High Estrogen Research Articles

Estrogen levels and mortality in elderly and senile women

Background: High estrogen levels in young and middle-aged women are considered a primary factor associated with lower mortality and morbidity rates due to cardiovascular diseases compared to men. However, population studies investigating the influence of estradiol on mortality in postmenopausal women have yielded mixed results. Aim: To evaluate the impact of estrogen levels on life expectancy in elderly and senile women. Materials and methods: A CRYSTAL prospective cohort study was conducted using a random sample of women aged 65 years and older (n = 280). The study collected data through surveys, medical record analyses, and laboratory tests. Key parameters included chronic co-morbidities, comprehensive geriatric assessments, and laboratory measurements of estradiol, thyroid-stimulating hormone, glycated hemoglobin, total protein, albumin, C-reactive protein, vitamin D, creatinine, complete blood count, and lipid profiles over a six-year follow-up period. Results: Analysis of the relationship between estradiol levels and six-year survival showed a positive association between high estradiol levels and increased all-cause mortality, with a hazard ratio of 1.005 (95% confidence interval 1.000–1.009). The average survival time over the six-year observation period for women with estradiol levels below 73 pmol/L was 62.9 ± 1.2 months, compared to 49.9 ± 3.0 months for women with estradiol levels of 73 pmol/L or higher. After adjusting for age, history of acute cerebrovascular events, obesity, elevated C-reactive protein, glycated hemoglobin, and reduced cognitive function, women with estradiol levels of 73 pmol/L or higher had a 1.6-fold higher risk of all-cause mortality compared to women with estradiol levels below 73 pmol/L. Conclusions: An estradiol level of 73 pmol/L or higher is an independent risk factor for mortality in postmenopausal women.

Assessment of toxicity and endocrine-disrupting activity of bisphenol analogues during ozone and UV treatments in zebrafish eleutheroembryos

In recent decades, increased regulations on the use of bisphenol A (BPA) have prompted a surge in the use of BPA alternatives. Consequently, a widespread occurrence of BPA substitutes in aquatic environments is currently being detected. While some evidence exists about the degradation of these compounds through various water treatment technologies, the evolution of the resulting toxicity and endocrine-disrupting activity during these processes remains scarcely evaluated. In this study, the acute toxicity and transcriptomic responses in zebrafish eleutheroembryos exposed to selected bisphenols (BPA, bisphenol AF (BPAF) and bisphenol CCl (BPC-Cl)) were assessed during their oxidation by ozone. In addition, the response of zebrafish eleutheroembryos exposed to BPC-Cl treated with UV radiation was also investigated. Results showed that both ozonation and UV treatment effectively reduced the intrinsic toxicity of the studied bisphenols. This was observed with the increase of the survival and swim bladder inflation rates of zebrafish eleutheroembryos, reaching control levels. In concordance with these results, the initially altered mRNA levels in genes related to xenobiotic stimulus (cyp2k18); lipid homeostasis and transport (apoa1a); retinoid metabolism (aldh1a2); neutrophil differentiation (alas1); and oxygen transport (hbae3) in zebrafish eleutheroembryos were generally mitigated during the ozonation and UV treatment of bisphenols. Similarly, the high estrogenicity of these bisphenols, observed by elevated mRNA levels of cyp19a1b, decreased significantly during the ozonation treatment, reaching control levels. On the contrary, an increase in mRNA levels of fads2 and cyp19a1b was observed in animals exposed to BPC-Cl treated with UV radiation. These results suggest that the photolysis products of BPC-Cl may induce disruption of the lipid biosynthesis and estrogenicity. This was further confirmed with RNA-sequencing analysis, which revealed that embryos exposed to BPC-Cl treated with UV radiation presented alterations in mRNA levels of genes specifically related to estrogenic stimulus.

Is Alcohol Consumption Pattern Dependent on Prenatal Sex-Steroids? A Digit Ratio (2D:4D) Study Among University Students.

