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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.

SUMMARY OBJECTIVE: The aim of this study was to investigate the predictive importance of the previously validated log(ER)*log(PgR)/Ki-67 predictive model in a larger patient population. METHODS: Patients with hormone receptor positive/HER-2 negative and clinical node positive before chemotherapy were included. Log(ER)*log(PgR)/Ki-67 values of the patients were determined, and the ideal cutoff value was calculated using a receiver operating characteristic curve analysis. It was analyzed with a logistic regression model along with other clinical and pathological characteristics. RESULTS: A total of 181 patients were included in the study. The ideal cutoff value for pathological response was 0.12 (area under the curve=0.585, p=0.032). In the univariate analysis, no statistical correlation was observed between luminal subtype (p=0.294), histological type (p=0.238), clinical t-stage (p=0.927), progesterone receptor level (p=0.261), Ki-67 cutoff value (p=0.425), and pathological complete response. There was a positive relationship between numerical increase in age and residual disease. As the grade of the patients increased, the probability of residual disease decreased. Patients with log(ER)*log(PgR)/Ki-67 above 0.12 had an approximately threefold increased risk of residual disease when compared to patients with 0.12 and below (odds ratio: 3.17, 95% confidence interval: 1.48–6.75, p=0.003). When age, grade, and logarithmic formula were assessed together, the logarithmic formula maintained its statistical significance (odds ratio: 2.47, 95% confidence interval: 1.07–5.69, p=0.034). CONCLUSION: In hormone receptor-positive breast cancer patients receiving neoadjuvant chemotherapy, the logarithmic model has been shown in a larger patient population to be an inexpensive, easy, and rapidly applicable predictive marker that can be used to predict response.

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 therapy forms the backbone treatment for patients with estrogen receptor (ER) positive tumors in both the adjuvant and metastatic setting. Aromatase inhibitors (AI) are the most common endocrine treatment option. Mutation of ESR1, the gene encoding ERα, is a common mechanism of resistance to AIs which leads to ligand independent activity of ERα. Camizestrant (AZD9833) is a next generation SERD and pure ER antagonist that is in Phase 3 trials (SERENA-4: NCT04711252; SERENA-6: NCT04964934). Here we report the preclinical and clinical activity of camizestrant in patients with ESR1 wild-type (ESR1wt) and mutant (ESR1m) tumors. The binding affinities of camizestrant, fulvestrant, and estradiol to wt ERα and ERα variants with mutations in the ligand binding domain were assessed. All three compounds exhibited reduced binding to mutant forms of ERα compared with wt ERα; the Y537S mutation had the greatest impact on binding. This was reflected in requirement for greater concentrations of camizestrant and fulvestrant to degrade and antagonize mutated ERα and to impact cellular proliferation in MCF-7 cells that expressed Y537S ESR1m compared to ESR1wt MCF-7 cells. Furthermore, while a 3 mg/kg dose of camizestrant achieved a maximal anti-tumor effect in a ESR1wt patient derived xenograft model, a 10 mg/kg was required for maximal effect in a D538G ESR1m model. Considering this difference between ESR1m and ESR1wt, pharmacokinetic/pharmacodynamic modelling of preclinical data predicted that a camizestrant dose of 75 mg would be maximally efficacious in patients with ESR1m tumors. Indeed, analysis of ESR1m circulating tumor DNA levels in patients from the SERENA-1 (NCT03616587) Phase 1 trial showed a clear effect of 14 days treatment with 75 mg camizestrant resulting in a >2-fold reduction in ESR1m variant allele frequency in 12/13 (92%) cases with complete clearance of ESR1m ctDNA in 7/13 (54%) cases. Interestingly, the clinical activity of camizestrant was higher in heavily pretreated patients with metastatic breast cancer with ESR1m tumors compared to those with no detectable mutation (ESR1m not detected). At a camizestrant dose of 75 mg, median progression-free survival was 8.3 months (maturity 12/15) in patients with ESR1m tumors compared to 5.6 months (8/9) in those with ESR1m not detected (data cut-off 6 October 2021). Camizestrant-induced ERα degradation was seen in both groups (mean reduction in H-score 42% in ESR1m tumors (n= 12 evaluable pairs) and 46% in tumors with ESR1m not detected (n=7)). Whole transcriptome analysis revealed a trend towards higher ERα activity at baseline in ESR1m tumors compared to ESR1m not detected; ERα activity reduced on treatment in both groups. Consistent with the clinical activity data, camizestrant induced more profound reductions in cell proliferation in ESR1m tumors compared to ESR1m not detected tumors (as seen by greater reductions in Ki67-positive tumor cells). These data demonstrate the activity of camizestrant in patients with ESR1m tumors. Clinical activity along with degradation and antagonism of the ERα is also seen in patients with tumors in which ESR1 mutations are not detected. In this heavily pre-treated Phase 1 patient population from SERENA-1, ESR1m may be a predictive biomarker to enrich for patients with maintained endocrine sensitivity. The SERENA-6 trial is investigating the efficacy and safety of camizestrant plus a CDK4/6 inhibitor in patients with metastatic breast cancer and detectable ESR1m. We acknowledge Helen Heffron, PhD, from InterComm International who provided medical writing support funded by AstraZeneca. Citation Format: Christopher Morrow, Larissa Carnevalli, Richard D. Baird, Tim Brier, Carmela Ciardullo, Natalie Cureton, Mandy Lawson, Robert McEwen, Myria Nikolaou, Anne Armstrong, Begoña Bermejo, Emiliano Calvo, Eva Ciruelos, Javier Garcia-Corbacho, Erika Hamilton, Jason Incorvati, Peter Kabos, Mafalda Oliveira, Manish R Patel, Manuel Ruiz-Borregó, Nicholas Turner, Chris Twelves, Christos Vaklavas, Danielle Carroll, Steven Ching, Nevena Cvetesic, Michelle DuPont, Lisa Gibbons, Alastair Mathewson, Rhiannon Maudsley, Pablo Morentin Gutierrez, Avinash Reddy, Jaime Rodriguez-Canales, Susana Ros, Dhivya Sudhan, Andy Sykes, David Whitson, Teresa Klinowska, Justin Lindemann. The next generation oral selective estrogen receptor degrader (SERD) camizestrant (AZD9833) is active against wild type and mutant estrogen receptor α [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-13.

