Association of ischemic stroke, hormone therapy, and right to left shunt in postmenopausal women.

BACKGROUND: Postmenopausal hormone therapy (HT) increases the risk of venous thrombosis and ischemic stroke. OBJECTIVES: We postulated that HT might increase the risk of ischemic stroke by promoting venous clots that travel to the brain through a right to left shunt (RLS). METHODS: A total of 2,389 records were studied. After eliminating the premenopausal patients, and those with TIAs and non-ischemic strokes, the medical records of 1846 postmenopausal women hospitalized at four institutions for ischemic stroke were reviewed to identify those who had undergone an adequate study to assess for RLS. The proportion of women with a shunt in users and non-users of HT was compared in stroke patients and in a reference population consisting of postmenopausal women undergoing elective cardiac catheterization. RESULTS: There were 363 (20%) records that had complete data and were included in the analysis. A shunt was more prevalent in patients with a cryptogenic stroke than in patients with a stroke of known cause (55/88 (63%) vs. 53/275 (19%), P < 0.001). In patients with a stroke of known cause, the frequency of a shunt was similar to that in reference women 31/136 (23%), and the proportion of women with a shunt was similar in non-users and current users of HT (14% vs. 20%, P = 0.40). However, among patients with a cryptogenic stroke, the prevalence of a shunt was 1.5 times higher in current users than non-users of HT (82% vs. 56%, P = 0.04). CONCLUSIONS: Approximately 23% of older women have a RLS. HT in these women may increase the risk of ischemic stroke by promoting paradoxical embolism.

Hypermethylation of adenosine triphosphate-binding cassette transporter genes in primary hyperparathyroidism and its effect on sestamibi imaging.

CONTEXT: Retention of technetium-(99m)-sestamibi ((99m)Tc-sestamibi) by parathyroid adenomas appears to be due to the loss of at least one membrane transporter, multidrug resistance 1 (MDR1), and possibly another, multidrug resistance-associated protein 1 (MRP1). OBJECTIVE: The objective was to determine whether hypermethylation of either gene plays a role in their expression and (99m)Tc-sestamibi retention. DESIGN: This was a retrospective study on a convenience sample of paraffin-embedded parathyroid glands. SETTING: The study was performed at the John Wayne Cancer Institute at Saint John's Health Center (Santa Monica, CA). PATIENTS: Forty-eight patients with primary hyperparathyroidism and five patients without parathyroid disease undergoing thyroid surgery provided 27 adenomatous, 10 hyperplastic, and 16 normal parathyroid glands. INTERVENTION: We performed immunohistochemistry, real-time quantitative RT-PCR, and methylation-specific PCR for MDR1 and MRP1 on archival parathyroid tissue and correlated these results with the patient's (99m)Tc-sestamibi scan. MAIN OUTCOME MEASURE: The main outcome measure was to determine whether hypermethylation of the genes for either transporter is associated with loss of their expression and with a positive (99m)Tc-sestamibi scan. RESULTS: The MDR1 gene was methylated in none of 12 normal glands, 19 of 27 adenomas, and three of 10 hyperplastic glands. Methylation of the MRP1 gene was uncommon (five of 48 tested glands). Methylation of the gene affected the transcript level only for MDR1. Among all glands, hypermethylation for MDR1 was more likely in (99m)Tc-sestamibi-positive scans (P < 0.001). CONCLUSION: In parathyroid tissue, hypermethylation of the MDR1 gene decreases its expression and is associated with increased detection of parathyroid adenomas by (99m)Tc-sestamibi parathyroid scans.

Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative.

