Prediagnostic use of menopausal hormone therapy and long-term survival of localized epithelial ovarian cancer: The Extreme study.

Use of menopausal hormone therapy (MHT) prior to an epithelial ovarian cancer (EOC) diagnosis has been suggested to be associated with improved survival. In a recent nationwide cohort study, we found that prediagnostic long-term MHT use, especially estrogen therapy (ET), was associated with improved long-term survival in women with nonlocalized EOC. Our aim was to investigate the influence of prediagnostic MHT use on long-term survival among women with localized EOC in the same nationwide study. Our study cohort comprised all women aged 50 years or older with an EOC diagnosis in Denmark 2000-2014 (n = 2097) identified from the Extreme study. We collected information on usage of systemic ET and estrogen plus progestin therapy (EPT) from the Danish National Prescription Registry. By using pseudo-values, 5- and 10-year absolute and relative survival probabilities were estimated with 95% confidence intervals (CIs) while adjusting for histology, comorbidity, and income. Relative survival probabilities >1 indicate better survival. The 5-year absolute survival probabilities were 61% and 56%, respectively, among women who were nonusers and users of prediagnostic MHT, whereas these numbers were 46% and 41%, respectively, regarding 10-year survival. Use of MHT was not significantly associated with an improved 5- or 10-year survival in women with localized EOC (5-year relative survival probability = 0.95, 95% CI: 0.89-1.02; 10-year relative survival probability = 0.92, 95% CI: 0.84-1.02). Similar findings were seen for systemic ET or EPT use. Our findings do not suggest a positive benefit from prediagnostic MHT use on long-term survival of localized EOC.

Menopausal hormone therapy and breast cancer risk: a population-based cohort study of 1.3 million women in Norway.

BACKGROUND: It is important to monitor the association between menopausal hormone therapy (HT) use and breast cancer (BC) risk with contemporary estimates, and specifically focus on HT types and new drugs. METHODS: We estimated hazard ratios (HR) of BC risk according to HT type, administration route and individual drugs, overall and stratified by body mass index (BMI), molecular subtype and detection mode, with non-HT use as reference. RESULTS: We included 1,275,783 women, 45+ years, followed from 2004, for a median of 12.7 years. Oral oestrogen combined with daily progestin was associated with the highest risk of BC (HR 2.42, 95% confidence interval (CI) 2.31-2.54), with drug-specific HRs ranging from Cliovelle®: 1.63 (95% CI 1.35-1.96) to Kliogest®: 2.67 (2.37-3.00). Vaginal oestradiol was not associated with BC risk. HT use was more strongly associated with luminal A cancer (HR 1.97, 95% CI 1.86-2.09) than other molecular subtypes, and more strongly with interval (HR 2.00, 95% CI: 1.83-2.30) than screen-detected (HR 1.33, 95% CI 1.26-1.41) BC in women 50-71 years. HRs for HT use decreased with increasing BMI. CONCLUSIONS: The use of oral and transdermal HT was associated with an increased risk of BC. The associations varied according to HT type, individual drugs, molecular subtype, detection mode and BMI.

Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.

BACKGROUND: Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. METHODS: We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed. RESULTS: A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy. CONCLUSIONS: Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.).

A novel intrauterine estrogen-releasing system for preventing the postoperative recurrence of intrauterine adhesion: a multicenter randomized controlled study.

BACKGROUND: Transcervical resection of adhesions (TCRA) is the standard treatment for intrauterine adhesion (IUA). Previous studies have shown that postoperative oral estrogen or an intrauterine physical barrier could reduce the recurrence of IUA by promoting the proliferation of the endometrium or inhibiting the reformation of adhesions. Our team designed an intrauterine stent that can release estrogen within the uterine cavity slowly. In this study, we aimed to investigate the efficacy and safety of the estrogen-releasing intrauterine system in preventing the recurrence of moderate to severe IUA. METHODS: This was a multicenter prospective randomized controlled 2-arm parallel trial that included patients who were diagnosed with moderate to severe IUA and who received TCRA. A total of 250 patients were randomly assigned, at a 1:1 ratio, to receive the intrauterine estrogen-releasing system or a Foley catheter balloon combined with oral estrogen therapy after surgery. The primary outcome was the rate of adhesion reduction in the two groups. The secondary outcomes included endometrial thickness at the ovulation period, menstrual improvement rates, and other reported adverse events during follow-up. RESULTS: The average daily drug release amount for all the tested stents was 0.21 mg/day. At 60 days postoperatively, the rate of adhesion reduction was significantly greater in the experimental group than in the control group (93.33% vs. 58.56%, p < 0.001). The endometrium of the experimental group was thicker than that of the control group (p < 0.001). Consistently, the rate of improvement in menstruation was greater in the experimental group than in the control group (p = 0.010). No grade 3-4 adverse events were found in the two groups during the 1-year follow-up. CONCLUSIONS: In the cohort of patients with moderate to severe IUA, the intrauterine estrogen-releasing system was more effective at reducing adhesion than traditional oral estrogen combined with an intrauterine Foley catheter after TCRA. This novel intrauterine system provides a new option for the management of IUA after surgery. TRIAL REGISTRATION: The registration number is NCT04972032. Date of registration: August 15, 2021.

