Lower Estradiol Concentrations Research Articles

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. To clarify associations of sex hormones with these outcomes. Systematic literature review to July 2019, with bridge searches to March 2024. Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. Observational study design, heterogeneity among studies, and imputation of missing data. Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Time-varying associations of gestational and childhood triclosan with pubertal and adrenarchal outcomes in early adolescence.

Triclosan is an endocrine-disrupting chemical, but associations with pubertal outcomes remain unclear. We examined associations of gestational and childhood triclosan with adolescent hormone concentrations and pubertal stage. We quantified urinary triclosan concentrations twice during pregnancy and seven times between birth and 12 years in participants recruited from Cincinnati, OH (2003-2006). We averaged concentrations across pregnancy and childhood and separately considered individual exposure periods in multiple informant models. At 12 years, we measured serum hormone concentrations (males [n = 72] and females [n = 84]-dehydroepiandrosterone-sulfate, luteinizing hormone, follicle-stimulating hormone; males-testosterone; females-estradiol). Also at age 12 years, participants self-reported physical development and menarchal timing. We estimated associations (95% confidence interval) of triclosan with hormone concentrations, more advanced physical development, and age at menarche. For females, each doubling of childhood triclosan was associated with 16% lower estradiol concentrations (-29%, 0%), with stronger associations for measures closer to adolescence. We found suggestive evidence that higher triclosan at any age was associated with ~10% (for gestational triclosan: -18%, -2%) lower follicle-stimulating hormone concentrations among males and early postnatal (1-3 years) triclosan was associated with 63% (5%, 96%) lower odds of advanced pubic hair development in females. In multiple informant models, each doubling of gestational triclosan concentrations was associated with 5% (0%, 9%) earlier age at menarche, equivalent to 5.5 months. Gestational and childhood triclosan concentrations were related to some pubertal outcomes including hormone concentrations and age at menarche. Our findings highlight the relevance of elucidating potential sex-specific and time-dependent actions of triclosan.

Estradiol mediates greater germinal center responses to influenza vaccination in female than male mice.

Adult females of reproductive age develop greater antibody responses to inactivated influenza vaccines (IIV) than males. How sex, age, and sex steroid concentrations impact B cells and durability of IIV-induced immunity and protection over 4 months post-vaccination (mpv) was analyzed. Vaccinated adult females had greater germinal center B cell and plasmablast frequencies in lymphoid tissues, higher neutralizing antibody responses 1-4 mpv, and better protection against live H1N1 challenge than adult males. Aged mice, regardless of sex, had reduced B cell frequencies, less durable antibody responses, and inferior protection after challenge than adult mice, which correlated with diminished estradiol among aged females. To confirm that greater IIV-induced immunity was caused by sex hormones, four core genotype (FCG) mice were used, in which the testes-determining gene, Sry, was deleted from chromosome Y (ChrY) and transferred to Chr3 to separate gonadal sex (i.e., ovaries or testes) from sex chromosome complement (i.e., XX or XY complement). Vaccinated, gonadal female FCG mice (XXF and XYF) had greater numbers of B cells, higher antiviral antibody titers, and reduced pulmonary virus titers following live H1N1 challenge than gonadal FCG males (XYM and XXM). To establish that lower estradiol concentrations cause diminished immunity, adult and aged females received either a placebo or estradiol replacement therapy prior to IIV. Estradiol replacement significantly increased IIV-induced antibody responses and reduced morbidity after the H1N1 challenge among aged females. These data highlight that estradiol is a targetable mechanism mediating greater humoral immunity following vaccination among adult females.IMPORTANCEFemales of reproductive ages develop greater antibody responses to influenza vaccines than males. We hypothesized that female-biased immunity and protection against influenza were mediated by estradiol signaling in B cells. Using diverse mouse models ranging from advanced-age mice to transgenic mice that separate sex steroids from sex chromosome complement, those mice with greater concentrations of estradiol consistently had greater numbers of antibody-producing B cells in lymphoid tissue, higher antiviral antibody titers, and greater protection against live influenza virus challenge. Treatment of aged female mice with estradiol enhanced vaccine-induced immunity and protection against disease, suggesting that estradiol signaling in B cells is critical for improved vaccine outcomes in females.

