Analysis of the clinical efficacy of leuprolide acetate in the treatment of obese patients with endometriosis and its role on the expression of MIF gene

Endometriosis is an invasive but benign disease of women that develops in endometrial glands outside the endometrium and uterine muscle. It affects about 15-20% of women of childbearing age. One effective way to treat endometriosis is to use GnRH agonists, which inhibit estrogen production. However, one of the possible side effects of this treatment is obesity and BMI increasing, which is a concern for some patients. This study investigated the role of leuprolide acetate in treating overweight patients (BMI≥30) and their comparison with non-overweight patients (BMI<30) for six months. Also, the effect of this medicine was evaluated on the expression of the MIF gene, which is an effective gene in obesity. For this purpose, a clinical trial was performed on 75 women with endometriosis aged 18 to 35 years. These patients were divided into two groups. The first group consisted of 38 patients with BMI<30. The second group consisted of 37 patients with BMI≥30. Both groups were treated with leuprolide acetate at a dose of 3.75 mg/month (intramuscularly) for six months. In addition to clinical evaluations, the expression of the MIF gene was assessed by the real-time PCR technique. The results showed that treatment with leuprolide acetate during six months in both groups reduced dysmenorrhea, dyspareunia, and chronic pelvic pain (P<0.05). Although this decrease was greater in the BMI <30 group, the difference was not significant. Also, after collecting the side effects of the medication, it was found that hypoestrogenism, such as cramps and spotting, was more in the first group; Endogenous complications such as oily skin, acne, and hirsutism were also more common in the second group. The results of MIF gene expression showed that the expression level before and after the start of the experiment in the second group (BMI≥ 30) is higher than the first group (BMI <30). The results also showed that the two groups increased the expression of the MIF gene after treatment with leuprolide acetate. This increase was statistically significant in the second group (P = 0.042). Generally, it was found that this medication causes more weight gain in obese people and increases the risk of obesity-related diseases among these patients. Therefore, it is recommended that this treatment be used with caution in obese patients with endometriosis.

A Case of Ovarian Dysplasia and a Vaginal Fibroleiomyoma in a Young Golden Retriever

This case demonstrates a unique ovarian congenital anomaly that likely contributed to the development of a rare fibroleiomyoma in the cranial vagina of a young bitch. A 13 month old intact female Golden Retriever presented to the veterinary teaching hospital for urinary incontinence, hematuria, and persistent vaginal discharge. Physical examination revealed a mucopurulent serosanguinous malodorous vulvar discharge, and after further diagnostics was reclassified as persistent estrus. Abdominal palpation and ultrasound revealed uterine thickening and poorly visualized ovaries. The reproductive tract was removed during an ovariohysterectomy, revealing small ovaries and a white anterior vaginal mass. Histopathology revealed dysplastic ovaries with hyperplastic granulosa cells and a benign vaginal fibroleiomyoma. These morphologic changes are consistent with elevated estrogen levels. It was thus concluded that her persistent estrus and the fibroleiomyoma were both secondary to persistent estrogen production by the hyperplastic granulosa cells.

The Effect of Smoking on Salivary Calcium Levels, Calcium Intake, and Bleeding on Probing in Female

Introduction. Smoking is a bad habit that affects both systemic and oral conditions. Nicotine in cigarettes reduces estrogen production that can alter salivary calcium levels. Nicotine also causes vasoconstriction of the gingival blood vessels and decreases gingival bleeding. Low dietary calcium intake is also suspected to influence the low serum calcium levels in smokers. In this study, we evaluated the effect of smoking on salivary calcium levels, calcium intake, and BOP in women. Method. This was an analytical study using a cross-sectional approach. The subjects were 26 female smokers and 37 nonsmokers. Unstimulated saliva was collected by the spitting method. Salivary calcium levels were measured using an Atomic Absorption Spectrophotometer (AAS). The calcium intake was obtained by the Semiquantitative Food Frequency Questionnaire. BOP was measured by a gingival bleeding index by Ainamo and Bay in 1975. Results. All the basic characteristics including age, BMI, level of education, and occupation were statistically different between groups. The mean calcium level of female smokers was significantly lower than that of nonsmokers, whereas the mean BOP of female smokers was significantly higher. The total calcium intake per day of the two groups was not statistically different. The mean salivary calcium level and BOP decreased when the duration of smoking was longer. There was a positive correlation between salivary calcium level and BOP in the smokers’ group. Conclusion. A low level of education may be contributing to the smoking habit of subjects in this study. Salivary calcium levels were correlated with BOP in female smokers, which might be affected by the duration of smoking.

