Lower E2 Levels Research Articles

Cocaine: A problem of the head and the heart

To investigate an association between sex hormones and inflammatory cytokines, and to determine whether baseline 17-β-estradiol (E2) and interleukin-8 (IL-8) are associated with visual field (VF) progression in postmenopausal women with primary angle closure glaucoma (PACG).A prospective cross-sectional and cohort study.The cross-sectional study enrolled 200 postmenopausal women with PACG and 151 healthy postmenopausal women as normal control subjects. A total of 105 postmenopausal women with PACG were included and followed up for ≥2 years in the cohort study.All participants were evaluated for levels of baseline sex hormones (follicle-stimulating hormone, prolactin, progesterone, testosterone, luteinizing hormone, and E2) and inflammatory cytokines (IL-1, IL-2, IL-6, IL-8, IL-10, and C-reactive protein) and underwent VF examinations. The cross-sectional study was conducted to establish risk factors for postmenopausal women with PACG using logistic regression analysis. The cohort study was designed to identify factors that could be used to predict VF progression in postmenopausal women with PACG using multivariate Cox regression analyses. The main outcome measures included factors associated with VF progression over time.Decreased E2 (odds ratio 0.88 [95% confidence interval {CI} 0.78-0.99], P = .007) and increased IL-8 (odds ratio 1.12 [95% CI 1.01-1.23], P < .001) levels were risk factors in postmenopausal women with PACG. A significant negative correlation was observed between IL-8 levels and E2 (r = −0.21, P = .02). Multivariable regression analyses revealed a significant correlation between E2 levels and visual field mean deviation (MD) (B = −0.16, P = .04 [95% CI −.09 to −.003) and between IL-8 levels and MD (B = 0.36, P < .001 [95% CI 0.01-0.02]). During follow-up, 48 (45.71%) patients showed VF progression. Lower baseline E2 (hazard ratio 0.85 [95% CI 0.82-0.88], P = .04) and higher baseline IL-8 levels (hazard ratio 1.01 [95% CI 1.00-1.02], P = .004) were associated with progression of glaucoma. Patients with lower E2 levels had a significantly higher rate of PACG progression (log-rank test P < .001), similar to those with higher IL-8 levels (log-rank test P = .04).Decreased E2 and increased IL-8 levels at baseline are significant predictors of VF progression in postmenopausal women with PACG.

Chronic estrogen affects TIDA neurons through IL-1β and NO: effects of aging.

Women are chronically exposed to estrogens through oral contraceptives, hormone replacement therapy or environmental estrogens. We hypothesized that chronic exposure to low levels of estradiol-17β (E2) can induce inflammatory and degenerative changes in the tuberoinfundibular dopaminergic (TIDA) system leading to reduced dopamine synthesis and hyperprolactinemia. Young (Y; 3–4 months) and middle-aged (MA; 10–12 months) Sprague-Dawley rats that were intact or ovariectomized (OVX) were either sham-implanted or implanted with a slow-release E2 pellet (20 ng E2/day for 90 days). To get mechanistic insight, adult 3- to 4-month-old WT, inducible nitric oxide synthase (iNOS) and IL-1 receptor (IL-1R) knockout (KO) mice were subjected to a similar treatment. Hypothalamic areas corresponding to the TIDA system were analyzed. E2 treatment increased IL-1β protein and nitrate levels in the arcuate nucleus of intact animals (Y and MA). Nitration of tyrosine hydroxylase in the median eminence increased with E2 treatment in both intact and OVX animals. There was no additional effect of age. This was accompanied by a reduction in dopamine levels and an increase in prolactin in intact animals. E2 treatment increased nitrate and reduced dopamine levels in the hypothalamus and increased serum prolactin in WT mice. In contrast, the effect of E2 on nitrate levels was blocked in IL-1R KO mice and the effect on dopamine and prolactin were blocked in iNOS KO animals. Taken together, these results show that chronic exposure to low levels of E2 decreases TIDA activity through a cytokine-nitric oxide-mediated pathway leading to hyperprolactinemia and that aging could promote these degenerative changes.

