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BACKGROUND: Dose-response and nonlinear relationships of cigarette exposure with sleep disturbances and depression are warranted, and the potential mechanism of sex hormones in such associations remains unclear. METHODS: Cigarette exposure, trouble sleeping, and depression were assessed by standard questionnaires, and the levels of cotinine and sex steroid hormones were determined among 9900 adults from the National Health and Nutrition Examination Survey (NHANES). Multiple linear regression, logistic regression, and mediation models were conducted to evaluate the associations between smoking, sex steroid hormones, trouble sleeping, and depression. RESULTS: With never smokers as a reference, current smokers had a higher prevalence of trouble sleeping (OR = 1.931, 95% CI: 1.680, 2.219) and depression (OR = 2.525, 95% CI: 1.936, 3.293) as well as testosterone level (ß = 0.083, 95% CI: 0.028, 0.140). Pack-years of smoking and cigarettes per day were positively associated with the prevalence of trouble sleeping and depression as well as testosterone level (Ptrend <0.05). The restricted cubic spline model showed linear relationships of cotinine with trouble sleeping, depression, and testosterone. The positive associations of cigarettes per day with trouble sleeping and depression were greater in females than that in males (Pmodification <0.05). However, the potential role of sex hormones was not observed in the association of cotinine with trouble sleeping or depression (Pmediation >0.05). CONCLUSION: Smoking may induce sex hormone disturbance and increase the risk of sleep problems and depression symptoms, and ceasing smoking may reduce the risk of such complications.

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Background: The relationship between systemic inflammatory index (SII), sex steroid hormones, dietary antioxidants (DA), and gout has not been determined. We aim to develop a reliable and interpretable machine learning (ML) model that links SII, sex steroid hormones, and DA to gout identification. Methods: The dataset we used to study the relationship between SII, sex steroid hormones, DA, and gout was from the National Health and Nutrition Examination Survey (NHANES). Six ML models were developed to identify gout by SII, sex steroid hormones, and DA. The seven performance discriminative features of each model were summarized, and the eXtreme Gradient Boosting (XGBoost) model with the best overall performance was selected to identify gout. We used the SHapley Additive exPlanation (SHAP) method to explain the XGBoost model and its decision-making process. Results: An initial survey of 20,146 participants resulted in 8,550 being included in the study. Selecting the best performing XGBoost model associated with SII, sex steroid hormones, and DA to identify gout (male: AUC: 0.795, 95% CI: 0.746- 0.843, accuracy: 98.7%; female: AUC: 0.822, 95% CI: 0.754- 0.883, accuracy: 99.2%). In the male group, The SHAP values showed that the lower feature values of lutein + zeaxanthin (LZ), vitamin C (VitC), lycopene, zinc, total testosterone (TT), vitamin E (VitE), and vitamin A (VitA), the greater the positive effect on the model output. In the female group, SHAP values showed that lower feature values of E2, zinc, lycopene, LZ, TT, and selenium had a greater positive effect on model output. Conclusion: The interpretable XGBoost model demonstrated accuracy, efficiency, and robustness in identifying associations between SII, sex steroid hormones, DA, and gout in participants. Decreased TT in males and decreased E2 in females may be associated with gout, and increased DA intake and decreased SII may reduce the potential risk of gout.

