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Gills, JL, Spliker, B, Glenn, JM, Szymanski, D, Romer, B, Lu, H-C, and Gray, M. Acute citrulline-malate supplementation increases total work in short lower-body isokinetic tasks for recreationally active females during menstruation. J Strength Cond Res XX(X): 000-000, 2021-Citrulline-Malate (CM) exhibits acute ergogenic benefits through nitric oxide production (NO) and augmentation of vasodilatory properties. Nitric oxide is upregulated by estrogen and may influence CM's ergogenic efficacy in women. Therefore, the objective of this study was to evaluate the acute effects of CM supplementation on lower-body isokinetic performance in recreationally active women. Nineteen women (23.5 ± 3.1 years; 164.8 ± 7.0 cm; 61.9 ± 27.4 kg; 28.8 ± 8.1% body fat) completed 2 randomized, double-blind, crossover trials consuming CM (8 g CM + 12 g dextrose) or placebo (12 g dextrose). For testing trials, subjects were in the menstruating portion of the follicular phase of their menstrual cycle. Subjects performed a 5-repetition isokinetic leg extension protocol (5RP) followed by a 50-repetition isokinetic leg extension protocol (50RP), 60 minutes after supplement consumption. Repeated measures analysis of variance analysis showed that CM significantly increased total work completed, relative total work, and total work during maximum repetition compared with placebo (p < 0.05); but no significant performance differences existed between trials for peak torque production (p = 0.14) for the 5RP. No significant differences were identified between trials for peak torque production (p = 0.69) or total work (p = 0.33) completed during the 50RP. CM increased total work completed during the 5RP, but provided no ergogenic benefit during the 50RP in recreationally active menstruating women. Citrulline-Malate amplifies power-based resistance exercise performance in women during the follicular phase of the menstrual cycle, potentially because of depressed estrogen levels. Additional research is needed to identify timing efficacy of CM to increase sport performance during each phase of the menstrual cycle.

PURPOSE Immunohistochemistry (IHC) is a newer technique for assessing the estrogen receptor (ER) status of breast cancers, with the potential to overcome many of the shortcomings associated with the traditional ligand-binding assay (LBA). The purpose of this study was to evaluate the ability of ER status determination by IHC, compared with LBA, to predict clinical outcome—especially response to adjuvant endocrine therapy—in a large number of patients with long-term clinical follow-up. PATIENTS AND METHODS ER status was evaluated in 1,982 primary breast cancers by IHC on formalin-fixed paraffin-embedded tissue sections, using antibody 6F11 and standard methodology. Slides were scored on a scale representing the estimated proportion and intensity of positive-staining tumor cells (range, 0 to 8). Results were compared with ER values obtained by the LBA in the same tumors and to clinical outcome. RESULTS An IHC score of greater than 2 (corresponding to as few as 1% to 10% weakly positive cells) was used to define ER positivity on the basis of a univariate cut-point analysis of all possible scores and disease-free survival (DFS) in patients receiving any adjuvant endocrine therapy. Using this definition, 71% of all tumors were determined to be ER-positive by IHC, and the level of agreement with the LBA was 86%. In multivariate analyses of patients receiving adjuvant endocrine therapy alone, ER status determined by IHC was better than that determined by the LBA at predicting improved DFS (hazard ratios/ P = 0.474/.0008 and 0.707/.3214, respectively) and equivalent at predicting overall survival (0.379/.0001 and 0.381/.0003, respectively). CONCLUSION IHC is superior to the LBA for assessing ER status in primary breast cancer because it is easier, safer, and less expensive, and has an equivalent or better ability to predict response to adjuvant endocrine therapy.

Endocrine disrupting compounds and in particular estrogenic substances have the ability to interact with the hormone system of organisms. Among them are not only synthetic but also natural substances that potentially stress the aquatic ecosystem. High human population densities such as around the Pearl River Estuary (PRE) are suspected of exerting significant anthropogenic pressure onto coastal areas. In this study, natural and synthetic estrogens as well as estrogen-like substances derived from plants and fungi were investigated in the PRE and at the adjacent northern shelf of the South China Sea. Maximum concentration of 3.6 ng L−1 for estrone (E1), 0.7 ng L−1 for 17α-ethinylestradiol (EE2), 12.9 ng L−1 for genistein (GEN), 11.9 ng L−1 for daidzein (DAI) and 1.9 ng L−1 for zearalenone (ZEN) were observed. While E1 and EE2 were detected in fresh and saltwater samples, GEN, DAI and ZEN were observed only at freshwater sampling sites. During the investigations, the analysis of 17β-estradiol (E2) and EE2 indicated a strong matrix dependence. Additionally, an estrogen screen observation showed estrogenic activity in form of estradiol equivalent quotients up to 0.18 ng L−1.

Circadian rhythms are ~24 h cycles of behavior and physiology that are generated by a network of molecular clocks located in nearly every tissue in the body. In mammals, the circadian system is organized hierarchically such that the suprachiasmatic nucleus (SCN) is the main circadian clock that receives light information from the eye and entrains to the light-dark cycle. The SCN then coordinates the timing of tissue clocks so internal rhythms are aligned with environmental cycles. Estrogens interact with the circadian system to regulate biological processes. At the molecular level, estrogens and circadian genes interact to regulate gene expression and cell biology. Estrogens also regulate circadian behavior across the estrous cycle. The timing of ovulation during the estrous cycle requires coincident estrogen and SCN signals. Studies using circadian gene reporter mice have also elucidated estrogen regulation of peripheral tissue clocks and metabolic rhythms. This review synthesizes current understanding of the interplay between estrogens and the circadian system, with a focus on female rodents, in regulating molecular, physiological, and behavioral processes.

Background: Triple Negative Breast Cancer (TNBC) commonly displays Epidermal growth factor receptor (EGFR). Effective EGFR degradation results in the suppression of tumor in various models. Studies have addressed the relevance of this strategy in the treatment of TNBC. In the present study, we examined the effect of 17 β- estradiol on EGFR expression in MDA-MB-231 (TNBC) cell line and assessed whether 17 β-estradiol degrades EGFR by ubiquitination pathway. Objectives: The objectives of this study are to treat MDA-MB-231 cell lines with Cycloheximide with or without 17β-estrdiol to observe whether 17β-estradiol leads to EGFR degradation and to treat with MG-132 to assess whether degradation occurs through ubiquitination pathway. Methods: MDA-MB-231 cells were treated with 17β-estradiol (E2) and EGFR expression was studied by western blotting at different intervals by using Cycloheximide chase. To assess ubiquitination pathway of degradation of EGFR in MDA-MB-231 cell line, MG-132 was used. Results: EGFR expression was reduced with β-estradiol treatment in MDA-MB-231 cell line with Cycloheximide chase. Upon Treatment with MG-132 and E2, EGFR expression did not reduce, suggesting that Estrogen degrades EGFR by ubiquitination pathway. Conclusion: Estrogen degrades EGFR in MDA-MB-231 cells and this degradation occurs by ubiquitination.