Modeling Sex-Bias in Anxiety: Pros and Cons of a Larval Zebrafish Model

Anxiety disorders are the most prevalent psychiatric disorders, exhibiting strong female bias. Clinical studies implicate declining estradiol levels in the exacerbation of anxiety symptoms in the premenstrual phase of the menstrual cycle. This study aimed to simulate estradiol fluctuation-linked anxiety behavior in larval zebrafish, using an estradiol treatment withdrawal model. Contrary to model aims, estradiol treatment withdrawal decreased both basal activity and anxiety-like hyperlocomotion (ANOVA main effect of dose, P < 0.0001 and P < 0.01, respectively) in the light/dark transition test. The accuracy of the estradiol washout model was not improved by longer durations of treatment or withdrawal. Basal activity was slightly altered by supraphysiological concentrations of WAY-200070 in the absence of added estradiol. Estrogen receptor (ER) β expression was not upregulated in larvae exposed to physiologically relevant, low concentrations of estradiol. Longer exposure to low concentrations of estradiol increased antioxidant capacity (P < 0.01). In addition, acute exposure to low concentrations of estradiol increased basal activity. Data suggest that in the current models, estradiol-associated altered activity levels were linked to more favorable redox status, rather than reflecting altered anxiety levels. As such, it is recommended that zebrafish larval behavioral analysis be conducted in parallel with mechanistic studies such as redox indicators, for investigations focused on ER signaling.

Оценка эффективности применения активированной глицирризиновой кислоты у пациенток с ВПЧ-ассоциированными поражениями шейки матки с учетом уровня половых стероидных и гонадотропных пептидных гормонов

Background: the persistence of human papillomavirus (HPV) infection with oncogenic protein expression causes changes in the stratified squamous epithelium, which is the immediate cause of cervical cancer manifestation. The use of the activated glycyrrhizic acid (GA) for HPV-associated cervical lesions is pathogenetically justified. During an experimental study on a culture of human cervical adenocarcinoma cells (HeLa line), it was shown that the antiproliferative effect of GA is enhanced by low concentrations of estradiol and weakened by testosterone. Aim: to evaluate the efficacy of the activated GA in female patients with HPV-associated cervical pathology with respect to the level of sex steroid and gonadotropin-releasing hormones Patients and Methods: a prospective study was conducted with the inclusion of 51 female patients with HPV-associated cervical pathology (ASCUS — atypical squamous epithelial cells of undetermined significance, LSIL — low-grade squamous intraepithelial lesion, HSIL— high-grade squamous intraepithelial lesion according to the Bethesda classification) and the absence of clinical and/or laboratory signs of hyperandrogenism. The following studies were performed: clinical examination, colposcopy, microscopic examination, cytology and immunocytochemistry, as well as hormonal status was evaluated. All female patients received Epigen Intim spray 0.1%, 3 times a day, for 30 days from the moment of inclusion in the study. If indicated, cervical conization was also performed. The treatment efficacy was evaluated 90±7 days after the therapy initiation based on the liquid-based HPV-PAP test results with the determination of p16/Ki67 oncogenic protein co-expression in the cervical epithelium. Changes in the colposcopy results were also evaluated. Results: it was found that the level of estradiol in patients with HSIL was lower versus the patients with ASCUS and LSIL (32 [32.0; 36.0] pg/ml versus 40 [34.5; 45.5] and 40 [33.0; 44.0] pg/ml, respectively, but the difference did not reach statistical significance (p=0.453). 90 days after the follow-up start, according to the cytology results of the cervical epithelium, 50 (98.0%) patients showed the absence of cervical intraepithelial lesions and the absence of p16/Ki67 oncogenic protein co-expression, 48 (94.1%) patients showed no high-risk (HR) HPV DNA, whereas HPV-associated colposcopy signs (anogenital warts, chronic cervicitis signs) persisted only in 6 (11.8%) patients. Conclusion: the use of activated GA in female patients of reproductive age with HPV-associated cervical lesions without clinical and/or laboratory signs of hyperandrogenism allowed to achieve high efficiency indicators: 98.5% — according to the cytology results, 83.3% — in reducing the HR-HPV viral load, 85.7% — in terms of p16/Ki67 oncogenic protein co-expression. KEYWORDS: human papillomavirus, squamous intraepithelial lesion of the cervix, oncogenic protein co-expression, sex steroid hormones, activated glycyrrhizic acid FOR CITATION: Mandrykina Zh.A., Dobrokhotova Yu.E., Ibragimova D.M., Kazieva M.D., Filimonova M.S., Shimanovsky N.L., Akhmetgaliev A.R. Assessment of the activated glycyrrhizic acid efficacy in female patients with HPV-associated cervical lesions with respect to the level of sex steroid and gonadotropin-releasing hormones. Russian Journal of Woman and Child Health. 2024;7(2):127–134 (in Russ.). DOI: 10.32364/2618-8430-2024-7-2-7.