There is evidence that alcohol consumption is influenced by prenatal sex steroids (as measured by digit ratio [2D:4D]). Here, we clarify the effect size of the relationship in a student (rather than a patient) population. There were 258 (169 women) participants. Digit length was measured directly with calipers. Alcohol use was evaluated by the Polish version of Alcohol Use Disorders Identification Test (AUDIT) and operationalized as total AUDIT scores and grams of alcohol/week. Digit ratios were sexually dimorphic (males < females). There were negative correlations between right 2D:4D and Dr-l (right 2D:4D minus left 2D:4D) and AUDIT scores and grams of alcohol/week in both sexes. Relationships varied from small (r = -0.29) to large (r = -0.69) and they were stronger in males in comparison to females and for right 2D:4D in comparison to Dr-l. In males only, there were small (r = 0.21) to moderate (r = 0.31) positive associations with body size (height, weight, and mean right digit length) and alcohol consumption. Multiple regression analyses showed relationships between digit ratios remained significant but those for body size did not. Alcohol consumption was negatively related to 2D:4D, suggesting high prenatal testosterone and low prenatal estrogen are linked to its consumption. Correlations varied in strength from small to large with the strongest found for right 2D:4D and for males. Positive relationships between body size and alcohol were small to moderate, confined to males, and were not independent of digit ratios. Prenatal androgenization may influence alcohol drinking patterns in non-clinical individuals.

Menstrual cycle phase differences in myofiber damage and macrophage infiltration following electrical stimulation-induced muscle injury.

The purpose of this study was to examine the effects of menstrual cycle phase on myofiber injury, regenerative events and inflammation after electrical-stimulation (ES) induced myofiber damage. 28 premenopausal women (21.3 ± 2 yrs) were randomized into an early follicular (EF; N=14) or late follicular (LF; N = 14) group. After menstrual cycle tracking and phase confirmation, subjects underwent 200 electrically stimulated eccentric muscle contractions one week after providing a muscle biopsy. 7 days post-ES, subjects provided a final biopsy. Primary outcomes included: serum estradiol, indirect markers of muscle damage, direct indicators of myofiber necrosis and regeneration, satellite cell number, and macrophage infiltration. Women in the LF group had higher serum estradiol (122.1 ± 23.4 vs. 81.7 ± 30.8 pg/ml; P<0.001)compared to the EF group on the day of ES. Whereas the EF group recovered baseline maximal isometric strength by 4 days post-ES, the LF group did not. Only women in the LF group showed significant and consistent evidence of myofiber necrosis and regeneration pre- to post-ES. Despite showing more evidence of myofiber damage, women in the LF group also experienced reduced total and CD206+ macrophage infiltration relative to the EF group. Satellite cell quantity increased significantly post-ES in both groups, with no differences between groups. Collectively, the data suggest that the high estrogen LF phase may be associated with increased susceptibility to myofiber injury while also limiting the subsequent intramuscular inflammatory response.

Estrous cycle regulates cephalic mechanical sensitivity and sensitization of the trigemino-cervical complex in a female rat model of chronic migraine.

The higher incidence of migraines in women compared with men has led to the inclusion of female animals in pain research models. However, the critical role of the hormonal cycle is frequently overlooked, despite its clear correlation with migraine occurrences. In this study, we show in a rat model of migraine induced by repeated dural infusions of an inflammatory soup (IS) that a second IS (IS2) injection performed in proestrus/estrus (PE, high estrogen) female rats evokes higher cephalic mechanical hypersensitivities than when performed in metestrus/diestrus (MD, low estrogen) or ovariectomized (OV) rats. This hypersensitivity induced by IS2 correlates with increased c-Fos expression in outer lamina II (IIo) neurons located in the periorbital projection area of the trigemino-cervical complex (TCC), in PE only. Four IS (IS4) repetition induced an enlargement of c-Fos expression in adjacent territories areas in PE, but not MD or OV animals. Unexpectedly, c-Fos expression in locus coeruleus neurons does not potentiate after IS2 or IS4 injections. To examine the impacts of the hormonal cycle on the physiology of lamina IIo TCC neurons, we performed whole-cell patch-clamp recordings. Second inflammatory soup depolarizes neurons in PE and MD but not in OV rats and enhances excitatory synaptic inputs in PE animals to a greater extent compared with MD and OV rats. These findings show that central TCC sensitization triggered by meningeal nociceptor activation and the resulting cephalic hypersensitivity are modulated by the estrous cycle. This highlights the crucial need to account for not just sex, but also the female estrous cycle in pain research.

The Influence of the Estrous Cycle on Neuropeptide S Receptor-Mediated Behaviors.

