The HeyL-Aromatase Axis Promotes Cancer Stem Cell Properties by Endogenous Estrogen-Induced Autophagy in Castration-Resistant Prostate Cancer

Treatment of patients with castration-resistant prostate cancer (CRPC) remains a major clinical challenge. We previously showed that estrogenic effects contribute to CRPC progression and are primarily caused by the increased endogenous estradiol produced via highly expressed aromatase. However, the mechanism of aromatase upregulation and its role in CRPC are poorly described. In this study, we report that HeyL is aberrantly upregulated in CRPC tissues, and its expression is positively correlated with aromatase levels. HeyL overexpression increased endogenous estradiol levels and estrogen receptor-α (ERα) transcriptional activity by upregulating CYP19A1 expression, which encodes aromatase, enhancing prostate cancer stem cell (PCSC) properties in PC3 cells. Mechanistically, HeyL bound to the CYP19A1 promoter and activated its transcription. HeyL overexpression significantly promoted bicalutamide resistance in LNCaP cells, which was reversed by the aromatase inhibitor letrozole. In PC3 cells, the HeyL-aromatase axis promoted the PCSC phenotype by upregulating autophagy-related genes, while the autophagy inhibitor chloroquine (CQ) suppressed the aromatase-induced PCSC phenotype. The activated HeyL-aromatase axis promoted PCSC autophagy via ERα-mediated estrogenic effects. Taken together, our results indicated that the HeyL-aromatase axis could increase endogenous estradiol levels and activate ERα to suppress PCSC apoptosis by promoting autophagy, which enhances the understanding of how endogenous estrogenic effects influence CRPC development.

Testosterone and estradiol in men with acute ischemic stroke: A North Indian case control

Background: One intriguing aspect of stroke is its higher incidence in men as compared to women. Endogenous sex hormones, testosterone and estradiol, may be responsible for this difference. This research aims to study serum testosterone and estradiol levels in men with acute ischemic stroke (AIS) and to correlate these levels with National Institutes of Health Stroke Scale (NIHSS) score and infarct size in computed tomography (CT). Methods: 100 male patients with AIS and 100 age-matched controls were included in this case-control study. Patients with hemorrhagic stroke, taking hormonal preparations, or suffering from chronic illnesses like tuberculosis (TB), cancer, etc. were excluded. Complete history was obtained including presence of established risk factors and physical examination was done in cases and controls with informed written consent. Severity of stroke in cases was assessed by the NIHSS. CT scan of brain was performed within 72 hours of patient’s admission to hospital. The infarct size was measured in centimeters as the largest visible diameter of the infarct on CT scan. Fasting blood samples were obtained for routine investigations and estimating estradiol and testosterone levels. Results: Mean total testosterone level in cases (223.30 ± 143.44 ng/dl) was significantly lower than that of controls (515.34 ± 172.11 ng/dl) (P < 0.001), while estradiol levels had no significant statistical difference (P = 0.260). A significant inverse correlation was found between total testosterone levels and stroke severity (r = -0.581, P < 0.001) and also, total testosterone levels and infarct size (r = -0.557, P < 0.001). Estradiol levels in patients had no significant correlation with stroke severity (P = 0.618) or infarct size (P = 0.463). Conclusion: Low testosterone levels are associated with increased stroke severity and infarct size in men. Further studies are required to establish whether low testosterone is a cause or effect of ischemic stroke and also to explore the potential benefits of testosterone supplementation in men with AIS.

Changes in the Serum Levels of Estradiol and Changes in Expression of Estrogen Receptor Alpha in the Bone Tissue of Ovariectomized Wistar Rats

Estradiol is an estrogen steroid hormone and is produced basically within the follicles of the ovaries. The decrease in serum estrogens concentration at menopause disrupts the metabolic balance, changes the lipid profile leading to visceral obesity, which caused an increase in serum estradiol levels, through aromatase activity. Estrogen deficiency also is a reason for the development of osteoporosis.We investigated the serum estradiol levels and changes in bone alpha estrogen receptor expression in ovariectomized rats. For this purpose, we used 20 female Wistar rats at reproductive age - 2 months divided into 2 groups: group 1 (G1)-10 animals were ovariectomized and group 2 (G2)-10 of which were sham-operated. All animals of G1 showed weight gain compared to group G2. The results showed that the values of serum 17β-estradiol in rats of G1 statistically increased compared to G2 (p <0.05). Immunohistochemical analysis revealed no difference in estrogen receptor expression between the both groups. Histomorphological analysis of femur from G1 showed the presence of pronounced osteoporosis. Ovariectomy led to the development of obesity, which caused an increase in serum estradiol levels, through aromatase activity, but this process did not prevent bone tissue from developing osteoporosis.

