Citations

AbstractOutcomes for older adults with acute myelogenous leukemia (AML) are poor due to both disease and host-related factors. In this phase 2 study, we tested the oral farnesyltransferase inhibitor tipifarnib in 158 older adults with previously untreated, poor-risk AML. The median age was 74 years, and a majority of patients had antecedent myelodysplastic syndrome. Complete remission (CR) was achieved in 22 patients (14%); partial remission or hematologic improvement occurred in 15 patients, for an overall response rate of 23%. The median duration of CR was 7.3 months and the median survival of complete responders was 18 months. Adverse karyotype, age 75 years or older, and poor performance status correlated negatively with survival. Early death in the absence of progressive disease was rare, and drug-related nonhematologic serious adverse events were observed in 74 patients (47%). Inhibition of farnesylation of the surrogate protein HDJ-2 occurred in the large majority of marrow samples tested. Baseline levels of phosphorylated mitogen-activated protein kinase and AKT did not correlate with clinical response. Tipifarnib is active and well tolerated in older adults with poor-risk AML and may impart a survival advantage in those patients who experience a clinical response.

Estrogen receptors are found on vascular endothelial and smooth muscle cells; their expression is influenced by exposure to the hormone. Estrogen receptors influence non-genomic events, which are rapid in onset and genomic events, which are longer acting responses. Estrogens affect vascular tone indirectly by modulating release of endothelium-derived vasoactive factors and directly by modulating intracellular calcium in vascular smooth muscle cells. Estrogens indirectly affect thrombotic events and inflammation by altering platelet aggregation and leukocyte adherence and migration, respectively. Estrogens also influence production of mitogens which, when released at sites of vascular injury, affect vascular remodeling. Although estrogens initiate vascular responses, genomic sex may influence and/or limit expression of estrogen receptors and therefore actions of sex steroid hormones throughout the vasculature.

Background: We compared forearm vasodilator responses between females and males after administration of compounds that stimulate nitric oxide (NO) release, act as NO donors, or are NO independent. Methods and results: We studied nine premenopausal females and nine age-matched males. Forearm blood flow (FBF) was measured with plethysmography. Graded doses of the endothelial dependent vasodilators acetylcholine and bradykinin and the endothelial-independent vasodilator sodium nitroprusside were given via a brachial artery catheter to the non-dominant arm. Reactive hyperemia was measured as an index of NO-independent vasodilation. In females estradiol levels were greater, and serum triglycerides were lower, but cholesterol was similar to that of males. FBF responses to all doses of the three drugs were ' 30% less in females. Females had smaller forearms and lower peak FBF during reactive hyperemia. Blood flow responses to the drugs as a fraction of the peak reactive hyperemia values were similar in females and males. In the females, but not in the males, FBF responses to all three drugs and reactive hyperemia correlated with estradiol levels. Conclusions: The smaller FBF responses in females were likely due to smaller forearm volume and muscle mass. Estradiol levels are associated with both NO-mediated and non-NO-mediated dilator responses in females.

Premenopausal women have a significant reduction in coronary artery disease compared to age matched males. Little is known about the mechanism underlying this cardio protective effect of estrogen. Contradictory evidence has been published and our lack of basic understanding of hormone interactions and bioavailability of different estrogens prevents definitive interpretation of these data. We demonstrate gender-specific effects in the proliferation of coronary artery vascular smooth muscle cells obtained from a sexually mature animal model. Vascular smooth muscle cells are an integral component of the atherosclerotic plaque, and inhibition of cell proliferation by estrogen may be one mechanism by which estrogen exerts its cardio protective effect. Various types of estrogen may also have different mechanistic actions on the vascular system. No differences are demonstrated in overall estradiol binding in vascular smooth muscle cells obtained from male or female animals; however, differences in c-jun, c-fos and TIEG gene expression were gender related. Inhibition of vascular smooth muscle cell proliferation may have important implications in the prevention of atherosclerotic disease and these studies may provide evidence for the cardio protective effect of estrogen.

