Comparison of Reproductive Function Between Normal and Hyperandrogenemia Conditions in Female Mice With Deletion of Hepatic Androgen Receptor.
Ontology highlight
ABSTRACT:
SUBMITTER: Feng M
PROVIDER: S-EPMC9218244 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The inhibins are gonadal transforming growth factor beta superfamily protein hormones that suppress pituitary follicle-stimulating hormone (FSH) synthesis. Recently, betaglycan and inhibin binding protein (InhBP/p120, also known as the product of immunoglobulin superfamily gene 1 [IGSF1]) were identified as candidate inhibin coreceptors, shedding light on the molecular basis of how inhibins may affect target cells. Activins, which are structurally related to the inhibins, act within the pituitary to stimulate FSH production. Betaglycan increases the affinity of inhibins for the activin type IIA (ACVR2) receptor, thereby blocking activin binding and signaling through this receptor. InhBP/p120 may not directly bind inhibins but may interact with the activin type IB receptor, ALK4, and participate in inhibin B's antagonism of activin signaling. To better understand the in vivo functions of InhBP/p120, we characterized the InhBP/p120 mRNAs and gene in mice and generated InhBP/p120 mutant mice by gene targeting in embryonic stem cells. InhBP/p120 mutant male and female mice were viable and fertile. Moreover, they showed no alterations in FSH synthesis or secretion or in ovarian or testicular function. These data contribute to a growing body of evidence indicating that InhBP/p120 does not play an essential role in inhibin biology.
| S-EPMC162213 | biostudies-literature
Project description:Intervention1: Chewing gum: sugarless chewing gums to chew 3 times daily at 15:00, 19:00, and, 10.00 hours until initiation of solid diet or, for 2 days whichever is earlier, starting from the day of surgery itself, each session of chewing to last 30 minutes.
Intervention2: Coffee: Coffee will be dispensed from a single vending machine using same brand of coffee capsules, containing fixed and known proportion of caffeine and other ingredients : to drink three cups of caffeinated coffee daily (100 mL at 08:00, 12:00, and 16:00), beginning on Post-operative day (POD) 1. Patients have to drink the entire 100 mL amounts within 20 min under the supervision of a nursing officer. This will be contined for 2 days or upto initiatiation of solid diet, whichever is earlier.
Control Intervention1: nil intervention: This group will receive post-operative care in form of hydration, antibiotics, anti-emetics, thrombo-prophylaxis, ambulation as per department protocol. They will receive analgesia by means of epidural infusion, and, paracetamol (no opioids)
Primary outcome(s): The time interval in hours between skin closure of surgery to first solid oral feedTimepoint: time when the patient takes first oral feed after surgery for first time
Study Design: Randomized, Parallel Group, Placebo Controlled Trial
Method of generating randomization sequence:Permuted block randomization, fixed Method of allocation concealment:On-site computer system Blinding and masking:Open Label
| 2603566 | ecrin-mdr-crc
Project description:BackgroundObesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Thus, we aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders.Methods and findingsLogistic regression, generalised additive models, and Mendelian randomisation (MR) (2-sample, non-linear, and multivariable) were applied to obesity and reproductive disease data on up to 257,193 women of European ancestry in UK Biobank and publicly available genome-wide association studies (GWASs). Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI were observationally (odds ratios [ORs] = 1.02-1.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06-2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Genetically predicted visceral adipose tissue (VAT) mass was associated with the development of HMB (OR [95% CI] per 1-kg increase in predicted VAT mass = 1.32 [1.06-1.64], P = 0.0130), PCOS (OR [95% CI] = 1.15 [1.08-1.23], P = 3.24 × 10-05), and pre-eclampsia (OR [95% CI] = 3.08 [1.98-4.79], P = 6.65 × 10-07). Increased waist circumference posed a higher genetic risk (ORs = 1.16-1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06-1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% and 50% of the total genetically predicted association of obesity with pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. This study was limited in power by the low prevalence of female reproductive conditions among women in the UK Biobank, with little information on pre-diagnostic anthropometric traits, and by the susceptibility of MR estimates to genetic pleiotropy.ConclusionsWe found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, large-scale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions. Our results suggest the utility of exploring the mechanisms mediating the causal associations of overweight and obesity with gynaecological health to identify targets for disease prevention and treatment.