The effects of estrogens on spatial learning and memory in female rodents - A systematic review and meta-analysis.

Estrogens have inconsistent effects on learning and memory in both the clinical and preclinical literature. Preclinical literature has the advantage of investigating an array of potentially important factors contributing to the varied effects of estrogens on learning and memory, with stringently controlled studies. This study set out to identify specific factors in the animal literature that influence the effects of estrogens on cognition, for possible translation back to clinical practice. The literature was screened and studies meeting strict inclusion criteria were included in the analysis. Eligible studies included female ovariectomized rodents with an adequate vehicle for the estrogen treatment, with an outcome of spatial learning and memory in the Morris water maze. Training days of the Morris water maze were used to assess acquisition of spatial learning, and the probe trial was used to evaluate spatial memory recall. Continuous outcomes were pooled using a random effects inverse variance method and reported as standardized mean differences with 95 % confidence intervals. Subgroup analyses were developed a priori to assess important factors. The overall analysis favoured treatment for the later stages of training and for the probe trial. Factors including the type of estrogen, route, schedule of administration, age of animals, timing relative to ovariectomy, and duration of treatment were all found to be important. The subgroup analyses showed that chronic treatment with 17ß-estradiol, either cyclically or continuously, to young animals improved spatial recall. These results, observed in animals, can inform and guide further clinical research on hormone replacement therapy for cognitive benefits.

Three-year outcomes of a randomized clinical trial of perioperative vaginal estrogen as adjunct to native tissue vaginal apical prolapse repair.

BACKGROUND: As the muscular and connective tissue components of the vagina are estrogen responsive, clinicians may recommend vaginal estrogen to optimize tissues preoperatively and as a possible means to reduce prolapse recurrence, but long-term effects of perioperative intravaginal estrogen on surgical prolapse management are uncertain. OBJECTIVE: This study aimed to compare the efficacy of perioperative vaginal estrogen vs placebo cream in reducing composite surgical treatment failure 36 months after native tissue transvaginal prolapse repair. STUDY DESIGN: This was an extended follow-up of a randomized superiority trial conducted at 3 tertiary US sites. Postmenopausal patients with bothersome anterior or apical vaginal prolapse were randomized 1:1 to 1-g conjugated estrogen cream (0.625 mg/g) or placebo, inserted vaginally twice weekly for ≥5 weeks preoperatively and continued twice weekly for 12 months postoperatively. All participants underwent vaginal hysterectomy (if the uterus was present) and standardized uterosacral or sacrospinous ligament suspension at the surgeon's discretion. The primary report's outcome was time to failure by 12 months postoperatively, defined by a composite outcome of objective prolapse of the anterior or posterior walls beyond the hymen or the vaginal apex descending below one-third the total vaginal length, subjective bulge symptoms, and/or retreatment. After 12 months, participants could choose to use-or not use-vaginal estrogen for atrophy symptom bother. The secondary outcomes included Pelvic Organ Prolapse Quantification points, subjective prolapse symptom severity using the Patient Global Impression of Severity and the Patient Global Impression of Improvement, and prolapse-specific subscales of the 20-Item Pelvic Floor Distress Inventory and the Pelvic Floor Impact Questionnaire-Short Form 7. Data were analyzed as intent to treat and "per protocol" (ie, ≥50% of expected cream use per medication diary). RESULTS: Of 206 postmenopausal patients, 199 were randomized, and 186 underwent surgery. Moreover, 164 postmenopausal patients (88.2%) provided 36-month data. The mean age was 65.0 years (standard deviation, 6.7). The characteristics were similar at baseline between the groups. Composite surgical failure rates were not significantly different between the estrogen group and the placebo group through 36 months, with model-estimated failure rates of 32.6% (95% confidence interval, 21.6%-42.0%) and 26.8% (95% confidence interval, 15.8%-36.3%), respectively (adjusted hazard ratio, 1.55; 95% confidence interval, 0.90-2.66; P=.11). The results were similar for the per-protocol analysis. Objective failures were more common than subjective failures, combined objective and subjective failures, or retreatment. Using the Patient Global Impression of Improvement, 75 of 80 estrogen participants (94%) and 72 of 76 placebo participants (95%) providing 36-month data reported that they were much or very much better 36 months after surgery (P>.99). These data included reports from 51 of 55 "surgical failures." Pelvic Organ Prolapse Quantification measurements, Patient Global Impression of Severity scores, and prolapse subscale scores of the 20-Item Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire-Short Form 7 all significantly improved for both the estrogen and placebo groups from baseline to 36 months postoperatively without differences between the groups. Of the 160 participants providing data on vaginal estrogen usage at 36 months postoperatively, 40 of 82 participants (49%) originally assigned to the estrogen group were using prescribed vaginal estrogen, and 47 of 78 participants (60%) assigned to the placebo group were using vaginal estrogen (P=.15). CONCLUSION: Adjunctive perioperative vaginal estrogen applied ≥5 weeks preoperatively and 12 months postoperatively did not improve surgical success rates 36 months after uterosacral or sacrospinous ligament suspension prolapse repair. Patient perception of improvement remained very high at 36 months.

