Ultra-low dose estradiol and dydrogesterone for the treatment of menopausal symptoms in a pooled, multi-ethnic population.

OBJECTIVES: Evidence suggests ethnicity-specific differences in postmenopausal symptoms, highlighting the need for therapies that are efficacious across different ethnicities. We evaluated the efficacy of an ultra-low dose combination of 0.5 mg estradiol and 0.25 mg dydrogesterone (E 0.5 mg/D 2.5 mg) in alleviating vasomotor symptoms across a multi-ethnic population. STUDY DESIGN: Data from two controlled trials were pooled to form a dataset of 583 postmenopausal women from across Europe and China. Participants were randomized to receive treatment with E 0.5 mg/D 2.5 mg or placebo for 12 weeks. MAIN OUTCOME MEASURES: The main efficacy variable was absolute change in the number of hot flushes from baseline to end of treatment. Health-related quality of life and safety were also assessed. RESULTS: Change in the number of hot flushes per day was greater with E 0.5 mg/D 2.5 mg versus placebo (mean difference - 1.5, 95 % confidence interval - 2.1, -1.0; p < 0.001). Participants treated with E 0.5 mg/D 2.5 mg reported improvement in health-related quality of life (including psychological symptoms, vaginal dryness), and high amenorrhea rates. Combined E 0.5 mg/D 2.5 mg was well tolerated: there were no differences between groups in the percentage of participants with at least one serious adverse event or treatment-emergent serious adverse events. Analysis of change in body weight indicated no differences between groups. CONCLUSIONS: This pooled analysis demonstrates the consistent efficacy of E 0.5 mg/D 2.5 mg in the treatment of menopause-related symptoms across a multi-ethnic population of postmenopausal women.

Ultra-low-dose estradiol and dydrogesterone for treatment of vasomotor symptoms in Europe and China.

OBJECTIVE: Among postmenopausal women, oral, ultra-low-dose continuous combined estradiol (E0.5 mg) plus dydrogesterone (D2.5 mg) reduces vasomotor symptoms (VMS). METHODS: This study was a post hoc analysis of data from two phase 3, double-blind studies. Postmenopausal women were randomized 2:1:2 to receive E0.5 mg/D2.5 mg, E1 mg/D5 mg (not included in this analysis) or placebo for 13 weeks (European study), or randomized 1:1 to receive E0.5 mg/D2.5 mg or placebo for 12 weeks (Chinese study). Endpoints assessed in ethnicity subgroups (European and Chinese) included changes from baseline in number of hot flushes, number of moderate-to-severe hot flushes and Menopause Rating Scale (MRS) score. RESULTS: Overall, 579 women were included in the analysis (E0.5 mg/D2.5 mg, n = 288; placebo, n = 291). European and Chinese women receiving E0.5 mg/D2.5 mg experienced greater reductions from baseline in mean daily number of hot flushes and mean daily number of moderate-to-severe hot flushes at week 4, week 8 and end of treatment versus those receiving placebo. Significant improvements in the 'hot flushes, sweating' MRS item score were reported in both European and Chinese women. CONCLUSION: Oral, ultra-low-dose continuous combined 0.5 mg 17ß-estradiol and 2.5 mg dydrogesterone improved VMS compared with placebo in European and Chinese postmenopausal women, with a positive impact on health-related quality of life.

Ultra-low-dose continuous combined estradiol and dydrogesterone in postmenopausal women: A pooled safety and tolerability analysis.

Objective: To assess the safety and tolerability of ultra-low dose estradiol and dydrogesterone (E0.5 mg/D2.5 mg) among postmenopausal women. Methods: This pooled analysis of data from three clinical studies assessed the effects of continuous combined ultra-low-dose estradiol and dydrogesterone among postmenopausal women. Participants received E0.5 mg/D2.5 mg or placebo for 13 weeks (double-blind, randomized, European study), E0.5 mg/D2.5 mg or placebo for 12 weeks (double-blind, randomized, Chinese study), or E0.5 mg/D2.5 mg for 52 weeks (open-label, European study). Safety outcomes included treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), treatment discontinuation due to a TEAE, and adverse events of special interest (AESIs). Results: Overall, 1027 women were included in the pooled analysis (E0.5 mg/D2.5 mg, n = 736; placebo, n = 291). Mean treatment exposure was 288.9 days in the E0.5 mg/D2.5 mg group and 86.6 days in the placebo group. The proportion of women experiencing ≥1 TEAE was similar in the E0.5 mg/D2.5 mg and placebo groups (50.1% vs 49.5%, respectively). TESAEs occurred in 12 (1.6%) women receiving E0.5 mg/D2.5 mg and 9 (3.1%) women receiving placebo. Discontinuation of study treatment was infrequent in both groups (E0.5 mg/D2.5 mg: 1.5%; placebo: 2.4%). The occurrence of breast pain was more common in the E0.5 mg/D2.5 mg group than in the placebo group (2.0% vs 0.3%) as was uterine hemorrhage (6.5% vs 2.4%). The incidence of acne, hypertrichoses and weight increased was similar between groups. Conclusions: Across three studies, ultra-low-dose estradiol plus dydrogesterone was well tolerated among postmenopausal women, with no increase in TEAEs or TESAEs compared with placebo.