The neuropeptide S receptor (NPSR) has been identified as a potential therapeutic target for anxiety and post-traumatic stress disorder. Central administration of neuropeptide S (NPS) in male mice produces anxiolytic-like effects, hyperlocomotion, and memory enhancement. Currently, the literature is limited in the number of studies investigating the effects of NPS in female test subjects despite females facing a higher prevalence of anxiety-related pathology, as well as greater risk for adverse effects while taking psychoactive drugs. Moreover, no previous studies have considered the influence of estrous cycle on the effects of NPS. The present study investigates whether NPS-mediated behavioral phenotypes seen in males translate to females, and whether they are affected by estrous cycle stage. Female C57BL/6NCr mice were intracerebroventricularly cannulated and underwent behavioral paradigms to test locomotion, anxiety, and memory. Estrous cycle stage was determined through examination of vaginal cytology. Our results provide evidence that NPS-mediated behaviors are influenced by the estrous cycle. Administration of NPS decreased anxiety-like behaviors more robustly when the female mice were in high estrogen stages of the estrous cycle. Therefore, the desired anxiolytic-like effects of targeting the NPSR are intact in female mice. However, these effects may to be influenced by the stage of the estrous cycle. The NPSR remains a strong potential drug target for new anxiolytic compounds and based on our initial observations further studies exploring the interaction of estrous cycle and the NPS system are warranted. SIGNIFICANCE STATEMENT: The neuropeptide S (NPS) receptor has been identified as a potential target for treating anxiety, a condition that is most prevalent in females. Therefore, the potential interaction of estrous cycle with the NPS system described in the present study is an important first step in understanding the function of the NPS system in females.

7426 Tamoxifen-Induced Ovarian Hyperstimulation in a Pre-Menopausal Patient with Breast Cancer History: Spontaneous Resolution with Conservative Management

Abstract Disclosure: S. Gondi: None. M. Contento: None. A. Leiter: None. Background: Tamoxifen is a selective estrogen receptor modulator (SERM) that competitively binds to estrogen receptors (ER) on tumors and inhibits the effect of estrogen, which is used in the treatment and prevention of ER-positive breast cancer. Tamoxifen therapy has been reported to increase serum estrogens and cause ovarian hyperstimulation in premenopausal women, but knowledge on how to manage these conditions is limited. Clinical Case: A 36-year-old pre-menopausal female with history of malignant neoplasm of the right breast (ER positive) who completed neoadjuvant chemotherapy, lumpectomy, and radiation, on tamoxifen for seven years presented with new-onset oligomenorrhea. Laboratory testing done by the patient’s gynecologist revealed total estrogen 2,723 pg/mL (reference range [RR] 34-501), testosterone 132 ng/dL (RR 8-60), anti-Mullerian hormone 12.7 ng/mL (RR for age 0.66-8.75), ovulation-phase follicle stimulating hormone 11.5 mIU/mL (RR 4.7-21.5) and luteinizing hormone (LH) 63.3 mIU/mL (RR 14-95.6). Further workup revealed that ovarian tumor markers alpha-fetoprotein and serum human chorionic gonadotropin and other labs including dehydroepiandrosterone sulfate, progesterone 17-OH, lactate dehydrogenase, prolactin, and thyroid stimulating hormone were normal. Transvaginal ultrasound (TVUS) showed a new 2.8 x 1.9 x 2.3 cm complex left ovarian cyst, which, along with the elevated estrogen level, was concerning for ovarian hyperstimulation. Treatment with LH-releasing hormone (LHRH) agonists, surgical consultation, and discontinuation of tamoxifen were offered as potential management strategies, but the patient opted for observation and continued tamoxifen. Two months later, estradiol was 989 pg/mL (RR 85-498), and then three months later decreased to 152 pg/mL with repeat TVUS showing resolution of the left ovarian cyst. The patient’s oligomenorrhea resolved with resumption of regular menstrual cycles. Conclusion: While it is well-known that tamoxifen causes elevated serum estrogen levels and can lead to ovarian hyperstimulation, there is limited research on the management of these side effects. Treatment strategies in past cases have included oophorectomy or medical management with LHRH agonists or gonadotropin-RH agonists. However, this case demonstrates that a tamoxifen-induced ovarian cyst and high estrogen levels can resolve on its own with continued tamoxifen treatment. Conservative management with monitoring via imaging and repeat estrogen levels may be sufficient in management of pre-menopausal women with tamoxifen-induced ovarian hyperstimulation. Presentation: 6/1/2024

Acquisition Of Novel Exercise During High Estrogen Facilitates Future Exercise Behavior

Acquisition Of Novel Exercise During High Estrogen Facilitates Future Exercise Behavior

Клиническое обоснование значимости оценки уровня эстрадиола у мужчин с синдромом гипогонадизма на фоне терапии по стабилизации уровня тестостерона.