Effect of menopausal hormonal therapy on cardiovascular risks in Korean postmenopausal women: A nationwide cohort study.

OBJECTIVE: To evaluate the association between menopausal hormonal therapy (MHT) and the risk of cardiovascular disease (CVD), according to various regimens, dosages, routes of administration and starting ages of MHT. DESIGN: A population-based cohort study using the Korean National Health Insurance Services database. SETTING: Nationwide health insurance database. POPULATION: Women who reported entering menopause at an age of ≥40 years with no history of CVD in the national health examination. METHODS: The study population comprised 1 120 705 subjects enrolled between 2002 and 2019, categorised according to MHT status (MHT group, n = 319 007; non-MHT group, n = 801 698). MAIN OUTCOME MEASURES: Incidence of CVD (a composite of myocardial infarction and stroke). RESULTS: The incidence of CVD was 59 266 (7.4%) in the non-MHT group and 17 674 (5.5%) in the MHT group. After adjusting for confounding factors, an increased risk of CVD was observed with the administration of tibolone (hazard ratio, HR 1.143, 95% CI 1.117-1.170), oral estrogen (HR 1.246, 95% CI 1.198-1.295) or transdermal estrogen (HR 1.289, 95% CI 1.066-1.558), compared with the non-MHT group; the risk was based on an increased risk of stroke. The risk trends were consistent regardless of the age of starting MHT or the physicians' specialty. Among tibolone users, a longer period from entering menopause to taking tibolone and the use of any dosage (1.25 or 2.5 mg) were linked with a higher risk of CVD, compared with non-MHT users. CONCLUSIONS: This nationwide cohort study demonstrated an increased risk of CVD, driven mainly by an increased risk of stroke, among tibolone and oral or transdermal estrogen users, compared with that of non-MHT users.

Should hormone replacement therapy (any route of administration) be considered in all postmenopausal women with lower urinary tract symptoms? Report from the ICI-RS 2023.

AIMS: This International Consultation on Incontinence-Research Society report aims to summarize the evidence and uncertainties regarding the use of hormone replacement therapy by any route in the management of lower urinary tract symptoms (LUTS) including recurrent urinary tract infections (rUTI), with a review of special considerations for the elderly. Research question proposals to further this field have been highlighted. METHODS: An overview of the existing evidence, guidelines, and consensus regarding the use of topical or systemic estrogens in the management of LUTS. RESULTS: There are currently evidence and recommendations to offer topical estrogens to postmenopausal women with overactive bladder symptoms as well as postmenopausal women with rUTIs. Systemic estrogens however have been shown in a meta-analysis to have a negative effect on LUTS and, therefore are not currently recommended. CONCLUSIONS: Although available evidence and recommendations exist for the use of topical estrogens, few women are commenced on these in primary care. There remain large gaps still within our knowledge of the use of estrogens within the management of LUTS, particularly on when it should be commenced, the length of time treatment should be continued for, and barriers to prescribing.