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Thyroid cancer more commonly affects women than men and is the third most frequently diagnosed cancer among women of reproductive age. We conducted a nested case-control study within the Finnish Maternity Cohort to evaluate pre-diagnostic sex steroid and thyroid function markers in relation to subsequent maternal papillary thyroid cancer. Cases (n = 605) were women ages 18-44 years, who provided an early-pregnancy (<20 weeks gestation) blood sample and were diagnosed with papillary thyroid cancer up to 11 years afterward. Controls (n = 1185) were matched to cases 2:1 by gestational age, mother's age, and date at blood draw. Odds ratios (ORs) for the associations of serum thyroid peroxidase antibodies (TPO-Ab), thyroglobulin antibodies (Tg-Ab), thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), progesterone, and estradiol with papillary thyroid cancer were estimated using conditional logistic regression. TPO-Ab and Tg-Ab positivity (>95th percentile among controls) were associated with more than 3-fold (OR = 3.32, 95% confidence interval [CI] 2.33-4.72) and 2-fold (OR = 2.03, 95% CI 1.41-2.93) increased odds of papillary thyroid cancer, respectively. These associations were similar by time since blood draw, parity, gestational age, smoking status, and age and stage at diagnosis. In models excluding TPO-Ab or Tg-Ab positivity, TPO-Ab (quartile 4 vs. 1: OR = 1.66, 95% CI 1.17-2.37, p-trend = .002) and Tg-Ab (quartile 4 vs. 1: OR = 1.74, 95% CI 1.22-2.49, p-trend = .01) levels were positively associated with papillary thyroid cancer. No associations were observed for estradiol, progesterone, TSH, fT3, or fT4 overall. Our results suggest that thyroid autoimmunity in early pregnancy may increase the risk of maternal papillary thyroid cancer.

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Introduction: Sex steroid hormones are emerging significant biomarkers of depression among Women with Epilepsy (WWE) with promising prognostic potential and therapeutic end point. Therefore, the study is aimed at exploring the association between sex steroids hormones, Anti-seizure Medication (ASM) and depression among WWE. Methodology: A baseline questionnaire was used to obtain socio-demographics and clinical characteristic from one hundred and twelve (112) WWE and 50 age matched healthy control. The diagnosis of epilepsy and Electroencephalography (EEG) description was based on 2017 International League Against Epilepsy (ILAE) criteria. Blood samples were collected from cases and control during Luteal Phase (LP) and Follicular Phase (FP). The Zung Self-Rating Depression Scale (ZSRDS) was used to assess depression. Result: The prevalence of depression among WWE is 18.8%, with a significant difference between the level of formal education (p0.000), age (p0.000), and mean ZSRDS (p0.000) among cases and control. There is a statistical difference in hormonal levels between cases and control with regards to higher testosterone [3.28 ± 9.99 vs. 0.31 ± 0.30; p0.037], lower FP prolactin [16.37 ± 20.14 vs. 17.20 ± 7.44; p0.778], and lower LP prolactin [15.74 ± 18.22 vs. 17.67 ± 7.27; p0.473]. Testosterone (p0.024), FP Follicle Stimulating Hormone (FSH) (p0.009), FP Estradiol (p0.006), LP FSH (p0.031), LP Progesterone (p0.023), and LP Prolactin (p0.000) were associated with depression. However, only prolactin (p0.042) and testosterone (p0.000) predicts depression among WWE. Conclusion: There was higher mean depression score, lower prolactin and higher testosterone level among cases compared to control. Furthermore, there was lower prolactin and higher testosterone level in Carbamazepine (CBZ) group compared to Levetiracetam (LEV) groups.

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Glyphosate, ranked as one of the most widely used herbicides in the world, has raised concerns about its potential disruptive effects on sex hormones. However, limited human evidence was available, especially for children and adolescents. The present study aimed to examine the associations between exposure to glyphosate and sex hormones among participants aged 6-19 years, utilizing data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2016. Children and adolescents who had available data on urinary glyphosate, serum sex steroid hormones, including testosterone (TT), estradiol (E2) and sex hormone binding globulin (SHBG), and covariates were selected. Additionally, the ratio of TT to E2 (TT/E2) and the free androgen index (FAI), which was calculated using TT/SHBG, were also included as sex hormone indicators. Survey regression statistical modeling was used to examine the associations between urinary glyphosate concentration and sex hormone indicators by age and sex group. Among the 964 participants, 83.71% had been exposed to glyphosate (>lower limit of detection). The survey regression revealed a marginally negative association between urinary glyphosate and E2 in the overall population, while this association was more pronounced in adolescents with a significant trend. In further sex-stratified analyses among adolescents, a significant decrease in E2, FAI, and TT (p trend <0.05) was observed in female adolescents for the highest quartile of urinary glyphosate compared to the lowest quartile. However, no similar association was observed among male adolescents. Our findings suggest that exposure to glyphosate at the current level may decrease the levels of sex steroids in adolescents, particularly female adolescents. Considering the cross-sectional study design, further research is needed to confirm our findings.