Background An increasing number of nonbinary patients are receiving gender-affirming procedures due to improved access to care. However, the preferred treatments for nonbinary patients are underdescribed. The purpose of this study was to investigate the goals and treatments of nonbinary patients. Methods A retrospective study of patients who self-identified as nonbinary from our institutional Gender Health Program was conducted. Patient demographics, clinical characteristics, surgical goals, and operative variables were analyzed. Results Of the 375 patients with gender dysphoria, 67 (18%) were nonbinary. Over half of the nonbinary patients were assigned male at birth (n = 57, 85%) and nearly half preferred the gender pronoun they/them/theirs (n = 33, 49%). A total of 44 patients (66%) received hormone therapy for an average of 2.5 ± 3.6 years, primarily estrogen (n = 39). Most patients (n = 46, 69%) received or are interested in gender-affirming surgery, of which, almost half were previously on hormone therapy (n = 32, 48%). The most common surgeries completed or desired were facial feminization surgery (n = 15, 22%), vaginoplasty (n = 15, 22%), mastectomy (n = 11, 16%), and orchiectomy (n = 9, 13%). Nonbinary patients who were assigned male at birth (NB-AMAB) were more often treated with hormones compared to nonbinary patients assigned female at birth (NB-AFAB) (72% vs. 30%, p = 0.010). Conversely, patients who were AFAB were more likely to complete or desire surgical intervention than those who were AMAB (100% vs. 63.0%, p Conclusion Majority of nonbinary patients were assigned male at birth. NB-AFAB patients all underwent surgical treatment, whereas NB-AMAB patients were predominantly treated with hormone 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.

Insufficient invasion of conceptus-derived trophoblast cells in the maternal decidua is a key event in the development of early-onset preeclampsia (PE), a subtype of PE associated with high maternal and fetal morbidity and mortality. Kisspeptins, a family of peptides previously shown to inhibit trophoblast cell invasion, have been implicated in the pathogenesis of early-onset PE. However, a role of kisspeptin signaling during the genesis of this syndrome has not been elucidated. Herein, we used the preeclamptic-like BPH/5 mouse model to investigate kisspeptin expression and potential upstream regulatory mechanisms in a PE-like syndrome. Expression of the kisspeptin encoding gene, Kiss1, and the 10-amino-acid kisspeptide (Kp-10), are upregulated in the non-pregnant uterus of BPH/5 females during diestrus and in the maternal-fetal interface during embryonic implantation and decidualization. Correspondingly, the dysregulation of molecular pathways downstream to kisspeptins also occurs in this mouse model. BPH/5 females have abnormal sex steroid hormone profiles during early gestation. In this study, the normalization of circulating concentrations of 17β-estradiol (E2) and progesterone (P4) in pregnant BPH/5 females not only mitigated Kiss1 upregulation, but also rescued the expression of multiple molecules downstream to kisspeptin and ameliorated adverse fetoplacental outcomes. Those findings suggest that uterine Kiss1 upregulation occurs pre-pregnancy and persists during early gestation in a PE-like mouse model. Moreover, this study highlights the role of sex steroid hormones in uteroplacental Kiss1 dysregulation and the improvement of placentation by normalization of E2, P4 and Kiss1.