Effect of estrogen exposure on pregnancy outcomes in artificial frozen-thawed embryo transfer cycles.

In contemporary times, the employment of vitrification freezing technology has led to the widespread adoption of frozen-thawed embryo transfer (FET) worldwide. Meanwhile, hormone replacement therapy (HRT) is a crucial protocol for priming the endometrium during FET cycles. Estrogen is required in HRT cycles for the induction of progesterone receptors and to promote endometrial thickness. However, there is no universal consensus on the treatment duration, dosage regimen, administration route, and target serum estrogen levels. Therefore, this study aimed to offer a comprehensive review of these topics. A shorter duration of estrogen exposure may elevate the risk of early miscarriage, while prolonged exposure to estrogen does not seem to confer advantages to general population and may be attempted in individuals with thin endometrium. Moreover, excessive estrogen levels on the day of progesterone administration may be associated with higher miscarriage rates and lower live birth rates (LBR). To offer more comprehensive guidance for clinical practice, extensive and prospective studies involving a large sample size are warranted to determine the optimal concentration and duration of estrogen exposure.

Effect of exogenous oestrogen treatment frequency on induction of artificial lactation in pseudopregnant sows.

In this study, we examined whether the frequency of exogenous oestrogen treatment affects the induction of artificial lactation and milk production. Furthermore, we analysed changes in milk components obtained from artificially lactating sows. Pseudopregnant induced by treatment with 30 mg of estradiol dipropionate (EDP) on Day 10 (Day 0 = the last day of estrus) were divided into three groups: those administered 5 mg of EDP once on Day 39 (n = 5), twice on Days 32 and 39 (n = 5) and three times on Days 25, 32 and 39 (n = 6). All animals were treated with prostaglandin F2α (PGF2α) on Day 46 for induced lactation. Artificial lactation was induced in 66.7%-80.0% of sows, and the EDP treatment frequency before PGF2α administration had no significant effect on either the induction rate of artificial lactation or the milk yield during the experimental period. The milk composition (levels of crude protein, crude fat, crude ash, lactose and immunoglobulin) did not differ among the groups. In conclusion, the number of EDP treatments prior to PGF2α administration had no effect on either the efficiency of artificial lactation induction or milk production.

Preoperative topical estrogen application in the management of hypospadias: a systematic review.

Local estrogen therapy has been explored as an alternative to conventional testosterone therapy in children requiring urethroplasty for hypospadias. Our objective is to evaluate if preoperative estrogen stimulation reduces post-urethroplasty complications and enhances penile dimensions. A systematic search was conducted on various databases, selecting only randomized controlled trials (RCTs) that tested estrogen on hypospadias patients under 18 years. Articles underwent sorting following PRISMA guidelines and bias risk was assessed using the JBI clinical appraisal tool for RCTs. Out of 607 screened records, 10 underwent full-text review, and 4 randomized controlled trials (RCTs) were selected for analysis. The total patient cohort across studies was 387 with 174 in the estrogen group. All studies utilized topical estrogen, but in different formulations and timings. Prudence is necessary for interpreting results due to variations in formulation, timing, and hypospadias type across studies. Limited by a small number of studies and outcome presentation non-uniformity, the review suggests no change in penile dimensions or postoperative complications with topical estrogen. Further research is needed to explore wound-healing properties of estrogen in hypospadias through animal and human studies.Registration and protocol: Registered in Prospero CRD42024502183.

Menopausal hormone therapy and risk of venous thromboembolism: The story so far.

