Cardiovascular Risk Associated with Tibolone Use in Postmenopausal Women

Plasma estrogen concentrations after oral and vaginal estrogen administration in women with atrophic vaginitis

Emerging evidence suggests that metformin may reduce breast cancer incidence, but reports are mixed and few provide information on tumor characteristics. Therefore, we assessed associations among diabetes, metformin use, and breast cancer in postmenopausal women participating in Women's Health Initiative clinical trials. In all, 68,019 postmenopausal women, including 3,401 with diabetes at study entry, were observed over a mean of 11.8 years with 3,273 invasive breast cancers diagnosed. Diabetes incidence status was collected throughout follow-up, with medication information collected at baseline and years 1, 3, 6, and 9. Breast cancers were confirmed by review of central medical records and pathology reports. Cox proportional hazards regression, adjusted for breast cancer risk factors, compared breast cancer incidence in women with diabetes who were metformin users or nonusers with breast cancer incidence in women without diabetes. Compared with that in women without diabetes, breast cancer incidence in women with diabetes differed by diabetes medication type (P = .04). Women with diabetes receiving medications other than metformin had a slightly higher incidence of breast cancer (hazard ratio [HR], 1.16; 95% CI, 0.93 to 1.45), and women with diabetes who were given metformin had lower breast cancer incidence (HR, 0.75; 95% CI, 0.57 to 0.99). The association was observed for cancers positive for both estrogen receptor and progesterone receptor and those that were negative for human epidermal growth factor receptor 2. Metformin use in postmenopausal women with diabetes was associated with lower incidence of invasive breast cancer. These results can inform future studies evaluating metformin use in breast cancer management and prevention.

The pros and cons of estrogen therapy for use in postmenopausal women continue to be a major topic of debate in women's health. Much of this debate focuses on the potential benefits vs. harm of estrogen therapy on the brain and the risks for cognitive impairment associated with aging and Alzheimer's disease. Many animal and human studies suggest that estrogens can have significant beneficial effects on brain aging and cognition and reduce the risk of Alzheimer's-related dementia; however, others disagree. Important discoveries have been made, and hypotheses have emerged that may explain some of the inconsistencies. This review focuses on the cholinergic hypothesis, specifically on evidence that beneficial effects of estrogens on brain aging and cognition are related to interactions with cholinergic projections emanating from the basal forebrain. These cholinergic projections play an important role in learning and attentional processes, and their function is known to decline with advanced age and in association with Alzheimer's disease. Evidence suggests that many of the effects of estrogens on neuronal plasticity and function and cognitive performance are related to or rely upon interactions with these cholinergic projections; however, studies also suggest that the effectiveness of estrogen therapy decreases with age and time after loss of ovarian function. We propose a model in which deficits in basal forebrain cholinergic function contribute to age-related changes in the response to estrogen therapy. Based on this model, we propose that cholinergic-enhancing drugs, used in combination with an appropriate estrogen-containing drug regimen, may be a viable therapeutic strategy for use in older postmenopausal women with early evidence of mild cognitive decline.

The cost effectiveness of estrogen use in postmenopausal women was analyzed with use of data from the medical and epidemiologic literature. Risks of endometrial cancer, uterine bleeding, and gallbladder disease were weighed against benefits associated with relief of menopausal symptoms and with prevention of osteoporosis and consequent fractures. Net effects on life expectancy are probably small in either direction, although they are likely to be positive in women with existing osteoporosis or prior hysterectomy. Treatment appears to be relatively cost effective in menopausal women with prior hysterectomy or osteoporosis but does not appear to be cost effective as a prophylactiv measure in asymptomatic women with intact uteri. For women with menopausal symptoms and intact uteri, the decision to prescribe estrogens for the individual patient and the cost effectiveness of estrogen use at the societal level depend critically on the subjective values assigned to symptomatic relief.

It is estimated that over 45% of women in the United States are menopausal. Many of these women suffer from vasomotor symptoms of menopause, for which the gold standard treatment is menopause hormone therapy (MHT). However, MHT use has been controversial since the Women's Health Initiative (WHI) study in 2001. Transdermal MHT has been shown to be effective for treatment of vasomotor symptoms and does not increase the risk of venous thromboembolism (VTE) when used in healthy postmenopausal women. However, there is little data on its safety in women at increased risk for VTE such as women with prior VTE, increased body mass index, thrombophilia, tobacco use, autoimmune disease, chronic inflammatory disorders, recent surgery, trauma, or immobilization. This scoping review of the literature provides clinicians with an overview of the evidence on the risk profile of transdermal MHT use in these postmenopausal women at increased risk of VTE. We searched all published studies from 2000 to 2020 and included 13 primary articles on transdermal MHT use in postmenopausal women at increased risk of VTE. In women with prior VTE, two studies found a decrease in coagulability and no increased risk of recurrent VTE with transdermal MHT use. In women with increased body mass index, three studies found no increased VTE risk in transdermal MHT users. In women with prothrombotic genetic polymorphisms, three studies found minimal to no increased VTE risk in transdermal MHT users. In women with various proinflammatory comorbidities, five studies found an improved thrombotic profile and no increased VTE risk with transdermal MHT use. This scoping review provides data regarding the safety of transdermal MHT use in postmenopausal women with risk factors for VTE, and clinicians should have risk versus benefit discussions with each patient regarding its use.