Although multiple hormonal treatment strategies are effective in decreasing heavy menstrual bleeding (HMB) in adolescents, few studies have compared the relative effectiveness of hormone therapy on the basis of dose.Retrospective chart review SETTING: Urban tertiary care institution PARTICIPANTS: Adolescents aged 9-19 years with acute HMB and anemia in 2008-2018 INTERVENTIONS: We used billing codes to identify encounters for acute HMB with hemoglobin less than 12 mg/dl and reviewed initial treatment and time until resolution of acute HMB. We excluded patients who had previously used gonadal steroids or did not complete follow-up. We then compared patients who received combined oral ethinyl estradiol with progestin (EE/P) in standard dosing (EE ≤35 mcg/day) vs taper dosing (EE35mcg/day in any step-down regimen).Time until patient-reported resolution of acute HMB, measured in days from initial treatment RESULTS: Of 207 patients with vaginal bleeding and anemia, 90 met the criteria for review of therapy type and dose. Users of combined EE/P were hormone-naïve in 28/33 (84.8%) of those who initiated standard EE/P and 22/32 (68.8%) who initiated taper dosing. Bleeding duration was available for 15/28 (53.6%) and 18/22 (81.8%). Resolution of HMB occurred in 0-9 days with standard dosing (mean ±SD 2.1 ± 2.3 days) versus 1-15 days for taper dosing (4.9 ± 4.7; p = 0.04). Excluding six outliers of zero or more than 10 days, HMB ceased by 2.6 and 3 days (n = 12 and 15; p = 0.62).Currently recommended higher dose combined hormonal regimens do not appear to shorten the time to resolution of acute HMB in adolescents.

Background: Many natural and synthetic flavonoids have been studied and documented by inhibiting aromatase enzymes for their anti-cancer activity against breast carcinoma. The aromatase enzyme is a possible target for the estrogen's positive breast cancer receptor. Objective: Hence, a series of flavonoids have been synthesized and assessed for their in vitro cytotoxicity and aromatase inhibitory activity. Methods: 39 Flavonoids were synthesized and characterized by spectroscopic techniques, and their computational study was performed using the maestro version of the Schrodinger. In-silico ADME properties were checked by QikProp software. A total of 18 compounds were evaluated based on the docking score using cytotoxicity assay in human breast cancer cell line MCF-7. Results: Of the 18 compounds tested, 07 compounds, namely 2b, 8b, 14b, 15b, 19b, 24b, and 30b flavonoids were found to be more active with their IC50 values of 20.73 μM, 1.636 μM, 16.08 μM, 22.02 μM, 15.75 μM, 0.345 μM and 16.08 μM, respectively, compared with the reference drug letrozole. The in-vitro aromatase inhibitory activity of six compounds 2b, 8b, 14b, 19b, 24b, and 30b was conducted using a fluorogenic assay kit. The values of IC50 for compounds 2b and 24b were found to be 0.31 μM and 0.36 μM, respectively. Conclusion: Therefore, it was concluded that compounds 2b and 24b had a potent inhibitory effect of aromatase compared with letrozole with an IC50 value of 0.86 μM. At the same time, the other compounds 8b, 14b, 30b, and 19b were considered to have similar aromatase inhibitory activity. Hence, their essential aromatase inhibitory activities make them good lead candidates for developing potent inhibitors of aromatase.

Objective: Medical contraindications to estrogen limit women's contraceptive options. This study assessed the association between selected medical contraindications to estrogen on contraceptive use...

STUDY QUESTION Is there a difference in the growth and vascularization between murine endometriotic lesions originating from menstrual or non-menstrual endometrial fragments? SUMMARY ANSWER Endometriotic lesions developing from menstrual and non-menstrual tissue fragments share many similarities, but also exhibit distinct differences in growth and vascularization, particularly under exogenous estrogen stimulation. WHAT IS KNOWN ALREADY Mouse models are increasingly used in endometriosis research. For this purpose, menstrual or non-menstrual endometrial fragments serve for the induction of endometriotic lesions. So far, these two fragment types have never been directly compared under identical experimental conditions. STUDY DESIGN, SIZE, DURATION This was a prospective experimental study in a murine peritoneal and dorsal skinfold chamber model of endometriosis. Endometrial tissue fragments from menstruated (n = 15) and non-menstruated (n = 21) C57BL/6 mice were simultaneously transplanted into the peritoneal cavity or dorsal skinfold chamber of non-ovariectomized (non-ovx, n = 17), ovariectomized (ovx, n = 17) and ovariectomized, estrogen-substituted (ovx+E2, n = 17) recipient animals and analyzed throughout an observation period of 28 and 14 days, respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS The engraftment, growth and vascularization of the newly developing endometriotic lesions were analyzed by means of high-resolution ultrasound imaging, intravital fluorescence microscopy, histology and immunohistochemistry. MAIN RESULTS AND THE ROLE OF CHANCE Menstrual and non-menstrual tissue fragments developed into peritoneal endometriotic lesions without differences in growth, microvessel density and cell proliferation in non-ovx mice. Lesion formation out of both fragment types was markedly suppressed in ovx mice. In case of non-menstrual tissue fragments, this effect could be reversed by estrogen supplementation. In contrast, endometriotic lesions originating from menstrual tissue fragments exhibited a significantly smaller volume in ovx+E2 mice, which may be due to a reduced hormone sensitivity. Moreover, menstrual tissue fragments showed a delayed vascularization and a reduced blood perfusion after transplantation into dorsal skinfold chambers when compared to non-menstrual tissue fragments, indicating different vascularization modes of the two fragment types. To limit the role of chance, the experiments were conducted under standardized laboratory conditions. Statistical significance was accepted for a value of P LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Endometriotic lesions were induced by syngeneic tissue transplantation into recipient mice without the use of pathological endometriotic tissue of human nature. Therefore, the results obtained in this study may not fully relate to human patients with endometriosis. WIDER IMPLICATIONS OF THE FINDINGS The present study significantly contributes to the characterization of common murine endometriosis models. These models represent important tools for studies focusing on the basic mechanisms of endometriosis and the development of novel therapeutic strategies for the treatment of this frequent gynecological disease. The presented findings indicate that the combination of different experimental models and approaches may be the most appropriate strategy to study the pathophysiology and drug sensitivity of a complex disease such as endometriosis under preclinical conditions. STUDY FUNDING/COMPETING INTEREST(S) There was no specific funding of this study. The authors have no conflicts of interest to declare.

The simultaneous assessment of the electrophysiological and neuroendocrine activity during sleep by the sleep electroencephalogram (EEG) and by the collection of hormone profiles respectively showed a bidirectional interaction between the non-rapid eye movement (non-REM)–REM cycle and nocturnal hormone secretion. Certain hormones (neuropeptides and neuroactive steroids) participate in sleep regulation. A reciprocal interaction of the sleep-promoting peptide growth hormone-releasing hormone (GHRH) and the sleep-impairing corticotropin-releasing hormone (CRH) plays a key role in sleep regulation. Besides GHRH, galanin, ghrelin, and neuropeptide Y also promote sleep, at least in male subjects. In contrast, somatostatin is another sleep-impairing endogenous substance. The influence of peptides on sleep depends on age, sex, and time of administration. For example, GHRH impairs sleep in women, opposite to its effects in men. Vasoactive intestinal polypeptide affects the duration of non-REM and REM periods. In addition to peptides, steroids are involved in sleep regulation. GABA A receptors are targets of various neuroactive steroids exerting specific effects on sleep EEG. Cortisol appears to promote REM sleep. Sleep EEG changes in postmenopausal women and the beneficial effect of estrogen and progesterone replacement therapy suggests a sleep-promoting effect of these hormones.

Implantation timing is key for a successful pregnancy. Short delay in embryo implantation caused by targeted gene ablation produced a cascading problem in the later stages of the pregnancy. Although several delayed implantation models have been established in wild mice, almost none of them is suitable for investigating the delay on the late events of pregnancy. Here, we report a new delayed implantation model established by the intraperitoneally administration of letrozole at 5 mg/kg body weight on the day 3 of pregnancy. In these mice, initiation of implantation was induced at will by the injection of estradiol (E2). When the estradiol (3 ng) was injected on day 4 of pregnancy (i.e., without delay), the embryo implantation restarted, and the pregnancy continued normally. However, high dose of estrogen (25 ng) caused compromised implantation. We also found that only 67% of the female mice could be pregnant normally and finally gave birth when the injection of estradiol (3 ng) was on day 5 of pregnancy (i.e., one day delay). Most of the failed pregnancies had impaired decidualization, decreased plasma progesterone levels and compromised angiogenesis. Progesterone supplementation could rescue decidualization failure in the mice. Collectively, we established a new model of delayed implantation by letrozole, which can be easily used to study the effect and mechanisms of delay of embryo implantation on the progression of late pregnancy events.