Different Estradiol Level's Impact on Appetite Regulation, Food Intake, and Concentrations of Leptin, Glucagon-Like Peptide-1, and High-Sensitivity C-Reactive Protein During a Long Agonist IVF Protocol

Background: Do different hormonal phases affect appetite regulation, food intake, and concentrations of leptin, glucagon-like peptide-1 (GLP-1), and high-sensitivity C-reactive protein (hs-CRP) during a long agonist in vitro fertilization (IVF) protocol? Does the IVF stimulation induce metabolic changes, which might impact maternal health? Methods: Fifty-four infertile women were encountered thrice, the first of which was at the beginning of their period (low estradiol). The other two were during a gonadotrophin-releasing hormone (GnRH) analog downregulation (low estradiol) and at the end of a follicle-stimulating hormone (FSH) stimulation (high estradiol). The first visit was the reference; the women served as their controls. The concentrations of leptin, GLP-1, and hs-CRP were assessed from plasma. Dietary intake was assessed using food records (FRs) three days before each visit. In addition, weight, height, body mass index (BMI), and plasma levels of estradiol, glucose, HbA1c, insulin, and lipids were monitored. Twenty-six of the subjects also had a postprandial test, in which the blood samples were taken at five time points at every three visits. They also filled visual analog scales to exhibit satiety and appetite. Twenty-eight of the subjects had only fasting blood samples. Results: During the stimulation protocol, leptin concentrations elevated (P<0.001), and energy intake decreased (P=0.03) while estradiol levels increased (P<0.001). GLP-1 levels unchanged (P=0.75) and hs-CRP (P=0.03) concentrations diminished while estradiol levels increased. Conclusions: No increased food intake or weight gain occurred during the stimulation protocol; thus, leptin may protect from overeating during high estradiol levels, and leptin resistance may not occur during a short follow-up. Also, a favorable anti-inflammatory effect was detected. During this study, no harmful metabolic effects occurred, which might have a disproportionate impact on maternal health. Trial registration: Not applicable. This study is a clinical study without intervention.

How safe is soy in infancy? Case report of thelarche in an infant

Soy protein based formulas are commonly used in infant nutrition for various indications like lactose intolerance and cow’s milk protein allergy. There are concerns regarding phytoestrogen related and other side effects of these formulas. We are describing a case of possible soy formula induced thelarche in a 7 months infant. There was normalization of estradiol levels with some clinical improvement after stopping soy formula over a follow-up of 12 months duration. We suggest further studies to evaluate hormone levels in infants on soy formulas and to consider it only for appropriate clinical indication and age group.

Differential Antibody Response to Inactivated COVID-19 Vaccines in Healthy Subjects

The appearance and magnitude of the immune response and the related factors correlated with SARS-CoV-2 vaccination need to be defined. Here, we enrolled a prospective cohort of 52 participants who received two doses of inactivated vaccines (BBIBP-CorV). Their serial plasma samples (n = 260) over 2 months were collected at five timepoints. We measured antibody responses (NAb, S-IgG and S-IgM) and routine blood parameter. NAb seroconversion occurred in 90.7% of vaccinated individuals and four typical NAb kinetic curves were observed. All of the participants who seroconverted after the first dose were females and had relatively high prevaccine estradiol levels. Moreover, those without seroconversion tended to have lower lymphocyte counts and higher serum SAA levels than those who experienced seroconversion. The NAb titers in young vaccine recipients had a significantly higher peak than those in elderly recipients. S-IgG and S-IgM dynamics were accompanied by similar trends in NAb. Here, we gained insight into the dynamic changes in NAbs and preliminarily explored the prevaccine blood parameters related to the kinetic subclasses, providing a reference for vaccination strategies.