Cardiovascular health and the menopause, metabolic health.

Estrogen depletion following menopause predisposes to increased risk of cardiovascular disease (CVD), mainly due to ischemic heart disease. This is mostly evident in cases with premature menopause. The pathophysiological basis for this atherosclerotic process is the accumulation of several risk factors, such as abdominal obesity, atherogenic dyslipidemia, insulin resistance and arterial hypertension. The presence of vasomotor symptoms may further augment this risk, especially in women younger than 60 years. Menopausal hormone therapy (MHT) exerts many beneficial effects on lipid profile and glucose homeostasis as well as direct arterial effects, and may reduce CVD risk if initiated promptly (i.e.,<60 years or within ten years of the final menstrual period). Transdermal estradiol and micronized progesterone or dydrogesterone are the safest regimens in terms of venous thromboembolic events (VTE) and breast cancer risk. In any case, an individualized approach, taking into account the patient's total CVD, VTE and breast cancer risk, is recommended.

Rheumatoid Arthritis-Linked Artificial Joint Infections Leading to Amputations.

Rheumatoid arthritis (RA) is a common autoimmune condition that can rarely cause more serious complications, such as permanent joint damage or infection, and may pose a significant additional risk during certain routine procedures. One major consequence of RA is that it can lead to serious and permanent joint damage requiring arthroplasty. Additionally, RA is a known cause of infection, with orthopedic prosthetic joint infections (PJIs) being documented. We explore one such serious case of a patient with long-term RA and a left knee joint replacement who presented to the emergency room with a serious PJI. History revealed that he repeatedly was affected by infections and had an extensive and severe clinical course, including nine revision surgeries. After a physical examination, imaging was performed, which further supported the diagnosis of joint infection. Considering the extensive number of attempts to salvage the joint, clinicians decided an above-knee amputation was necessary. This case highlights the fact that RA both increases the need for orthopedic arthroplasties and the risk of complications from these procedures, complicating clinical decision-making for physicians. Additionally, this patient had other underlying medical conditions and social habits that may have contributed to his severe clinical course, and we hope to explore these, discuss possible methods of modifying them, and assist clinicians in not only better treating similar patients but also emphasizing the importance of further developing standardized predictive algorithms and scoring tools.

Researcher Views of Barriers to Clinical and Translational Research in a Statewide Program.

The Tracking and Evaluation Core of Rhode Island Advance-CTR conducted an online needs assessment survey at the program's inception in 2016 and again in 2021. Now dealing with well-established support systems provided by the grant, we were particularly interested in how the perceived needs of the research community in Rhode Island might have changed over five years. Specifically, what barriers have been reduced or eliminated and which have persisted or increased? How do those barriers vary by demographic status and what implications do those differences have for the CTR? An online survey was completed by 199 researchers, who reported the extent to which they perceived the lack of access to a range of research supports as a barrier to conducting research at their institution. Overall, researchers indicated statistically significant changes from 2016 to 2021 such that a lack of pilot project funding and proposal development support had decreased as barriers, while space for research, and advice on commercial development, had increased. Statistically significant differences in the salience of particular barriers by some demographic variables were also noted and the results of this study suggest Centers for Clinical and Translational Research can have salutary effects on the research paradigm within their partnering institutions in a relatively short time.

Evaluating systemic changes to support clinical and translational health research.