Accuracy-based proficiency testing for estradiol measurements

ObjectivesAccuracy of estradiol measurements is important but conventional proficiency testing (PT) cannot assess accuracy when possibly non-commutable samples are used and method peer-group means are the targets. Accuracy-based assessment of estradiol measurements is needed. Design and MethodsFive serum samples were prepared from single donors, frozen, and distributed overnight to 76 New York State Department of Health (NYSDOH)-certified laboratories. Participants analyzed samples for estradiol. The biases of group means were assessed against the Centers for Disease Control and Prevention (CDC)-defined targets, evaluated using the Hormone Standardization Program (HoSt) E2 performance criterion of ±12.5 %. Each laboratory’s performance was evaluated using total allowable error (acceptance limits) of target ±25 % or ±15 pg/mL (55 pmol/L) (whichever was greater, NYSDOH), target ±30 % (Clinical Laboratory Improvement Amendments [CLIA]), and target ±26 % (minimal limit based on biological variation [BV]). ResultsThe biases (range) were 34 % (−17 % to 175 %), 40 % (−33 % to 386 %), 16 % (−45 % to 193 %), 5 % (−27 % to 117 %), and −4% (−31 % to 21 %), for samples at estradiol of 24.1, 28.4, 61.7, 94.1, and 127 pg/mL, or 89, 104, 227, 345, and 466 pmol/L, respectively. Large positive method/analytical systematic biases were revealed for 9 commonly used method/analytical systems in the United States at low estradiol concentrations. Of the 9 analytical systems, 0, 0, 3, 7 and 6 met the HoSt criterion for the samples with estradiol at the five respective concentrations. PT evaluation showed that 59 %, 69 % and 87 % of laboratories would receive a PT event passing (satisfactory) score when the CDC-defined target and a criterion of NYSDOH, CLIA or BV was used, respectively. However, >95 % laboratories would obtain PT passing score if method peer-group means were used as targets regardless of the criterion used. ConclusionsImprovement in accuracy of estradiol measurements is needed, particularly at low estradiol concentrations. Accuracy-based PT provides unambiguous information about the accuracy of methods/analytical systems.

Bone Mineral Density in Transgender Adolescents Treated With Puberty Suppression and Subsequent Gender-Affirming Hormones

Bone mineral density (BMD) z scores in transgender adolescents decrease during puberty suppression with a gonadotropin-releasing hormone (GnRH) agonist. Previous research found that after short-term use of gender-affirming hormones (GAH), pretreatment z scores were not restored. Long-term follow-up studies are lacking. To assess BMD after long-term GAH treatment in transgender adults who used puberty suppression in adolescence. This single-center cohort study with follow-up duration of 15 years selected participants from a database containing all people visiting a gender identity clinic at an academic hospital in the Netherlands between 1972 and December 31, 2018. Recruitment occurred from March 1, 2020, to August 31, 2021. A total of 75 participants diagnosed with gender dysphoria who had used puberty suppression before age 18 years prior to receiving at least 9 years of long-term GAH were included. Puberty suppression with a GnRH agonist followed by GAH treatment. Lumbar spine, total hip, and femoral neck BMD and z scores before the start of puberty suppression, at start of GAH, and at short- and long-term follow-up. Among 75 participants, 25 were assigned male at birth, and 50 were assigned female at birth. At long-term follow-up, the median (IQR) age was 28.2 (27.0-30.8) years in participants assigned male at birth and 28.2 (26.6-30.6) years in participants assigned female at birth. The median (IQR) duration of GAH treatment was 11.6 (10.1-14.7) years among those assigned male at birth and 11.9 (10.2-13.8) years among those assigned female at birth. The z scores decreased during puberty suppression. In individuals assigned male at birth, the mean (SD) z score after long-term GAH use was -1.34 (1.16; change from start of GnRH agonist: -0.87; 95% CI, -1.15 to -0.59) at the lumbar spine, -0.66 (0.75; change from start of GnRH agonist: -0.12; 95% CI, -0.31 to 0.07) at the total hip, and -0.54 (0.84; change from start of GnRH agonist: 0.01; 95% CI, -0.20 to 0.22) at the femoral neck. In individuals assigned female at birth, after long-term GAH use, the mean (SD) z score was 0.20 (1.05; change from start of GnRH agonist: 0.09; 95% CI, -0.09 to 0.27) at the lumbar spine, 0.07 (0.91; change from start of GnRH agonist: 0.10; 95% CI, -0.06 to 0.26) at the total hip, and -0.19 (0.94; change from start of GnRH agonist: -0.20; 95% CI, -0.26 to 0.06) at the femoral neck. In this cohort study, after long-term use of GAH, z scores in individuals treated with puberty suppression caught up with pretreatment levels, except for the lumbar spine in participants assigned male at birth, which might have been due to low estradiol concentrations. These findings suggest that treatment with GnRH agonists followed by long-term GAH is safe with regard to bone health in transgender persons receiving testosterone, but bone health in transgender persons receiving estrogen requires extra attention and further study. Estrogen treatment should be optimized and lifestyle counseling provided to maximize bone development in individuals assigned male at birth.