Effect of the Trends of Estradiol Level on the Outcome of in Vitro Fertilization-embryo Transfer With Antagonist Regimens: a Single Center Retrospective Cohort Study

Background: The outcome of in vitro fertilization-embryo transfer is often determined according to follicles and estradiol levels following gonadotropin stimulation. However, there is no accurate indicator to predict pregnancy outcome, and it has not been determined how to choose subsequent drugs and dosage based on the ovarian response. This study aimed to make timely adjustments to follow-up medication to improve clinical outcomes based on the potential value of estradiol growth rate.Methods: Serum estradiol levels were measured on the day of gonadotrophin treatment (Gn0), four days later (Gn4), seven days later (Gn7), and on the trigger day (HCG). The ratio was used to determine the increase in estradiol levels. According to the ratio of estradiol increase, the patients were divided into four groups: group A1 (Gn4/Gn0≤6.44), group A2 (6.44˂Gn4/Gn0≤10.62), group A3 (10.62˂Gn4/Gn0≤21.33), and group A4 (Gn4/Gn0>21.33); group B1 (Gn7/Gn4≤2.39), group B2 (2.39˂Gn7/Gn4≤3.03), group B3 (3.03˂Gn7/Gn4≤3.84), and group B4 (Gn7/Gn4>3.84). We analyzed and compared the relationship between data in each group and pregnancy outcome.Results: In the statistical analysis, the estradiol levels of Gn4 (P = 0.029, P = 0.042), Gn7 (P< 0.001, P = 0.001), and HCG (P< 0.001, P = 0.002), as well as the ratios of Gn4/Gn0 (P = 0.004, P = 0.006), Gn7/Gn4 (P = 0.001, P = 0.002), and HCG/Gn0 (P< 0.001, P< 0.001) both had clinical guiding significance, and the lower one significantly reduced the pregnancy rate. The outcomes were positively linked to groups A (P = 0.040, P = 0.041) and B (P = 0.015, P = 0.017). The logistical regression analysis revealed that group A1 (OR = 0.440 [0.223–0.865]; P = 0.017, OR = 0.368 [0.169–0.804]; P = 0.012) and B1 (OR = 0.261 [0.126–0.541]; P< 0.001, OR = 0.299 [0.142–0.629]; P = 0.001) had opposite influence on outcomes.Conclusion: Maintaining a serum estradiol increase ratio at least above 2.39 on Gn7/Gn4 may result in a higher pregnancy rate. When estradiol growth is not ideal, gonadotrophin dosage should be adjusted appropriately to ensure the desired outcome.

Steroid Hormone Secretion Over the Course of the Perimenopause: Findings From the Swiss Perimenopause Study

Background: Perimenopause is characterized by a decline in the steroid hormones, estradiol, and progesterone. By contrast, the steroid hormone cortisol, a marker of the hypothalamic–pituitary–adrenal (HPA) axis, increases. Recent longitudinal studies reported fluctuations in steroid hormone levels during perimenopause, and even increases in estradiol levels. To understand these confounding results, it is necessary to conduct a longitudinal, highly standardized assessment of steroid hormone secretion patterns in perimenopausal women.Methods: This longitudinal study investigated 127 perimenopausal women aged 40–56 years for 13 months. Estradiol, progesterone, and cortisol were assessed using saliva samples, which were collected for two (during months 2 and 12 for estradiol and progesterone) or three (during months 2, 7, and 12 for cortisol) non-consecutive months over the course of the study. A total of 14 saliva samples per participant were analyzed to investigate the courses of estradiol and progesterone. Cortisol awakening response and fluctuations of cortisol throughout the day were measured using a total of 11 saliva samples per participant (on awakening, +30 min, +60 min, at 12:00 p.m., and before going to bed) for months 2, 7, and 12.Results: Multilevel analyses revealed variance in intercept and slope across participants for estradiol [intercept: SD = 5.16 (95% CI: 4.28, 6.21), slope: SD = 0.50 (95% CI: 0.39, 0.64)], progesterone [intercept: SD = 34.77 (95% CI: 25.55, 47.31), slope: SD = 4.17 (95% CI: 2.91, 5.99)], and cortisol (intercept: SD = 0.18 (95% CI: 0.14, 0.23), slope: SD = 0.02 (95% CI: 0.01, 0.02)]. Time predicted cortisol levels [b = −0.02, t(979) = −6.63, p &lt; 0.0001]. Perimenopausal status (early vs. late) did not predict estradiol [b = −0.36, t(1608) = −0.84, p = 0.400], progesterone [b = −4.55, t(1723) = −0.87, p = 0.385], or cortisol [b = 0.01, t(1124) = 0.61, p = 0.542] scores over time.Discussion: Our results are consistent with previous findings emphasizing highly individual fluctuations of estradiol and progesterone levels during perimenopause. However, our findings do not suggest a continuous decline during the observed transition phase, implying relatively stable periods of fluctuating hormone levels. Furthermore, given the lack of significant group differences, it may not be necessary to differentiate between early and late perimenopause from the standpoint of hormonal progression.