In evaluation research, "programs" are often conceptualized as clearly bounded, narrow in scope, focused on specific outcomes, using a well-defined linear causal model, and hence, suitable for standard evaluation methods. The evaluation work reported here was carried out in a more challenging context, where large, complex, interwoven systems were targets for change as a means to influence a diffuse array of outcomes. Our evaluation of an NIH-funded program to improve statewide infrastructure for clinical and translational health research ("Advance-CTR") used qualitative data provided by investigators who used the program's services, were funded awardees, or were members of an internal advisory committee (leadership representatives from partnering institutions). We examined perceived barriers to systemic changes to enhance research, as well as how systems have changed due to the Rhode Island Advance-CTR program's efforts, to what degree, and with what effects. Using the causal logic of our program to connect these more distal systemic outcomes to the services and components of Advance-CTR, we discuss the effects this program has had on researchers and their environments, contributing to the development of sustainable programs of research that ultimately improve the health and well-being of our state's residents.

Menopause-associated risk of cardiovascular disease.

Cardiovascular disease (CVD) is of major concern in women entering menopause. The changing hormonal milieu predisposes them to increased CVD risk, due to a constellation of risk factors, such as visceral obesity, atherogenic dyslipidemia, dysregulation in glucose homeostasis, non-alcoholic fatty liver disease and arterial hypertension. However, an independent association of menopause per se with increased risk of CVD events has only been proven for early menopause (<45 years). Menopausal hormone therapy (MHT) ameliorates most of the CVD risk factors mentioned above. Transdermal estrogens are the preferable regimen, since they do not increase triglyceride concentrations and they are not associated with increased risk of venous thromboembolic events (VTE). Although administration of MHT should be considered on an individual basis, MHT may reduce CVD morbidity and mortality, if commenced during the early postmenopausal period (<60 years or within ten years since the last menstrual period). In women with premature ovarian insufficiency (POI), MHT should be administered at least until the average age of menopause (50-52 years). MHT is contraindicated in women with a history of VTE and is not currently recommended for the sole purpose of CVD prevention. The risk of breast cancer associated with MHT is generally low and is mainly conferred by the progestogen. Micronized progesterone and dydrogesterone are associated with lower risk compared to other progestogens.

Perspective: A Proposed Diagnostic and Treatment Algorithm for Management of Lumbar Spinal Stenosis: An Integrated Team Approach.

BACKGROUND: Newly-introduced minimally invasive interventions have filled a gap between conservative care and open surgical procedures in the treatment and management of lumbar spinal stenosis (LSS), allowing expanded access to patient care. This spectrum of care involves an important interplay between advanced practice providers, interventional pain physicians, and spine surgeons. OBJECTIVES: Using an integrated team approach starting with history taking; static and dynamic imaging; and conservative care, we developed a simple, understandable clinical algorithm that serves as a foundation for physicians to confidently make objective decisions regarding diagnosing and treating LSS throughout the entire clinical course of the condition. We believe this could potentially lead to more efficient and effective care for patients suffering from LSS with neurogenic claudication. METHODS: A decision tree approach was utilized with "either/or" choices at each branch or node in the algorithm. Activities are divided into examination procedures and corresponding treatment interventions. Symptom and radiographic severity grading as well as assessing clinical status employed published validated standards. Commensurate treatment choices were selected based on published LSS-specific clinical practice guidelines and/or meta-analyses. RESULTS: This algorithm recommends a systematic rule set for LSS diagnostic and treatment options. Initially, LSS symptom severity is graded based on the patient's pain relief with spinal flexion. This is correlated with radiographic severity assessment graded as mild, moderate, or severe. Radiographic severity combined with dynamic imaging prescribes a choice of treatment options and a risk/benefit discussion with the patient. These options include conservative management, minimally invasive methods such as interspinous process decompression, and more invasive surgical procedures such as laminectomy for increasing grades of radiographic severity. LIMITATIONS: Understanding that each patient with LSS is managed on a case-by-case basis, the treatment options recommended by this algorithm should be considered "soft guidance." As such, integrated team/patient consultation is recommended to ensure maximum clinical benefit. A risk/benefit assessment and discussion should be performed with each individual patient. CONCLUSIONS: Our proposed algorithm offers an easy-to-use clinical tool and general foundation for identifying, evaluating, and treating patients with intermittent neurogenic claudication associated with LSS.

Improving the quality and quantity of clinical and translational research statewide: An application of group concept mapping.