Estrogen-secreting adrenocortical tumors (ACTs) are quite rare with feminizing adrenocortical tumors (FATs) accounting for 0.37-2% of all ACTs. The aim was to evaluate clinical and hormonal characteristics of FATS as well as treatment options and follow-up in the pediatric age group.Medical records of children with ACTs presenting to a single center in the last two decades were reviewed. Literature review within Pubmed revealed 34 pediatric patients (22 boys) with FAT among 192 articles.Among the 25 children presenting with ACTs in the last two decades, two new pediatric cases of FAT were identified, one benign and the other malignant, in two genders with different clinical presentations. Literature review showed that FATs are extremely rare tumors that are most commonly seen in men and boys presenting with gynecomastia. FATs are more common in children ≤8 years of age, with a median age at diagnosis of six years. While boys present with contrasexual pseudopuberty signs, girls present with isosexual pseudopuberty. A high estrogen level strongly supports diagnosis, while elevations in other adrenal hormones may be seen. FATs are usually malignant in adults and prognosis is generally very poor. However, in children approximately half are benign although assessment of malignant potential depends on clinical behavior of the tumor. FATs are very unpredictable so even after surgery long-term follow-up is required. FATs presenting in childhood may have a better prognosis than adult presentation tumors as most FATs in children are followed without recurrence of tumor.FATs are more common in children ≤8 years of age, with a median age at diagnosis of six years. FATs in childhood may have a better prognosis than in adult males.

Introduction Increased fiber intake has been associated with decreased breast cancer risk, while increased animal protein intake with increased risk. The objective of this study is to examine the relationship of dietary fiber and protein intake to estrogen and sex hormone–binding globulin (SHBG) concentrations at puberty onset. Methods These analyses were conducted using the Cincinnati puberty cohort of the Breast Cancer and the Environment Research Program, with girls followed every 6 months from ages 6 and 7. The analyses included serum measurements at 6-month intervals for estrogen and SHBG concentrations, from 18 months prior to breast stage 2 (onset of puberty). Dietary intake was documented via 24-hour dietary recalls every 3 months. Dietary factors of interest included total energy intake; total and animal protein; total, soluble, and insoluble fiber; and lignan and flavanol intake. Results This study included 260 participants who generated 871 serum specimens and 3,000 days of diet intake. In longitudinal models, estradiol was associated inversely with insoluble fiber intake; estrone positively with animal protein intake; SHBG with greater insoluble fiber and lower total protein intake; and ratio of estrone to SHBG, a measure of bioavailable estrogen, positively with animal protein. Conclusions Greater protein intake, especially animal protein, led to greater estrogen concentrations and lower SHBG; greater animal protein and greater caloric intake led to increased bioavailable estrogen. This relationship may have served an evolutionary advantage in the past for greater fertility with adequate high-quality protein; in contemporary women, a modest decrease in animal protein may be beneficial in reducing breast cancer risk.

Androgen receptor (AR) inhibitor therapy is a developing treatment for AR-positive breast cancer (BC) with ongoing clinical trials. AR splice variant-7 (AR-V7) is a truncated variant of AR that leads to AR inhibitor therapy resistance in prostate cancer; recent studies have identified AR-V7 in BC and theorized that AR-V7 can have a similar impact. This study assessed the prevalence and clinicopathologic features associated with AR-V7 in a large BC cohort. BC samples were evaluated by MSK-Fusion targeted RNAseq for AR-V7 detection and MSK-IMPACT targeted DNAseq, including triple-negative tumors with no driver alteration and estrogen receptor-positive/ESR1 wildtype tumors progressing on therapy. Among 196 primary and metastatic/recurrent cases (196 RNAseq, 194DNAseq), 9.7% (19/196) were AR-V7 positive and 90.3% (177/196) AR-V7 negative. All AR-V7 positive BC were AR-positive by immunohistochemistry (19/19). The prevalence of AR-V7 by receptor subtype (N = 189) was: 18% (12/67) in ER-/PgR-/HER2-negative BC, 3.7% (4/109) in ER-positive/HER2-negative BC, and 15.4% (2/13) in HER2-positive BC; AR-V7 was detected in one ER-positive/HER2-unknown BC. Apocrine morphology was observed in 42.1% (8/19) of AR-V7 positive BC and 3.4% (6/177) AR-V7 negative BC (P

Females display changes in distinct behaviors along the estrous cycle. Levels of circulating ovarian sex steroid hormones peak around ovulation, which occur around estrus phase of the cycle. This increase of sex hormones is thought to be important for changes in behaviors, however, neural circuit mechanisms of periodic behavioral changes in females are not understood well. Different lines of research indicate sex hormonal effects on several forms of neuronal plasticity. This review provides an overview of behavioral and plastic changes that occur in an estrous cycle-dependent manner and explores the current research linking these changes to understand neural circuit mechanisms that control female behaviors.

We empirically investigated genomic clusters associated with both height and postmenopausal breast cancer (BC) or colorectal cancer (CRC) (or both) in the Netherlands Cohort Study to unravel shared underlying mechanisms between height and these cancers. The Netherlands Cohort Study (1986–2006) includes 120,852 participants (case-cohort study: nsubcohort = 5,000; 20.3 years of follow-up). Variants in clusters on chromosomes 2, 4, 5, 6 (2 clusters), 10, and 20 were genotyped using toenail DNA. Cluster-specific genetic risk scores were modeled in relation to height and postmenopausal BC and CRC risk using age-adjusted linear regression and multivariable-adjusted Cox regression, respectively. Only the chromosome 10 cluster risk score was associated with all 3 phenotypes in the same sex (women); that is, it was associated with increased height (βcontinuous = 0.34, P = 0.014), increased risk of hormone-receptor–positive BC (for estrogen-receptor–positive BC, hazard ratio (HRcontinuous score) = 1.10 (95% confidence interval (CI): 1.02, 1.20); for progesterone-receptor–positive BC, HRcontinuous score = 1.15 (95% CI: 1.04, 1.26)), and increased risk of distal colon (HRcontinuous score = 1.13, 95% CI: 1.01, 1.27) and rectal (HRcontinuous score = 1.14, 95% CI: 0.99, 1.30) cancer. The chromosome 10 cluster variants were all annotated to the zinc finger MIZ-type containing 1 gene (ZMIZ1), which is involved in androgen receptor activity. This suggests that hormone-related growth mechanisms could influence both height and postmenopausal BC and CRC.