Effects of different cryopreservation methods on canine isolated preantral follicles

The aim of the present study was to compare the survival and developmental rate of canine isolated preantral follicles (PAFs) after cryopreservation with different methods (closed vs open vitrification). Follicles were isolated from ovaries randomly divided into three groups: fresh control, OPS (open pulled straw) vitrified and cryotube (CT) vitrified. Post-thaw viability of follicles and oocytes was assessed. Fresh and vitrified/thawed PAFs were cultured in 20 µl drops of FSH-supplemented medium for 10 days. Follicular growth, survival rate, estradiol production and ovulation rate were examined. CT method resulted in lower rate of live cells (58.7%) and oocytes (38.8%) than that of fresh ones (83.6% and 64%, respectively) and OPS (80.3% and 79.3%, respectively). Survival rate was similar to fresh follicles in OPS group (98.5% and 95.4%, respectively), while CT decreased the survival to 81.2%. Fresh follicles showed continuous growth, while CT follicles stopped to increase their size after 2 day. In the OPS vitrified follicles, this halting occurred between Day5 and Day10. Fresh follicles showed the highest estradiol production (range: 26.9 – 266.2 pg/ml). Comparing the two vitrified groups, lower estradiol concentration range was measured in the CT group (7.8–48.7 pg/ml vs. 15.4–89.6 pg/ml). Ovulation rate in each group was lowest in the OPS group (1.7% vs 7% and 8.9% in fesh and CT, respectively). Our data show that OPS vitrification provides superior survival rate, in vitro growth and hormonal production to CT. To our knowledge, these are the first results on comparing different cryopreservation protocols on canine isolated preantral follicles.

The association of sex steroid hormone concentrations with hearing loss: a cross-sectional study

Background Hearing loss is the most prevalent sensory disorder worldwide. Several studies have indicated that sex steroid hormone levels may be vital to hearing. Objective We aimed to explore the associations between speech-frequency hearing loss and sex steroid hormones. Methods We conducted a secondary analysis based on 3558 adult participants’ data from the National Health and Nutrition Examination Survey (NHANES) from 2015 to 2016. We defined hearing loss as a pure-tone average (PTA) at 0.5, 1, 2, and 4 kHz ≥20 dB in the better ear. Multivariate logistic regression analysis was used to evaluate the association between sex steroid hormones and hearing loss risk. A nomogram model for the risk of hearing loss was constructed. Results There were 560 (15.7%) cases who had hearing loss among the participants enrolled in this study. Participants with hearing loss had a higher total testosterone level and a lower estradiol level. Individuals with estradiol levels in the highest tertile still had lower hearing loss risks than those in the lowest tertile. Nevertheless, the total testosterone level had no influence on the risk of hearing loss. Conclusion Our research indicated that low estradiol concentrations were significantly associated with hearing loss, especially in menopausal women.

Correlates of serum estradiol concentration among postmenopausal women in Ilorin, North-Central Nigeria.

There are limited data on the associated factors of circulating endogenous estradiol among Nigerian postmenopausal women. The main objective of this study is to assess the relationship between serum estradiol levels and some menstrual, clinical, and sociodemographic factors in postmenopausal women attending a family medicine clinic in Nigeria. This was a hospital-based cross-sectional study involving 372 postmenopausal women. Sociodemographic, menstrual, and clinical data of the participants were collected, and their serum estradiol concentrations were assayed. The collected data were analyzed using IBM SPSS version 21 statistical software. A χ2 test of association and logistic regression analysis were done to identify significant correlates of serum estradiol concentration among the participants. The mean ages at menarche and menopause among the participants were 15.6 and 48.1 years respectively. Approximately half of them (51.1%) were receiving chronic medical care for systemic hypertension and/or diabetes. The mean estradiol concentration of the participants in the study was 20.69 pg/mL. The participants' marital status and clinical presentation pattern (chronic vs others) were found to have statistically significant associations with their serum estradiol concentration; P = 0.048 and P = 0.001, respectively. Logistic regression analysis revealed that only the clinical presentation pattern had a significant relationship with serum estradiol concentration among the participants ( P = 0.002). Of all the studied factors, the only significant correlate of low serum estradiol concentration found in this study was chronic medical care presentation for hypertension and/or diabetes.