Long-term exposure to waterborne nonylphenol alters reproductive physiological parameters in economically important marine fish

Low concentrations of nonylphenol (NP) in aquatic environment can induce drastic effects on the endocrine system in animals. In this study, we examined the modulatory effects of NP on reproductive and physiological parameters in juveniles of the red seabream and black rockfish following waterborne NP exposure (0, 1, 10, and 50 μg L−1) for 60 days. In red seabream exposed to 50 μg L−1 NP, plasma levels of 17β-estradiol (E2) and 11-ketotestosterone (11-KT) were significantly lower at 30 and 60 days, while E2 levels were slightly higher in 10 μg L−1-exposed individuals at day 30. Similarly, significantly lower levels of E2 and 11-KT were observed in 10 and 50 μg L−1-exposed black rockfish at 60 days, whereas the E2 level was higher in 1 μg L−1-exposed individuals at day 30. After exposure to NP, plasma and mRNA levels of vitellogenin (VTG) were significantly higher in both species at 30 and 60 days, similar to the inducible effects from synthetic estrogen. Plasma cortisol levels were significantly elevated by relatively higher concentrations of NP (10 and 50 μg L−1) at 30 and 60 days. Finally, 60 days of exposure of 50 μg L−1 NP significantly decreased the gonadosomatic index (GSI) and increased the hepatosomatic index (HSI) in both species. The results obtained from this study provide an evidence of the endocrine disrupting potential of waterborne NP on early stages of economically important marine fish. The NP-triggered endocrine modulation can induce effects on the development of reproductive and metabolic organs in fish species.

262 - Investigating the anti-oxidant effects of estrogen in RAW cell macrophages

The female sex hormone, estrogen (E2) is proposed to have cardioprotective effects due to its anti-oxidant properties. Previous studies have shown that as women enter the post-menopausal period, cardiovascular incidences increase dramatically. This may be due to a decrease in E2 and its protective properties. E2 receptors can be found on the surface of the RAW macrophage cell as well as the nucleus and mitochondria, where E2 can modulate both nuclear and mitochondrial genes in response to inflammatory stimuli. We hypothesize that in the RAW murine macrophage cell line E2 increases cell viability, decreases reactive oxygen species (ROS) and increases mitochondrial function. PCR analysis confirmed ER-α presence in RAW cells. 48 hours after plating RAW cells, they were treated with low (100nM) and high (1mM) levels of E2 in serum and phenol-free DMEM. The cells were pretreated with E2 or vehicle for 15hrs, followed by treatment with the inflammation-inducing endotoxin, Lipopolysaccharide (LPS) for 6hrs. The Calcein AM Assay showed greater cell concentrations when cells were pretreated with E2. ROS production measurement via DCF Fluorescence of post-LPS treatment showed that E2 pretreatment of cells decreased ROS production. Changes in ROS production may be due alterations in mitochondrial membrane potential. Therefore, mitochondrial membrane potential was measured using TMRM Fluorescence and showed that E2 pretreatment increased mitochondrial membrane potential. A greater mitochondrial membrane potential may infer a more efficient mitochondria. Seahorse measurement of mitochondrial function confirmed that low and high levels of E2 pretreatment increases mitochondrial function in RAW cells. We hope to further explore cellular localization of ROS production and the effects of estrogen on mitochondrial function after LPS treatment. This data suggests that estrogen is anti-oxidant and may exert these effects by modulating mitochondrial function. Overall this data suggests that the anti-oxidant properties of estrogen may be beneficial to cardiovascular health.

Chronic estradiol exposure - harmful effects on behavior, cardiovascular and reproductive functions.

Estradiol (E2) is a female hormone that is produced largely by the ovaries, but also by the adrenal glands, fat and liver. It is present in the circulation of both males and females. Many studies in the literature have described how E2 is beneficial to the body in terms of preventing bone loss, affording protection in ischemia reperfusion injury, relieving symptoms of menopause, maintaining vaginal health and helping with ovarian failure or hypogonadism. Beneficial effects on the brain have been reported to include protection against memory loss, neuronal degeneration, changes in cognition, mood and behavior. However, the effects of E2 exposure on the neuroendocrine system have not been understood completely. This is because differences in doses, preparation and duration of exposure have produced variable results ranging from beneficial, to no change, or to detrimental. Studies in our lab over the last few years have shown that chronic exposures to low levels of E2 in young rats can produce specific effects on the neuroendocrine system. We have observed that these exposures can induce reproductive senescence, hypertension, anxiety-like behavior and cause degenerative changes in specific neuronal populations leading to hyperprolactinemia. The purpose of the review is to present evidence from the literature for these effects and to discuss the underlying molecular mechanisms.

A Retrospective Study of Letrozole Treatment Prior to Human Chorionic Gonadotropin in Women with Polycystic Ovary Syndrome Undergoing In Vitro Fertilization at Risk of Ovarian Hyperstimulation Syndrome.