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There are considerable sex differences regarding the risk of cardiovascular disease (CVD), including arterial hypertension, coronary artery disease (CAD) and stroke, as well as chronic renal disease. Women are largely protected from these conditions prior to menopause, and the risk increases following cessation of endogenous estrogen production or after surgical menopause. Cardiovascular diseases in women generally begin to occur at a later age than in men (on average with a delay of 10 years). Cessation of estrogen production also impacts metabolism, increasing the risk of developing obesity and diabetes. In middle-aged individuals, hypertension develops earlier and faster in women than in men, and smoking increases cardiovascular risk to a greater degree in women than it does in men. It is not only estrogen that affects female cardiovascular health and plays a protective role until menopause: other sex hormones such as progesterone and androgen hormones generate a complex balance that differentiates heart and blood vessel function in women compared to men. Estrogens improve vasodilation of epicardial coronary arteries and the coronary microvasculature by augmenting the release of vasodilating factors such as nitric oxide and prostacyclin, which are mechanisms of coronary vasodilatation that are more pronounced in women compared to men. Estrogens are also powerful inhibitors of inflammation, which in part explains their protective effects on CVD and chronic renal disease. Emerging evidence suggests that sex chromosomes also play a significant role in shaping cardiovascular risk. The cardiovascular protection conferred by endogenous estrogens may be extended by hormone therapy, especially using bioidentical hormones and starting treatment early after menopause.

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The occurrence of benign prostate hyperplasia (BPH) was related to disrupted sex steroid hormones, and metformin (Met) had a clinical response to sex steroid hormone-related gynaecological disease. However, whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear. Here, our clinical study showed that along with prostatic epithelial cell (PEC) proliferation, sex steroid hormones were dysregulated in the serum and prostate of BPH patients. As the major contributor to dysregulated sex steroid hormones, elevated dihydrotestosterone (DHT) had a significant positive relationship with the clinical characteristics of BPH patients. Activation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor (AR)-mediated Yes-associated protein (YAP1)-TEA domain transcription factor (TEAD4) heterodimers. Met's anti-proliferative effects were blocked by AMPK inhibitor or YAP1 overexpression in DHT-cultured BPH-1 cells. Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.