As women age, there is an overall decrease in androgen production due to decline of ovarian and adrenal function during menopause. Androgens have been demonstrated to play an important role in sexual motivation in women. As a result, many postmenopausal women experience Female Sexual Dysfunction (FSD) which are a group of disorders that pertain to sexual arousal, desire, orgasm, and pain. A prevalent manifestation of FSD is Hypoactive Sexual Desire Disorder (HSDD) or the absence of sexual fantasies, thoughts, and/or desire for or receptivity to sexual activity. There is gaining interest in the use of Testosterone Replacement Therapy (TRT) for the treatment of HSDD in postmenopausal women. This article reviews the literature on the relationship of androgen decline and HSDD, describes our methodology for evaluation, diagnosis of HSDD, and the use of TRT in treating postmenopausal women with HSDD. Our results conclude that testosterone is a vital hormone in women in maintaining sexual health and function. TRT is an effective treatment option for postmenopausal people with HSDD. There is still limited data on the effectiveness in premenopausal people with HSDD. Further research in the strengths and weaknesses for the long-term effect of TRT in women of all ages is needed.

Estradiol (E2) affects both reproductive and non-reproductive tissues, and the sensitivity to different doses of E2 varies between tissues. Membrane estrogen receptor α (mERα)-initiated signaling plays a tissue-specific role in mediating E2 effects, however, it is unclear if mERα signaling modulates E2 sensitivity. To determine this, we treated ovariectomized C451A females, lacking mERα signaling, and wildtype (WT) littermates with physiological (0.05μg/mouse/day (low); 0.6μg/mouse/day (medium)) or supraphysiological (6μg/mouse/day (high)) doses of E2 (17β-estradiol-3-benzoate) for three weeks. Low-dose treatment increased uterus weight in WT, but not C451A mice, while non-reproductive tissues (gonadal fat, thymus, trabecular and cortical bone) were unaffected in both genotypes. Medium-dose treatment increased uterus weight and bone mass and decreased thymus and gonadal fat weights in WT mice. Uterus weight was also increased in C451A mice, but the response was significantly attenuated (-85%) compared to WT mice, and no effects were triggered in non-reproductive tissues. High-dose treatment effects in thymus and trabecular bone were significantly blunted (-34% and -64%, respectively) in C451A compared to WT mice, and responses in cortical bone and gonadal fat were similar between genotypes. Interestingly, the high dose effect in uterus was enhanced (+ 26%) in C451A compared to WT mice. In conclusion, loss of mERα signaling reduces the sensitivity to physiological E2 treatment in both non-reproductive tissues and uterus. Furthermore, the E2 effect after high-dose treatment in uterus is enhanced in the absence of mERα, suggesting a protective effect of mERα signaling in this tissue against supraphysiological E2 levels.

ObjectiveThe association of sex-specific hormones with coronary computed tomography angiography(CCTA)-based plaque characteristics in women without cardiovascular disease is not well understood. We investigated the association of sex-specific hormones with coronary artery plaque characteristics in a contemporary multiracial cohort with no clinical coronary artery disease (CAD).MethodsIn this cross-sectional analysis, we utilized data from 2,325 individuals with no clinical CAD from the Miami Heart (MiHeart) study. Multivariable logistic regression models were used to investigate the association of sex hormones: sex hormone binding globulin (SHBG), dehydroepiandrosterone (DHEA), free and total testosterone, estradiol, with plaque characteristics among women and men.ResultsOf the 1,155 women, 34.2% had any plaque and 3.4% had any high-risk plaque features (HRP) while among men (n=1170), 63.1% had any plaque and 10.4% had HRP. Among women, estradiol and SHBG were associated with lower odds of any plaque after adjusting for age and race-ethnicity (estradiol OR per SD increase: 0.87, 95%CI: 0.76-0.98; SHBG OR per SD increase: 0.82, 95%CI: 0.72-0.93) but the significance did not persist after adjustment of cardiovascular risk factors. High free testosterone was associated with higher odds of HRP (aOR:3.48, 95%CI:1.07-11.26) but null associations for the other sex hormones with HRP, in the context of limited sample size. Among men, there were no significant associations between sex-specific hormones and plaque or HRP.ConclusionAmong young to middle-aged women with no clinical CAD, increasing estradiol and SHBG were associated with lower odds of any plaque and higher free testosterone was associated with HRP. Larger cohorts may be needed to validate this.

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4 and 6) are approved for the treatment of subsets of patients with hormone receptor positive (HR+) breast cancer (BC). In metastatic disease, strategies involving endocrine therapy combined with CDK4 and 6 inhibitors (CDK4 and 6i) improve clinical outcomes in HR+ BCs. CDK4 and 6i prevent retinoblastoma tumor suppressor protein phosphorylation, thereby blocking the transcription of E2F target genes, which in turn inhibits both mitogen and estrogen-mediated cell proliferation. In this review, we summarize preclinical data pertaining to the use of CDK4 and 6i in BC, with a particular focus on several of the unique chemical, pharmacologic, and mechanistic properties of abemaciclib. As research efforts elucidate the novel mechanisms underlying abemaciclib activity, potential new applications are being identified. For example, preclinical studies have demonstrated abemaciclib can exert antitumor activity against multiple tumor types and can cross the blood-brain barrier. Abemaciclib has also demonstrated distinct activity as a monotherapeutic in the treatment of BC. Accordingly, we also discuss how a greater understanding of mechanisms related to CDK4 and 6 blockade highlight abemaciclib’s unique in-class properties, and could pave new avenues for enhancing its therapeutic efficacy.