BackgroundWomen with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization (IVF) are given letrozole before a trigger injection of human chorionic gonadotropin (hCG) to lower estrogen (E2) levels, but can experience ovarian hyperstimulation syndrome (OHSS). The aim of this study was to evaluate the effect of oral letrozole, prior to administration of hCG, on the outcome of IVF and development of OHSS.Material/MethodsRetrospective clinical review included 181 cases of women with PCOS who underwent IVF cycles with intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) (IVF/ICSI-ET). The day before the use of hCG, cases were divided into a letrozole-treated group (N=78) and a non-letrozole group (N=103). An oral dose of 2.5 mg qd of letrozole was given when the peak level of E2 was ≥4000 pg/ml during ovarian stimulation and ceased before the day of egg retrieval.ResultsThe letrozole-treated group had a significant increase in the number of retrieved oocytes, viable embryos, and fresh ET rate (P>0.05); peak levels of E2, and E2 levels on the day of the egg retrieval, were significantly higher, and the fertilization rate was significantly lower (P<0.001). No significant differences were found in the rates of pregnancy, abortion, or ectopic pregnancy between the two groups (P>0.05). The incidence OHSS was lower in the letrozole-treated group, but this difference did not reach statistical significance (P>0.05).ConclusionsWomen with PCOS who underwent IVF, oral treatment with letrozole a day prior to treatment with hCG lowered E2 levels, but did not significantly reduce the incidence of OHSS.

Estrogen Protects Neurotransmission Transcriptome During Status Epilepticus

Women with epilepsy commonly have premature onset of menopause. The decrease in estrogen levels is associated with increased occurrence of neurodegenerative processes and cognitive decline. Previously, we found that estradiol (E2) replacement in ovariectomized (OVX) female rats significantly reduced the seizure-related damage in the sensitive hilar region of hippocampal dentate gyrus (DG). However, the complex mechanisms by which E2 empowers the genomic fabrics of neurotransmission to resist damaging effects of status epilepticus (SE) are still unclear. We determined the protective effects of the estradiol replacement against kainic acid-induced SE-associated transcriptomic alterations in the DG of OVX rats. Without E2 replacement, SE altered expression of 44% of the DG genes. SE affected all major functional pathways, including apoptosis (61%), Alzheimer's disease (47%), cell cycle (59%), long-term potentiation (62%), and depression (55%), as well as synaptic vesicle cycle (62%), glutamatergic (53%), GABAergic (49%), cholinergic (52%), dopaminergic (55%), and serotonergic (49%) neurotransmission. However, in rats with E2 replacement the percentage of significantly affected genes after SE was reduced to the average 11% (from 8% for apoptosis to 32% for GABAergic synapse). Interestingly, while SE down-regulated most of the synaptic receptor genes in oil-injected females it had little effect on these receptors after E2-replacement. Our novel Pathway Protection analysis indicated that the E2-replacement prevented SE-related damage from 50% for GABA to 75% for dopaminergic transmission. The 15% synergistic expression between genes involved in estrogen signaling (ESG) and neurotransmission explains why low E2 levels result in down-regulation of neurotransmission. Interestingly, in animals with E2-replacement, SE switched 131 synergistically expressed ESG-neurotransmission gene pairs into antagonistically expressed gene pairs. Thus, the ESG pathway acts like a buffer against SE-induced alteration of neurotransmission that may contribute to the E2-mediated maintenance of brain function after the SE injury in postmenopausal women. We also show that the long-term potentiation is lost in OVX rats following SE but not in those with E2 replacement. The electrophysiological findings in OVX female rats with SE are corroborated by the high percentage of long-term potentiation regulated genes (62%) in oil-injected while only 13% of genes were regulated following SE in E2-replaced rats.

Influence of peroxisome proliferator-activated receptor-γ exon 2 and exon 6 and insulin receptor substrate (IRS)-1 Gly972Arg polymorphisms on insulin resistance and beta-cell function in southern mediterranean women with polycystic ovary syndrome