Re: Vaginal Estrogen Use in Postmenopausal Women with Pelvic Floor Disorders: Systematic Review and Practice Guidelines

Introduction Testosterone therapy is increasingly used for the treatment of female sexual dysfunction (FSD), particularly hypoactive sexual desire disorder (HSDD). While evidence and guidelines support its use in postmenopausal women, its role in premenopausal populations remains less clear. Clarifying how menopausal status influences treatment response is essential for optimizing individualized care. Objective To systematically assess the effectiveness of testosterone replacement therapy (TRT) for FSD in premenopausal and postmenopausal women, with specific attention to improvements in libido, sexual satisfaction, and related outcomes. Methods A systematic review was conducted following PRISMA guidelines. Databases searched included Scopus (n=565), PubMed (n=186), and CINAHL (n=31), yielding 782 records. After removal of duplicates (n=230) and screening (n=552), a total of 32 studies were included. Studies were eligible if they evaluated TRT in pre- or postmenopausal cisgender women with FSD and reported relevant sexual function outcomes. Study quality and design were considered in the synthesis, and subgroup analysis by menopausal status was performed. Results Among the 32 included studies, 4 RCTs involved premenopausal women and 6 high-quality studies (including RCTs and reviews) involved postmenopausal women. In premenopausal populations, transdermal and vaginal testosterone therapies were associated with improved libido, frequency of satisfactory sexual events, and sexual satisfaction. Sample sizes in these trials ranged from 10 to 261. In postmenopausal cohorts, large-scale RCTs (including one with >800 participants) demonstrated significant improvements in sexual desire and HSDD symptoms with transdermal testosterone (300 μg/day). Benefits were consistent across studies, although androgen levels and long-term safety data were inconsistently reported. Conclusions TRT is effective for improving key aspects of sexual function in both premenopausal and postmenopausal women. The strongest evidence exists for postmenopausal women, where randomized trials show robust benefit and support guideline-based use. For premenopausal women, preliminary evidence is promising but limited by smaller sample sizes and fewer trials. Further high-quality studies are needed to establish optimal indications, dosing, and safety in this younger cohort. Disclosure No

The evidence regarding the risks, benefits, and quality of life impact of tamoxifen and raloxifene for prevention of breast cancer in postmenopausal women was reviewed. Five placebo-controlled trials were identified, four with tamoxifen and one with raloxifene. The individual placebo-controlled trials of tamoxifen for breast cancer prevention vary in size and risk status of the women who participated. An overview of the four trials found a 30% to 40% reduction in the risk of breast cancer. Serious adverse events include an increased risk of uterine cancer, venous thromboembolic events, and cataracts. Fracture risk was reduced. Quality of life was not significantly impaired, but women treated with tamoxifen had more vasomotor symptoms and vaginal discharge. In the single trial of raloxifene in postmenopausal women, there was a substantial reduction in the risks of breast cancer and fracture and no increased risk of uterine cancer. However, there was an increased risk of venous thromboembolic events. In the trial directly comparing tamoxifen with raloxifene in postmenopausal high-risk women, there was no significant difference in the risk of invasive breast cancer, but tamoxifen significantly reduced noninvasive breast cancer. The toxicity profiles for the two drugs were similar, with the exception of fewer hysterectomies, pulmonary emboli, and deep vein thrombosis in the raloxifene-treated group. There are now two effective Selective estrogen-receptor modulators available for use in postmenopausal women to reduce the risk of breast cancer. Women at high risk of breast cancer should be offered this therapy, and if one drug is not well tolerated, the other should be considered.

The Woman's Health Initiative has conducted 2 full-scale, placebo-controlled clinical trials to determine the influence of menopausal therapy on breast cancer incidence and outcome. Estrogen plus progestin use in postmenopausal women with a uterus increases breast cancer incidence and deaths from breast cancer. Despite a short-term reduction in risk after stopping estrogen plus progestin use, an increase in breast cancer risk persists postintervention. Estrogen-alone use in postmenopausal women with prior hysterectomy reduces breast cancer incidence and reduces deaths from breast cancer. The reduced breast cancer risk persists for several years after stopping estrogen-alone use but is lost in late postintervention. These findings suggest recalibration of breast cancer risk and benefit consideration for both regimens, with estrogen plus progestin use associated with greater risk and estrogen-alone use associated with greater benefit. Use of either regimen in clinical practice requires careful consideration of all clinical risks and benefits.