Background: Breast cancer incidence in the United States is lower in Hispanic/Latina (H/L) compared with African American/Black or Non-Hispanic White women. An Indigenous American breast cancer–protective germline variant (rs140068132) has been reported near the estrogen receptor 1 gene. This study tests the association of rs140068132 and other polymorphisms in the 6q25 region with subtype-specific breast cancer risk in H/Ls of high Indigenous American ancestry. Methods: Genotypes were obtained for 5,094 Peruvian women with (1,755) and without (3,337) breast cancer. Associations between genotype and overall and subtype-specific risk for the protective variant were tested using logistic regression models and conditional analyses, including other risk-associated polymorphisms in the region. Results: We replicated the reported association between rs140068132 and breast cancer risk overall [odds ratio (OR), 0.53; 95% confidence interval (CI), 0.47–0.59], as well as the lower odds of developing hormone receptor negative (HR−) versus HR+ disease (OR, 0.77; 95% CI, 0.61–0.97). Models, including HER2, showed further heterogeneity with reduced odds for HR+HER2+ (OR, 0.68; 95% CI, 0.51–0.92), HR−HER2+ (OR, 0.63; 95% CI, 0.44–0.90) and HR−HER2− (OR, 0.77; 95% CI, 0.56–1.05) compared with HR+HER2−. Inclusion of other risk-associated variants did not change these observations. Conclusions: The rs140068132 polymorphism is associated with decreased risk of breast cancer in Peruvians and is more protective against HR− and HER2+ diseases independently of other breast cancer-associated variants in the 6q25 region. Impact: These results could inform functional analyses to understand the mechanism by which rs140068132-G reduces risk of breast cancer development in a subtype-specific manner. They also illustrate the importance of including diverse individuals in genetic studies.

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.

Objective An evidence-based pubertal induction scheme in hypogonadal girls is still to be established. Interestingly, literature data reports suboptimal uterine longitudinal diameter (ULD) in >50% of treated hypogonadal women, negatively influencing their pregnancy outcomes. This study aims to investigate auxological and uterine outcomes of pubertal induction in girls in the light of underlying diagnosis and therapeutic schemes used. Design Retrospective analysis of longitudinal data from a multicentric registry. Methods Auxological, biochemical and radiological data were collected at baseline and during follow-up in 95 hypogonadal girls (chronological age>10.9 years, Tanner stage≤2) treated with transdermal 17β-oestradiol patches for at least one year. Induction was started at a median dose of 0.14 mcg/kg/day with a six-monthly increase and was considered completed for 49/95 patients who started progesterone with concomitant oestrogen adult dose. Results At the end of induction, the achievement of the complete breast maturation was associated with 17β-oestradiol dose at progesterone introduction. ULD showed a significant correlation with 17β-oestradiol dosage. Final ULD was>65 mm in only 17/45 girls. At multiple regression analysis, pelvic irradiation represented the major determinant of reduced final ULD. After correction for uterine irradiation, ULD was associated with the 17β-oestradiol dose at progesterone introduction. Final ULD was not significantly different from the one assessed after progesterone introduction. Conclusions Our results provide evidence that progestins, hampering further changes in uterine volume and breast development, should be introduced only in the presence of a concomitant adequate 17β-oestradiol dose and an appropriate clinical response.

BackgroundMaternal migraine has been linked to adverse birth outcomes including low birth weight and preterm birth, as well as congenital anomalies in offspring. It has been speculated that this may be due to the use of medications in pregnancy, but lifestyle, genetic, hormonal, and neurochemical factors could also play a role. There is evidence for varying cancer incidences among adults with migraine. Here, we utilized data from national registries in Denmark to examine associations between maternal diagnoses of migraine and risk for cancer in offspring.MethodsWe linked several national registries in Denmark to identify cases from the Cancer Registry among children less than 20years (diagnoses 1996–2016) and controls from the Central Population Register, matched to cases by birth year and sex (25:1 matching rate). Migraine diagnoses were identified from the National Patient Register using International Classification of Diseases, versions 8 and 10 codes and migraine-specific acute or prophylactic treatment recorded in the National Pharmaceutical Register. We used logistic regression to estimate the risk of childhood cancers associated with maternal migraine.ResultsMaternal migraine was positively associated with risk for non-Hodgkin lymphoma (odds ratio [OR]=1.70, 95% confidence interval [CI]: 1.01–2.86), central nervous system tumors ([OR=1.31, 95% CI: 1.02–1.68], particularly glioma [OR=1.64, 95% CI: 1.12–2.40]), neuroblastoma (OR=1.75, 95% CI: 1.00–3.08), and osteosarcoma (OR=2.60, 95% CI: 1.18–5.76).ConclusionsAssociations with maternal migraine were observed for several childhood cancers, including neuronal tumors. Our findings raise questions about the role of lifestyle factors, sex hormones, genetic, and neurochemical factors in the relationship between migraine and childhood cancers.