Endocrine profiles and cycle characteristics of infertile 17α-hydroxylase/17,20-lyase Deficiency Patients undergoing assisted Reproduction Treatment: a retrospective cohort study

Background17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare form of congenital adrenal hyperplasia caused by CYP17A1 gene variants. Female patients with 17-OHD demonstrate a broad clinical spectrum, including oligomenorrhea or amenorrhea and infertility, often as the sole manifestation. However, no spontaneous pregnancies in affected women have been reported.ObjectiveThis retrospective cohort study aimed to explore the endocrine characteristics and assisted reproductive technique (ART) performance in women with 17-OHD.MethodsFive women were referred for primary infertility in a university-affiliated hospital over an eight-year period. The endocrine profiles and cycle characteristics during a total of nine cycles of ovarian stimulation and eight cycles of frozen-thawed embryo transfer (FET) were described in details.ResultsThree cases had homozygous variants and two cases had compound heterozygous variants, including one novel missense variant (p.Leu433Ser) in the CYP17A1 gene. Despite dual-suppression of progesterone (P) production by glucocorticoid and gonadotropin releasing hormone agonist, gradually increased P level, relatively low estradiol concentrations and thin endometrium were observed, negating fresh embryo transfer. During FET cycles, appropriate treatment resulted in low serum P levels and adequate endometrial thickness, leading to four live births.ConclusionsOur findings demonstrate that continuous elevation of serum P during follicular growth impairs endometrial receptivity, the likely cause of female infertility in 17-OHD. Therefore, female infertility caused by 17-OHD is suggested as an indication for freeze-all strategy, with promising reproductive prognoses following segmented ovarian stimulation and FET treatment.

Associations of prenatal and postnatal exposure to perfluoroalkyl substances with pubertal development and reproductive hormones in females and males: The HOME study

BackgroundPrenatal and childhood exposure to per- and polyfluoroalkyl substances (PFAS) may be associated with lower reproductive hormones and later puberty, but epidemiological studies evaluating these associations are scarce. ObjectivesWe examined associations of PFAS concentrations assessed from pregnancy to adolescence with pubertal development and reproductive hormones at age 12 years. MethodsWe studied 200 mother-child pairs from the HOME Study in Cincinnati, OH (enrolled: 2003–2006). We quantified serum concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoate (PFNA), and perfluorohexane sulfonate (PFHxS) in pregnant women and their children at age 3, 8 and 12 years. At age 12 years, children self-assessed pubertal development using Tanner staging of pubic hair growth (males and females) and breast growth (females), and age at menarche. We quantified serum concentrations of dehydroepiandrosterone sulfate, luteinizing hormone, and follicle-stimulating hormone in both sexes; estradiol in females; testosterone in males. We estimated associations of PFAS with pubertal outcomes and reproductive hormones using a combination of ordinal regression, Cox proportional-hazard regression, and linear regression. Quantile-based g-computation was used for PFAS mixture. ResultsIn females, adolescent PFAS concentrations and their mixture were associated with later pubic hair growth, breast maturation, and age at menarche, but there was no pattern for prenatal or other postnatal concentrations. For instance, in females, each doubling in adolescent PFAS concentrations was associated with 79 % (PFOA), 63 % (PFOS), 56 % (PFNA), and 47 % (PFHxS) lower odds of attaining a higher stage for breast growth. In addition, adolescent PFAS concentrations were consistently associated with lower estradiol concentrations in females. No pattern was observed for associations of PFAS concentrations with pubic hair growth or reproductive hormones in males. ConclusionsWe observed associations between PFAS concentrations in adolescence and later pubertal development in females, but this could be due to reverse causation induced by excretion of PFAS through menstrual fluid.