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Background: Estrogen and progesterone levels undergo changes throughout the menstrual cycle. Existing literature regarding the effect of menstrual phases on cardiovascular and autonomic regulation during central hypovolemia is contradictory. Aims and study: This study aims to explore the influence of menstrual phases on cardiovascular and autonomic responses in both resting and during the central hypovolemia induced by lower body negative pressure (LBNP). This is a companion paper, in which data across the menstrual phases from healthy young females, whose results are reported in Shankwar et al. (2023), were further analysed. Methods: The study protocol consisted of three phases: (1) 30 min of supine rest; (2) 16 min of four LBNP levels; and (3) 5 min of supine recovery. Hemodynamic and autonomic responses (assessed via heart rate variability, HRV) were measured before-, during-, and after-LBNP application using Task Force Monitor® (CNSystems, Graz, Austria). Blood was also collected to measure estrogen and progesterone levels. Results: In this companion paper, we have exclusively assessed 14 females from the previous study (Shankwar et al., 2023): 8 in the follicular phase of the menstrual cycle (mean age 23.38 ± 3.58 years, height 166.00 ± 5.78 cm, weight 57.63 ± 5.39 kg and BMI of 20.92 ± 1.96 25 kg/m2) and 6 in the luteal phase (mean age 22.17 ± 1.33 years, height 169.83 ± 5.53 cm, weight 62.00 ± 7.54 kg and BMI of 21.45 ± 2.63 kg/m2). Baseline estrogen levels were significantly different from the follicular phase as compared to the luteal phase: (33.59 pg/ml, 108.02 pg/ml, respectively, p < 0.01). Resting hemodynamic variables showed no difference across the menstrual phases. However, females in the follicular phase showed significantly lower resting values of low-frequency (LF) band power (41.38 ± 11.75 n.u. and 58.47 ± 14.37 n.u., p = 0.01), but higher resting values of high frequency (HF) band power (58.62 ± 11.75 n.u. and 41.53 ± 14.37 n.u., p = 0.01), as compared to females in the luteal phase. During hypovolemia, the LF and HF band powers changed only in the follicular phase F(1, 7) = 77.34, p < 0.0001 and F(1, 7) = 520.06, p < 0.0001, respectively. Conclusions: The menstrual phase had an influence on resting autonomic variables, with higher sympathetic activity being observed during the luteal phase. Central hypovolemia leads to increased cardiovascular and autonomic responses, particularly during the luteal phase of the menstrual cycle, likely due to higher estrogen levels and increased sympathetic activity.

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The pituitary gland is a small endocrine gland located below the hypothalamus. This gland releases several important hormones and controls the function of many other endocrine system glands to release hormones. Fish pituitary hormonal cells are controlled by neuroendocrine and sex steroid feedback. To study the complex pituitary function in vivo, we established an in vitro pituitary spheroid assay and evaluated its suitability for monitoring the annual reproductive physiological conditions in Takifugu rubripes, also known as torafugu, is one of the most economically important species distributed in the northwestern part of the Pacific Ocean, in the western part of the East China Sea, and in more northern areas near Hokkaido, Japan. Fish pituitary spheroids can be easily constructed in liquid or solid plates. The culture medium (L-15) made the aggregation faster than MEM (Hank's). A Rho-kinase inhibitor (Y-27632, 10 µM) and/or fish serum (2.5 %) also promoted spheroid formation. Laser confocal microscopy analysis of spheroids cultured with annual serum of both sexes revealed that luteinizing hormone (LH) synthesis has the highest peak in the final maturation stage (3 years old, May) in accordance with the highest serum sex steroid levels; in contrast, follicle stimulating hormone (FSH) synthesis has no correlation with the dose of serum or nutrients. Similarly, 3D cell propagation assays using female serum showed that total pituitary cells displayed the highest proliferation at puberty onset (2 years old, October) before half a year of the spawning season. These results indicate that pituitary spheroids are useful in vitro models for monitoring the reproductive physiological status of fish in vivo and may be applicable to the in vitro screening of environmental chemicals and bioactive compounds affecting reproductive efficiency in aquaculture.

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PURPOSE: Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways. METHODS: This analysis included 1208 women from a case-cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex-hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders. RESULTS: Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI 1.03 to 1.44), androstenedione (RR 1.20, 95% CI 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI 0.98 to 1.28), estrone (RR 1.21, 95% CI 0.99 to 1.48), total estradiol (RR 1.19, 95% CI 1.02 to 1.39) and free estradiol (RR 1.22, 95% CI 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR 0.83, 95% CI 0.66 to 1.05). CONCLUSION: Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex-hormone-driven nature of postmenopausal breast cancer.