Sex differences in auditory processing vary across estrous cycle

In humans, females process a sound’s harmonics more robustly than males. As estrogen regulates auditory plasticity in a sex-specific manner in seasonally breeding animals, estrogen signaling is one hypothesized mechanism for this difference in humans. To investigate whether sex differences in harmonic encoding vary similarly across the reproductive cycle of mammals, we recorded frequency-following responses (FFRs) to a complex sound in male and female rats. Female FFRs were collected during both low and high levels of circulating estrogen during the estrous cycle. Overall, female rodents had larger harmonic encoding than male rodents, and greater harmonic strength was seen during periods of greater estrogen production in the females. These results argue that hormonal differences, specifically estrogen, underlie sex differences in harmonic encoding in rodents and suggest that a similar mechanism may underlie differences seen in humans.

Cis-acting super-enhancer lncRNAs as biomarkers to early-stage breast cancer

Background Increased breast cancer screening over the past four decades has led to a substantial rise in the diagnosis of ductal carcinoma in situ (DCIS). Although DCIS lesions precede invasive ductal carcinoma (IDC), they do not always transform into cancer. The current standard-of-care for DCIS is an aggressive course of therapy to prevent invasive and metastatic disease resulting in over-diagnosis and over-treatment. Thus, there is a critical need to identify functional determinants of progression of DCIS to IDC to allow discrimination between indolent and aggressive disease. Recent studies show that super-enhancers, in addition to promoting other gene transcription, are themselves transcribed producing super-enhancer associated long noncoding RNAs (SE-lncRNAs). These SE-lncRNAs can interact with their associated enhancer regions in cis and influence activities and expression of neighboring genes. Furthermore, they represent a novel, untapped group of therapeutic targets. Methods With an integrative analysis of enhancer loci with global expression of SE-lncRNAs in the MCF10A progression series, we have identified differentially expressed SE-lncRNAs which can identify mechanisms for DCIS to IDC progression. Furthermore, cross-referencing these SE-lncRNAs with patient samples in the The Cancer Genome Atlas (TCGA) database, we have unveiled 27 clinically relevant SE-lncRNAs that potentially interact with their enhancer to regulate nearby gene expression. To complement SE-lncRNA expression studies, we conducted an unbiased global analysis of super-enhancers that are acquired or lost in progression. Results Here we designate SE-lncRNAs RP11-379F4.4 and RP11-465B22.8 as potential markers of progression of DCIS to IDC through regulation of the expression of their neighboring genes (RARRES1 and miR-200b, respectively). Moreover, we classified 403 super-enhancer regions in MCF10A normal cells, 627 in AT1, 1053 in DCIS, and 320 in CA1 cells. Comparison analysis of acquired/lost super-enhancer regions with super-enhancer regions classified in 47 ER positive patients, 10 triple negative breast cancer (TNBC) patients, and 11 TNBC cell lines reveal critically acquired pathways including STAT signaling and NF-kB signaling. In contrast, protein folding, and local estrogen production are identified as major pathways lost in progression. Conclusion Collectively, these analyses identify differentially expressed SE-lncRNAs and acquired/lost super-enhancers in progression of breast cancer important for promoting DCIS lesions to IDC.

Cyp17a1 is required for female sex determination and male fertility by regulating sex steroid biosynthesis in fish

In teleost fish, sex steroids are involved in sex determination, sex differentiation, and fertility. Particularly, Cyp17a1 (Cytochrome P450 family 17 subfamily A member 1) is thought to play essential roles in fish steroidogenesis. Therefore, to further understand its roles in steroidogenesis, sex determination, and fertility in fish, we constructed a cyp17a1 gene mutant in Nile tilapia (Oreochromis niloticus). In XX fish, mutation of cyp17a1 gene led to a female-to-male sex reversal with a significant decline in 17β-estradiol (E2) and testosterone (T) production, and ectopic expression of male-biased markers (Dmrt1 and Gsdf) in gonads from the critical window of sex determination. Sex reversal was successfully rescued via T or E2 administration, and ovarian characteristics were maintained after termination of E2 supplementation in the absence of endogenous estrogen production in cyp17a1 -/--XX fish. Likewise, deficiencies in T and 11-KT production in both cyp17a1 -/--XX sex reversed males and cyp17a1 -/--XY mutants resulted in meiotic initiation delays, vas deferens obstruction and sterility due to excessive apoptosis and abnormal mitochondrial morphology. However, 11-KT treatment successfully rescued the dysspermia to produce normal sperm in cyp17a1 -/- male fish. Significant increases in fshβ, lhβ, and gth receptors in cyp17a1 -/- mutants may excessively upregulate steroidogenic gene expression in Leydig cells through a feedback loop. Taken together, our findings demonstrate that Cyp17a1 is indispensable for E2 production, which is fundamental for female sex determination and differentiation in XX tilapia. Additionally, Cyp17a1 is essential for T and 11-KT production, which further promotes spermatogenesis and fertility in XY males.