Background Breast tumors consist of heterogeneous cellular subpopulations that differ in molecular properties and functional attributes. Cancer stem cells (CSCs) play pivotal roles in cancer therapeutic failure and metastasis. However, it remains indeterminate how CSCs determine the progression of the bulk cancer cell population. Methods Co-culture systems in vitro and co-implantation systems in vivo were designed to characterize the interactions between breast cancer stem cells (BCSCs) and bulk cancer cells. RNA sequencing was performed to study the functional and mechanistic implications of the BCSC secretome on bulk cancer cells. A cytokine antibody array was employed to screen the differentially secreted cytokines in the BCSC secretome. Tail vein injection metastatic models and orthotopic xenograft models were applied to study the therapeutic potential of targeting IL8. Results We identified that the BCSC secretome potentiated estrogen receptor (ER) activity in the bulk cancer cell population. The BCSC secretome rendered the bulk cancer cell population resistant to anti-estrogen and CDK4/6 inhibitor therapy; as well as increased the metastatic burden attributable to bulk cancer cells. Screening of the BCSC secretome identified IL8 as a pivotal factor that potentiated ERα activity, endowed tamoxifen resistance and enhanced metastatic burden by regulation of bulk cancer cell behavior. Pharmacological inhibition of IL8 increased the efficacy of fulvestrant and/or palbociclib by reversing tamoxifen resistance and abrogated metastatic burden. Conclusion Taken together, this study delineates the mechanism by which BCSCs determine the therapeutic response and metastasis of bulk cancer cells; and thereby suggests potential therapeutic strategies to ameliorate breast cancer outcomes.

Introduction: Ovarian cancer is the 8th most common cancer in women globally, and is responsible for majority of gynaecological cancer deaths. Epidemiological evidence suggests that steroid hormones are implicated in ovarian carcinogenesis, therefore a role for targeted hormonal therapies. Objectives: This study is aimed at determining the histopathological pattern of ovarian epithelial cancers and steroid hormone receptor expression at the Jos University Teaching Hospital between the 1st January 2004 and 31st December, 2013. Methods: This was a hospital based retrospective study of ovarian surface epithelial cancers. Patients' biodata were obtained from the hospital records and cancer registry. Tissue slides and blocks were retrieved from the archives. Specimens confirmed as epithelial ovarian cancers by Haematoxylin and Eosin were subjected to immunohistochemistry to demonstrate estrogen receptor and progesterone receptor positivity. Results: A total of 75 ovarian cancers were seen, 46 (61.3%) of which were epithelial ovarian cancers, out of which forty 40 (53.3% of ovarian cancers and 87% of epithelial ovarian cancers) cases met the inclusion criteria. The age range, mean age, median age and peak age at diagnosis were: 20 to 75 years; 45.43±14.46 years; 46 years and fifth decade of life respectively. Serous carcinoma was the most common histological subtype accounting for 25(62.5%) cases. The high grades (grades 2 and 3) were commoner in all the histological subtypes. Estrogen positivity was seen in 17 (42.5%) and progesterone positivity in 29 (72.5%) of the cancers. Conclusion: Serous adenocarcinoma, the commonest histological variants of ovarian cancers in this study, exhibits higher expression of estrogen receptor and showed significant correlation between ER expression and the serous histological morphology