Although osteoporosis has traditionally been considered a disease of women, men also incur substantial bone loss with aging, and elderly men have age-specific hip fracture incidence rates and vertebral fracture prevalence rates that are at least half those in women. Early postmenopausal bone loss (which results in the syndrome of type I osteoporosis) is due to the direct skeletal consequences of estrogen deficiency, manifested by an increase in bone resorption without an adequate increase in bone formation. Recent evidence indicates that even late postmenopausal bone loss (type II or ‘senile’ osteoporosis) in women may be due to estrogen deficiency. In particular, the late consequences of estrogen deficiency in elderly women result in abnormalities in calcium homeostasis and increases in parathyroid hormone secretion, leading to increased bone resorption and bone loss. The etiology of bone loss in aging men has remained relatively unclear. Recent evidence from a male deficient in estrogen receptor-alpha and in two males with aromatase deficiency indicate that estrogen may play a significant role in bone metabolism in men. Moreover, several large epidemiologic studies have found that bone mineral density correlates better with serum estrogen than testosterone in aging men. Thus estrogen deficiency may lead to bone loss in men.

Estrogen deficiency results in increased bone turnover and net bone loss in rats as well as humans. The respective roles of bone turnover and mechanical strain in mediating estrogen deficiencyinduced cancellous bone loss were investigated in ovariectomized rats. Ovariectomy resulted in increased bone turnover in long bones. However, cancellous bone was preferentially lost in the metaphysis, a site that experiences low strain energy during normal physical activity. No bone loss was observed in the epiphysis, a site experiencing higher strain energy, despite a similar increase in bone turnover. The role of mechanical strain in maintaining bone balance was investigated by altering the strain history. Mechanical strain was increased or decreased in long bones of ovariectomized rats by treadmill exercise or functional unloading, respectively. Increasing mechanical loading reduced bone loss in the metaphysis. In contrast, decreasing weight bearing accentuated bone loss in the metaphysis and resulted in bone loss in the epiphysis. Finally, administration of estrogen to ovariectomized rats reduced bone loss in unloaded limbs and prevented bone loss in the loaded limbs. These results suggest that estrogen alters the mechanosensory (mechanostat) set point for skeletal adaptation, effectively reducing the minimum strain energy levels at which bone is added. Additionally, these studies suggest that physical activity as well as endocrine status play an important role in maintenance of the female skeleton during aging.

Background: The relative risk of cardiovascular disease (CVD) associated with diabetes is greater for women than men, and diabetic women did not experience temporal declines in CVD mortality observed for the general population and diabetic men. Objective: To examine sex differences in CVD risk factors for persons with diabetes over time. Design: Population-based historical cohort study. Methods: The provider-linked medical records of all Rochester, MN, residents assigned a clinical diagnosis of diabetes were reviewed to confirm case status and assign diagnosis date. Data on fasting glucose, obesity, persistent proteinuria, smoking, hypertension, and dyslipidemia were obtained at diagnosis for confirmed incidence cases. Results: There were 1330 diabetes cases 1970–1989. Compared to men, women at diagnosis were older and more likely hypertensive, had similar levels of fasting glucose and persistent proteinuria, and less likely to smoke. Among persons diagnosed at younger ages, women were more likely than men to be obese. Comparison with published data for the Rochester population revealed the excess obesity and hypertension associated with diabetes were highest for women < age 55 y. Temporal trends in CVD risk factors did not differ between diabetic men and women.

We examined trends in heart disease (HD) mortality and the delivery of cardiac in Olmsted County, MN. Between 1979 and 1994, women experienced 51% of the total number of HD (ICD9 codes 390 — 398,402,404 — 429) deaths (3095). Age-adjusted HD mortality rate declined from 123 per 100,000 (95%CI 102, 144) in 1979 to 81 (67,95) in 1994. The risk ratio (RR) of HD death in 1994 compared to 1979 was 0.69 for women vs 0.53 for men (P = 0.06). This equates to a decline in HD mortality of 2.5%=y in women and 4.2%=y in men. The decline in HD mortality was less pronounced in older age groups (P < 0.001), reflecting a shift of the burden of HD towards women and the elderly. Compared to men, there was less use of stress tests among women, of cardiology visits after stress testing, and of cardiac procedures among women presenting to the emergency room with unstable angina. Further studies are needed to examine causal links between these trends.