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Purpose In the Women’s Health initiative (WHI) randomized clinical trial, conjugated equine estrogen (CEE)-alone significantly reduced breast cancer incidence ( P  = 0.005). As cohort studies had opposite findings, other randomized clinical trials were identified to conduct a meta-analysis of estrogen-alone influence on breast cancer incidence. Methods We conducted literature searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analysis and reviews. In the meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, the corresponding log-RR = (O – E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP. Results Findings from 10 randomized trials included 14,282 participants and 591 incident breast cancers. In 9 smaller trials, with 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) (RR 0.65 95% CI 0.38–1.11, P  = 0.12). For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34–1.16, P  = 0.15. Combining the 10 trials, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo (overall RR 0.77 95% CI 0.65–0.91, P  = 0.002). Conclusion The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use significantly reduces breast cancer incidence.

Oestrogens and their receptors contribute broadly to physiology and diseases. In premenopausal women, endogenous oestrogens protect against cardiovascular, metabolic and neurological diseases and are involved in hormone-sensitive cancers such as breast cancer. Oestrogens and oestrogen mimetics mediate their effects via the cytosolic and nuclear receptors oestrogen receptor-α (ERα) and oestrogen receptor-β (ERβ) and membrane subpopulations as well as the 7-transmembrane G protein-coupled oestrogen receptor (GPER). GPER, which dates back more than 450 million years in evolution, mediates both rapid signalling and transcriptional regulation. Oestrogen mimetics (such as phytooestrogens and xenooestrogens including endocrine disruptors) and licensed drugs such as selective oestrogen receptor modulators (SERMs) and downregulators (SERDs) also modulate oestrogen receptor activity in both health and disease. Following up on our previous Review of 2011, we herein summarize the progress made in the field of GPER research over the past decade. We will review molecular, cellular and pharmacological aspects of GPER signalling and function, its contribution to physiology, health and disease, and the potential of GPER to serve as a therapeutic target and prognostic indicator of numerous diseases. We also discuss the first clinical trial evaluating a GPER-selective drug and the opportunity of repurposing licensed drugs for the targeting of GPER in clinical medicine.The 7-transmembrane G protein-coupled receptor GPR30 has been recognized as a G protein-coupled oestrogen receptor (GPER) since 2008. This Review discusses progress in GPER research in physiology and disease and its potential implications for clinical medicine.

In two identical, double-blind, randomized, 6-month phase 3 trials, elagolix (an oral gonadotropin-releasing hormone antagonist), administered with hormonal add-back therapy (estradiol, 1 mg, and norethindrone acetate, 0.5 mg, once daily) was more effective in reducing heavy menstrual bleeding in women with uterine fibroids than placebo. Bone loss was attenuated with add-back therapy, as compared with elagolix alone.

In the first complete history of hormone replacement therapy (HRT), Elizabeth Siegel Watkins illuminates the complex and changing relationship between the medical treatment of menopause and cultural conceptions of aging. Describing the development, spread, and shifting role of HRT in America from the early twentieth century to the present, Watkins explores how the interplay between science and society shaped the dissemination and reception of HRT and how the medicalization—and subsequent efforts toward the demedicalization—of menopause and aging affected the role of estrogen as a medical therapy. Telling the story from multiple perspectives—physicians, pharmaceutical manufacturers, government regulators, feminist health activists, and the media, as well as women as patients and consumers—she reveals the striking parallels between estrogen's history as a medical therapy and broad shifts in the role of medicine in an aging society. Today, information about HRT is almost always accompanied by a laundry list of health risks. While physicians and pharmaceutical companies have striven to develop the safest possible treatment for the symptoms of menopause and aging, many specialists question whether HRT should be prescribed at all. Drawing from a wide range of scholarly research, archival records, and interviews, The Estrogen Elixir provides valuable historical context for one of the most pressing debates in contemporary medicine.