Menopausal hormone therapy (MHT) is known to increase the risk of venous thromboembolism (VTE), which includes deep vein thrombosis, pulmonary embolism, and less frequently cerebral vein thrombosis, but the absolute risk for a given patient is very low. After starting MHT, the risk of VTE seems to be at its highest, declining to the non-HRT user baseline level of risk after stopping. Whether estrogen-only or estrogen-progestin HRT combination is linked to a similar risk of VTE is unclear from the available evidence. The aim of this study is to evaluate the risks of developing VTE in relation to different types as well as different modes of administration of MHT through a database search including PubMed, MEDLINE, Google Scholar, Cochrane Library, and others in order to provide the women carers with the up-to-date and evidence-based guidelines and recommendations while counseling the post-menopausal women enquiring on use of hormonal therapies either to alleviate the menopausal symptoms or to prevent the long-term sequelae of estrogen deficiency.

On sait que l'hormonothérapie ménopausique (MHT) augmente le risque de thromboembolie veineuse (TEV), qui comprend la thrombose veineuse profonde, l'embolie pulmonaire et, moins fréquemment, la thrombose veineuse cérébrale, mais le risque absolu pour un patient donné est très faible. Après le début du MHT, le risque de TEV semble être à son plus haut niveau, diminuant jusqu'au niveau de risque de base des non-utilisatrices de THS après l'arrêt. Les preuves disponibles ne permettent pas de savoir si un THS à base d'œstrogène seul ou d'association œstroprogestative est lié à un risque similaire de TEV. Le but de cette étude est d'évaluer les risques de développer une TEV par rapport à différents types ainsi qu'à différents modes d'administration du MHT grâce à une recherche dans des bases de données comprenant PubMed, MEDLINE, Google Scholar, Cochrane Library et autres afin de fournir aux femmes les soignants avec les lignes directrices et recommandations à jour et fondées sur des preuves tout en conseillant les femmes ménopausées qui se renseignent sur l'utilisation de thérapies hormonales, soit pour soulager les symptômes de la ménopause, soit pour prévenir les séquelles à long terme d'une carence en œstrogènes.

Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme.

BACKGROUND: Androgen suppression is a central component of prostate cancer management but causes substantial long-term toxicity. Transdermal administration of oestradiol (tE2) circumvents first-pass hepatic metabolism and, therefore, should avoid the cardiovascular toxicity seen with oral oestrogen and the oestrogen-depletion effects seen with luteinising hormone releasing hormone agonists (LHRHa). We present long-term cardiovascular follow-up data from the Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. METHODS: PATCH is a seamless phase 2/3, randomised, multicentre trial programme at 52 study sites in the UK. Men with locally advanced or metastatic prostate cancer were randomly allocated (1:2 from August, 2007 then 1:1 from February, 2011) to either LHRHa according to local practice or tE2 patches (four 100 µg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks [defined as testosterone ≤1·7 nmol/L]). Randomisation was done using a computer-based minimisation algorithm and was stratified by several factors, including disease stage, age, smoking status, and family history of cardiac disease. The primary outcome of this analysis was cardiovascular morbidity and mortality. Cardiovascular events, including heart failure, acute coronary syndrome, thromboembolic stroke, and other thromboembolic events, were confirmed using predefined criteria and source data. Sudden or unexpected deaths were attributed to a cardiovascular category if a confirmatory post-mortem report was available and as other relevant events if no post-mortem report was available. PATCH is registered with the ISRCTN registry, ISRCTN70406718; the study is ongoing and adaptive. FINDINGS: Between Aug 14, 2007, and July 30, 2019, 1694 men were randomly allocated either LHRHa (n=790) or tE2 patches (n=904). Overall, median follow-up was 3·9 (IQR 2·4-7·0) years. Respective castration rates at 1 month and 3 months were 65% and 93% among patients assigned LHRHa and 83% and 93% among those allocated tE2. 157 events from 145 men met predefined cardiovascular criteria, with a further ten sudden deaths with no post-mortem report (total 167 events in 153 men). 26 (2%) of 1694 patients had fatal cardiovascular events, 15 (2%) of 790 assigned LHRHa and 11 (1%) of 904 allocated tE2. The time to first cardiovascular event did not differ between treatments (hazard ratio 1·11, 95% CI 0·80-1·53; p=0·54 [including sudden deaths without post-mortem report]; 1·20, 0·86-1·68; p=0·29 [confirmed group only]). 30 (34%) of 89 cardiovascular events in patients assigned tE2 occurred more than 3 months after tE2 was stopped or changed to LHRHa. The most frequent adverse events were gynaecomastia (all grades), with 279 (38%) events in 730 patients who received LHRHa versus 690 (86%) in 807 patients who received tE2 (p<0·0001) and hot flushes (all grades) in 628 (86%) of those who received LHRHa versus 280 (35%) who received tE2 (p<0·0001). INTERPRETATION: Long-term data comparing tE2 patches with LHRHa show no evidence of a difference between treatments in cardiovascular mortality or morbidity. Oestrogens administered transdermally should be reconsidered for androgen suppression in the management of prostate cancer. FUNDING: Cancer Research UK, and Medical Research Council Clinical Trials Unit at University College London.