Background: SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in women with ER+/HER2− advanced breast cancer. Parts A/B and C/D (escalation/expansion) examined camizestrant as monotherapy and in combination with palbociclib respectively and have been presented previously.1,2 Here we present data from parts G/H which examined camizestrant in combination with abemaciclib. Methods: The primary objective was to determine the safety and tolerability of camizestrant 75 mg once daily (QD) in combination with abemaciclib 150 mg twice daily (BID). Secondary objectives included investigation of anti-tumor response and pharmacokinetics (PK). Participants were previously treated women of any menopausal status (pre-menopausal women received this combination alongside ongoing ovarian function suppressors). Prior treatment with ≤2 lines of chemotherapy in the advanced setting was permitted. There was no limit on the number of lines of prior endocrine treatment in the advanced setting; previous treatment with CDK4/6 inhibitors (CDK4/6i) and fulvestrant was permitted. Results: As of 1st June 2022, 24 patients had received camizestrant in combination with abemaciclib with a median 7.7 month follow up. Tolerability of the combination of camizestrant and abemaciclib was consistent with that of each drug individually. No patient required camizestrant dose reduction. All camizestrant-related heart rate decreases were Grade 1 (asymptomatic). PK data for camizestrant in combination with abemaciclib were consistent with camizestrant as monotherapy and published abemaciclib steady-state PK data, indicating no clinically relevant drug-drug interaction. In these heavily pre-treated patients (46% prior chemotherapy, 75% prior CDK4/6i, 54% prior fulvestrant; all in the advanced disease setting) and of whom 67% had visceral metastases, the objective response rate was 5/19 (26.3%), the clinical benefit rate at 24 weeks was 16/24 (66.7%) and the median progression-free survival had not been reached, with 8/24 patients experiencing a progression event. These data support the use of camizestrant 75 mg QD combined with the approved abemaciclib dose. Conclusions: Camizestrant 75 mg QD in combination with abemaciclib 150 mg BID was well tolerated with encouraging clinical activity. The inclusion of this regimen in the ongoing Phase 3, SERENA-6 trial 3, of camizestrant combined with CDK4/6i versus an aromatase inhibitor, will further clarify the role of this combination in the treatment of patients with ER+/HER2− advanced breast cancer with tumors expressing ESR1 mutations. References 1. Baird R, Oliveira M, Ciruelos Gil EM, et al. SABCS 2020 Virtual Meeting. Abstract PS11-05. 2. Oliveira M, Hamilton EP, Incorvati J, et al. J Clin Oncol 40, 2022 (suppl 16; abstr 1032). 3. SERENA-6 trial. Available at https://clinicaltrials.gov/ct2/show/NCT04964934 We acknowledge Helen Heffron, PhD, from InterComm International who provided medical writing support funded by AstraZeneca. Citation Format: Nicholas Turner, Christos Vaklavas, Emiliano Calvo, Javier Garcia-Corbacho, Jason Incorvati, Manuel Ruiz Borrego, Chris Twelves, Anne Armstrong, Begoña Bermejo, Erika Hamilton, Mafalda Oliveira, Eva Ciruelos, Peter Kabos, Manish R Patel, Maria Borrell, Howard Burris, Bruno de Paula, Alejandro Falcon, Cristina Hernando, Irene Moreno, Ciara S. O’Brien, Elena Shagisultanova, Ivan Victoria Ruiz, Judy S. Wang, Mei Wei, Tim Brier, Danielle Carroll, Carmela Ciardullo, Lisa Gibbons, itziar irurzun-Arana, Tony Jack, bistra kirova, Teresa Klinowska, Justin Lindemann, Julie Maidment, Alastair Mathewson, Rhiannon Maudsley, Robert McEwen, Christopher Morrow, Andy Sykes, Richard D. Baird. SERENA-1: Updated analyses from a Phase 1 study of the next generation oral selective estrogen receptor degrader camizestrant (AZD9833) combined with abemaciclib, in women with ER-positive, HER2-negative advanced breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-28.

This study aimed to provide alternative information and solutions in an effort to increase reproductive productivity in etawah crossbreed goats (PE). The sample used in this study was 10 female PE with an average age of 2.5 - 3 years and primiparous at least . Ovulation induction was performed using 0.1 mg intra-muscular Gonadotropin-Releasing Hormone (GnRH), after seven days injection of Prostaglandin F2α (PGF2α) was given as much as 2.5 mg submucosa of the vulva, followed by a second injection of GnRH as much as 0,2 mg intramuscular in samples that have really experienced heat and selected selectively according to the signs of natural heat shown by the sample and followed by insemination as much as 2 doses or 0.50 ml of frozen semen. Blood sampling was performed at H0, H7th, H14th and H21th after insemination. All blood samples were collected and progesterone and estrogen hormone profiles were examined using the ELISA method. From the results of the ELISA test, the mean progesterone hormone profile H0 = 4.798 ng / ml, H7th = 4.887 ng / ml, H14th = 4.824 ng / ml, H21th = 5.148 ng / ml. The profile of the hormone estrogen at H0 = 19,461 pg / ml, H7th = 17,457 pg / ml, H14th = 18,248 pg / ml, H21th = 17,515 pg / ml. This study showed an increase in the levels of the progesterone hormone at H0 to H7th, then slightly decreased in H14th and a significant increase in H21th. For the estrogen hormone, there is a decrease from H0 to H7th then there is a slight increase in H14th and decreases again in H21th.

