Thomas B. Clarkson

Bio: Thomas B. Clarkson is an academic researcher from Wake Forest University. The author has contributed to research in topics: Estrogen & Cholesterol. The author has an hindex of 68, co-authored 309 publications receiving 16831 citations. Previous affiliations of Thomas B. Clarkson include Population Council & University of Pittsburgh.

Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone.

Abstract: Although controversy continues, the preponderance of evidence indicates that estrogen replacement therapy favorably influences the risk of coronary heart disease in postmenopausal women. It remains uncertain how this effect is mediated and whether the cyclic addition of a progestin may influence adversely an estrogen-related cardioprotective effect. We investigated the influence of sex hormone replacement therapy on diet-induced coronary artery atherosclerosis in estrogen-deficient (ovariectomized) adult female cynomolgus monkeys. Monkeys were assigned randomly to one of three treatment groups: 1) no hormone replacement (n = 17), 2) continuously administered 17-beta estradiol plus cyclically administered progesterone (n = 20), and 3) continuously administered 17-beta estradiol (n = 18). The physiologic patterns of plasma estradiol and progesterone concentrations were maintained by administering the hormones in sustained-release subcutaneous Silastic implants. The experiment lasted 30 months. At necropsy, coronary artery atherosclerosis was inhibited similarly (reduced by approximately one-half) in animals in both hormone replacement groups (p less than or equal to 0.05). Antiatherogenic effects of hormone replacement were independent of variation in total plasma cholesterol, lipoprotein cholesterol, apoprotein A-1 and B concentrations, high density lipoprotein subfraction heterogeneity, and low density lipoprotein molecular weight. We conclude that physiologic estrogen replacement therapy with or without added progesterone inhibits atherosclerosis progression in ovariectomized monkeys. This may explain why estrogen replacement therapy results in reduced risk of coronary heart disease in postmenopausal women.

Soybean isoflavones improve cardiovascular risk factors without affecting the reproductive system of peripubertal rhesus monkeys.

Abstract: Although the beneficial effects of dietary soybean protein compared with animal proteins on plasma lipids, lipoproteins and atherosclerosis have been known for about 50 years, it has been uncertain whether these effects are due to its amino acid concentrations or other components in soybeans. To assess the effect of soybean protein's alcohol-extractable components (including the isoflavonic phytoestrogens genistein and daidzein) on plasma lipid and lipoprotein concentrations and to establish its lack of effect on the reproductive system, we fed 27 peripubertal male and female rhesus monkeys moderately atherogenic diets in which the source of dietary protein was a soy isolate (20% by weight), either containing phytoestrogens (also termed isoflavones) or with the phytoestrogens removed by alcohol extraction. The study was a crossover design with each period lasting for 6 mo. The phytoestrogen-intact soy protein (compared with the alcohol-extracted soy protein) had favorable effects on plasma lipid and lipoprotein concentrations, specifically by significantly reducing LDL+VLDL cholesterol concentrations in both males and females (approximately 30-40% lower), significantly increasing high density lipoprotein cholesterol (HDLC) concentrations for females (approximately 15% higher) and significantly lowering total plasma cholesterol (TPC):HDLC ratios (approximately 20% lower for males and 50% lower for females). The phytoestrogens had no adverse effects on the reproductive systems of either the males or females, as evaluated by reproductive hormone concentrations and organ weights at necropsy. Thus, the isoflavones in soy protein improve cardiovascular disease risk factors without apparent deleterious effects on the reproductive system of peripubertal rhesus monkeys.

Estrogen replacement therapy, atherosclerosis, and vascular function.

Abstract: There is strong evidence from both human and nonhuman primate studies supporting the conclusion that estrogen deficiency increases the progression of atherosclerosis. More controversial is the conclusion that postmenopausal estrogen replacement inhibits the progression of atherosclerosis. Estrogen treatment of older women (>65 years) with pre-existing coronary artery atherosclerosis had no beneficial effects. In contrast, estrogen treatment of younger postmenopausal women or monkeys in the early stages of atherosclerosis progression has marked beneficial effects. Whether progestogens attenuate the cardiovascular benefits of estrogen replacement therapy has been controversial for more than a decade. Current evidence from studies of both monkeys and women suggest little or no attenuation of estrogen benefits for coronary artery atherosclerosis. Lack of compliance with estrogen replacement therapy, usually because of fear of breast cancer, remains a major problem. Future regimens may overcome that fear by the co-administration of a breast cancer preventive agent (i.e., selective estrogen receptor modulators, phytoestrogens) with low dose estrogen.