Introduction. A significant reason for the decrease in the effectiveness of testosterone replacement therapy (TRT) in men is the increased activity of the aromatase enzyme in overweight and obese patients, when under its influence estrogens are converted from androgens (the transition of testosterone to estradiol) mainly in adipose tissue, leading to an increase in estradiol levels. That is, with exogenous administration of testosterone, estradiol becomes overabundant, thereby the positive effects of TRT are weakened and even often leveled, dangerous side effects of hyperestradiolemia appear, that is, without careful monitoring and normalization of estradiol levels, the effectiveness of TRT turns out to be low, and the side effect of therapy, due to high estrogens, on the body is high. The aim of research was to increase the effectiveness of testosterone replacement therapy for hypogonadism in obese patients. Material and methods. A two-center prospective study was conducted to study TRT for hypogonadism. The results of examination and treatment of 106 men aged 35-59 years (average age 45.9±7.2 years) with hypogonadism syndrome, who were prescribed TRT Omnadren 250 mg 1 ml/m, were analyzed. The levels of total testosterone, estradiol, and prolactin were monitored 48 hours after injection (Omnadren pharmacokinetics: Cmax of testosterone in blood plasma occurs within 24-48 hours), as well as level of hormones on day 10 with Aging Male Screening (AMS) control. Results. In patients with TRT, on the second day after 48 hours, as well as after 10 days inclusive, an increase in testosterone and estradiol was statistically significant (p&lt;0.01), but in overweight and obese individuals, the aromatization of testosterone into estradiol was significantly higher than in patients with normal body mass index (BMI), with at the same time, according to the scores of the AMS questionnaire, there was an improvement clinically, however, in patients with obesity it was clinically less significant due to significantly increased level of estradiol at the time of treatment. Conclusions. It was found that patients with increased BMI have worse treatment results with elevated estradiol, which requires monitoring of estradiol starting from 2-3 days and later on day 10 in order to titrate the frequency of injections of testosterone preparations and correct the level of estradiol to physiological ones.

High concentration of estrogen resulted by COH may affect the secretion of pro-angiogenic factors in uNK cells by downregulating the expression of IL-11 in decidual stromal cells.

High serum estrogen concentrations after controlled ovarian hyperstimulation (COH) and fresh embryo transfers are associated with the increased risk of pregnancy complications resulting from aberrant placentation. Uterine natural killer (uNK) cells are important for establishment of pregnancy and normal placentation. It has been found that the proliferation and function of uNK cells are compromised by COH. However, the underlying role of high concentration of estrogen following COH in the abnormalities of uNK cells is poorly understood. Expression of cytokines and immunophenotype study of uNK was performed by flow cytometry analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to quantify RNA expression; Western blot was performed to quantify protein levels. The secretion level of pro-angiogenic factors in uNK cells is significantly reduced by co-culture with decidual stromal cells (DSCs) induced by high estrogen. It was discovered that COH and supraphysiologic levels of estrogen downregulated IL-11 in decidual tissue of mice. Additionally, we found that the downregulation of IL-11 is a major factor contributing to the downregulation of VEGF and PLGF in uNK cells. Moreover, we found that uNK cells may acquire IL-11Rα sequentially during differentiation and that only a portion of uNK cells are IL-11Rα positive. Lastly, we discovered that IL-11 may regulate VEGF and PLGF secretion in uNK cells via the ERK signaling pathway. These results suggested the downregulation of IL-11 expression in DSCs caused by high estrogen levels affects the secretion of pro-angiogenic factors in uNK cells, which provided an explanation for the pregnancy complications caused by COH.