INTRODUCTION: Advance Clinical and Translational Research (Advance-CTR) serves as a central hub to support and educate clinical and translational researchers in Rhode Island. Understanding barriers to clinical research in the state is the key to setting project aims and priorities. METHODS: We implemented a Group Concept Mapping exercise to characterize the views of researchers and administrators regarding how to increase the quality and quantity of clinical and translational research in their settings. Participants generated ideas in response to this prompt and rated each unique idea in terms of how important it was and feasible it seemed to them. RESULTS: Participants generated 78 unique ideas, from which 9 key themes emerged (e.g., Building connections between researchers). Items rated highest in perceived importance and feasibility included providing seed grants for pilot projects, connecting researchers with common interests and networking opportunities. Implications of results are discussed. CONCLUSIONS: The Group Concept Mapping exercise enabled our project leadership to better understand stakeholder-perceived priorities and to act on ideas and aims most relevant to researchers in the state. This method is well suited to translational research enterprises beyond Rhode Island when a participatory evaluation stance is desired.

Cardiovascular health after menopause transition, pregnancy disorders, and other gynaecologic conditions: a consensus document from European cardiologists, gynaecologists, and endocrinologists.

Women undergo important changes in sex hormones throughout their lifetime that can impact cardiovascular disease risk. Whereas the traditional cardiovascular risk factors dominate in older age, there are several female-specific risk factors and inflammatory risk variables that influence a woman's risk at younger and middle age. Hypertensive pregnancy disorders and gestational diabetes are associated with a higher risk in younger women. Menopause transition has an additional adverse effect to ageing that may demand specific attention to ensure optimal cardiovascular risk profile and quality of life. In this position paper, we provide an update of gynaecological and obstetric conditions that interact with cardiovascular risk in women. Practice points for clinical use are given according to the latest standards from various related disciplines (Figure 1).

Effects of Sequential Prepaid Incentives on Response Rates, Data Quality, Sample Representativeness, and Costs in a Mail Survey of Physicians.

While collecting high quality data from physicians is critical, response rates for physician surveys are frequently low. A proven method for increasing response in mail surveys is to provide a small, prepaid monetary incentive in the initial mailing. More recently, researchers have begun experimenting with adding a second cash incentive in a follow-up contact in order to increase participation among more reluctant respondents. To assess the effects of sequential incentives on response rates, data quality, sample representativeness, and costs, physicians (N = 1,500) were randomly assigned to treatments that crossed the amount of a first ($5 or $10) and second ($0, $5, or $10) incentive to form the following groups: Group $5/$5; Group $5/$10; Group $10/$0; Group $10/$5; and Group $10/$10. Overall, second incentives were associated with higher response rates and lower costs per completed survey, and while they had no effect on item nonresponse, they increased sample representativeness.

Progestogens as a component of menopausal hormone therapy: the right molecule makes the difference.

Optimizing menopausal hormone therapy (MHT) requires an awareness of the benefits and risks associated with the available treatments. This narrative review, which is based on the proceedings of an Advisory Board meeting and supplemented by relevant articles identified in literature searches, examines the role of progestogens in MHT, with the aim of providing practical recommendations for prescribing physicians. Progestogens are an essential component of MHT in menopausal women with a uterus to prevent endometrial hyperplasia and reduce the risk of cancer associated with using unopposed estrogen. Progestogens include natural progesterone, dydrogesterone (a stereoisomer of progesterone), and a range of synthetic compounds. Structural differences and varying affinities for other steroid receptors (androgen, glucocorticoid, and mineralocorticoid) confer a unique biological and clinical profile to each progestogen that must be considered during treatment selection. MHT, including the progestogen component, should be tailored to each woman, starting with an estrogen and a progestogen that has the safest profile with respect to breast cancer and cardiovascular effects, while addressing patient-specific needs, risk factors, and treatment goals. Micronized progesterone and dydrogesterone appear to be the safest options, with lower associated cardiovascular, thromboembolic, and breast cancer risks compared with other progestogens, and are the first-choice options for use in 'special situations,' such as in women with high-density breast tissue, diabetes, obesity, smoking, and risk factors for venous thromboembolism, among others.

Efficacy and safety of a low-dose continuous combined hormone replacement therapy with 0.5 mg 17ß-estradiol and 2.5 mg dydrogesterone in subgroups of postmenopausal women with vasomotor symptoms.