A case of primary ovarian failure with Nijmegen Breakage a chromosomal instability syndrome

Abstract Introduction Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive chromosomal instability syndrome, characterized by dysmorphic facial features, intrauterine growth retardation and short stature, recurrent sinopulmonary infections, combined immune deficiency, radiosensitivity, increased risk for cancer, as well as premature ovarian failure. Nibrin gene mutation is responsible for the pathogenesis of the disease. The mechanism of gonadal failure in NBS is thought to be meiotic arrest in gametocytes. Clinical Case A 23-year-old female was admitted to the Marmara University endocrinology outpatient clinic because of secondary amenorrhea. Her first menarche occurred spontaneously at the age of 13, but she has never bled again afterwards. In physical examination, blood pressure was 109/68 mmHg, pulse was 80/min, and temperature was 36°C. Her height was 163 cm, and weight was 67 kg, BMI: 25.6 kg/m2. Midfacial prominent appearance, micrognathia, microcephaly was observed. Breast was assessed for II stage in Tanner scale. Ferriman–Gallwey score was 5. Psychomotor development was natural, cognitive dysfunction was not observed. Her three siblings and aunt had a history of infertility, also her parents were third degree consanguineous. The patient stated that she had recurrent sinopulmonary infections and used several antibiotics since childhood. However, there was no hospitalization due to infection by now. Her two older sisters died due to cancer when they were 10 and 21 years old. The patient had primary ovarian insufficiency according to elevated serum gonadotropins concentration and low serum estradiol concentration (Table 1). The uterus was 50 mm in size, its contours were smooth, and the echo of myometrium was diffusely homogeneous. Bilateral ovaries were not observed in the suprapubic pelvic US examination. Karyotype analysis was performed that was found 46, XX. When considering her family history, facial dysmorphic appearance, and findings of primary ovarian failure, genetic analysis revealed NM_001024688.2 c.625C&amp;gt;T(p.Q209*) homozygous mutation. The patient was started on hormone replacement therapy (estrogen 2 mg once daily, dydrogesterone 10 mg once daily) after the diagnosis. Genetic counseling, immunodeficiency and malignancy screenings were performed. Interestingly, despite the history of recurrent infection, total Ig levels and vaccine responses were normal. Although no malignancy was observed in our case, it is noteworthy that two older sisters died due to cancer. It was recommended to continue the annual screenings. Conclusion Family history should be thoroughly questioned in patients presenting with hypogonadism. NBS should be kept in mind as a rare cause in the presence of a typical phenotypic appearance, recurrent infections, and a family history of infertility and malignancy.

Blood hormone concentrations as markers and predictors of porcine meat production and quality?

Context The applicability of hormones in the prediction of meat production in non-ruminant species has been poorly examined. Aims To examine the applicability of plasma concentrations of leptin, estradiol, progesterone and insulin-like growth-factor I (IGF-I) for characterisation and early prediction of the production and quality of meat in gilts. Methods Animals were compared at 150 days of age with below (‘low’) and above (‘high’) median hormone concentrations and their traits of meat production and quality at the age of 200 days. Key results Animals with a high leptin concentration in blood at the age of 150 days had higher slaughter and carcass weights and weight of ham, but a lower lean meat content at the age of 200 days, than did the gilts with a low leptin concentration. Animals with a high estradiol concentration had a higher carcass weight, weight of ham and backfat thickness and a lower electrical conductivity of musculus semimembranosus than did animals with a low estradiol concentration. High blood IGF-I concentration was associated with a higher slaughter weight, carcass weight and lean meat content. No significant differences between the animals with ‘high’ and ‘low’ progesterone concentration and meat characteristics have been found. Conclusions These observations confirm the involvement of leptin, IGF-I and estradiol in up-regulation of meat production in pigs. Furthermore, they suggest that leptin can be useful for characterisation and prediction of fat production, whereas IGF-I and estradiol (but not progesterone) could be both markers and predictors of porcine growth and meat production. Implications The blood concentrations of these hormones could help in characterisation and selection of pigs for meat production.

Transcriptome analysis of changes in M. aeruginosa growth and microcystin production under low concentrations of ethinyl estradiol

Ethinyl estradiol (EE2) is a synthetic environmental estrogen with considerable estrogenic activity. It has been found to consequently pose a significant threat to the aquatic ecosystem. Harmful algal blooms are a major aquatic ecological issue. However, the relationship between EE2 and cyanobacterial bloom is mainly unknown. In this study, the physiological and molecular responses of Microcystis aeruginosa to EE2 exposure were investigated. A low level of EE2 (0.02 μg/L) significantly enhanced the growth of algal cells (P < 0.05), whereas higher concentrations of EE2 (0.2–200 μg/L) inhibited it. EE2 at doses ranging from 0.02 to 200 μg/L promoted the production of microcystins (MCs), with genes mcyABD playing a key role in the regulation of MC synthesis. The alterations of chlorophyll–a, carotenoid, and phycocyanin contents caused by EE2 showed the same trend as cell growth. At the molecular level, 200 μg/L EE2 significantly down–regulated genes in photosynthetic pigment synthesis, light harvesting, electron transfer, NADPH, and ATP generation. High concentrations of EE2 caused oxidative damage to algal cells on the 4th d. After 12d exposure, although there was no significant change in superoxide dismutase (SOD) content and no damage observed in membrane lipids, genes related to SOD and glutathione were changed. In addition, due to the down–regulation of pckA, PK, gltA, nrtA, pstS, etc., carbon fixation, glycolysis, TCA cycle, nitrogen and phosphorus metabolism were hindered by EE2 (200 μg/L). Gene fabG in fatty acid biosynthesis was significantly up–regulated, promoting energy storage in cells. These findings provide important clues to elucidate the effects and mechanisms of cyanobacterial blooms triggered by EE2 and help to effectively prevent and control cyanobacterial blooms.