Outcomes of IVF treatments in women with antiphospholipid antibodies or antiphospholipid syndrome

BackgroundOvulation induction for in vitro fertilization (IVF) may increase intravascular thromboses among patients with antiphospholipid autoantibodies (aPLs) or antiphospholipid syndrome (APS) due to the high estrogen levels. While natural or modified natural IVF treatment cycles (MNC) are sometimes used instead of stimulated cycles with empiric anticoagulant treatment among these infertile patients, their efficacy is unclear. Materials and methodsA retrospective cohort study including all IVF cycles of patients diagnosed with aPLs or APS in a tertiary, university-affiliated hospital between 2012 and 2022. The outcomes of stimulated cycles with anticoagulants and MNC and natural IVF cycle attempts were compared. Results121 oocyte retrievals from 38 women were analyzed: 93 stimulated and 28 MNC or natural IVF cycles. The rates of cycle cancellation (0 % vs. 17.9 %, p < 0.001) and cycles in which no oocytes were retrieved (0 % vs. 43.5 %, p < 0.001) were significantly lower following stimulated cycles vs. natural and MNC. In parallel, positive β-hCG (31.9 % vs. 10.9 %, p = 0.03), clinical pregnancy rate (23.6 % and 3.6 %, p < 0.001) and live birth rates (18.1 % vs. 3.6 %, p = 0.01) were significantly higher following stimulated cycles. No thrombotic events or bleeding occurred in any cycle. ConclusionOvarian stimulation for IVF is more effective for successful pregnancy and delivery than natural cycles and MNC and can be safely undertaken in aPLs or APS women undergoing IVF. Rates of complication from hormonal treatment are not increased when treated with LMWH during ovarian stimulation.

Unexpected nuclear hormone receptor and chromatin dynamics regulate estrous cycle dependent gene expression.

Chromatin changes in response to estrogen and progesterone are well established in cultured cells, but how they control gene expression under physiological conditions is largely unknown. To address this question, we examined in vivo estrous cycle dynamics of mouse uterus hormone receptor occupancy, chromatin accessibility and chromatin structure by combining RNA-seq, ATAC-seq, HiC-seqand ChIP-seq. Two estrous cycle stages were chosen for these analyses, diestrus (highest estrogen) and estrus (highest progesterone). Unexpectedly, rather than alternating with each other, estrogen receptor alpha (ERα) and progesterone receptor (PGR) were co-bound during diestrus and lost during estrus. Motif analysis of open chromatin followed by hypoxia inducible factor 2A (HIF2A) ChIP-seq and conditional uterine deletion of this transcription factor revealed a novel role for HIF2A in regulating diestrus gene expression patterns that were independent of either ERα or PGR binding. Proteins in complex with ERα included PGR and cohesin, only during diestrus. Combined with HiC-seq analyses, we demonstrate that complex chromatin architecture changes including enhancer switching are coordinated with ERα and PGR co-binding during diestrus and non-hormone receptor transcription factors such as HIF2A during estrus to regulate most differential gene expression across the estrous cycle.

Therapeutic response and outcomes with uncommon breast cancer subtypes in the I-SPY trial 2010-2022.

1 Background: Uncommon histologies are over-represented among high-risk breast cancer (BC) and denote an area with limited trial data and of significant unmet medical need. To better understand trial outcomes in this group and identify signals of tumor responsiveness, we report pathologic complete response (pCR) and early event-free survival (EFS) by disease subtype in the I-SPY2 trial. Additionally, the I-SPY2 trial currently utilizes a combination of tumor molecular signature and receptor status to determine response predictive subtype (RPS) first developed from 987 I-SPY2 patients [Wolf et al, Cancer Cell 2022]. We report disease response rates for those who received what is now known to be optimal RPS guided therapy. Methods: The I-SPY2 platform trial tests novel agents given neo-adjuvantly with a chemotherapy backbone in high-risk BC (HER2 positive, triple negative and high molecular risk estrogen receptor positive BC). Histologic images of research biopsies, local biopsy and surgical pathology reports were reviewed centrally by I-SPY pathologists. Receptor subtype distribution and pCR rates were summarized; and EFS was estimated using the Kaplan Meier method. Association between pCR and EFS was evaluated using the Cox proportional hazard model with significance assessed by the log rank test. Results: 144/2118 (7%) of I-SPY2 participants were identified with metaplastic (60), lobular (55), mucinous (9), micropapillary (8), neuroendocrine (4) and other (8) BCS. Tumor receptor status, pCR rate and EFS by tumor type are shown in the Table. For the full cohort, pCR was associated with better EFS (hazard ratio (95% CI): 0.12 (0.02 - 0.88), p = 0.01). Within metaplastic (metapBC) 11/32 (34%) and 5/28 (18%) patients had a pCR with or without checkpoint blockade, respectively. By RPS group, 9 of 18 (50%) (13 metapBC, 3 other, 2 lobular) in the HER2-Immune+ group who received RPS optimized therapy had a pCR. In this group 6/13 (46%) with metapBC had a pCR. In the HER2+ driven RPS groups, pCR rate in the HER+HER2orBasal was 88% (7/8) and 0% (0/3) in the HER2+Luminal. Conclusions: High pCR rates observed in metapBC and other among subsets of often difficult to treat BC subtypes support novel approaches and provide a roadmap for future study of uncommon BCs. Outcomes were improved when therapy matched RPS vulnerabilities. Participants presenting with uncommon BC subtypes will be prospectively identified in the I-SPY2.2 trial to further develop effective approaches for this group. Clinical trial information: NCT01042379 .[Table: see text]