Vaginal estrogen and association with dementia: A nationwide population-based study.

INTRODUCTION: Use of systemic hormone therapy has been positively associated with development of dementia. Little is known about the dose-dependent effect of vaginal estradiol on dementia risk. METHODS: We assessed associations between cumulative dose of vaginal estradiol tablets and dementia in a case-control study nested in a nationwide Danish cohort of women aged 50 to 60 years at study initiation, who did not use systemic hormone therapy. Each case was age-matched to 10 female controls. RESULTS: A total of 4574 dementia cases were matched to 45,740 controls. Cumulative use of vaginal estradiol tablets was not associated with all-cause dementia; adjusted hazard ratio 1.02 (95% confidence interval [CI] 0.89-1.18) for low dose (< 750 mcg), 1.07 (0.94-1.21) for medium dose (750-2000 mcg), and 0.93 (0.84-1.03) for high dose (> 2000 mcg). Similarly, Alzheimer's disease (AD) only was not associated with vaginal estradiol. DISCUSSION: Exposure to vaginal estradiol tablets was not associated with all-cause dementia or AD only.

The Influence of Intravaginal Gestagens Treatment on the Morphological Features and Endometrial Steroid Hormone Receptors Content during Anestrus Type II in Dairy Cattle.

BACKGROUND: Gestagens are the most widely used therapy in anestrus type II. The aim of this research is to evaluate the effectiveness of the vaginal progesterone inserts therapy in anestrus type II in cows. METHODS: The study was conducted on 33 cows. Progesterone (PR) and estrogen (ER) receptors expression in endometrium was assessed on a molecular level based on mRNA tissue expression. Additionally, blood 17ß-estradiol and progesterone levels were evaluated. RESULTS: A decrease in mRNA expression of A and B PR and ER α was noted in treated and untreated animals. In the treated group, an increase of ERß mRNA expression was observed, while a decreased was found in untreated animals. There was increased PR, ERα and ß expression in endometrial tissue in treated cows, and decreased expression of these factors in untreated cows. In the treated group, recurrence of ovarian cyclicity was noted in 52% of animals and pregnancy was obtained in 34.8% of them, while in the untreated group, recurrence did not occur. In the control group, spontaneous recurrence of ovarian cyclicity was not observed. An increase of PR expression was correlated with increased proliferation of endometrial cells. CONCLUSIONS: It seems likely that the endometrium is well developed and ready for placentation after removing the exogenous source of progesterone and preventing the recurrence of cyclicity of ovaries.

An immune-humanized patient-derived xenograft model of estrogen-independent, hormone receptor positive metastatic breast cancer.

BACKGROUND: Metastatic breast cancer (MBC) is incurable, with a 5-year survival rate of 28%. In the USA, more than 42,000 patients die from MBC every year. The most common type of breast cancer is estrogen receptor-positive (ER+), and more patients die from ER+ breast cancer than from any other subtype. ER+ tumors can be successfully treated with hormone therapy, but many tumors acquire endocrine resistance, at which point treatment options are limited. There is an urgent need for model systems that better represent human ER+ MBC in vivo, where tumors can metastasize. Patient-derived xenografts (PDX) made from MBC spontaneously metastasize, but the immunodeficient host is a caveat, given the known role of the immune system in tumor progression and response to therapy. Thus, we attempted to develop an immune-humanized PDX model of ER+ MBC. METHODS: NSG-SGM3 mice were immune-humanized with CD34+ hematopoietic stem cells, followed by engraftment of human ER+ endocrine resistant MBC tumor fragments. Strategies for exogenous estrogen supplementation were compared, and immune-humanization in blood, bone marrow, spleen, and tumors was assessed by flow cytometry and tissue immunostaining. Characterization of the new model includes assessment of the human tumor microenvironment performed by immunostaining. RESULTS: We describe the development of an immune-humanized PDX model of estrogen-independent endocrine resistant ER+ MBC. Importantly, our model harbors a naturally occurring ESR1 mutation, and immune-humanization recapitulates the lymphocyte-excluded and myeloid-rich tumor microenvironment of human ER+ breast tumors. CONCLUSION: This model sets the stage for development of other clinically relevant models of human breast cancer and should allow future studies on mechanisms of endocrine resistance and tumor-immune interactions in an immune-humanized in vivo setting.