Background and objectiveThe Pro12Ala (exon 2) and His447His (exon 6) polymorphisms of PPAR-γ, and Gly972Arg polymorphism of IRS-1 have been implicated in insulin resistance (IR) and adiposity. Our aim was to investigate the influence of these polymorphisms on metabolic features of polycystic ovary syndrome (PCOS). MethodsFifty-three PCOS women and 26 control women underwent a clinical and biochemical evaluation, including a 75-g oral glucose tolerance test. Insulin secretion and insulin sensitivity indices were calculated. ResultsFrequencies of PPAR-γ polymorphisms did not differ from those predicted by the Hardy-Weinberg equilibrium. Instead, the IRS-1 Gly972Arg allele was significantly more frequent in the PCOS group compared to controls. The most frequent allelic combinations were IRS1+/exon2-/exon6- (which prevailed in PCOS) and IRS-1-/exon2-/exon6- (which prevailed in controls). Among PCOS women, compared with the wild type patients, carriers of the Gly972Arg IRS-1 allele had lower E2 levels, while carriers of the Pro12Ala PPAR-γ (exon 2) allele had lower free testosterone levels. No other significant relationships were noted. When compared with the wild type, in PCOS group IR and beta-cell function were: (i) trendwise greater in carriers of the variant IRS-1 allele; (ii) trendwise lower in carriers of the variant PPAR-γ exon 6 allele; (iii) significantly lower in carriers of the variant PPAR-γ exon 2 allele. ConclusionsOur data support the protective influence of PPAR-γ-exon 2 and exon 6 variants on IR and beta cell function, whereas IRS-1 polymorphism is associated with an unfavorable metabolic profile. However, these associations do not fully explain the high metabolic risk associated with PCOS.

Physiological low-dose oestrogen promotes the development of experimental autoimmune thyroiditis through the up-regulation of Th1/Th17 responses

Previous studies have reported a preponderance of autoimmune thyroiditis (AIT) in females, but the detailed mechanisms have not been elucidated. In this study, we explored the effects of oestrogen on experimental AIT (EAT) and its potential mechanisms in an ovariectomised mouse model through the supplementation of high (equivalent to the level during pregnancy) or low (equivalent to the level at the oestrus stage) doses of oestradiol (E2). We found that EAT incidence, the intrathyroidal inflammatory score, serum anti-thyroglobulin IgG2b levels, splenic mRNA expression of Th1- and Th17-specific transcription factors and typical cytokines and the proportion of IL-12-producing dendritic cells were significantly increased in EAT mice treated with low-dose E2 compared with those in the control group. However, they were not changed when administered with high-dose E2. These findings indicate that low physiological levels of E2 can stimulate the occurrence and development of EAT through the up-regulation of Th1/Th17 responses.

Association between serum estradiol levels and carotid atherosclerosis in middle-aged and elderly men with type 2 diabetes

Objective To investigate the association between serum estradiol levels and macrovascular complication of atherosclerosis in mid-aged and elderly male patients with type 2 diabetes mellitus (T2DM). Methods One hundred and twenty nine male diabetic patients aged over 45 years were recruited in this study. Serum estriol (E2), testosterone (T) and lipid levels were detected using chemiluminescent immunoassay. Carotid ultrasonography was taken to evaluate macrovascular complication of atherosclerosis. The demographic characteristics, clinical features including duration of diabetes and prevalence of carotid atherosclerosis and biochemical features were compared among patients with different serum E2 levels. Correlation analysis was also performed using binary logistic analysis. Results There were 43 patients with low serum E2 level ( 198.2 pmol/L). Among 129 patients the carotid artery lesions were detected in 64 cases. There were significant differences in body weight [(61.0±10.4), (67.4±13.0)and(76.8±10.5)kg, t=3.40, P=0.00], waist circumference [(81.5±7.9), (86.6±10.7)and(90.0±8.0)cm, t=3.57, P=0.00], body mass index (BMI) [(21.6±3.2), (23.5±3.8)and(26.2±3.0)kg/m2,t=3.72, P=0.00], systolic pressure [(140.2±14.8), (143.9±18.1)and (155.0±13.1)mmHg(1 mmHg=0.133 kPa), t=3.18, P=0.04] and TG [(1.46±0.88), (2.23±1.08)and(3.35±0.9)mmol/L, t=2.66, P=0.04] among patients with low, intermediate and high serum E2 levels. The age-adjusted incidence of carotid atherosclerotic plaque in patients with low, intermediate and high E2 levels were 25.6%(11/43), 56.8%(25/44) and 66.7%(28/42), respectively (χ2=15.73, P=0.00). Compared to low E2 level, the risk ratio of carotid atherosclerosis in intermediate and high E2 levels was 1.60 (95%CI: 1.04-2.46, P<0.05) and 1.80 (95%CI: 1.17-2.76, P<0.05), respectively. Conclusion Serum E2 level is closely associated with carotid atherosclerotic plaque in middle-aged and elderly male type 2 diabetic patients. Key words: Arteriosclorosis, carotid arteries; Testosterone; Diabetes mellitus, type 2; Meddle aged; Aged

Role of serum steroid hormones in women with stress urinary incontinence: a case-control study.