The purpose of this study was to determine the ratio of estrogen concentrations given cassava peel feed supplementation. A total of 24 cows of Friesian Holstein, weighing 250-300 kg were divided into two groups and each group contains 12 replications. The first group is Friesian Holstein breeds with the condition that they are given elephant grass feed ad libitum and 25 kg of tofu dregs. The second group is Friesian Holstein breeds with the condition that they are fed ad libitum elephant grass, 25 kg of tofu dregs, and 25 kg of cassava peel. The milk samples were then taken to be tested for estrogen levels using the direct competitive ELISA. Analysis of estrogen concentration data was then carried out by normality test using Shapiro Wilk test then followed by the Paired T-test with a significance level of 5%. Based on the Paired T sample correlation test was 0.072 (p>0.05), which means that the feed gave the cassava peel and not the cassava peel was negatively associated. Based on the Paired T-test is 0.193 (p>0.05), which means there is no significant relationship between the 2 test groups. It can be concluded that there is no significant difference in the estrogen concentration of Friesian Holstein cattle fed with and without cassava peel supplementation.

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...

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

Postmenopausal osteoporosis is a systemic disease characterized by the loss of bone mass and increased bone fracture risk largely resulting from significantly reduced levels of the hormone estrogen after menopause. Besides the direct negative effects of estrogen-deficiency on bone, indirect effects of altered immune status in postmenopausal women might contribute to ongoing bone destruction, as postmenopausal women often display a chronic low-grade inflammatory phenotype with altered cytokine expression and immune cell profile. In this context, it was previously shown that various immune cells interact with osteoblasts and osteoclasts either via direct cell-cell contact, or more likely via paracrine mechanisms. For example, specific subtypes of T lymphocytes express TNFα, which was shown to increase osteoblast apoptosis and to indirectly stimulate osteoclastogenesis via B cell-produced receptor-activator of NF-κB ligand (RANKL), thereby triggering bone loss during postmenopausal osteoporosis. Th17 cells release interleukin-17 (IL-17), which directs mesenchymal stem cell differentiation towards the osteogenic lineage, but also indirectly increases osteoclast differentiation. B lymphocytes are a major regulator of osteoclast formation via granulocyte colony-stimulating factor secretion and the RANKL/osteoprotegerin system under estrogen-deficient conditions. Macrophages might act differently on bone cells dependent on their polarization profile and their secreted paracrine factors, which might have implications for the development of postmenopausal osteoporosis, because macrophage polarization is altered during disease progression. Likewise, neutrophils play an important role during bone homeostasis, but their over-activation under estrogen-deficient conditions contributes to osteoblast apoptosis via the release of reactive oxygen species and increased osteoclastogenesis via RANKL signaling. Furthermore, mast cells might be involved in the development of postmenopausal osteoporosis, because they store high levels of osteoclastic mediators, including IL-6 and RANKL, in their granules and their numbers are greatly increased in osteoporotic bone. Additionally, bone fracture healing is altered under estrogen-deficient conditions with the increased presence of pro-inflammatory cytokines, including IL-6 and Midkine, which might contribute to healing disturbances. Consequently, in addition to the direct negative influence of estrogen-deficiency on bone, immune cell alterations contribute to the pathogenesis of postmenopausal osteoporosis., publishedVersion

Osteoporosis is an age-dependent serious skeletal disease that leads to great suffering for the patient and high social costs, especially as the global population reaches higher age. Decreasing estrogen levels after menopause result in a substantial bone loss and increased fracture risk, whereas estrogen treatment improves bone mass in women. RSPO3, a secreted protein that modulates WNT signaling, increases trabecular bone mass and strength in the vertebrae of mice, and is associated with trabecular density and risk of distal forearm fractures in humans. The aim of the present study was to determine if RSPO3 is involved in the bone-sparing effect of estrogens. We first observed that estradiol (E2) treatment increases RSPO3 expression in bone of ovariectomized (OVX) mice, supporting a possible role of RSPO3 in the bone-sparing effect of estrogens. As RSPO3 is mainly expressed by osteoblasts in the bone, we used a mouse model devoid of osteoblast-derived RSPO3 (Runx2-creRspo3flox/flox mice) to determine if RSPO3 is required for the bone-sparing effect of E2 in OVX mice. We confirmed that osteoblast-specific RSPO3 inactivation results in a substantial reduction in trabecular bone mass and strength in the vertebrae. However, E2 increased vertebral trabecular bone mass and strength similarly in mice devoid of osteoblast-derived RSPO3 and control mice. Unexpectedly, osteoblast-derived RSPO3 was needed for the full estrogenic response on cortical bone thickness. In conclusion, although osteoblast-derived RSPO3 is a crucial regulator of vertebral trabecular bone, it is required for a full estrogenic effect on cortical, but not trabecular, bone in OVX mice. Thus, estradiol and RSPO3 regulate vertebral trabecular bone mass independent of each other.

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.

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.

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.