Perinatal activation of ERα and ERß but not GPER-1 masculinizes female rat caudate-putamen medium spiny neuron electrophysiological properties.

Exposure to steroid sex hormones such as 17ß-estradiol (estradiol) during early life potentially permanently masculinize neuron electrophysiological phenotype. In rodents, one crucial component of this developmental process occurs in males, with estradiol aromatized in the brain from testes-sourced testosterone. However, it is unknown whether most neuron electrophysiological phenotypes are altered by this early masculinization process, including medium spiny neurons (MSNs) of the rat caudate-putamen. MSNs are the predominant and primary output neurons of the caudate-putamen and exhibit increased intrinsic excitability in females compared to males. Here, we hypothesize that since perinatal estradiol exposure occurs in males, then a comparable exposure in females to estradiol or its receptor agonists would be sufficient to induce masculinization. To test this hypothesis, we injected perinatal female rats with estradiol or its receptor agonists and then later assessed MSN electrophysiology. Female and male rats on postnatal day 0 and 1 were systemically injected with either vehicle, estradiol, the estrogen receptor (ER)α agonist PPT, the ERß agonist DPN, or the G-protein-coupled receptor 1 (GPER-1) agonist G1. On postnatal days 19 ± 2, MSN electrophysiological properties were assessed using whole cell patch clamp recordings. Estradiol exposure abolished increased intrinsic excitability in female compared to male MSNs. Exposure to either an ERα or ERß agonist masculinized female MSN evoked action potential firing rate properties, whereas exposure to an ERß agonist masculinized female MSN inward rectification properties. Exposure to ER agonists minimally impacted male MSN electrophysiological properties. These findings indicate that perinatal estradiol exposure masculinizes MSN electrophysiological phenotype via activation of ERα and ERß.NEW & NOTEWORTHY This study is the first to demonstrate that estradiol and estrogen receptor α and ß stimulation during early development sexually differentiates the electrophysiological properties of caudate-putamen medium spiny neurons, the primary output neuron of the striatal regions. Overall, this evidence provides new insight into the neuroendocrine mechanism by which caudate-putamen neuron electrophysiology is sexually differentiated and demonstrates the powerful action of early hormone exposure upon individual neuron electrophysiology.

The Urinary Microbiome in Postmenopausal Women with Recurrent Urinary Tract Infections.

PURPOSE: The etiology of postmenopausal recurrent urinary tract infection (UTI) is not completely known, but the urinary microbiome is thought to be implicated. We compared the urinary microbiome in menopausal women with recurrent UTIs to age-matched controls, both in the absence of acute infection. MATERIALS AND METHODS: This is a cross-sectional analysis of baseline data from 64 women enrolled in a longitudinal cohort study. All women were using topically applied vaginal estrogen. Women >55 years of age from the following groups were enrolled: 1) recurrent UTIs on daily antibiotic prophylaxis, 2) recurrent UTIs not on antibiotic prophylaxis and 3) age-matched controls without recurrent UTIs. Catheterized urine samples were collected at least 4 weeks after last treatment for UTI and at least 6 weeks after initiation of vaginal estrogen. Samples were evaluated using expanded quantitative urine culture (EQUC) and 16S rRNA gene sequencing. RESULTS: With EQUC, there were no significant differences in median numbers of microbial species isolated among groups (p=0.96), even when considering Lactobacilli (p=0.72). However, there were trends toward different Lactobacillus species between groups. With 16S rRNA sequencing, the majority of urine samples contained Lactobacillaceae, with nonsignificant trends in relative abundance among groups. Using a Bayesian analysis, we identified significant differences in anaerobic taxa associated with phenotypic groups. Most of these differences centered on Bacteroidales and the family Prevotellaceae, although differences were also noted in Actinobacteria and certain genera of Clostridiales. CONCLUSIONS: Associations between anaerobes within the urinary microbiome and postmenopausal recurrent UTI warrants further investigation.