The role of central estrogen in cognitive, metabolic, and reproductive health has long fascinated the lay public and scientists alike. In the last two decades, insight into estrogen signaling in the brain and its impact on female physiology is beginning to catch up with the vast information already established for its actions on peripheral tissues. Using newer methods to manipulate estrogen signaling in hormone-sensitive brain regions, neuroscientists are now identifying the molecular pathways and neuronal subtypes required to establish crucial sex differences in energy allocation. However, the immense cellular complexity of these hormone-sensitive brain regions makes it clear that more research is needed to fully appreciate how estrogen modulates neural circuits to regulate physiological and behavioral end points. Such insight is essential for understanding how natural or drug-induced hormone fluctuations across lifespan affect women's health. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Study Objective To assess nerve fiber density and expression of hormone receptors in bowel endometriosis. Design Cross-sectional study. Setting Private hospital. Patients Women with endometriosis undergoing laparoscopic segmental bowel resection (n = 54). Interventions Tissue samples were obtained from patients with surgically treated rectosigmoid endometriosis. Measurements and Main Results The rectosigmoid specimen containing the endometriosis nodule was manually sectioned and divided into 3 areas: core of the nodule, margin of the nodule, and healthy bowel tissue. The intensity of expression of estrogen and progesterone receptors was evaluated by immunohistochemistry and measured according to the Allred score. Nerve fibers were stained by immunohistochemistry using Protein Gene Product 9.5, and the density of nerve fillets was counted and expressed in number/mm². All glandular and stromal cells stained for estrogen; however, glandular cells stained more strongly than stromal cells (61.1% vs 35.2%; p = .01). Most of glandular and stromal cells stained strongly for progesterone receptors (90.7% vs 98.1%; p = .2). The density of nerve fibers was very high in the margin of the nodule (172.22±45.66/mm²), moderate in healthy bowel tissue (111.48±48.57/mm²), and very low in the core of the nodule (7.31±4.9/mm²); p = .01. Conclusion Both glandular and stromal cells within the rectosigmoid endometriosis nodule express estrogen and progesterone receptors. Higher intensity of expression of estrogen receptors occurs in glandular cells. The density of nerve fibers is extremely high at the nodule margin and very low in the center of the nodule.

Background. The climacteric period in women with type 1 diabetes mellitus (DM1) initiates an additional damaging effect on the existing cardinal pathology associated with DM. The purpose was to establish the features of geometric remodeling of the left ventricle (LV) of the heart in women with DM1 during the climacteric period. Materials and methods. The study involved 60 women with type 1 diabetes at the age of 48.74 ± 0.65 years, inclu­ding 41 perimenopausal and 19 postmenopausal ones. The control group consisted of 20 women without diabetes mellitus at the age of 50.02 ± 0.71 years. According to echocardiography, taking into account the stage of menopause, the indicators of the end-diastolic volume (EDV) and size (EDS), the posterior wall thickness of the LV (LVPWT) and the interventricular septum (IVST) were analyzed. The frequency of various types of geometric remodeling of the left ventricle of the heart was analyzed using the Penn Convention formula; for this, the LV myocardial mass index (LVMI) was calculated according to the formulas LVMI = 1.04 [(EDS + LVPWT + IVST)3 – EDS3] – 13.6 (LVMI = ratio LVMI to the plane of the body surface (A) in m2; AM2 = 1 + Weight + Δh / 100, where Δh is the difference between the height of a woman and 160 cm) and the relative wall thickness of the LV (LVRWT) LVRWT = 2LVPWT / EDS. Based on these data, the frequency of various types of geometric remodeling was established: normal geometry, concentric remode­ling, concentric or eccentric LV hypertrophy. Results. The data obtained indicate that postmenopausal women present a significant decrease in the frequency of normal heart geometry compared to perimenopausal women (26.4 versus 75.6 %, p, Актуальність. Клімактеричний період у жінок із цукровим діабетом 1-го типу (ЦД1) ініціює додатковий пошкоджуючий вплив на існуючу пов’язану з ЦД кардіальну патологію. Мета: встановити особливості геометричного ремоделювання лівого шлуночка серця в жінок із ЦД1 клімактеричного періоду. Матеріали та методи. Обстежені 60 жінок із ЦД1 віком 48,74 ± 0,65 року, у тому числі 41 — у перименопаузі та 19 — у постменопаузі. Контрольну групу становили 20 жінок без ЦД віком 50,02 ± 0,71 року. За даними ехокардіографії, з урахуванням стадії клімактерію, проаналізовані показники кінцевого діастолічного об’єму (КДО) і кінцевого діастолічного розміру (КДР), товщини задньої стінки лівого шлуночка (ТЗСЛШ) і міжшлуночкової перегородки (ТМШП). За формулою Penn Сonvention проаналізовано частоту різних типів геометричного ремоделювання лівого шлуночка (ЛШ) серця. Для цього за формулами розраховані: 1) індекс маси міокарда ЛШ (ІММЛШ): ІММЛШ = 1,04 • [(КДР + ТЗСЛШ + ТМШП)3 – КДР3] – 13,6 (ІММЛШ розраховували як співвідношення ММЛШ до площини поверхні тіла (А) у м2; Ам2 = 1 + вага + ∆h/100, де ∆h — різниця між ростом жінки та 160 см); 2) відносна товщина стінок ЛШ (ВТСЛШ): ВТСЛШ = 2 • ТЗСЛШ/КДР. За цими даними встановлено частоту різних типів геометричного ремоделювання: нормальна геометрія, концентричне ремоделювання, концентрична або ексцентрична гіпертрофія ЛШ. Результати. Отримані дані свідчать, що в жінок постменопаузального періоду вірогідно зменшується частота нормальної геометрії серця щодо жінок у перименопаузальному періоді (26,4 % проти 75,6 %, р

Objective To evaluate the association between hysterectomy and ovarian cancer, and to understand how hormone therapy (HT) use and endometriosis affect this association. Methods We conducted a pooled analysis of self-reported data from 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC). Women with (n = 5350) and without ovarian cancer (n = 7544) who never used HT or exclusively used either estrogen-only therapy (ET) or estrogen+progestin therapy (EPT) were included. Risk of invasive epithelial ovarian cancer adjusted for duration of ET and EPT use and stratified on history of endometriosis was determined using odds ratios (ORs) with 95% confidence intervals (CIs). Results Overall and among women without endometriosis, there was a positive association between ovarian cancer risk and hysterectomy (OR = 1.19, 95% CI 1.09-1.31 and OR = 1.20, 95% CI 1.09-1.32, respectively), but no association upon adjusting for duration of ET and EPT use (OR = 1.04, 95% CI 0.94-1.16 and OR = 1.06, 95% CI 0.95-1.18, respectively). Among women with a history of endometriosis, there was a slight inverse association between hysterectomy and ovarian cancer risk (OR = 0.93, 95% CI 0.69-1.26), but this association became stronger and statistically significant after adjusting for duration of ET and EPT use (OR = 0.69, 95% CI 0.48-0.99). Conclusions The hysterectomy-ovarian cancer association is complex and cannot be understood without considering duration of ET and EPT use and history of endometriosis. Failure to take these exposures into account in prior studies casts doubt on their conclusions. Overall, hysterectomy is not risk-reducing for ovarian cancer, however the inverse association among women with endometriosis warrants further investigation.

Objective To evaluate the clinical effect of scraping therapy in the treatment of perimenopausal syndrome (PMS). Methods Thirty recruited PMS subjects were treated with scraping therapy in the Outpatient Department, Acupuncture-Moxibustion Hospital, China Academy of Chinese Medical Sciences, at the areas including Shenting (神庭GV24)—Bǎihui (百会GV20), Qihǎi (气海CV6)—Guānyuan (关元CV4), Zǐgōng (子宫EX-CA1), Zusānlǐ (足三里ST36)—Xiajuxū (下巨虚ST39), Dijī (地机SP8)—Sanyīnjiāo (三阴交SP6), Taichōng (太冲LR3)—Xingjiān (行间LR2), Gānshū (肝俞BL18)—Dǎnshū (胆俞BL19), Pishū (脾俞BL20)—Weishū (胃俞BL 21), and Sānjiāoshū (三焦俞BL 22)—Shenshū (肾俞BL 23), with an even reinforcing-reducing method. Before and after treatment, the serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) were tested. And before treatment and at the 4th week, 8th week, and 12th week of treatment, the Kupperman index (KI) and menopause-specific quality of life questionnaire (MENQOL) symptom scores were recorded for evaluating the clinical efficacy. Results Comparing with before treatment, the modified Kupperman symptom scores were all decreased after treatment, the difference was statistically significant (P 0.05); the total effective rate was 86% after the 4 weeks’ treatment, 97% after the 8 weeks’ treatment, and 96% after the 12 weeks’ treatment. Conclusion scraping therapy can relieve the PMS symptoms to some extent. It can improve the life quality of PMS subjects. Its influence on the estrogen levels of PMS subjects was not obvious.