To investigate the potential relationship between endogenous sex steroids and presence of stress urinary incontinence (SUI). A total of 47 peri- and postmenopausal women with SUI were matched 1:1 with 47 continent women based on age, menopausal status, body mass index (BMI) and parity. Blood samples were drawn from all the women for assessment of oestradiol (E2), follicle-stimulating hormone, luteinizing hormone, testosterone, androstendion (AEON), dehydroepiandrosterone sulphate and sex hormone-binding globulin with an electrochemiluminescence immunoassay. Women with SUI had significantly lower serum levels of E2 (8.49 ± 7.47 vs 13.09 ± 13.80; P = 0.048) and AEON (0.59 ± 0.41 vs 1.20 ± 0.87; P = 0.033) compared with controls. This difference in E2 levels remained significant after controlling for age, menopausal age, years from menopause, BMI, parity, testosterone and AEON. In addition, hypertension and history of hysterectomy were observed significantly more frequently in the SUI group (P < 0.001). There was no significant association between hormone levels and degree of SUI (P > 0.05). The results of the present study indicate that a low E2 level might have a negative impact on the lower urinary tract and continence mechanism and a low E2 level is a possible risk factor for SUI in women.

Role of SDF-1/CXCR4 and cytokines in the development of ovary injury in chemotherapy drug induced premature ovarian failure mice

ObjectiveTo explore the mechanism of chemotherapy drug induced ovarian injury in premature ovarian failure (POF) mice. MethodsC57BL/6 mice were treated with Cyclophosphamide and Busulfan by intraperitoneal injection. One week after treatment, the estrous cycles, folliculogenesis, ovarian endocrine function and ovarian histopathological changes were evaluated the ovarian function. The serum levels of cytokines, follicle stimulating hormone (FSH) and estradiol (E2) were measured by enzyme-linked immunosorbent assay (ELISA). The protein levels of SDF-1/CXCR4 and FSHR in ovary were evaluated by immunohistochemistry and Western blot analysis. The ovarian cells apoptosis was measured by TUNEL Assay. ResultsThe ovaries from POF mice show the evidence of reduced ovarian function such as irregular estrous cycles, stromal hyperplasia, decreased follicle numbers, atresia follicles and less granular cell layer as well as corpora luteum. The lower levels of E2 and higher levels of FSH in serum characterize the ovarian injury; a great number of granular apoptotic cells were observed in the POF mice; the serum concentrations of pro-inflammatory cytokines of IL-6, IL-8 and TNF-α level were increased but anti-inflammatory cytokine of IL-10 was decreased. SDF-1/CXCR4 and FSHR expressed in ovaries were detected in the cytoplasm of preantral and antral follicles; the expression of SDF-1/CXCR4 was increased and FSHR was decreased in POF mice. ConclusionOur data suggest that the inflammatory regulation, SDF-1/CXCR4 and cellular apoptosis in ovarian tissues are involved in the development of ovarian injury of POF. These data provide useful information to develop new therapeutic approach to treat POF disorders in the future.

Abstract P118: Cardioprotective Association Between High Density Lipoprotein Cholesterol and Endothelial Function Attenuated at Lower Levels of Estradiol in Women at Midlife. The SWAN Heart Study