Subcortical Volume Changes in Early Menopausal Women and Correlation With Neuropsychological Tests

Background: The aging process and declining estradiol levels are two important factors that cause structural brain alterations. Many prior studies have investigated these two elements and revealed controversial results in menopausal women. Here, a cross-sectional study was designed to individually evaluate estradiol-related structural changes in the brain.Methods: A total of 45 early menopausal women and 54 age-matched premenopausal controls were enrolled and subjected to magnetic resonance imaging (MRI) scans, blood biochemistry tests, and neuropsychological tests. MRI structural images were analyzed using FreeSurfer to detect changes in subcortical and cortical volumes as well as cortical thickness. Finally, structural brain data as well as clinical and neuropsychological data were used for Pearson’s correlation analyses to individually determine estradiol-related structural and functional changes in the brains of early menopausal women.Results: Compared with the premenopausal controls, the early menopausal women showed significant subcortical volumetric loss in the left amygdala and right amygdala, higher serum follicle-stimulating hormone (FSH) levels, more recognizable climacteric and depressive symptoms, decreased quality of sleep, and decreased working memory and executive functions. Simultaneously, FSH levels were related to lower working memory accuracy and longer working memory reaction time. Decreased subcortical volume in the bilateral amygdala was also related to lower working memory accuracy and longer executive reaction time in early menopausal women.Conclusion: The data suggest that estradiol deficiency in early menopausal women can lead to subcortical volume and functional brain changes, which may contribute to further understanding the neurobiological role of declined estradiol levels in early menopausal women.

Role of hormone replacement therapy in relieving oral dryness symptoms in postmenopausal women: a case control study

Background To evaluate the efficacy of hormone replacement therapy in relieving oral symptoms in postmenopausal women presenting with genitourinary symptoms along with oral dryness. Methods A case–control study was conducted after selecting 60 postmenopausal women. Oral dryness status of all the patients was evaluated with the help of questionnaire related to oral dryness. These subjects were divided into case group and control group on the basis of response to questionnaire of oral dryness. Unstimulated saliva samples were obtained and analyzed for estimation of salivary estradiol levels by enzyme linked immune sorbent assay technique. After analyzing the result of salivary estradiol levels, case group was subjected to hormone replacement therapy (HRT). The patients were followed up for their response towards oral dryness as well as salivary estradiol levels after the therapy. Results The mean salivary estradiol level before HRT was significantly more among control group as compared to case group (p value < 0.001). Most of the patients complained of dry mouth (26 out of 30); reduced amount of saliva in the mouth (25 out of 30); dry mouth at night (28 out of 30); dry mouth during the day (25 out of 30) before HRT. These complains were significantly reduced after the therapy. The mean salivary estradiol in the case group levels increased significantly after HRT (p value < 0.001). Conclusion The salivary estradiol levels were reduced in post menopausal women with the complain of xerostomia as compared to those without the complain of xerostomia. Further these levels can be recovered with the help of hormone replacement therapy.