Estrogen markedly reduces circulating low-density neutrophils and enhances pro-tumoral gene expression in neutrophil of tumour-bearing mice.

BACKGROUND: Neutrophils are important for immune surveillance of tumour cells. Neutrophils may also be epigenetically programmed in the tumour microenvironment to promote tumour progression. In addition to the commonly known high-density neutrophils (HDN) based on their separation on density gradient, recent studies have reported the presence of high levels of low-density neutrophils (LDN) in tumour-bearing mice and cancer patients. We reported previously that estrogen promotes the growth of estrogen receptor α-negative mammary tumours in mice undergoing mammary involution through stimulating pro-tumoral activities of neutrophils in the mammary tissue. METHODS: Female BALB/cAnNTac mice at 7-8 weeks old were mated and bilateral ovariectomy was performed 2 days post-partum. At 24 h after forced-weaning of pups to induce mammary involution, post-partum female mice were injected with either E2V, or vehicle control on alternative days for 2-weeks. On 48 h post-weaning, treated female mice were inoculated subcutaneously with 4 T1-Luc2 cells into the 9th abdominal mammary gland. Age-matched nulliparous female was treated similarly. Animals were euthanized on day 14 post-tumour inoculation for analysis. To evaluate the short-term effect of estrogen, post-partum females were treated with only one dose of E2V on day 12 post-tumour inoculation. RESULTS: Estrogen treatment for 2-weeks reduces the number of blood LDN by more than 10-fold in tumour-bearing nulliparous and involuting mice, whilst it had no significant effect on blood HDN. The effect on tumour-bearing mice is associated with reduced number of mitotic neutrophils in the bone marrow and increased apoptosis in blood neutrophils. Since estrogen enhanced tumour growth in involuting mice, but not in nulliparous mice, we assessed the effect of estrogen on the gene expression associated with pro-tumoral activities of neutrophils. Whilst 48 h treatment with estrogen had no effect, 2-weeks treatment significantly increased the expression of Arg1, Il1b and Tgfb1 in both HDN and LDN of involuting mice. In contrast, estrogen increased the expression of Arg1 and Ccl5 in HDN and LDN of nulliparous mice. CONCLUSIONS: Prolonged estrogenic stimulation in tumour-bearing mice markedly hampered tumour-associated increase of LDN plausibly by inhibiting their output from the bone marrow and by shortening their life span. Estrogen also alters the gene expression in neutrophils that is not seen in tumour-free mice. The results imply that estrogen may significantly influence the tumour-modulating activity of blood neutrophils.

Protective Effects of Estrogen via Nanoparticle Delivery to Attenuate Myelin Loss and Neuronal Death after Spinal Cord Injury.

Spinal cord injury (SCI) is associated with devastating neurological deficits affecting more than 11,000 Americans each year. Although several therapeutic agents have been proposed and tested, no FDA-approved pharmacotherapy is available for SCI treatment. We have recently demonstrated that estrogen (E2) acts as an antioxidant and anti-inflammatory agent, attenuating gliosis in SCI. We have also demonstrated that nanoparticle-mediated focal delivery of E2 to the injured spinal cord decreases lesion size, reactive gliosis, and glial scar formation. The current study tested in vitro effects of E2 on reactive oxygen species (ROS) and calpain activity in microglia, astroglia, macrophages, and fibroblasts, which are believed to participate in the inflammatory events and glial scar formation after SCI. E2 treatment decreased ROS production and calpain activity in these glial cells, macrophages, and fibroblast cells in vitro. This study also tested the efficacy of fast- and slow-release nanoparticle-E2 constructs in a rat model of SCI. Focal delivery of E2 via nanoparticles increased tissue distribution of E2 over time, attenuated cell death, and improved myelin preservation in injured spinal cord. Specifically, the fast-release nanoparticle-E2 construct reduced the Bax/Bcl-2 ratio in injured spinal cord tissues, and the slow-release nanoparticle-E2 construct prevented gliosis and penumbral demyelination distal to the lesion site. These data suggest this novel E2 delivery strategy to the lesion site may decrease inflammation and improve functional outcomes following SCI.