Abnormal HCK/glutamine/autophagy axis promotes endometriosis development by impairing macrophage phagocytosis.

The presence of extensive infiltrated macrophages with impaired phagocytosis is widely recognised as a significant regulator for the development of endometriosis (EMs). Nevertheless, the metabolic characteristics and the fundamental mechanism of impaired macrophage phagocytosis are yet to be clarified. Here, we observe that there is the decreased expression of haematopoietic cellular kinase (HCK) in macrophage of peritoneal fluid from EMs patients, which might be attributed to high oestrogen and hypoxia condition. Of note, HCK deficiency resulted in impaired macrophage phagocytosis, and increased number and weight of ectopic lesions in vitro and in vivo. Mechanistically, this process was mediated via regulation of glutamine metabolism, and further upregulation of macrophage autophagy in a c-FOS/c-JUN dependent manner. Additionally, macrophages of EMs patients displayed insufficient HCK, excessive autophagy and phagocytosis dysfunction. In therapeutic studies, supplementation with glutamine-pre-treated macrophage or Bafilomycin A1 (an autophagy inhibitor)-pre-treated macrophage leads to the induction of macrophage phagocytosis and suppression of EMs development. This observation reveals that the aberrant HCK-glutamine-autophagy axis results in phagocytosis obstacle of macrophage and further increase the development risk of Ems. Additionally, it offers potential therapeutic approaches to prevent EMs, especially patients with insufficient HCK and macrophage phagocytosis dysfunction.

Metagenomic characterization of the equine endometrial microbiome during anestrus

The equine uterus is highly interrogated during estrus prior to breeding and establishing pregnancy. Many studies in mares have been performed during estrus under the influence of high estrogen concentrations, including the equine estrual microbiome. To date, it is unknown how the uterine microbiome of the mare is influenced by cyclicity; while, the equine vaginal microbiome is stable throughout the estrous cycle. We hypothesized that differences would exist between the equine endometrial microbiome of mares in estrus and anestrus. The aim of this study was two-fold: to characterize the resident endometrial microbiome of healthy mares during anestrus and to compare this with estrus. Double-guarded endometrial swabs were taken from healthy mares during estrus (n = 16) and in the following non-breeding season during anestrus (n = 8). Microbial population was identified using 16S rRNA sequencing. Our results suggest that the equine uterine microbiome in estrus has a low diversity and low richness, while during anestrus, a higher diversity and higher richness were seen compared to estrus. Despite this difference, both the estrus and anestrus endometrial microbiome were dominated by Proteobacteria, Firmicutes, and Bacteroidota. The composition of the microbial community between anestrus and estrus was significantly different. This may be explained by the difference in the composition of the endometrial immune milieu based on the stage of the cycle. Further research investigating the function of the equine endometrial microbiome and dynamics changes within the uterine environment is required.