OBJECTIVES: Various combinations of estrogens and progestogens are available for menopausal hormone therapy that differ in their efficacy and safety profile. We evaluated the efficacy and long-term safety of low-dose estradiol (0.5 mg) / dydrogesterone (2.5 mg) in subgroups of postmenopausal women with vasomotor symptoms. ANALYSIS: Efficacy analysis was performed on data from 2 previously published studies for subgroups defined by age, duration of menopause, and body mass index at baseline. The primary efficacy variable was the number of moderate to severe hot flushes from baseline to week 13. Long-term safety was evaluated in relation to age and duration of menopause. Safety variables included adverse events to week 52 and change from baseline to endpoint in laboratory and vital sign values. RESULTS: The treatment difference seen in the overall population in favour of low-dose estradiol/dydrogesterone was also observed in the subgroups of patients aged 45 to < 55 years (p < 0.01) and ≥55 years (p < 0.05), with menopause duration of >12 months to <60 months (p < 0.05) and ≥ 60 months (p < 0.005), and with a BMI at baseline of <25 kg/m2 (p < 0.05) and 25 to <30 kg/m2 (p < 0.01). Low-dose estradilol/dydrogesterone was well tolerated across the different subgroups. The incidence of breast-related adverse events was very low. No breast malignancy was reported. Only one adverse endometrial outcome of simple hyperplasia was observed. CONCLUSION: The results of our analyses confirmed the consistent treatment effect on vasomotor symptoms and the favourable safety profile of 0.5 mg 17ß estradiol and 2.5 mg dydrogesterone in different patient subgroups.

Cardiovascular Complications in Patients with Turner's Syndrome.

Turner's or Turner syndrome (TS) is the most prevalent chromosomal abnormality in live female births. Patients with TS are predisposed to an increased risk of cardiovascular diseases (CVD), mainly due to the frequently observed congenital structural cardiovascular defects, such as valvular and aortic abnormalities (coarctation, dilatation, and dissection). The increased prevalence of cardiometabolic risk factors, such as arterial hypertension, insulin resistance, diabetes mellitus, dyslipidaemia, central obesity, and increased carotid intima-media thickness, also contribute to increased morbidity and mortality in TS patients. Menopausal hormone therapy (MHT) is the treatment of choice, combined with growth hormone (GH). Although MHT may, in general, ameliorate CVD risk factors, its effect on CVD mortality in TS has not yet been established. The exact effect of GH on these parameters has not been clarified. Specific considerations should be provided in TS cases during pregnancy, due to the higher risk of CVD complications, such as aortic dissection. Optimal cardiovascular monitoring, including physical examination, electrocardiogram, CVD risk factor assessment, and transthoracic echocardiography, is recommended. Moreover, the cardiac magnetic resonance from the age of 12 years is recommended due to the high risk of aortic aneurysm and other anatomical vascular complications.

Global FKRP Registry: observations in more than 300 patients with Limb Girdle Muscular Dystrophy R9.

OBJECTIVE: The Global FKRP Registry is a database for individuals with conditions caused by mutations in the Fukutin-Related Protein (FKRP) gene: limb girdle muscular dystrophy R9 (LGMDR9, formerly LGMD2I) and congenital muscular dystrophies MDC1C, Muscle-Eye-Brain Disease and Walker-Warburg Syndrome. The registry seeks to further understand the natural history and prevalence of FKRP-related conditions; aid the rapid identification of eligible patients for clinical studies; and provide a source of information to clinical and academic communities. METHODS: Registration is patient-initiated through a secure online portal. Data, reported by both patients and their clinicians, include: age of onset, presenting symptoms, family history, motor function and muscle strength, respiratory and cardiac function, medication, quality of life and pain. RESULTS: Of 663 registered participants, 305 were genetically confirmed LGMDR9 patients from 23 countries. A majority of LGMDR9 patients carried the common mutation c.826C > A on one or both alleles; 67.9% were homozygous and 28.5% were compound heterozygous for this mutation. The mean ages of symptom onset and disease diagnosis were higher in individuals homozygous for c.826C > A compared with individuals heterozygous for c.826C > A. This divergence was replicated in ages of loss of running ability, wheelchair-dependence and ventilation assistance; consistent with the milder phenotype associated with individuals homozygous for c.826C > A. In LGMDR9 patients, 75.1% were currently ambulant and 24.6%, nonambulant (unreported in 0.3%). Cardiac impairment was reported in 23.2% (30/129). INTERPRETATION: The Global FKRP Registry enables the collection of patient natural history data, which informs academics, healthcare professionals and industry. It represents a trial-ready cohort of individuals and is centrally placed to facilitate recruitment to clinical studies.