BACKGROUND: In recent randomized trials, conjugated equine estrogens (CEE) with continuous medroxyprogesterone acetate provided no protection against coronary heart disease in postmenopausal women and may have increased cardiac risk. These trials did not address the role of unopposed estrogen for coronary protection. METHODS: A total of 10 739 women aged 50 to 79 years at baseline (mean age, 63.6 years) who had previously undergone hysterectomy were randomized to receive CEE, 0.625 mg/d, or placebo at 40 US clinical centers beginning in 1993. The trial was terminated early after 6.8 years of follow-up (planned duration, 8.5 years). This report includes final, centrally adjudicated results for the primary efficacy outcome (myocardial infarction or coronary death), secondary coronary outcomes, and subgroup analyses. RESULTS: During the active intervention period, 201 coronary events were confirmed among women assigned to receive CEE compared with 217 events among women assigned to receive placebo (hazard ratio, 0.95; nominal 95% confidence interval, 0.79-1.16). Among women aged 50 to 59 years at baseline, the hazard ratio for the primary outcome was 0.63 (nominal 95% confidence interval, 0.36-1.08). In that age group, coronary revascularization was less frequent among women assigned to receive CEE (hazard ratio, 0.55; nominal 95% confidence interval, 0.35-0.86), as were several composite outcomes, which included the primary outcome and coronary revascularization (hazard ratio, 0.66; nominal 95% confidence interval, 0.44-0.97). CONCLUSIONS: Conjugated equine estrogens provided no overall protection against myocardial infarction or coronary death in generally healthy postmenopausal women during a 7-year period of use. There was a suggestion of lower coronary heart disease risk with CEE among women 50 to 59 years of age at baseline.

Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial.

PURPOSE: In an open-label trial we have previously demonstrated that paroxetine reduces hot flashes. We initiated a stratified, randomized, double-blind, cross-over, placebo-controlled trial to investigate the efficacy of paroxetine 10 mg and 20 mg compared to placebo in reducing hot flash frequency and composite score. A secondary objective was to evaluate quality of life (QOL) parameters. PATIENTS AND METHODS: Women who suffered at least two hot flashes a day for 1 month or longer were eligible. Women were randomly assigned to 4 weeks of paroxetine 10 mg or 20 mg followed by placebo for 4 weeks, or placebo for 4 weeks followed by paroxetine 10 mg or 20 mg for 4 weeks. Participants completed baseline daily hot flash diaries for one week prior to the start of the study and throughout the study, and QOL questionnaires at baseline, week 5 and week 9. RESULTS: 279 women were screened, and 151 were randomly assigned. Paroxetine 10 mg reduced hot flash frequency and composite score by 40.6% and 45.6%, respectively, compared to 13.7% and 13.7% for placebo (P = .0006 and P = .0008, respectively). Paroxetine 20 mg reduced hot flash frequency and composite score by 51.7% and 56.1%, respectively, compared with 26.6% and 28.8% for placebo (P = .002 and P = .004, respectively). Efficacy was similar between the two doses, but women were less likely to discontinue low-dose paroxetine. Paroxetine 10 mg was associated with a significant improvement in sleep compared with placebo (P = .01). CONCLUSION: Paroxetine is an effective treatment for hot flashes in women with or without a prior breast cancer.

The effects of adjuvant chemotherapy on bone density in postmenopausal women with early breast cancer.

PURPOSE: Adjuvant chemotherapy for breast cancer can have adverse effects on bone. We investigated the effects of adjuvant chemotherapy on bone mineral density in postmenopausal women with early-stage breast cancer. METHODS: We performed a chart review of all our breast center patients who had spine or hip bone density measured by dual-energy X-ray absorptiometry at our institution after treatment for stage I or II breast cancer. Patients who had other causes of metabolic bone disease were excluded. Multivariate regression analysis was used to adjust for confounding factors. Results were expressed as age-adjusted standard deviation units (Z scores). RESULTS: Of the 130 eligible women, 36 (28%) received adjuvant chemotherapy and 94 (72%) did not. Mean adjusted bone density scores in both the hip (0.65 SD units; 95% confidence interval [CI]: 0.32 to 0.98 SD units; P = 0.0002) and spine (0.60 SD units; 95% CI: 0.01 to 1.19 SD units; P = 0.05) were significantly lower in patients who had received adjuvant chemotherapy compared with those who had not. CONCLUSION: Women who were postmenopausal when they developed breast cancer and who received adjuvant chemotherapy had lower bone density than those who did not. Whether this effect is caused by adjuvant chemotherapy remains to be determined.