Objective: Growing evidence suggests that the cardioprotective effects of high density lipoproteins (HDL) may be diminished over the menopause transition. Estradiol (E2), the leading ovarian estrogen that declines substantially during the menopause transition, is considered a potent antioxidant with potential impact on lipid peroxidation and formation of reactive oxygen species that could affect HDL cardioprotective capacities. Whether the cardioprotective effects of HDL on atherosclerotic subclinical measures are apparent only in the presence of high levels of E2 in women at midlife is not clear. We hypothesized that the expected positive association between levels of high density lipoprotein cholesterol (HDL-C) and endothelial function as indexed by flow-mediated dilation (FMD) is weaker at lower levels of E2. Methods: Participants were fromthe baseline visit of the Study of Women’s Health Across the Nation (SWAN) Heart study. Women with hysterectomy and/or bilateral oophorectomy and those on hormone therapy were excluded. B-mode ultrasound images of the right brachial artery before and after deflation were obtained to estimate % change in FMD. Linear regression analyses were utilized to model the difference between log-baseline arterial diameter and log-post-deflation arterial diameter as a function of the interaction between log-E2 and HDL-C levels. To illustrate, the interaction between E2 tertiles and HDL-C was presented as well. The final model adjusted for log-baseline arterial diameter, race, study site, cycle day of blood draw, menopause status, body mass index, and diastolic blood pressure. Results were presented as % change in FMD (95% CI). Results: The study included 322 women (60% White and 40% Black) aged 50.7±2.8 years who were either in pre-/early perimenopause (63%) or late peri-/postmenopause (37%). In the final model, a significant interaction between HDL-C and log-E2 levels on %FMD was found, P value for interaction=0.01; such that a positive association between HDL-C and %FMD was only evident among women in the high E2 tertile (E2 ≥51.1 pg/ml) [%FMD (95%CI) per 1 SD increase in HDL-C: 0.93%(0.21%, 1.64%)] and that %FMD per 1 SD increase in HDL-C was significantly lower in women in the low E2 tertile (E2 &lt;21.5 pg/ml) compared to women in the high E2 tertile [%FMD difference (95%CI): low E2 tertile vs. high E2 tertile: -0.98 (-1.88, -0.07), P-value=0.03]. Conclusions: The cardioprotective association of HDL-C on endothelial function depends on levels of E2 in women at midlife, such that HDL-C may not be protective to the vascular endothelium in the setting of low endogenous E2. Our analyses should be replicated in longitudinal settings. Future studies should investigate potential mechanistic pathways by which dynamic changes in E2 levels may impact HDL composition and functionality over the menopausal transition.

AKT2 Gene Polymorphisms, sRANKL/OPG and Hormone Measurements in Polycystic Ovarian Syndrome (PCOS) Women

Objective: Polycystic Ovarian Syndrome (PCOS) is a common endocrinologic disorder diagnosed in 6-10% of female population at reproductive age. Altered expression of AKT2 gene has been correlated to increased insulin tolerance and reduced glucose disposal, both of which are PCOS features. The goal of this study was to investigate the association between AKT2 gene polymorphisms, serum biomarkers OPG and sRANKL as cardiovascular biomarkers, hormones (DHEAS, SHBG, testosterone, E2, LH, FSH, prolactin, insulin, 17-OH progesterone) and clinical characteristics as well (amenorrhea, oligomenorrhea, dysmenorrhea, acne, hirsutism, oily skin). Study design: A total of 60 Greek Caucasian PCOS patients and another 30 healthy women that were age- and BMI-matched, were recruited in the study and their blood specimens and clinical characteristics collected. Serum OPG and sRANKL were measured with ELISA kits and hormones with Roche Cobas e411 immunochemical analyzer. Four AKT2 gene DNA SNPs (Single Nucleotide polymorphisms) were selected; rs11671439, rs8100018, rs3730051 and rs2304188 and novel real-time qPCR methods were developed using either the dual probe or the single probe format for their genotyping in the Light Cycler platform. All findings were confirmed with DNA Sequencing and statistical analysis was performed using SNP stats and SPSS software. Results: PCOS women had higher serum levels of sRANKL, DHEAS, testosterone and 17-OH progesterone and lower levels of E2, SHBG and prolactin than controls. There was a statistically important difference for SNP rs2304188 between patients and controls regarding Minor Allele Frequency (MAF%): it was found to be more frequent in PCOS patients compared to controls [OR 4.04 (C.I. 1.12-14.54)], whereas concerning the entire population, studied individuals bearing the rs2304188 SNP have higher values of DHEAS and 17-OH progesterone, both biomarkers of PCOS. Furthermore, an association between hirsutism and SNP rs2304188 was found in PCOS patients (p=0.044). Eight participants had SNP rs8100018 in their DNA in combination with either rs11671439 or rs2304188; all were PCOS women. Conclusions: Our results adjudicate further study on AKT2 gene SNPs in relation with PCOS.

Nitric oxide/Asymmetric Dimethylarginine Axis may Interplay With Some Sex Hormones for Pathogenesis and Severity of Pre-eclampsia: Study controlled by Uterine Arterial Doppler.