In this pragmatic, randomized trial of women with menorrhagia, the levonorgestrel-releasing intrauterine system was more effective than the usual (oral) medical treatment in reducing the effect of this problem on quality of life. Heavy menstrual bleeding, or menorrhagia, is a common problem that can have a significant effect on women's lives and can burden both patients and health care systems. 1 , 2 Menorrhagia accounts for 18.5% of gynecologist office visits in the United States 3 and for 20% in the United Kingdom 4 ; more than 5% of women who are 30 to 49 years of age consult family physicians each year in the United Kingdom with this problem. 5 Rates of surgical procedures for menorrhagia are 17.8 per 10,000 women 25 to 44 years of age in the United States 6 and 14.3 per 10,000 women 24 . . .

Many women with schizophrenia remain symptomatic despite optimal use of current therapies. While previous studies suggest that adjunctive oestrogen therapy might be effective, large-scale clinical trials are required before clinical applications are possible. This study is the first large-scale randomized-controlled trial in women with treatment-resistant schizophrenia. This Definitive Oestrogen Patch Trial was an 8-week, three-arm, double-blind, randomized-controlled trial conducted between 2006 and 2011. The 183 female participants were aged between 18 and 45 (mean=35 years), with schizophrenia or schizoaffective disorder and ongoing symptoms of psychosis (Positive and Negative Syndrome Scale, PANSS score>60) despite a stable dose of antipsychotic medication for at least 4 weeks. Mean duration of illness was more than 10 years. Participants received transdermal estradiol 200 μg, transdermal estradiol 100 μg or an identical placebo patch. For the 180 women who completed the study, the a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56. Cognition was assessed at baseline and day 56 using the Repeatable Battery of Neuropsychological Status. Data were analysed using latent growth curve modelling. Both estradiol groups had greater decreases in PANSS positive, general and total symptoms compared with the placebo group ( P <0.01), with a greater effect seen for 200 μg than 100 μg estradiol. The largest effect size was for the positive subscale of PANSS in the estradiol 200 μg treatment group (effect size 0.44, P <0.01). This study shows estradiol is an effective and clinically significant adjunctive therapy for women with treatment-resistant schizophrenia, particularly for positive symptoms.

A dysbiotic vaginal microbiome (VMB) is associated with clinical conditions such as bacterial vaginosis (BV) and an increased risk of human immunodeficiency virus (HIV-1) infection. Considering the high prevalence of BV among African, Caribbean and Black (ACB) women, we conducted a prospective, randomized, open-label phase 1 clinical trial to determine the feasibility, safety and tolerability of administering low-dose estrogen, probiotics or both in combination to improve vaginal health and decrease HIV-1 susceptibility. ACB women aged 18-49 from the Greater Toronto Area (GTA) were randomized to one of four study arms: intravaginal estradiol (Estring©; 7.5mg/day); a vaginal probiotic (RepHresh™ Pro-B™) administered twice daily; a combination of Estring© and vaginal RepHresh™ Pro-B™ (twice daily); or the Estring© and oral RepHresh™ Pro-B™ (twice daily), for a duration of 30 days. Feasibility was evaluated through enrolment, retention, and adherence rates, while safety and tolerability were determined by a pre- and post-treatment blood panel and reported adverse events (AEs). Overall, 63 ACB women were screened, 50 were enrolled and received the intervention while 41 completed the study, resulting in 80% enrollment and 82% retention rates. Overall adherence to the study protocol was high at 93%, with an adherence of 92% for RepHresh™ Pro-B™ and 97% for Estring©. A total of 88 AEs were reported by 29 participants which were mild (66/88; 75%) and largely resolved (82/88;93%) by the end of the study, with no serious AEs (SAEs) noted. In addition, a panel of safety blood markers measured pre- and post-intervention confirmed no clinically significant changes in blood chemistry or blood cell count. Overall, the administration of intravaginal estrogen and/or probiotics in pre-menopausal ACB women is feasible, safe, and well tolerated. The trial was registered with Clinicaltrials.gov (NCT03837015) and CIHR HIV Clinical Trials (CTN308).