Inflammatory markers and the risk of hip fracture: the Women's Health Initiative.

Cytokines play a major role in bone remodeling in vitro and in animal models, with evidence supporting the involvement of inflammatory markers in the pathogenesis of osteoporosis. However, less is known about the longitudinal association of inflammatory markers with hip fracture. We tested whether high receptor levels of proinflammatory cytokines are associated with an increased risk of hip fracture in older women. We used a nested case-control study design from the Women's Health Initiative Observational Study (WHI-OS) and selected 400 cases with physician-adjudicated incident hip fractures and 400 controls matched on age, race, and date of blood draw. Participants were chosen from 39,795 postmenopausal women without previous hip fractures, not using estrogens or other bone-active therapies. Incident hip fractures (median follow-up 7.1 years) were verified by review of radiographs and confirmed by blinded central adjudicators. Hip fractures with a pathological cause were excluded. In multivariable models, the risk of hip fracture for subjects with the highest levels of inflammatory markers (quartile 4) compared with those with lower levels (quartiles 1, 2, and 3) was 1.43 (95% confidence interval [CI], 0.98-2.07) for interleukin-6 (IL-6) soluble receptor (SR), 1.40 (95% CI, 0.97-2.03) for tumor necrosis factor (TNF) SR1, and 1.56 (95% CI, 1.09-2.22) for TNF SR2. In subjects with all three markers in the highest quartile, the risk ratio of fracture was 2.76 (95% CI, 1.22-6.25) in comparison with subjects with 0 or 1 elevated marker(s) (p trend = 0.018). Elevated levels of inflammatory markers for all three cytokine-soluble receptors were associated with an increased risk of hip fractures in older women. Future clinical trials should test whether interventions to decrease inflammatory marker levels reduces hip fractures.

Vasomotor symptoms and cardiovascular events in postmenopausal women.

OBJECTIVE: Emerging evidence suggests that women with menopausal vasomotor symptoms (VMS) have increased cardiovascular disease (CVD) risk as measured by surrogate markers. We investigated the relationships between VMS and clinical CVD events and all-cause mortality in the Women's Health Initiative Observational Study (WHI-OS). METHODS: We compared the risk of incident CVD events and all-cause mortality between four groups of women (total N = 60,027): (1) no VMS at menopause onset and no VMS at WHI-OS enrollment (no VMS [referent group]), (2) VMS at menopause onset but not at WHI-OS enrollment (early VMS), (3) VMS at both menopause onset and WHI-OS enrollment (persistent VMS [early and late]), and (4) VMS at WHI-OS enrollment but not at menopause onset (late VMS). RESULTS: For women with early VMS (n = 24,753), compared with no VMS (n = 18,799), hazard ratios (95% CIs) in fully adjusted models were as follows: major coronary heart disease (CHD), 0.94 (0.84-1.06); stroke, 0.83 (0.72-0.96); total CVD, 0.89 (0.81-0.97); and all-cause mortality, 0.92 (0.85-0.99). For women with persistent VMS (n = 15,084), there was no significant association with clinical events. For women with late VMS (n = 1,391), compared with no VMS, hazard ratios (95% CIs) were as follows: major CHD, 1.32 (1.01-1.71); stroke, 1.14 (0.82-1.59); total CVD, 1.23 (1.00-1.52); and all-cause mortality, 1.29 (1.08-1.54). CONCLUSIONS: Early VMS were not associated with increased CVD risk. Rather, early VMS were associated with decreased risk of stroke, total CVD events, and all-cause mortality. Late VMS were associated with increased CHD risk and all-cause mortality. The predictive value of VMS for clinical CVD events may vary with the onset of VMS at different stages of menopause. Further research examining the mechanisms underlying these associations is needed. Future studies will also be necessary to investigate whether VMS that develop for the first time in the later postmenopausal years represent a pathophysiologic process distinct from the classic perimenopausal VMS.