Objectives: To evaluate relations of asymmetric dimethylarginine (ADMA) and nitric oxide (NO) with estrogen (E2) and progesterone (Pg) and its role in pathogenesis and severity of pre-eclampsia (PE). Patients & Methods: At 12th week gestational age (GA) constitutional data, systolic and diastolic blood pressures (SBP and DBP), uterine artery pulsatility index (UAPI) and serum NO, ADMA, E2 and Pg levels were determined for primigravida attending the antenatal care unit. During pregnancy, women who developed PE were categorized as early or late and mild or severe according to ACOG Practice Bulletin of PE guidelines. Studied parameters were evaluated statistically as early predictors for development and severity of PE. Results: Ninety pregnant women developed PE; 39 early and 51 late. Only 13 women had severe and 77 women had mild PE. At 12th week GA, UAPI and serum ADMA levels were significantly higher with significantly lower E2 and NO levels in PE women than women free of PE and in early than in late PE. High SBP at time of PE diagnosis showed positive significant correlation with body mass index (BMI) and serum ADMA levels but showed negative significant correlation with serum NO and E2 levels. Serum ADMA levels showed positive significant correlation with BMI, but negative significant correlation with serum E2 levels. High UAPI, serum ADMA and high BMI were significant early predictors for PE development and severity. Conclusion: Disturbed maternal serum ADMA/NO axis and low E2 serum levels may underlie PE development. High BMI and low E2 level may have a role in PE pathogenesis through induction of high serum ADMA levels. High UAPI and serum ADMA at 12th week GA could be used as early predictors of PE especially early-onset and severe PE.

The expression of cancerous inhibitor protein phosphatase 2A in chronic rhinosinusitis with nasal polyps

Conclusion: The study suggests that cancerous inhibitor of protein phosphatase 2A (CIP2A) expression and eosinophilia associate with chronic rhinosinusitis with nasal polyps with aspirin exacerbated respiratory disease (CRSwNP + AERD). Further studies with a larger sample size are needed to evaluate further the role of CIP2A and related pathways in CRSwNP + AERD.Objectives: Low prostaglandin E2 levels putatively associate with CRSwNP + AERD and decreased c-Myc levels. The aim of this study was to evaluate the expression and revision-predictive role of oncoprotein CIP2A, another c-Myc modulator, in CRSwNP with/without AERD, and in antrochoanal polyps.Method: Ninety retrospective archival objective glasses of nasal polyp tissue from CRSwNP or ACP patients were used for assessing mucosal eosinophilia. Of this population, 90 archival nasal polyp specimens were available for immunohistochemical staining with a polyclonal anti-CIP2A antibody, together with 19 control nasal mucosa specimens. CIP2A staining intensity and tissue eosinophilia were assessed by two blinded observers with a light microscope. Subject characteristics from 90 patients and 19 controls were obtained from patient records and additionally by a questionnaire from controls. The follow-up data was available from patient records of 84 patients and 16 controls.Results: The expression of epithelial CIP2A was detected both in control inferior turbinate mucosa and nasal polyps. The expression was significantly lower in the CRSwNP + AERD group compared to controls and CRSwNP without AERD (p < 0.01). High mucosal eosinophilia associated with CRSwNP (p < 0.01). Neither CIP2A nor eosinophilia predicted the need for revision surgery (p > 0.05), whereas previous surgery, allergic rhinitis, and use of corticosteroids did predict the need for revision surgery (p < 0.05).

Comparison between pulsatile GnRH therapy and gonadotropins for ovulation induction in women with both functional hypothalamic amenorrhea and polycystic ovarian morphology

Context: Ovulation induction in patients having both functional hypothalamic amenorrhea (FHA) and polycystic ovarian morphology (PCOM) has been less studied in the literature. As results remain contradictory, no recommendations have yet been established.Objective: To compare pulsatile GnRH therapy versus gonadotropins for ovulation induction in “FHA-PCOM” patients and to determine if one treatment strikes as superior to the other.Methods: A 12-year retrospective study, comparing 55 “FHA-PCOM” patients, treated either with GnRH therapy (38 patients, 93 cycles) or with gonadotropins (17 patients, 53 cycles).Results: Both groups were similar, defined by low serum LH and E2 levels, low BMI, excessive follicle number per ovary and/or high serum AMH level. Ovulation rates were significantly lower with gonadotropins (56.6% versus 78.6%, p = 0.005), with more cancellation and ovarian hyper-responses (14% versus 34% per initiated cycle, p < 0.005). Pregnancy rates were significantly higher with GnRH therapy, whether per initiated cycle (26.9% versus 7.6%, p = 0.005) or per patient (65.8% versus 23.5%, p = 0.007).Conclusion: In our study, GnRH therapy was more successful and safer than gonadotropins, for ovulation induction in “FHA-PCOM” patients. If results were confirmed by prospective studies, it could become a first-line treatment for this population, just as it is for FHA women without PCOM.