Objective: This study aims to investigate the mechanism of long non-coding RNA NNT-AS1 in the proliferation of estrogen-mediated endometrial carcinoma (EC). Materials and methods: NNT-AS1, miR-30c, and Nucleophosmin 1 (NPM1) expressions were measured by quantitative real-time PCR and Western blotting. Cell Counting Kit-8 assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay were used to detect the viability and proliferation of Ishikawa and HEC-1-A cells, respectively. RNA immunoprecipitation assay was used to confirm the interaction between NNT-AS1 and miR-30c. Luciferase reporter assay was performed to confirm the interaction between miR-30c and NPM1. Results: NNT-AS1 and NPM1 expressions in EC tissues and cell lines were higher than in benign endometrium and normal endometrial epithelial cells (EECs). miR-30c expression in EC tissues and cell lines was lower than in benign endometrium and normal EECs. NNT-AS1 interacted with miR-30c, and miR-30c negatively regulated NPM1 expression. Overexpression of NNT-AS1 increased NPM1 expression in EC cells, while overexpression of miR-30c reversed the effect. NNT-AS1 interference inhibited the mRNA level of NPM1, while the miR-30c inhibitor reversed the result. Estradiol (E2) promoted the proliferation of EC cells, small interfering RNA (siRNA) against NNT-AS1 inhibited EC cell proliferation, miR-30c inhibitor promoted cell proliferation, and NPM1 siRNA inhibited cell proliferation. E2 increased tumor volume, and NNT-AS1 interference reduced tumor volume in vivo. Conclusion: NNT-AS1 promoted the proliferation of estrogen-mediated EC by regulating miR-30c/NPM1.

Transcription factors (TFs) play a key role in development and in cellular responses to the environment by activating or repressing the transcription of target genes in precise spatial and temporal patterns. In order to develop a catalog of target genes of Drosophila melanogaster TFs, the modERN consortium systematically knocked down the expression of TFs using RNAi in whole embryos followed by RNA-seq. We generated data for 45 TFs which have 18 different DNA-binding domains and are expressed in 15 of the 16 organ systems. The range of inactivation of the targeted TFs by RNAi ranged from log2fold change −3.52 to +0.49. The TFs also showed remarkable heterogeneity in the numbers of candidate target genes identified, with some generating thousands of candidates and others only tens. We present detailed analysis from five experiments, including those for three TFs that have been the focus of previous functional studies (ERR, sens, and zfh2) and two previously uncharacterized TFs (sens-2 and CG32006), as well as short vignettes for selected additional experiments to illustrate the utility of this resource. The RNA-seq datasets are available through the ENCODE DCC (http://encodeproject.org) and the Sequence Read Archive (SRA). TF and target gene expression patterns can be found here: https://insitu.fruitfly.org. These studies provide data that facilitate scientific inquiries into the functions of individual TFs in key developmental, metabolic, defensive, and homeostatic regulatory pathways, as well as provide a broader perspective on how individual TFs work together in local networks during embryogenesis.

This systematic review and meta analysis will quantitatively describe the risk of ischemic stroke among women with concurrent migraine and estrogen use.

This is the registration of a scoping review protocol titled, "The role of dietary interventions on the gut microbiome involved in estrogen metabolism: A scoping review protocol". There are no prior registrations known. This scoping review aims to explore and synthesize the evidence available for dietary interventions found to influence the estrobolome – gut microbial members involved in estrogen metabolism.

AimsExposure to endocrine-disrupting chemicals (EDCs) during critical neurodevelopmental windows has been associated with the risk of autistic traits. This systematic review of epidemiological studies examined the association between maternal exposure to EDCs during pregnancy and the risk of autism spectrum disorder (ASD) in the offspring.MethodsWe searched PubMed, Web of Science, Scopus, and Google Scholar from inception to November 17, 2022, for studies investigating the association between prenatal exposure to EDCs and outcomes related to ASD. Two independent reviewers screened studies for eligibility, extracted data, and assessed the risk of bias. The review was registered in PROSPERO (CRD42023389386).ResultsWe included 27 observational studies assessing prenatal exposure to phthalates (8 studies), polychlorinated biphenyls (8 studies), organophosphate pesticides (8 studies), phenols (7 studies), perfluoroalkyl substances (6 studies), organochlorine pesticides (5 studies), brominated flame retardants (3 studies), dioxins (1 study), and parabens (1 study). The number of examined children ranged from 77 to 1,556, the age at the assessment of autistic traits ranged from 3 to 14 years, and most studies assessed autistic traits using the Social Responsiveness Scale. All but one study was considered to have a low risk of bias. Overall, there was no association between maternal exposure to specific ECDs during pregnancy and the occurrence of autistic traits in offspring.ConclusionsFindings from the epidemiological studies evaluated here do not support an association between prenatal exposure to ECDs and the likelihood of autistic traits in later in life. These findings should not be interpreted as definitive evidence of the absence of neurodevelopment effects of EDCs affecting ASD risk, given the limitations of current studies such as representative exposure assessment, small sample sizes, inadequacy to assess sexually dimorphic effects, or the effects of EDC mixtures. Future studies should carefully address these limitations.