| S-EPMC8806071 | biostudies-literature
Project description:Thrombosis and cardiovascular disease (CVD) represent major causes of morbidity and mortality. Low androgen correlates with higher incidence of CVD/thrombosis. Tissue Factor Pathway Inhibitor (TFPI) is the major inhibitor of tissue factor-factor VIIa (TF-FVIIa)-dependent FXa generation. Because endothelial cell (EC) dysfunction leading to vascular disease correlates with low EC-associated TFPI, we sought to identify mechanisms that regulate the natural expression of TFPI. Data mining of NCBI's GEO microarrays revealed strong coexpression between TFPI and the uncharacterized protein encoded by C6ORF105, which is predicted to be multispan, palmitoylated and androgen-responsive. We demonstrate that this protein regulates both the native and androgen-enhanced TFPI expression and activity in cultured ECs, and we named it androgen-dependent TFPI-regulating protein (ADTRP). We confirm ADTRP expression and colocalization with TFPI and caveolin-1 in ECs. ADTRP-shRNA reduces, while over-expression of ADTRP enhances, TFPI mRNA and activity and the colocalization of TF-FVIIa-FXa-TFPI with caveolin-1. Imaging and Triton X-114-extraction confirm TFPI and ADTRP association with lipid rafts/caveolae. Dihydrotestosterone up-regulates TFPI and ADTRP expression, and increases FXa inhibition by TFPI in an ADTRP- and caveolin-1-dependent manner. We conclude that the ADTRP-dependent up-regulation of TFPI expression and activity by androgen represents a novel mechanism of increasing the anticoagulant protection of the endothelium.
| S-EPMC3204913 | biostudies-literature
Project description:Maternal hormones in vertebrate eggs can mediate important forms of maternal effects. However, the function of hormone transfer to the eggs is still debated, especially because long-term fitness consequences have been little studied. We investigated the effect of prenatal exposure to physiologically elevated yolk testosterone (T) levels on reproduction of female pheasants (Phasianus colchicus) in captivity. We found that females hatching from T-injected eggs (T-females) had a lower egg-laying rate than controls, and their eggs were more frequently infertile than those laid by control females. There were no effects of prenatal maternal treatment on egg size and yolk T concentration, but eggs carrying a female embryo laid by T-females had smaller yolks than eggs with a male embryo, while there was no sex difference in yolk size among the eggs laid by control females. Progeny sex ratio was unaffected by maternal treatment. These findings suggest that the transfer of high androgen levels to the eggs by the mother is constrained by complex trade-offs between direct effects on her daughters' reproduction and by trans-generational differential consequences on male and female descendants.
| S-EPMC1679874 | biostudies-literature
Project description:Gepotidacin is a novel triazaacenaphthylene bacterial topoisomerase inhibitor. This phase 1 nonrandomized, open-label, multicenter, 2-part study evaluated the pharmacokinetics, safety, and tolerability of oral gepotidacin 1500 mg in 3 different hepatic settings (normal, moderate impairment, and severe impairment). Gepotidacin was safe and generally tolerated in all subjects. Compared to subjects with normal hepatic function, gepotidacin plasma area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞ ) and maximum concentration significantly increased by 1.7- and 1.9-fold, respectively, in severe hepatic impairment; increases in moderate impairment were not statistically significant. No significant effect was observed for gepotidacin plasma elimination half-life (geometric mean range, 8.2-9.1 hours) across hepatic groups. Renal clearance increased in moderate (16%) and severe (52%) hepatic impairment vs normal. The mean fraction of gepotidacin dose excreted in urine increased with increasing hepatic impairment (normal, 7.5%; moderate, 11.2%; and severe, 19.9%). Urine gepotidacin concentrations remained high for 12 hours in all hepatic groups after dosing. Saliva gepotidacin concentrations displayed a linear relationship with plasma concentrations (R2 = 0.76). The ratio of saliva AUC to unbound plasma AUC and elimination half-life were not affected by hepatic impairment. These data indicate that gepotidacin dose adjustment is not required in mild to moderate hepatic impairment; severe hepatic impairment may require increases in dosing interval or dose reduction.
| S-EPMC8248074 | biostudies-literature
Project description:BackgroundQuantitative biomechanical characterization of pelvic supportive structures and functions in vivo is thought to provide insight into pathophysiology of pelvic organ prolapse (POP). An innovative approach-vaginal tactile imaging-allows biomechanical mapping of the female pelvic floor to quantify tissue elasticity, pelvic support, and pelvic muscle functions. The Vaginal Tactile Imager (VTI) records high definition pressure patterns from vaginal walls under an applied tissue deformation and during pelvic floor muscle contractions.ObjectiveTo explore an extended set of 52 biomechanical parameters for differentiation and characterization of POP relative to normal pelvic floor conditions.Methods96 subjects with normal and POP conditions were included in the data analysis from multi-site observational, case-controlled studies; 42 subjects had normal pelvic floor conditions and 54 subjects had POP. The VTI, model 2S, was used with an analytical software package to calculate automatically 52 biomechanical parameters for 8 VTI test procedures (probe insertion, elevation, rotation, Valsalva maneuver, voluntary muscle contractions in 2 planes, relaxation, and reflex contraction). The groups were equalized for subject age and parity.ResultsThe ranges, mean values, and standard deviations for all 52 VTI parameters were established. 33 of 52 parameters were identified as statistically sensitive (p < 0.05; t-test) to the POP development. Among these 33 parameters, 11 parameters show changes (decrease) in tissue elasticity, 8 parameters show deteriorations in pelvic support and 14 parameters show weakness in muscle functions for POP versus normal conditions.ConclusionsThe biomechanical mapping of the female pelvic floor with the VTI provides a unique set of parameters characterizing POP versus normal conditions. These objectively measurable biomechanical transformations of pelvic tissues, support structures, and functions under POP may be used in future research and practical applications.