Clinical features and management of 33 patients with 46,XX pure gonadal dysgenesis

The objective of the study is to summarize the clinical characteristics of 33 patients’ cohort (46,XX pure gonadal dysgenesis, 46,XX PGD), discuss the management, and propose treatment suggestions. Patients’ information, medical history, and medical records were obtained. All patients were closely followed up. At the time of diagnosis, the patients presented 19.53 ± 3.60 years old, 165 ± 6.49 cm height, breast development of Tanner stage I, and infantile female genitalia. High level of follicle-stimulating hormone (87.41 ± 21.50 mIU/mL) and LH (27.10 ± 8.47 mIU/mL) and low level of E2 (8.85 ± 6.13 pg/mL) were observed. Individualized hormone replacement therapy (HRT) was initiated after diagnosis. After 2 years of treatment, all patients had obvious breast development; the uterus showed (2.38 ± 0.60) × (1.38 ± 0.70) × (1.38 ± 0.55) cm growth. The incidence of osteopenia changed from 69.70% to 22.22% and that of osteoporosis changed from 18.18% to 0. Dysgeminoma was found in one patient. We concluded that gonadal dysgenesis in 46,XX PGD causes secondary sexual characteristic absence, tendency of taller, osteoporosis, infertility, and sexual health problems. There is minor chance of tumor occurrence for the patients. Optimal care including HRT and close follow-up are required.

Decreased serum levels of sex steroids associated with osteoporosis in a group of Romanian male patients

Abstract Introduction. With age, sex hormone deficiency leads to reduced bone mineral density (BMD) in men. The aim of our research is to analyze the role of serum sex steroids in assessing BMD in the men included in this study. Materials and methods. This cross-sectional study included 146 men aged 65-85 years old with osteopenia or osteoporosis (study group) and 121 men with normal BMD (control group). Serum levels of total testosterone (Tt) and free testosterone (Tf) were measured by immunoassay, and estradiol (E2) levels were measured by the immunoenzymatic method. Femoral neck and lumbar spine BMD was examined by dual-energy X-ray absorptiometry. Results. Tf and E2 deficiency was significantly associated with low BMD (p=0.007). No association was found between Tt deficiency and reduced BMD. Tf levels (p&lt;0.001) and E2 levels (p=0.003) were significantly lower in patients with reduced BMD compared to those with normal BMD. Significant more cases with low levels of Tf (p=0.015) and E2 (p&lt;0.001) were found in patients with osteoporosis compared to those with osteopenia. Conclusions. Sex hormones deficiency in men was significantly correlated with the decrease of BMD. Determination of serum Tf and E2 levels is important in assessing the risk of osteoporosis in male subjects.

The effects of high fat diet and estradiol on hypothalamic prepro-QRFP mRNA expression in female rats

Estradiol (E2) is a potent regulator of feeding behavior, body weight and adiposity in females. The hypothalamic neuropeptide, QRFP, is an orexigenic peptide that increases the consumption of high fat diet (HFD) in intact female rats. Therefore, the goal of the current series of studies was to elucidate the effects of E2 on the expression of hypothalamic QRFP and its receptors, QRFP-r1 and QRFP-r2, in female rats fed a HFD. Alterations in prepro-QRFP, QRFP-r1, and QRFP-r2 expression across the estrous cycle, following ovariectomy (OVX) and following estradiol benzoate (EB) treatment were assessed in the ventral medial nucleus of the hypothalamus/arcuate nucleus (VMH/ARC) and the lateral hypothalamus. In intact females, consumption of HFD increased prepro-QRFP and QRFP-r1 mRNA levels in the VMH/ARC during diestrus, a phase associated with increased food intake and low levels of E2. To assess the effects of diminished endogenous E2, rats were ovariectomized. HFD consumption and OVX increased prepro-QRFP mRNA in the VMH/ARC. Ovariectomized rats consuming HFD expressed the highest levels of QRFP. In the third experiment, all rats received EB replacement every 4days following OVX to examine the effects of E2 on QRFP expression. Prepro-QRFP, QRFP-r1 and QRFP-r2 mRNA were assessed prior to and following EB administration. EB replacement significantly reduced prepro-QRFP mRNA expression in the VMH/ARC. Overall these studies support a role for E2 in the regulation of prepro-QRFP mRNA in the VMH/ARC and suggest that E2's effects on food intake may be via a direct effect on the orexigenic peptide, QRFP.