Understanding the divergent data on postmenopausal hormone therapy.

Abstract: In contrast to observational studies, randomized clinical trials of hormone-replacement therapy have not shown a cardioprotective effect. The authors propose several methodologic and biologic explanations for these discrepant results.

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial

Abstract: Context Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain Objective To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States Design Estrogen plus progestin component of the Women's Health Initiative, a randomized controlled primary prevention trial (planned duration, 85 years) in which 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline were recruited by 40 US clinical centers in 1993-1998 Interventions Participants received conjugated equine estrogens, 0625 mg/d, plus medroxyprogesterone acetate, 25 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102) Main outcomes measures The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome A global index summarizing the balance of risks and benefits included the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other causes Results On May 31, 2002, after a mean of 52 years of follow-up, the data and safety monitoring board recommended stopping the trial of estrogen plus progestin vs placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse effect and the global index statistic supported risks exceeding benefits This report includes data on the major clinical outcomes through April 30, 2002 Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 129 (102-163) with 286 cases; breast cancer, 126 (100-159) with 290 cases; stroke, 141 (107-185) with 212 cases; PE, 213 (139-325) with 101 cases; colorectal cancer, 063 (043-092) with 112 cases; endometrial cancer, 083 (047-147) with 47 cases; hip fracture, 066 (045-098) with 106 cases; and death due to other causes, 092 (074-114) with 331 cases Corresponding HRs (nominal 95% CIs) for composite outcomes were 122 (109-136) for total cardiovascular disease (arterial and venous disease), 103 (090-117) for total cancer, 076 (069-085) for combined fractures, 098 (082-118) for total mortality, and 115 (103-128) for the global index Absolute excess risks per 10 000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures The absolute excess risk of events included in the global index was 19 per 10 000 person-years Conclusions Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 52-year follow-up among healthy postmenopausal US women All-cause mortality was not affected during the trial The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD

Harrison's Principles of Internal Medicine

Abstract: The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women

Abstract: Context.—Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials.Objective.—To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease.Design.—Randomized, blinded, placebo-controlled secondary prevention trial.Setting.—Outpatient and community settings at 20 US clinical centers.Participants.—A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years.Intervention.—Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n=1380) or a placebo of identical appearance (n=1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years.Main Outcome Measures.—The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered.Results.—Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38).Conclusions.—During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue.

Protective and Damaging Effects of Stress Mediators

Abstract: Over 60 years ago, Selye1 recognized the paradox that the physiologic systems activated by stress can not only protect and restore but also damage the body. What links these seemingly contradictory roles? How does stress influence the pathogenesis of disease, and what accounts for the variation in vulnerability to stress-related diseases among people with similar life experiences? How can stress-induced damage be quantified? These and many other questions still challenge investigators. This article reviews the long-term effect of the physiologic response to stress, which I refer to as allostatic load.2 Allostasis — the ability to achieve stability through change3 — . . .

Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research.

Abstract: This meta-analysis reviews 208 laboratory studies of acute psychological stressors and tests a theoretical model delineating conditions capable of eliciting cortisol responses. Psychological stressors increased cortisol levels; however, effects varied widely across tasks. Consistent with the theoretical model, motivated performance tasks elicited cortisol responses if they were uncontrollable or characterized by social-evaluative threat (task performance could be negatively judged by others), when methodological factors and other stressor characteristics were controlled for. Tasks containing both uncontrollable and social-evaluative elements were associated with the largest cortisol and adrenocorticotropin hormone changes and the longest times to recovery. These findings are consistent with the animal literature on the physiological effects of uncontrollable social threat and contradict the belief that cortisol is responsive to all types of stressors.