Sex differences in the nervous system have gained recent academic interest. While the prominent differences are observed in mood and anxiety disorders, growing number of evidences also suggest sex difference in pain perception. This review focuses on estrogen as the key molecule underlying such difference, because estrogen plays many functions in the nervous system, including modulation of transient receptor potential vanilloid 1 (TRPV1) and P2X purinoceptor 3 (P2X3), two important nociceptive receptors. Estrogen was shown in various studies to up-regulate TRPV1 expression through two distinct pathways, resulting in pro-nociceptive effect. However, estrogen alleviated pain in other studies, by down-regulating nerve growth factor (NGF)–activated pathways and TRPV1. Estrogen may also attenuate nociception by inhibiting P2X3 receptors and ATP-signaling. Understanding the mechanism underlying the pro- and anti-nociceptive effect of estrogen might be crucial to understand pathophysiology of the burning mouth syndrome (BMS), a common chronic orofacial pain disorder in menopausal women. The involvement of TRPV1 is strongly suspected because of burning sensation. Reduced estrogen level of the BMS patient might have caused increased activity of P2X3 receptors. Interestingly, the increased expression of TRPV1 and P2X3 in oral mucosa of BMS patients was reported. The combinational impact of differential modulation of TRPV1/P2X3 during menopause might be an important contributing factor of etiology of BMS. Understanding the estrogen-dependent regulation of nociceptive receptors may provide a valuable insight toward the peripheral mechanism of sex-difference in pain perception.

INTRODUCTION The aim of this study was to determine the anti-inflammatory effect of female sex hormones on the level of intracellular molecules of cytokine signaling pathway after diffuse traumatic brain injury (TBI) in ovariectomized rats. METHODS Female rats were divided into 10 groups: control, sham, TBI, Vehicle (oil), Vehicle E1 (33.3 µg/kg), E2 (1 mg / kg), P1 (1.7 mg/kg), P2 (8 mg / kg), E2 + P1. All drugs were injected 0.5 h after TBI. Brain edema and the brain levels of P-STAT-3, NFκB-P52, NFκB-P65, P-IκB, and SOCS-3 by immunohistochemistry measured at 24 h after TBI. RESULTS Increased brain edema after TBI was inhibited by different doses of estrogen, progesterone (P

Summary After the discovery of ERβ, a novel role for dihydrotestosterone (DHT) in estrogen signaling was revealed. Instead of just being a better androgen, DHT was found to be a precursor of the ERβ agonist 5α-androstane-3β, 17β-diol (3βAdiol), an estrogen which does not require aromatase for its synthesis. ERβ was found to oppose androgen signaling and thus is a potential target for treatment of prostate cancer. ERβ was also found to have effects that were independent of androgen signaling, particularly in the CNS. Although in rodent models of neurodegenerative diseases (Parkinson’s disease, multiple sclerosis, and Alzheimer’s disease), ERβ agonists are very effective in relieving symptoms and improving pathologies, this has not proven to be the case in humans. In this review we will focus on the main differences in ERβ signaling between rodents and humans and will make the point that a very important difference between the two species is in the splice variants which are expressed in humans and not rodents. The main conclusion at this point is that before we think of using ERβ agonists clinically, much more work on ERβ signaling in the human or in primates needs to be done.

BACKGROUND The impact of estrogen and testosterone on atherosclerotic cardiovascular disease is well known, but the role of the gonadotropins follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) to some extent remain less studied. OBJECTIVES To explore the angiogenic potential of gonadotropins on endothelial colony-forming cells (ECFCs). METHODS We examined the effects of various doses of gonadotropins on ECFCs obtained from cord blood by assessing colony number, proliferation, migration, and sprouting ability. Moreover, we studied thrombin generation in ECFCs exposed to gonadotropins by performing a thrombin generation assay. Finally, we determined the levels of circulating gonadotropins in 30 men, to exclude the effect of estrogen, with lower extremity arterial disease (LEAD), in comparison with age- and sex-matched controls. RESULTS Exposure to FSH, LH, or PRL resulted in an increase in ECFC migration but showed no effect on proliferation or ECFC commitment from cord blood mononuclear cells. Using a three-dimensional fibrin gel assay, we showed that ECFC sprouting was significantly enhanced by gonadotropins. Exposure to FSH also increased the thrombin generation of ECFCs exposed to FSH. Finally, FSH and LH levels in men with LEAD were higher than those in controls. CONCLUSION Gonadotropins increase ECFC-related angiogenesis and may be involved in thrombin generation in cardiovascular disease. Gonadotropins may act as biomarkers; moreover, we hypothesize that gonadotropin-blocking strategies may be a novel interesting therapeutic approach in atherosclerotic cardiovascular disease.

Cyclical changes in hormone profiles across the menstrual cycle are associated with alterations in metabolic control. MicroRNAs (miRNAs) contribute to regulating metabolic control, including adipose tissue metabolism. How fluctuations in hormonal profiles across the menstrual cycle affect adipose tissue miRNA expression remains unknown. Eleven healthy, regularly menstruating females underwent four sampling visits across their menstrual cycle. Subcutaneous abdominal adipose tissue and venous blood samples were collected at each sampling visit. Luteinizing hormone (LH) tests, calendar counting, and serum hormone concentrations were used to determine menstrual cycle phases: early-follicular (EF), late-follicular (LF), postovulatory (PO), and midluteal (ML). Serum follicle-stimulating hormone, LH, estrogen, progesterone, and testosterone were determined using multiplex magnetic bead panels and enzyme-linked immunosorbent assays. Global adipose tissue miRNA expression levels were determined via microarray in a subset of participants ( n = 8) and 17 candidate miRNAs were validated by RT-qPCR in the whole cohort ( n = 11). Global analysis of adipose tissue miRNA expression identified 33 miRNAs significantly altered across the menstrual cycle; however, no significant differences remained after correcting for multiple testing ( P > 0.05). RT-qPCR analysis of candidate miRNAs revealed miR-497-5p expression was significantly altered across the menstrual cycle ([Formula: see text] = 0.18, P = 0.03); however, post hoc tests did not reveal any significant differences between menstrual cycle phases ( P > 0.05). miR-30c-5p was associated with testosterone concentration ( R2 = 0.13, P = 0.033). These pilot data indicate differences in adipose tissue miRNAs in healthy women across the menstrual cycle and a weak association with ovarian hormones. Further research in larger sample sizes is required to confirm regulation of miRNA expression across the menstrual cycle.

The importance of defining sex differences across various biological and physiological mechanisms is more pervasive now than it has been over the past 15–20 years. As the muscle biology field pushes to identify small molecules and interventions to prevent, attenuate, or even reverse muscle wasting, we must consider the effect of sex as a biological variable. It should not be assumed that a therapeutic will affect males and females with equal efficacy or equivalent target affinities under conditions where muscle wasting is observed. With that said, it is not surprising to find that we have an unclear or even a poor understanding of the effects of sex or sex hormones on muscle wasting conditions. Although recent investigations are beginning to establish experimental approaches that will allow investigators to assess the impact of sex-specific hormones on muscle wasting, the field still needs rigorous scientific tools that will allow the community to address critical hypotheses centered around sex hormones. The focus of this review is on female sex hormones, specifically estrogens, and the roles that these hormones and their receptors play in skeletal muscle wasting conditions. With the overall review goal of assembling the current knowledge in the area of sexual dimorphism driven by estrogens with an effort to provide insights to interested physiologists on necessary considerations when trying to assess models for potential sex differences in cellular and molecular mechanisms of muscle wasting.