This study aimed to evaluate the effect of estrogen replacement therapy on verbal cognitive performance of middle-aged postmenopausal women. Middle-aged (40 to 59 years) hysterectomized, oligosymptomatic women receiving 0.625 mg/day of conjugated equine estrogens ( N  = 27) or placebo ( N  = 32) in a double-blind parallel group design were compared according to their performance on a verbal memory battery before and after six 28-day cycles of treatment. Both groups had similar age and educational level. The estrogen group performed better on digit span-forward and on the recall of the easy stimuli on the verbal-paired associates test regardless of age, education, physical symptoms, number of years of menopause, or blood estradiol levels. However, the small magnitude of difference in the effect on attentional span suggests that the estrogen-related improvement is unlikely to be of clinical relevance. Estrogen replacement therapy did not improve verbal memory in middle-aged, hysterectomized, postmenopausal, asymptomatic women.

PurposeThe development of oestrogen resistance is a major challenge in managing hormone-sensitive metastatic breast cancer. Saracatinib (AZD0530), an oral Src kinase inhibitor, prevents oestrogen resistance in animal models and reduces osteoclast activity. We aimed to evaluate the efficacy of saracatinib addition to aromatase inhibitors (AI) in patients with hormone receptor-positive metastatic breast cancer.MethodsThis phase II multicentre double-blinded randomised trial allocated post-menopausal women to AI with either saracatinib or placebo (1:1 ratio). Patients were stratified into an “AI-sensitive/naïve” group who received anastrozole and “prior-AI” group who received exemestane. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR) and toxicity. Results140 patients were randomised from 20 UK centres to saracatinib/AI (n = 69) or placebo/AI (n = 71). Saracatinib was not associated with an improved PFS (3.7 months v. 5.6 months placebo/AI) and did not reduce likelihood of bony progression. There was no benefit in OS or ORR. Effects were consistent in “AI-sensitive/naive” and “prior-AI” sub-groups. Saracatinib was well tolerated with dose reductions in 16% and the main side effects were gastrointestinal, hypophosphatemia and rash. ConclusionSaracatinib did not improve outcomes in post-menopausal women with metastatic breast cancer. There was no observed beneficial effect on bone metastases.CRUKE/11/023, ISRCTN23804370.

Objective To investigate the long term effect of hormone replacement therapy on cardiovascular outcomes in recently postmenopausal women.Design Open label, randomised controlled trial.Setting Denmark, 1990-93.Participants 1006 healthy women aged 45-58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone values. 502 women were randomly allocated to receive hormone replacement therapy and 504 to receive no treatment (control). Women who had undergone hysterectomy were included if they were aged 45-52 and had recorded values for postmenopausal serum follicle stimulating hormone.Interventions In the treatment group, women with an intact uterus were treated with triphasic estradiol and norethisterone acetate and women who had undergone hysterectomy received 2 mg estradiol a day. Intervention was stopped after about 11 years owing to adverse reports from other trials, but participants were followed for death, cardiovascular disease, and cancer for up to 16 years. Sensitivity analyses were carried out on women who took more than 80% of the prescribed treatment for five years.Main outcome measure The primary endpoint was a composite of death, admission to hospital for heart failure, and myocardial infarction.Results At inclusion the women on average were aged 50 and had been postmenopausal for seven months. After 10 years of intervention, 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group (hazard ratio 0.48, 95% confidence interval 0.26 to 0.87; P=0.015) and 15 died compared with 26 (0.57, 0.30 to 1.08; P=0.084). The reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group v 39 in control group, 0.92, 0.58 to 1.45; P=0.71) or in breast cancer (10 in treated group v 17 in control group, 0.58, 0.27 to 1.27; P=0.17). The hazard ratio for deep vein thrombosis (2 in treated group v 1 in control group) was 2.01 (0.18 to 22.16) and for stroke (11 in treated group v 14 in control group) was 0.77 (0.35 to 1.70). After 16 years the reduction in the primary composite outcome was still present and not associated with an increase in any cancer.Conclusions After 10 years of randomised treatment, women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke.Trial registration ClinicalTrials.gov NCT00252408.