Novel Insights into the Antagonistic Effects of Losartan against Angiotensin II/AGTR1 Signaling in Glioblastoma Cells

New avenues for glioblastoma therapy are required due to the limited mortality benefit of the current treatments. The renin-angiotensin system (RAS) exhibits local actions and works as a paracrine system in different tissues and tumors, including glioma. The glioblastoma cell lines U-87 MG and T98G overexpresses Angiotensin II (Ang II)/Angiotensin II type I receptor (AGTR1) signaling, which enhances in vitro and in vivo local estrogen production through a direct up-regulation of the aromatase gene promoters p I.f and p I.4. In addition, Ang II/AGTR1 signaling transactivates estrogen receptor-α in a ligand-independent manner through mitogen-activated protein kinase (MAPK) activation. The higher aromatase mRNA expression in patients with glioblastoma was associated with the worst survival prognostic, according to The Cancer Genome Atlas (TCGA). An intrinsic immunosuppressive glioblastoma tumor milieu has been previously documented. We demonstrate how Ang II treatment in glioblastoma cells increases programmed death-ligand 1 (PD-L1) expression reversed by combined exposure to Losartan (LOS) in vitro and in vivo. Our findings highlight how LOS, in addition, antagonizes the previously documented neoangiogenetic, profibrotic, and immunosuppressive effects of Ang II and drastically inhibits its stimulatory effects on local estrogen production, sustaining glioblastoma cell growth. Thus, Losartan may represent an adjuvant pharmacological tool to be repurposed prospectively for glioblastoma treatment.

Female-dominant estrogen production in healthy young children before adrenarche

Objective: Ultra-sensitive hormone assays have detected slight sex differences in blood estradiol (E2) levels in young children before adrenarche. However, the origin of circulating E2 in these individuals remains unknown. This study aimed to clarify how E2 is produced in young girls before adrenarche. Design: This is a satellite project of the Japan Environment and Children’s Study organized by the National Institute for Environmental Studies. Methods: We collected blood samples from healthy 6-year-old Japanese children (79 boys and 71 girls). Hormone measurements and data analysis were performed in the National Institute for Environmental Studies and the Medical Support Center of the Japan Environment and Children’s Study, respectively. Results: E2 and follicle stimulating hormone (FSH) levels were significantly higher in girls than in boys, while dehydroepiandrosterone sulfate (DHEA-S) and testosterone (T) levels were comparable between the two groups. Girls showed significantly higher E2/T ratios than boys. In children of both sexes, a correlation was observed between E2 and T levels, and between T and DHEA-S levels. Moreover, E2 levels were correlated with FSH levels only in girls. Conclusions: The results indicate that in 6-year-old girls, circulating E2 is produced primarily in the ovary from adrenal steroids through FSH-induced aromatase upregulation. This study provides evidence that female-dominant E2 production starts several months or years before adrenarche. The biological significance of E2 biosynthesis in these young children needs to be clarified in future studies.

Cis-acting Super-Enhancer lncRNAs as Biomarkers of Early-Stage Breast Cancer

Background Increased breast cancer screening over the past four decades has led to a substantial rise in the diagnosis of ductal carcinoma in situ (DCIS). Although DCIS lesions precede invasive ductal carcinoma (IDC), they do not always transform into cancer. The current standard-of-care for DCIS is an aggressive course of therapy to prevent invasive and metastatic disease resulting in over-diagnosis and over-treatment. Thus, there is a critical need to identify functional determinants of progression of DCIS to IDC to allow discrimination between indolent and aggressive disease. Recent studies show that super-enhancers, in addition to promoting other gene transcription, are themselves transcribed producing super-enhancer associated long noncoding RNAs (SE-lncRNAs). These SE-lncRNAs can interact with their associated enhancer regions in cis and influence activities and expression of neighboring genes. Furthermore, they represent a novel, untapped group of therapeutic targets.MethodsWith an integrative analysis of enhancer loci with global expression of SE-lncRNAs in the MCF10A progression series, we have identified differentially expressed SE-lncRNAs which can identify mechanisms for DCIS to IDC progression. Furthermore, cross-referencing these SE-lncRNAs with patient samples in the TCGA database, we have unveiled 31 clinically relevant SE-lncRNAs that potentially interact with their enhancer to regulate nearby gene expression. To complement SE-lncRNA expression studies, we conducted an unbiased global analysis of super-enhancers that are acquired or lost in progression. ResultsHere we designate SE-lncRNAs RP11-379F4.4 and RP11-465B22.8 as potential markers of progression of DCIS to IDC through regulation of the expression of their neighboring genes (RARRES1 and miR200b respectively). Moreover, we classified 403 super-enhancer regions in MCF10A normal cells, 627 in AT1, 1053 in DCIS, and 320 in CA1 cells. Comparison analysis of acquired/lost super-enhancer regions with super-enhancer regions classified in 47 ER positive patients, 10 Triple Negative Breast Cancer (TNBC) patients, and 11 TNBC cell lines reveal critically acquired pathways including STAT signaling and NF-kB signaling. In contrast, protein folding and local estrogen production are identified as major pathways lost in progression.ConclusionCollectively, these analyses identify differentially expressed SE-lncRNAs and acquired/lost super-enhancers in progression of breast cancer important for promoting DCIS lesions to IDC.