У статті наведені причини розвитку саркопенії у людей старших вікових груп — синдрому, що характеризується прогресивним і генералізованим зниженням скелетної м’язової маси, сили та її функції. Висвітлено дані літератури щодо впливу соматотропного гормона на скелетну м’язову тканину, а також результати дослідження, проведеного на базі ДУ «Інститут геронтології імені Д.Ф. Чеботарьова НАМН України». Метою дослідження було вивчити зв’язок між показниками скелетної мускулатури та рівнем соматотропного гормона, загального та вільного тестостерону. Стан знежиреної маси всього тіла, верхніх та нижніх кінцівок оцінювали за допомогою двофотонної рентгенівської абсорбціометрії (Prodigy, GEHC Lunar, Madison, WI, США). Силу скелетної мускулатури оцінювали за допомогою кистьового пружинного динамометра, що пацієнт стискає кистю витягнутої верхньої кінцівки. Для визначення функціональних можливостей скелетних м’язів оцінювали швидкість ходьби обстежених жінок за чотириметровим тестом. Визначення рівня загального та вільного тестостерону та соматотропного гормона в сироватці крові обстежених жінок проведено за допомогою імунохемілюмінесцентного методу з використанням обладнання Immulite 2000 виробництва компанії Siemens DPC (США). Під час дослідження встановлено зв’язок рівня соматотропного гормона та апендикулярної знежиреної маси; рівня загального, вільного тестостерону, соматотропного гормона та сили скелетної мускулатури; рівня загального, вільного тестостерону та функціональних можливостей скелетної м’язової тканини.

The literature data regarding changes in thyroid function during pregnancy were analyzed. There has been described a number of factors (increased levels of human chorionic gonadotropin, estrogen, changes in deiodination processese, the need for iodine, etc.) influencing the synthesis of free and bound fractions of thyroid hormones. Characteristic differences of the above data in different trimesters of pregnancy are presented. It is shown that some pregnant women may have thyroid hormone levels beyond the normal range. According to the literature, in 9.7–30 % of women, thyroid-stimulating hormone level does not meet the trimester-specific intervals. The intense functioning of the thyroid gland in the mother increases the risk of pathological changes in it, and a violation of its functions is the risk of thyroid disease in the fetus too. In view of the above, timely diagnosis of thyroid function, control of the activity of adaptive processes in the pituitary-thyroid system in pregnant women are important.

BACKGROUND A new fertility monitor is now available that provides quantitative measurement of urinary hormones, but clinical use requires validation against an established fertility monitor that provides only qualitative results. RESEARCH DESIGN AND METHODS Two fertility monitors were compared using daily first morning urine samples over 3 cycles of use in 21 women users with experience using a fertility monitor with the Marquette Method of Natural Family Planning. RESULTS Women were aged 33.4 ± 5.5 years and had menstrual cycles ranging between 23 and 41 days. The quantitative Mira Monitor estimates of ovulation were highly correlated with the qualitative ClearBlue Fertility Monitor (CBFM) estimates of ovulation. Both monitors provided an accurate estimate of the fertile window. CONCLUSIONS In this preliminary trial, the Mira monitor was shown to be effective at delineating the fertile window and ovulation. We demonstrated the feasibility of applying the Marquette Method algorithm with the use of the Mira monitor. Satisfaction differences between the two monitors did not reach statistical significance. We anticipate that quantitative fertility monitoring will give couples and health-care providers new and unprecedented insights into the menstrual cycle and fertility.

Endothelial barrier integrity is required for maintaining vascular homeostasis and fluid balance between the circulation and surrounding tissues. In contrast, abnormalities of endothelial cell function and loss of the integrity of the endothelial monolayer constitute a key step in the onset of atherosclerosis. Endothelial erosion is directly responsible for thrombus formation and cardiovascular events in about one-third of the cases of acute coronary syndromes. Thus, after endothelial injury, the vascular repair process is crucial to restore endothelial junctions and rehabilitate a semipermeable barrier, preventing the development of vascular diseases. Endothelial healing can be modulated by several factors. In particular, 17β-estradiol (E2), the main estrogen, improves endothelial healing, reduces neointimal accumulation of smooth muscle cells and atherosclerosis in several animal models. The aim of this review is to highlight how various experimental models enabled the progress in the cellular and molecular mechanisms underlying the accelerative E2 effect on arterial endothelial healing through the estrogen receptor (ER) α, the main receptor mediating the physiological effects of estrogens. We first summarize the different experimental procedures used to reproduce vascular injury. We then provide an overview of how the combination of transgenic mouse models impacting ERα signalling with pharmacological tools demonstrated the pivotal role of non-genomic actions of ERα in E2-induced endothelial repair. Finally, we describe recent advances in the action of selective estrogen receptor modulators (SERMs) on this beneficial vascular effect, which surprisingly involves different cell types and activates different ERα subfunctions compared to E2.

Studies investigating the relationship between sex hormones, inflammatory mediators and joint disorders have reported that sex hormones affect the pathogenesis of joint disorders. We aimed to investigate temporomandibular joint disorder (TJD) in polycystic ovary syndrome (PCOS) and the possible role of systemic mediators and sex hormones in TJD pathogenesis.PCOS patients (n = 45) and controls (n = 30) aged 20-40 years, were enrolled in this case-control study. TJD diagnosis was performed by the specialist and blood samples were tested in the early follicular phase and on the 21 st (midluteal) day to investigate the levels of estrogen, progesterone, matrix metalloproteinase (MMP) 1-8-9, interleukin (IL)-1ß and Tumor necrosis factor (TNF)-α.TJD incidence was significantly higher in PCOS than the control group (51.1% and 6.9% respectively, p 0.01). Midluteal progesterone (p 0.01) was lower in PCOS group than the controls (p 0.01). TNF-α (p 0.01), MMP 1 (p 0.01) and MMP 8 (p = 0.02) levels were found significantly higher in PCOS than the control group. Further, Progesterone levels were found significantly lower in TJD (+) PCOS patients than TJD (-) PCOS patients. However, significant difference was not found between the PCOS TJD (+) and PCOS TJD (-) patients for estrogen, MMP 1, MMP 8, MMP 9, TNF-α and IL-1ß.TJD frequency was found significantly increased in PCOS patients. Related with this, TJD co-occurrence should be kept in mind in the diagnosing and treatment process of PCOS due to hormonal alteration.

Hidradenitis Suppurativa (HS) is a chronic inflammatory disease of the skin with a predilection for women. The role of sex hormones, including estrogen and progesterone, is incompletely understood, but alterations in hormone levels may play a role in disease activity for many patients. Specific clinical considerations should be made for women with HS, particularly in the setting of pregnancy, childbirth, breastfeeding, and menopause. Current knowledge gaps regarding HS include the cumulative impact of disease across an individual's lifespan, as well as the mechanistic role of sex hormones in the disease. An improved understanding of the pathophysiologic role of hormones in HS would optimize our ability to utilize targeted therapies for hormonally driven disease. Psychological and psychosexual support for women with HS is an important facet of any holistic management strategy for the disease. This article integrates up to date pathogenic and mechanistic insights with evidence based clinical management to optimize care for women with HS.