| S-EPMC6508651 | biostudies-literature
Project description:ContextReproductive function may improve after bariatric surgery, although the mechanisms and time-related changes are unclear.ObjectiveThe objective of the study was to determine whether ovulation frequency/quality as well as associated reproductive parameters improve after Roux en Y gastric bypass surgery.DesignThis was a prospective cohort study that enrolled female subjects from 2005 to 2008 with study visits at baseline and then 1, 3, 6, 12, and up to 24 months after surgery.SettingThe study was conducted at an academic health center.PatientsTwenty-nine obese, reproductive-aged women not using confounding medications participated in the study.Main outcome measuresThe primary outcome was integrated levels of urinary progestin (pregnanediol 3-glururonide) from daily urinary collections at 12 months postoperatively. Secondary outcomes were changes in vaginal bleeding, other biometric, hormonal, ultrasound, dual-energy x-ray absorptiometry measures, and Female Sexual Function Index.ResultsNinety percent of patients with morbid obesity had ovulatory cycles at baseline, and the ovulatory frequency and luteal phase quality (based on integrated pregnanediol 3-glururonide levels) were not modified by bariatric surgery. The follicular phase was shorter postoperatively [6.5 d shorter at 3 months and 7.9-8.9 d shorter at 6-24 months (P < 0.01)]. Biochemical hyperandrogenism improved, largely due to an immediate postoperative increase in serum SHBG levels (P < 0.01), with no change in clinical hyperandrogenism (sebum production, acne, hirsutism). Bone density was preserved, contrasting with a significant loss of lean muscle mass and fat (P < 0.001), reflecting preferential abdominal fat loss (P < 0.001). Female sexual function improved 28% (P = 0.02) by 12 months.ConclusionsOvulation persists despite morbid obesity and the changes from bypass surgery. Reproductive function after surgery is characterized by a shortened follicular phase and improved female sexual function.
| S-EPMC3513539 | biostudies-literature
Project description:Women with endometriosis can suffer from decreased fecundity or complete infertility via abnormal oocyte function or impaired placental-uterine interactions required for normal pregnancy establishment and maintenance. Although AT-rich interactive domain 1A (SWI-like) (ARID1A) is a putative tumor suppressor in human endometrial cancers and endometriosis-associated ovarian cancers, little is known about its role in normal uterine function. To study the potential function of ARID1A in the female reproductive tract, we generated mice with a conditional knockout of Arid1a using anti-Müllerian hormone receptor 2-Cre Female Arid1a conditional knockout mice exhibited a progressive decrease in number of pups per litter, with a precipitous decline after the second litter. We observed no tumors in virgin mice, although one knockout mouse developed a uterine tumor after pregnancy. Unstimulated virgin female knockout mice showed normal oviductal, ovarian, and uterine histology. Uteri of Arid1a knockout mice showed a normal decidualization response and appropriate responses to estradiol and progesterone stimulation. In vitro studies using primary cultures of human endometrial stromal fibroblasts revealed that small interfering RNA knockdown of ARID1A did not affect decidualization in vitro. Timed pregnancy studies revealed the significant resorption of embryos at Embryonic Day 16.5 in knockout mice in the third pregnancy. In addition to evidence of implantation site hemorrhage, pregnant Arid1a knockout mice showed abnormal placental morphology. These results suggest that Arid1a supports successful pregnancy through its role in placental function.
| S-EPMC4861168 | biostudies-literature
Project description:The water flea Daphnia are planktonic crustaceans commonly found in freshwater environment that can switch their reproduction mode from parthenogenesis to sexual reproduction to adapt to the external environment. As such, Daphnia are great model organisms to study the mechanism of reproductive switching, the underlying mechanism of reproduction and development in cladocerans and other animals. However, little is known about the Daphnia's reproductive behaviour at a molecular level. We constructed a genetic database of the genes expressed in a sexual female (SF) and a parthenogenetic female (PF) of D. similoides using Illumina HiSeq 2500. A total of 1,763 differentially expressed genes (865 up- and 898 down-regulated) were detected in SF. Of the top 30 up-regulated SF unigenes, the top 4 unigenes belonged to the Chitin_bind_4 family. In contrast, of the top down-regulated SF unigenes, the top 3 unigenes belonged to the Vitellogenin_N family. This is the first study to indicate genes that may have a crucial role in reproductive switching of D. similoides, which could be used as candidate genes for further functional studies. Thus, this study provides a rich resource for investigation and elucidation of reproductive switching in D. similoides.
| S-EPMC5037449 | biostudies-literature