Identifying the Optimal Birth Control for Patients

Despite decreases in pregnancy and abortion rates over the past few decades, unintended pregnancy remains a personal and public health challenge.1 In the 1960s, the first birth control pills (progestin only and combined) revolutionized contraceptive effectiveness despite their high estrogen doses. In the 1980s, safety became front of mind, as older intra-uterine devices (IUDs) and implants were removed from the market, leading to the development of newer, safer options we enjoy today. In the 1990s, pill-related venous thromboembolism (VTE) scares led to surges in unintended pregnancy rates in the United Kingdom and Europe, only to be repeated in the 2000s. In the 2010s, long-acting reversible contraception (LARC) was hailed as the path forward for reducing pregnancy rates and, indeed, this has contributed to modest reductions in unintended pregnancy and abortion rates. This decade has seen two major shifts in contraceptive care: the transition to blended models of service delivery (especially virtual and subscription-based options) and a transition toward “needs-based” counselling.

Vaginal candidiasis, predisposing factors, symptoms and treatment

Introduction: Vulvovaginal candidiasis is a disease caused by Candida species, mainly Candida albicans species, which can be colonizing the vaginal microbiota of healthy women, without causing disease. Due to its high prevalence, it is one of the most frequent causes of gynecological consultation. It occurs mainly in women after puberty, worldwide it is estimated that at least 75% of women have had candidiasis at least once in their lives. Its clinical signs are itching, vaginal inflammation and white discharge. It is diagnosed by laboratory tests or culture. A higher frequency of candidiasis occurs in women with high estrogen load or some degree of immunodeficiency. Treatment consists of azole antifungals, particularly fluconazole. The present study consists of a systematic review of the existing literature related to vulvovaginal candidiasis, focusing on epidemiology, clinical signs, diagnosis and treatment. Material and methods: The study design is a literature review for which a search and evaluation of the existing literature and previous research on vaginal candidiasis will be carried out through the databases PubMed, Google Academic, Scielo, Sciendirect, among others. For this purpose, inclusion criteria will be used through searches related to "Candida", "vaginal candidiasis", "recurrent vaginal candidiasis", "vaginal candidiasis predisposing factors" and "candidiasis literature review". Results: Vaginal candidiasis is an infection caused by the overgrowth of Candida albicans, a type of yeast-like fungus that normally lives in the vagina. Predisposing factors include antibiotic use, increased estrogen levels, uncontrolled diabetes, overweight, pregnancy, premenstrual period, taking corticosteroids, and high doses of estrogen. Treatment of vaginal candidiasis includes antifungal medications, such as single-dose oral fluconazole, and avoidance of excess moisture. In uncomplicated vulvovaginal candidiasis, all available forms of antifungals are highly effective, both oral and topical, whereas in complicated vulvovaginal candidiasis, a longer course of 5-7 to 10-14 days of conventional therapy should be performed. Patients who have frequent recurrences require their long-term pressure with oral medications. Conclusion: It is important for health care professionals and patients to be aware of the risks of recurrence so that timely treatment can be provided to patients

High estrogen induces trans-differentiation of vascular smooth muscle cells to a macrophage-like phenotype resulting in aortic inflammation via inhibiting VHL/HIF1a/KLF4 axis.

Estrogen is thought to have a role in slowing down aging and protecting cardiovascular and cognitive function. However, high doses of estrogen are still positively associated with autoimmune diseases and tumors with systemic inflammation. First, we administered exogenous estrogen to female mice for three consecutive months and found that the aorta of mice on estrogen develops inflammatory manifestations similar to Takayasu arteritis (TAK). Then, in vitro estrogen intervention was performed on mouse aortic vascular smooth muscle cells (MOVAS cells). Stimulated by high concentrations of estradiol, MOVAS cells showed decreased expression of contractile phenotypic markers and increased expression of macrophage-like phenotypic markers. This shift was blocked by tamoxifen and Krüppel-like factor 4 (KLF4) inhibitors and enhanced by Von Hippel-Lindau (VHL)/hypoxia-inducible factor-1α (HIF-1α) interaction inhibitors. It suggests that estrogen-targeted regulation of the VHL/HIF-1α/KLF4 axis induces phenotypic transformation of vascular smooth muscle cells (VSMC). In addition, estrogen-regulated phenotypic conversion of VSMC to macrophages is a key mechanism of estrogen-induced vascular inflammation, which justifies the risk of clinical use of estrogen replacement therapy.

Therapeutic response and outcomes with less common breast cancer subtypes in the I-SPY trial 2011-2022.