Maternal exposure of rats to sodium saccharin during gestation and lactation on male offspring†.

We investigated the effects of fetal programming in Sprague-Dawley rats through the maternal consumption of sodium saccharin on the testicular structure and function in male offspring. Feed intake and efficiency, organ and fat weight, quantification and expression of androgen receptor (AR), and proliferating cell nuclear antigen (PCNA) proteins, sperm count, and hormone levels were determined. Consumption alterations were found in the final weeks of the experiment. Decreases in AR and PCNA expression and quantification, tubular diameter, and luminal volume, and increases in epithelial and interstitial relative volumes were observed. Lower sperm count and transit, and lower estradiol concentration were also found. Sodium saccharin consumption by dams programmed male offspring by affecting the hypothalamic-pituitary-gonad axis with alterations in the Sertoli cell population, in spermatogonia proliferation, the expression and quantification of AR, and in sperm count. We hypothesized that these changes may be due to an estradiol reduction that caused the loosening of adhesion junctions of the blood-testis barrier, causing cell losses during spermatogenesis, also reflected by a decrease in tubular diameter with an increase in epithelial volume and consequent decrease in luminal volume. We conclude that maternal sodium saccharin consumption during pregnancy and lactation programmed alterations in the reproductive parameters of male offspring, thus influencing spermatogenesis.

Estrogen Receptor Subtypes Elicit a Distinct Gene Expression Profile of Endothelial-Derived Factors Implicated in Atherosclerotic Plaque Vulnerability.

In the presence of established atherosclerosis, estrogens are potentially harmful. MMP-2 and MMP-9, their inhibitors (TIMP-2 and TIMP-1), RANK, RANKL, OPG, MCP-1, lysyl oxidase (LOX), PDGF-β, and ADAMTS-4 play critical roles in plaque instability/rupture. We aimed to investigate (i) the effect of estradiol on the expression of the abovementioned molecules in endothelial cells, (ii) which type(s) of estrogen receptors mediate these effects, and (iii) the role of p21 in the estrogen-mediated regulation of the aforementioned factors. Human aortic endothelial cells (HAECs) were cultured with estradiol in the presence or absence of TNF-α. The expression of the aforementioned molecules was assessed by qRT-PCR and ELISA. Zymography was also performed. The experiments were repeated in either ERα- or ERβ-transfected HAECs and after silencing p21. HAECs expressed only the GPR-30 estrogen receptor. Estradiol, at low concentrations, decreased MMP-2 activity by 15-fold, increased LOX expression by 2-fold via GPR-30, and reduced MCP-1 expression by 3.5-fold via ERβ. The overexpression of ERα increased MCP-1 mRNA expression by 2.5-fold. In a low-grade inflammation state, lower concentrations of estradiol induced the mRNA expression of MCP-1 (3.4-fold) and MMP-9 (7.5-fold) and increased the activity of MMP-2 (1.7-fold) via GPR-30. Moreover, p21 silencing resulted in equivocal effects on the expression of the abovementioned molecules. Estradiol induced different effects regarding atherogenic plaque instability through different ERs. The balance of the expression of the various ER subtypes may play an important role in the paradoxical characterization of estrogens as both beneficial and harmful.

Physiological interindividual variability in endogenous estradiol concentration does not influence adipose tissue and hepatic lipid kinetics in women.