Free fatty acid (FFA) deposition in non-adipose tissues such as the heart is a characteristic of insulin resistant states which feature hyperinsulinemia and dipeptidyl peptidase-4 (DPP-4) activation. Estrogen–progestin oral contraceptives (OC) treatment reportedly increased DPP-4 activity in rat tissue, and DPP-4 inhibitors have anti-diabetic and anti-inflammatory properties. This study aims to investigate the effects of DPP-4 inhibition on cardiac FFA deposition in estrogen–progestin-treated female rats. From our data, estrogen–progestin OC exposure in female rats led to elevated plasma insulin, cardiac DPP-4 activity, FFA and triglyceride (TG) accumulation, TG/high-density lipoprotein cholesterol (TG/HDL-C) ratio, adenosine deaminase/xanthine oxidase/uric acid pathway (ADA/XO/UA), lipid peroxidation, glycogen synthase activity, and alanine phosphatase; whereas cardiac glucose-6-phosphate dehydrogenase, Na+/K+-ATPase and nitric oxide (NO) were decreased. However, DPP-4 inhibition resulted in decreased plasma insulin, cardiac DPP-4 activity, FFA, TG, TG/HDL-C ratio, and alkaline phosphatase. These were accompanied by reduced ADA/XO/UA pathway, lipid peroxidation, and augmented NO and Na+/K+-ATPase in estrogen–progestin OC-treated rats. DPP-4 inhibition attenuated cardiac lipid deposition accompanied by reduced activity in the ADA/XO/UA pathway in estrogen–progestin OC-treated female rats. DPP-4 is therefore a plausible therapeutic target in cardiometabolic disorders.

Abstract: Breast cancer is the most frequent diagnosed cancer in women and the second most common form of cancer, causing death after lung cancer, all across the globe at an alarming rate. The level of estrogens, in breast cancer tissues of postmenopausal women is 10-40 folds higher than the non-carcinogenic breast tissues. As a result of this greater level of estrogen, breast tissue becomes more prone to develop breast cancer; mainly estradiol plays a significant role in the initiation and development of hormone dependent breast cancer. Androstenedione, Adrenal dehydroepiandrosterone sulfate and estrone-sulfate also plays an important role of precursor for estrogen biosynthesis. Estrogens deprivation exhibits an attractive phenomena in the advancement of most ideal therapeutics for the treatment of breast cancer. Inhibition of aromatase and sulphatase emerged as attractive therapy for the treatment of hormone dependent breast cancer via deprivation of estrogen by different pathways. The cocktail of aromatase and sulphatase inhibitors known as dual aromatase-sulphatase inhibitors (DASIs) emerged as an attractive approach for the effective estrogen deprivation. The present review article focused on the journey of dual aromatase-sulphatase inhibitors from the beginning to till date (2020). Keeping in view the key observations, this review may be helpful for medicinal chemists to design and develop new and efficient dual aromatase-sulphatase inhibitors for the possible treatment of hormone-related breast cancer.

Background Prior reports demonstrate the expression of estrogen and progesterone receptors in high-grade gliomas (HGGs), but the relationship between hormone receptor-positive disease and risk of HHGs in patients with breast cancer (BC) remains uncharacterized. Methods Using the SEER 18 registries (2000–2017), we examined the temporal trend of the incidence of HGGs and BC. The standardized incidence ratio was calculated to assess the risk of subsequent HGG in BC patients. Results During the study period, the incidence of BC and HGGs remained comparable for men and women. Among 976,134 patients with BC, we found a decreased incidence of HGGs in females, but not in males. Female BC patients with hormone receptor-positive disease were at a lower risk of developing glioblastoma and anaplastic astrocytoma. Conclusion Our study findings allude to the protective role of hormone exposure in the development of HGGs, which may lead to the development of therapies targeting hormonal pathways.

G protein-coupled estrogen receptor (GPER), which is different from traditional estrogen nuclear receptors (ERs), mediates the rapid transduction of nongenomic signals in cells, and works by regulating transcription and intracellular second messengers. Studies have shown that GPER may regulate oocyte maturation, but the relevant mechanism is not entirely clear. Here, goat cumulus-oocyte complexes (COCs) were used as a model to explore the regulation and mechanism of GPER on oocyte maturation. Our study showed that 17β-estradiol (E2) significantly reduced cyclic guanosine monophosphate (cGMP) synthesis in COCs and accelerated the meiotic resumption of goat oocytes via GPER. Further investigation found that GPER mediated the downregulation of natriuretic peptide receptor 2 (NPR2) protein expression in goat cumulus cells by E2. In addition, we found that E2 significantly upregulated the mRNA levels of epidermal growth (EGF)-like factors in goat cumulus cells through GPER, and activated the downstream EGF receptor (EGFR) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways. Both AG1478 (EGFR inhibitor) and U0126 (ERK1/2 inhibitor) abolished the inhibitory effect of E2 on the protein expression of NPR2. These results indicate that, through GPER, E2 upregulates the mRNA levels of EGF-like factors in goat cumulus cells and activates the downstream EGF signaling network to suppress the expression of NPR2 protein, which results in a decrease in cGMP synthesis and acceleration of meiotic resumption in goat oocytes.

Biochanin A (Bioch A) is a natural plant estrogen, with various biological activities such as anti-apoptosis, anti-oxidation, and suppression of inflammation. In this study, we investigated the protective effects of Bioch A on angiotensin II (AngII) – induced dopaminergic (DA) neuron damage in vivo and on molecular mechanisms. Spontaneous activity and motor ability of mice among groups was detected by open-field test and swim-test. The expression of TH, microtubule-associated proteins light chain 3B II (LC3BII)/LC3BI, beclin-1, P62, forkhead box class O3 (FoxO3), phosphorylated (p) FoxO3a/FoxO3a, FoxO3, and endophilin A2 were determined by Western blot and immunohistochemistry or immunofluorescence staining. Our results showed that AngII treatment significantly increased the behavioral dysfunction of mice and DA neuron damage. Meanwhile, AngII treatment increased the expression of LC3BII/LC3BI, beclin-1, P62, and FoxO3a and decreased the expression of endophilin A2 and p-FoxO3a/FoxO3a, however, Bioch A treatment alleviate these changes. In summary, these results suggest that Bioch A exerts protective effects on AngII-induced mouse model may be related to regulating endophilin A2, FoxO3a, and autophagy-related proteins; however, the specific mechanism is not yet clear and needs further study.

Background In China, the association between estrogen metabolism and breast cancer risk and the differences in metabolic pattern between breast cancer patients and controls are poorly understood. Methods A total of 84 patients with invasive breast cancer and 47 controls with benign breast diseases were included in this study. Estrogen metabolites from their morning urine were determined by HPLC-MS/MS and evaluated in both groups, and the predictive value of each estrogen metabolite in the malignant group according to their menstrual status was analyzed. Results Urinary concentration of estrogen metabolites 2-hydroxyestrone (2-OHE1), 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), 4-methoxyestrone (4-MeOE1), and 16α-hydroxyestrone were lower in postmenopausal patients with breast cancer, compared with benign controls. In logistic regression model, breast cancer risk increased with the decline in the levels of 4-OHE2 and 4-MeOE1. In premenopausal patients, a difference in the level of 2-OHE2 was observed between both groups, and 2-OHE2 was found to have predictive value for breast cancer. Additionally, urinary 2-OHE2 level in premenopausal hormone receptor positive (HR+) patients was considerably higher compared with hormone receptor negative patients. Conclusions We found that lower urinary levels of 4-OHE2 and 4-MeOE1 had predictive value for breast cancer, and higher 2-OHE1 were associated with HR+ breast cancer in premenopausal women.

In vitro systems capable of reconstituting the process of mouse oogenesis are now being established to help develop further understanding of the mechanisms underlying oocyte/follicle development and differentiation. These systems could also help increase the production of useful livestock or genetically modified animals, and aid in identifying the causes of infertility in humans. Recently, we revealed, using an in vitro system for recapitulating oogenesis, that the activation of the estrogen signaling pathway induces abnormal follicle formation, that blocking estrogen-induced expression of anti-Müllerian hormone is crucial for normal follicle formation, and that the production of α-fetoprotein in fetal liver tissue is involved in normal in vivo follicle formation. In mouse fetuses, follicle formation is not carried out by factors within the ovaries but is instead orchestrated by distal endocrine factors. This review outlines findings from genetics, endocrinology, and in vitro studies regarding the factors that can affect the formation of primordial follicles in mammals.