582 Background: Uncommon histologies are over-represented among high-risk breast cancer (BC) and denote an area with limited trial data and of significant unmet medical need. To better understand trial outcomes in this group and identify signals of tumor responsiveness, we report pathologic complete response (pCR) and early event-free survival (EFS) by disease subtype in the I-SPY2 trial. Additionally, the I-SPY2 trial currently utilizes a combination of tumor molecular signature and receptor status to determine response predictive subtype (RPS) first developed from 987 I-SPY2 patients (1). We report disease response rates for those who received what is now known to be optimal RPS guided therapy. Methods: The I-SPY2 platform trial tests novel agents given neo-adjuvantly with a chemotherapy backbone in high-risk BC (HER2 positive, triple negative and high molecular risk estrogen receptor positive BC). Histologic images of research biopsies, local biopsy and surgical pathology reports were reviewed centrally by I-SPY pathologists. Receptor subtype distribution and pCR rates were summarized. EFS was estimated using the Kaplan Meier method. Association between pCR and EFS was evaluated using the Cox proportional hazard model with significance assessed by the log rank test. Results: 144/2118 (7%) of I-SPY2 participants were identified with metaplastic (60), lobular (55), mucinous (9), micropapillary (8), neuroendocrine (4) and other (8) BCs. Tumor receptor status, pCR rate and EFS by tumor type are shown in the Table. For the full cohort, pCR was associated with better EFS (hazard ratio (95% CI): 0.12 (0.02 - 0.88), p = 0.01). Within metaplastic (metapBC) 11/32 (34%) and 5/28 (18%) patients had a pCR with or without checkpoint blockade, respectively. By RPS group, 9 of 18 (50%) (13 metapBC, 3 other, 2 lobular) in the HER2-Immune+ group who received RPS optimized therapy had a pCR. In this group 6/13 (46%) with metapBC had a pCR. In the HER2+ driven RPS groups, pCR rate in the HER+HER2orBasal was 88% (7/8) and 0% (0/3) in the HER2+Luminal. Conclusions: High pCR rates observed in metapBC and other among subsets of often difficult to treat BC subtypes support novel approaches and provide a roadmap for future study of uncommon BCs. Outcomes were improved when therapy matched RPS vulnerabilities. Participants presenting with uncommon BC subtypes will be prospectively identified in the I-SPY2.2 trial to further develop effective approaches for this group. 1. Wolf et al, Cancer Cell 2022. Clinical trial information: NCT01042379 . [Table: see text]

17β-estradiol induces hyperresponsiveness in guinea pig airway smooth muscle by inhibiting the plasma membrane Ca2+-ATPase

High serum estrogen concentrations are associated with asthma development and severity, suggesting a link between estradiol and airway hyperresponsiveness (AHR). 17β-estradiol (E2) has non-genomic effects via Ca2+ regulatory mechanisms; however, its effect on the plasma membrane Ca2+-ATPases (PMCA1 and 4) and sarcoplasmic reticulum Ca2+-ATPase (SERCA) is unknown. Hence, in the present study, we aim to demonstrate if E2 favors AHR by increasing intracellular Ca2+ concentrations in guinea pig airway smooth muscle (ASM) through a mechanism involving Ca2+-ATPases.In guinea pig ASM, Ca2+ microfluorometry, muscle contraction, and Western blot were evaluated. Then, we performed molecular docking analysis between the estrogens and Ca2+ ATPases.In tracheal rings, E2 produced AHR to carbachol. In guinea pig myocytes, acute exposure to physiological levels of E2 modified the transient Ca2+ peak induced by caffeine to a Ca2+ plateau. The incubation with PMCA inhibitors (lanthanum and carboxyeosin, CE) partially reversed the E2-induced sustained plateau in the caffeine response. In contrast, cyclopiazonic acid (SERCA inhibitor), U-0126 (an inhibitor of ERK 1/2), and choline chloride did not modify the Ca2+ plateau produced by E2. The mitochondrial uniporter activity and the capacitative Ca2+ entry were unaffected by E2. In guinea pig ASM, Western blot analysis demonstrated PMCA1 and PMCA4 expression. The results from the docking modeling demonstrate that E2 binds to both plasma membrane ATPases. In guinea pig tracheal smooth muscle, inhibiting the PMCA with CE, induced hyperresponsiveness to carbachol. 17β-estradiol produces hyperresponsiveness by inhibiting the PMCA in the ASM and could be one of the mechanisms responsible for the increase in asthmatic crisis in women.