Increased triglyceride (TG) and apolipoprotein B-100 (apoB-100) concentrations in plasma are important risk factors for cardiovascular disease in women. Administration of some estrogen preparations raises plasma TG and apoB-100 concentrations by increasing hepatic very low-density lipoprotein (VLDL) TG and apoB-100 secretion rates. However, the influence of physiological variation in endogenous estradiol on VLDL-TG and VLDL-apoB-100 metabolism and on free fatty acid (FFA) release into plasma (the major source of fatty acids for VLDL-TG production) is not known. We measured basal VLDL-TG, VLDL-apoB-100, and plasma FFA kinetics by using stable isotopically labeled tracers in 36 eumenorrheic, premenopausal women (age: 33 ± 2 years, BMI: 31 ± 1 kg/m2; mean ± s.e.m.) during the follicular phase of the menstrual cycle; participants were divided into two groups based on low (n = 18) or high (n = 18) plasma estradiol concentrations (defined as below or above the median value of 140 pmol/L in the whole group). Mean plasma estradiol concentration was >3-fold higher in the high-estradiol than in the low-estradiol group (299 ± 37 and 96 ± 7 pmol/L, P < 0.001); there was no difference in plasma progesterone concentrations between the two groups (P = 0.976). There were no significant differences in plasma FFA concentration, FFA rate of appearance in plasma, VLDL-TG and VLDL-apoB-100 concentrations, hepatic VLDL-TG and VLDL-apoB-100 secretion rates, VLDL-TG and VLDL-apoB-100 plasma clearance rates, and mean residence times (all P ≥ 0.45). No significant associations were found between plasma estradiol concentration and FFA, VLDL-TG, and VLDL-apoB-100 concentrations and kinetics (all P > 0.19). Plasma estradiol concentration is not an important correlate of basal plasma FFA, VLDL-TG, and VLDL-apoB-100 kinetics in premenopausal women.

The role of central serotonergic markers and estradiol changes in perinatal mental health.

Women have an increased risk for mental distress and depressive symptoms in relation to pregnancy and birth. The serotonin transporter (SERT) may be involved in the emergence of depressive symptoms postpartum and during other sex-hormone transitions. It may be associated with cerebrospinal fluid (CSF) levels of the main serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA). In 100 healthy pregnant women, who were scheduled to deliver by cesarean section (C-section), we evaluated 5-HIAA and estradiol contributions to mental distress 5 weeks postpartum. Eighty-two women completed the study. CSF collected at C-section was analyzed for 5-HIAA, with high performance liquid chromatography. Serum estradiol concentrations were quantified by liquid chromatography tandem mass spectrometry before C-section and postpartum. Postpartum mental distress was evaluated with the Edinburgh Postnatal Depression Scale (EPDS). Associations between EPDS, 5-HIAA, and Δestradiol were evaluated in linear regression models adjusted for age, parity and SERT genotype. Higher levels of postpartum mental distress symptoms were negatively associated with a large decrease in estradiol concentrations (βΔE2 =0.73, p=0.007) and, on a trend level, positively associated with high antepartum 5-HIAA levels (β5-HIAA =0.002, p=0.06). In a cohort of healthy pregnant women, postpartum mental distress was higher in women with high antepartum 5-HIAA (trend) and lower in women with a large perinatal estradiol decrease. We speculate that high antepartum 5-HIAA is a proxy of SERT levels, that carry over to the postpartum period and convey susceptibility to mental distress. In healthy women, the postpartum return to lower estradiol concentrations may promote mental well-being.

Association of Serum Vitamin D and Estradiol Levels with Metabolic Syndrome in Rural Women of Northwest China: A Cross-Sectional Study.

Objectives: We aimed to determine the association of serum vitamin D and estradiol levels with metabolic syndrome (MS) in rural women of northwest China. Methods: This research is a cross-sectional study. MS was defined according to the updated China Diabetes Society (CDS) criteria. Fasting serum 25-hydroxyvitamin D [25(OH)D] and estradiol levels were measured using a chemiluminescence immunoassay. Differences between variables were analyzed using the chi-square test and t-test. Logistic regression analysis models were used to estimate the odds ratios (ORs) and 95% confidence intervals. Results: In total, 1893 women participated, of whom 641 (33.9%) had MS. The serum levels of 25(OH)D and estradiol were higher in the non-MS group. There was no significant association between 25(OH)D and estradiol levels. After adjusting for potential confounders, we compared first, second, and third quartiles with the highest quartile. Adjusted ORs for MS with respect to 25(OH)D level quartiles were 1.555, 1.281, and 1.568, respectively. Adjusted ORs for MS with respect to estradiol level quartiles were 0.671, 0.785, and 0.996, respectively. In the vitamin D-deficient (VD-deficient) group, adjusted ORs for MS with respect to estradiol level quartiles were 0.635, 0.753, and 0.918, respectively. Conclusions: There is a negative correlation between MS and vitamin D level and a positive correlation between MS and estradiol level. Low estradiol concentrations increased the risk of MS in the VD-deficient group. The results suggest a potential synergism between low 25(OH)D concentration and estradiol in MS in women.