Postmenopausal osteoporosis reduces circulating estrogen levels, which leads to osteoclast resorption, bone loss, and fracture. This review addresses emerging evidence that osteoporosis is not simply a disease of bone loss but that mechanosensitive osteocytes that regulate both osteoclasts and osteoblasts are also impacted by estrogen deficiency. At the onset of estrogen deficiency, the osteocyte mechanical environment is altered, which coincides with temporal changes in bone tissue composition. The osteocyte microenvironment is also altered, apoptosis is more prevalent, and hypermineralization occurs. The mechanobiological responses of osteocytes are impaired under estrogen deficiency, which exacerbates osteocyte paracrine regulation of osteoclasts. Recent research reveals changes in osteocytes during estrogen deficiency that may play a critical role in the etiology of the disease. A paradigm change for osteoporosis therapy requires an advanced understanding of such changes to establish the efficacy of osteocyte-targeted therapies to inhibit resorption and secondary mineralization.

Circulating estrogens in breast cancer patients and survivors are often extremely low due to menopause and estrogen-reducing cancer treatments. Simultaneously, circulating inflammatory markers, and inflammatory proteins in brains of rodent tumor models, can be elevated and correlate with debilitating neurological and psychological comorbidities. Because estrogen has anti-inflammatory properties in the brain, we hypothesized that mammary tumor-induced neuroinflammation is driven, in part, by reduced brain estrogen signaling. An ovariectomized mouse model of postmenopausal breast cancer utilizing the ERα-positive 67NR mammary tumor cell line was used for these experiments. A novel, orally bioavailable, and brain penetrant ERβ agonist was administered daily via oral gavage. Following treatment, estrogen-responsive genes were measured in brain regions. Central and circulating inflammatory markers were measured via RT-qPCR and a multiplex cytokine array, respectively. We present novel findings that peripheral mammary tumors alter estrogen signaling genes including receptors and aromatase in the hypothalamus, hippocampus, and frontal cortex. Mammary tumors induced peripheral and central inflammation, however, pharmacological ERβ activation was not sufficient to reduce this inflammation. Data presented here suggest that compensating for low circulating estrogen with ERβ brain activation is not sufficient to attenuate mammary tumor-induced neuroinflammation, and is therefore not a likely candidate for the treatment of behavioral symptoms in patients. The novel finding that mammary tumors alter estrogen signaling-related genes is a clinically relevant advancement to the understanding of how peripheral tumor biology modulates neurobiology. This is necessary to predict and prevent behavioral comorbidities (e.g., cognitive impairment) prevalent in cancer patients and survivors.

Objectives The purpose of this study was to evaluate serum G protein-coupled estrogen receptor-1 (GPER1) levels in non-pregnant and pregnant with and without gestational diabetes mellitus (GDM). Methods The study comprised 40 pregnant women with (n=20) and without GDM (n=20) and 20 healthy non-pregnant women. Data as maternal age, gestational age, and body mass index (BMI) of participants were recorded and serum samples were collected. Serum GPER1 levels were measured by enzyme-linked immunosorbent assays. Results Serum GPER1 level was significantly higher in GDM (p=0.03) and non-pregnant women (p=0.005) than those of normal pregnancy. There was no significant correlation between the serum GPER1 levels age (r=0.18, p=0.34), gestational age (r=−0.22, p=0.47), and BMI (r=0.004, p=0.975). Conclusions Our results suggest that changes in serum GPER1 levels in pregnancy and GDM may be associated with estrogen. More detailed studies should be conducted to monitor the changes and their interactions in serum sex hormones and serum GPER1 levels during GDM.

Rapid effects of steroid hormones were discovered in the early 1950s, but the subject was dominated in the 1970s by discoveries of estradiol and progesterone stimulating protein synthesis. This led to the paradigm that steroid hormones regulate growth, differentiation, and metabolism via binding a receptor in the nucleus. It took 30 years to appreciate not only that some cellular functions arise solely from membrane-localized steroid receptor (SR) actions, but that rapid sex steroid signaling from membrane-localized SRs is a prerequisite for the phosphorylation, nuclear import, and potentiation of the transcriptional activity of nuclear SR counterparts. Here, we provide a review and update on the current state of knowledge of membrane-initiated estrogen (ER), androgen (AR) and progesterone (PR) receptor signaling, the mechanisms of membrane-associated SR potentiation of their nuclear SR homologues, and the importance of this membrane-nuclear SR collaboration in physiology and disease. We also highlight potential clinical implications of pathway-selective modulation of membrane-associated SR.

Menopausal hormone therapy (MHT) has been widely used for the clinical treatment of symptoms associated with menopause in women. However, the exact nature of the relationship between MHT and the increased risk of breast cancer has not been fully elucidated. The results of the Women’s Health Initiative’s randomized controlled clinical studies showed that estrogen monotherapy was associated with a lower incidence of breast cancer as compared to estrogen-progesterone combined therapy, with an elevated risk of breast cancer. The evidence currently available from randomized trials and observational studies is based on data from different populations, drug formulations, and routes of administration. Even though the risks of MHT and breast cancer have received a great deal of attention, information regarding the unpredictable toxicological risks of estrogen and progestogen metabolism needs to be further analyzed. Furthermore, the diversity and complexity of the metabolic pathways of estrogen and different progestogens as well as the association of the different estrogen and progestogen metabolites with the increased risk of breast cancer need to be adequately studied. Therefore, this review aimed to describe the biological effects of estrogen, progesterone, and their metabolites on the proliferation of breast cancer cells, based on relevant basic research and clinical trials, to improve our understanding of the biological functions of estrogen and progestogen as well as the safety of MHT.

Aim & Objectives: To study the MRM specimens for size, grade of the tumor, LVI and LN metastases and the ER/PR receptors of the tumor. To study the association of ER/PR status with the above mentioned prognostic parameters. Materials and Methods: This three-year study includes 72 histopathologically confirmed cases of carcinoma breast. The tumor type, grade, LNM, LVE were reported on H & E. The ER-PR study was done of all 72 cases. The tumor size, grade, LNM, LVE were correlated with receptor status. Observation: Out of 72 cases majority (53%) of cases were in 41-50 years of age group, and tumor size was between 2-4 cm in (54.16%) cases; majority were of grade II carcinoma (60%) of which 59% were ER-PR positive. Out of 46 cases with negative LNM and LVE, 30 cases (65%) were ER-PR positive. Conclusion: In our observation there is no association between higher histological grade and ER-PR status. No obvious correlation with tumor size was noted. But increase in tumor size could also be a poor predictor of ER-PR status. LNM, LVE is poor predictor of ER-PR status. Keywords: Breast carcinoma, Estrogen and progesterone receptor.

Phthalate esters (PAEs) are important pollutants in the environment, which can interfere with the endocrine system by mimicking estrogen. However, limited information is available on modulating the estrogen receptor (ER) of five PAEs including di (2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), benzyl butyl phthalate (BBP), diphenyl phthalate (DPhP) and dicyclohexyl phthalate (DCHP). This study evaluated the agonistic effects of PAEs on human ER. The cytotoxicity assay showed that there were a significant inhibition of the cell proliferation with treatment of five PAEs. Moreover, DPhP does-dependently enhanced ER-mediated transcriptional activity in the reporter gene assay. The increased expression of estrogen-responsive genes (TFF1, CTSD, and GREB1) was also observed in MCF-7 cells treated with DPhP. The result of molecular docking showed that DPhP tended to bind to the agonist conformation of ER compared with the antagonist conformation of ER, demonstrating its agonist characteristic that has been confirmed in the reporter gene assay. Thus, we found that DPhP may be evaluated as an ER agonist in vitro and it can interfere with the normal function of human ER.