The present study examined the association between body composition measurements, using dual-energy x-ray absorptiometry and anthropometry, with serum 25-hydroxyvitamin D levels in nonosteoporotic, postmenopausal women. Serum 25-hydroxyvitamin D, intact parathyroid hormone, insulin-like growth factor I levels, dual-energy x-ray absorptiometry measurements of fat and fat-free mass, anthropometric and handgrip strength measurements, dietary intake estimations, ultraviolet B radiation exposure, and physical activity levels were collected from 112 nonosteoporotic, postmenopausal women (age, 60.3 +/- 5.0 y; body mass index, 29.5 +/- 4.8 kg/m). At a bivariate level, serum 25-hydroxyvitamin D levels were inversely associated with regional and total body fat mass (P < 0.05), whereas positive associations were observed with regional and total body fat-free mass (P < 0.05). After controlling for age, serum intact parathyroid hormone, insulin-like growth factor I levels, ultraviolet B radiation exposure, and physical activity levels, most of the associations observed at a bivariate level between serum 25-hydroxyvitamin D levels and body composition indices (as obtained by dual-energy x-ray absorptiometry) remained significant. No significant associations were observed between anthropometric indices of body mass and serum 25-hydroxyvitamin D levels. An independent inverse association between serum 25-hydroxyvitamin D levels and dual-energy x-ray absorptiometry measurements of total body and regional fat mass was observed in nonosteoporotic, overweight, postmenopausal women. Further clinical trials are required to come to safe conclusions on whether it is the fat mass that affects serum 25-hydroxyvitamin D levels or vice versa and whether there is a need to also take into account body composition when providing recommendations for vitamin D intake in postmenopausal women.

Panel: Hormone Therapy Isn't for Chronic Conditions

Endocrinology and metabolism: an annotated bibliography of recent literature. References to journal articles and other papers.

1031 Background: In vitro studies have demonstrated that statins (HMG CoA reductase inhibitors) suppress tumor growth and proliferation in breast cancer cell lines. Published clinical data on the chemoprotective role of statins in breast cancer are conflicting. Moreover, there are no published studies specifically examining the impact of statin use on breast cancer risk biomarkers in high risk women. We have previously demonstrated that cytologic atypia detected by RPFNA is associated with a 5 fold increase in short term risk of breast cancer in high risk women. The aim of this study was to explore the effect of statin use on breast RPFNA cytomorphology in postmenopausal women at high risk of developing breast cancer (based on personal and family history). Methods: Thehigh risk breast clinic database at the University of Kansas Medical Center was queried from April 2002 to September 2005 for statin use in postmenopausal women. We first identified postmenopausal women who underwent RPFNA while on a statin (cases). Postmenopausal women who underwent RPFNA while not on a statin (controls) were then identified and matched with statin users for known breast cancer risk factors (age, 5 year Gail risk and BMI). Frequencies of categorical variables were assessed using chi-square analysis. Continuous variables were assessed using Mann-Whitney non parametric test. Results: 504 postmenopausal women were identified. Thirty five of these 504 women underwent RPFNA while on statin therapy. For statin users (cases), the median age was 56 years, median 5 year Gail risk was 3.6%, median BMI was 28 and the median duration of statin use was 1.4 years (range 0.3 to 13 yrs). Sixty nine controls were identified. There was no difference between cases and controls with respect to HRT use (54% vs 40%, p=0.22), duration of HRT use (p=0.30) and visual breast density (p=0.80). RPFNA atypia was detected in 11% of cases and 26% of controls (p=0.13). Conclusion: Although prevalence of RPFNA atypia was less frequent among statin users, this difference was not statistically significant in this small cohort of high risk women with relatively short duration of statin use. Larger studies are warranted to investigate this further. No significant financial relationships to disclose.

Clinical efficacy of raloxifene in postmenopausal women

SUMMARYThis commentary article provides an overview of recent clinical research trials involving anastrozole and its evolving role in the management of breast cancer.Anti-aromatase agents inhibit the cytochrome P-450 component of the aromatase enzyme complex responsible for the final step of estrogen biosynthesis in peripheral tissues which are the main source of estrogen in postmenopausal women. Anastrozole is a third-generation non-steroidal aromatase inhibitor. It has been shown to be superior to megestrol acetate, in terms of survival and adverse effects, as a second-line therapy in postmenopausal women with estrogen receptor (ER)- and/or progesterone receptor (PgR)-positive advanced breast cancer. Phase III clinical trials have also demonstrated that anastrozole significantly prolongs the time to tumour progression compared with tamoxifen as a first-line therapy for ER- and/or PgR-positive advanced breast cancer in postmenopausal women. Furthermore, the preliminary results of the Arimidex, Tamoxifen, Alone and in Combination (ATAC) study have shown that adjuvant anastrozole is superior to tamoxifen in terms of disease-free survival (DFS), non-musculoskeletal adverse effects and prevention of contralateral breast cancer in postmenopausal women with early, ER-positive breast cancer. Although longer follow-up is required to assess the long-term effects of anastrozole on bone mineral density, cognitive function and overall survival, the drug has been recently approved for adjuvant use in postmenopausal women with early, ER-positive breast cancer who are unable to tolerate tamoxifen or at an increased risk of developing thromboembolism or endometrial cancer.* Arimidex (anastrozole) is a registered tradename of AstraZeneca Pharmaceuticals, Concord Pike, Wilmington DE, USAThe potential role of anastrozole in the neoadjuvant setting, the management of DCIS, premenopausal breast cancer and breast cancer prevention is currently being investigated.