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Excessive fluoride exposure can disturb the balance of sex hormones. Zinc is essential for sex hormone synthesis and spermatogenesis. But it is not clear how zinc affects the relationship of fluoride exposure with abnormal sex steroid hormones. Here, a total of 1008 pubertal males from the National Health and Nutrition Examination Survey (NHANES) in two cycles (2013-2014, 2015-2016) were enrolled. The concentrations of water fluoride and plasma fluoride and the levels of serum testosterone, estradiol, and sex hormone binding globulin (SHBG) were measured. Two 24-h dietary recall interviews were conducted to assess the dietary zinc intake. The relationships of fluoride exposure and zinc intake with sex hormones were examined using linear regression and logistic regression models, while the generalized additive model was used to evaluate their non-linear relationship. Our findings revealed that for every two-fold increase in plasma fluoride concentration, testosterone levels decreased by 7.27% (95% CI - 11.49%, - 2.86%) and estradiol levels decreased by 8.73% (95% CI - 13.61%, - 3.57%). There was also significant non-linear association observed between zinc intake and SHBG levels. Being in the first tertile of plasma fluoride had a 60% lower risk of high SHBG (OR = 0.40, 95% CI 0.18, 0.89) compared with being in the second tertile. When compared to the first tertile, being in the second tertile of zinc intake was associated with a 63% (OR = 0.37, 95% CI 0.14, 0.98) lower risk of high SHBG. Furthermore, we observed an interactive effect between the plasma fluoride and zinc intake on estradiol and SHBG, as well as the risk of high SHBG (P-interaction < 0.10). These findings suggest that fluoride exposure and zinc intake can affect sex steroid hormone levels and the risk of high SHBG. Notably, zinc intake may alleviate the increased risk of high SHBG and the abnormal changes of estradiol and SHBG caused by higher fluoride exposure.

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The occurrence of benign prostate hyperplasia(BPH)was related to disrupted sex steroid hormones,and metformin(Met)had a clinical response to sex steroid hormone-related gynaecological disease.How-ever,whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains unclear.Here,our clinical study showed that along with prostatic epithelial cell(PEC)proliferation,sex steroid hormones were dysregulated in the serum and prostate of BPH patients.As the major contributor to dysregulated sex steroid hormones,elevated dihydrotestosterone(DHT)had a significant positive rela-tionship with the clinical characteristics of BPH patients.Activation of adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor(AR)-mediated Yes-associated protein(YAP1)-TEA domain transcription factor(TEAD4)heterodimers.Met's anti-proliferative effects were blocked by AMPK inhibitor or YAP1 over-expression in DHT-cultured BPH-1 cells.Our findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.

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BACKGROUND: Sex hormones play important roles in the estrus return of post-weaning sows. Previous studies have demonstrated a complex and bi-directional regulation between sex hormones and gut microbiota. However, the extent to which the gut microbiota affects estrus return of post-weaning sows is largely unknown. RESULTS: In this study, we first screened 207 fecal samples from well-phenotyped sows by 16S rRNA gene sequencing and identified significant associations between microbes and estrus return of post-weaning sows. Using metagenomic sequencing data from 85 fecal samples, we identified 37 bacterial species that were significantly associated with estrus return. Normally returning sows were characterized by increased abundances of L. reuteri and P. copri and decreased abundances of B. fragilis, S. suis, and B. pseudolongum. The changes in gut microbial composition significantly altered the functional capacity of steroid hormone biosynthesis in the gut microbiome. The results were confirmed in a validation cohort. Significant changes in sex steroid hormones and related compounds were found between normal and non-return sows via metabolome analysis. An integrated analysis of differential bacterial species, metagenome, and fecal metabolome provided evidence that normal return-associated bacterial species L. reuteri and Prevotella spp. participated in the degradation of pregnenolone, progesterone, and testosterone, thereby promoting estrogen biosynthesis. Furthermore, the microbial metabolites related to sow energy and nutrient supply or metabolic disorders also showed relationships with sow estrus return. CONCLUSIONS: An integrated analysis of differentially abundant bacterial species, metagenome, and fecal metabolome revealed the involvement of L. reuteri and Prevotella spp. in sow estrus return. These findings provide deep insight into the role of gut microbiota in the estrus return of post-weaning sows and the complex cross-talk between gut microbiota and sex hormones, suggesting that the manipulation of the gut microbiota could be an effective strategy to improve sow estrus return after weaning.