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Biomedical subjects

Thomas B Clarkson

Publications and source records attributed to Thomas B Clarkson.

At least 19 recordsLinked to original sources
PubMed2006

Destruction of primordial ovarian follicles in adult cynomolgus macaques after exposure to 4-vinylcyclohexene diepoxide: a nonhuman primate model of the menopausal transition.

OBJECTIVE: To determine whether the 4-vinylcyclohexene diepoxide (VCD)-treated mouse menopause model, which involves accelerated atresia of primordial follicles and induces gradual ovarian failure (while sparing the ovarian stroma), can be adapted to nonhuman primates. DESIGN: Controlled periclinical trial (nonhuman primates). SETTING: Comparative Medicine Clinical Research Center. ANIMAL(S): Four adult female cynomolgus monkeys. INTERVENTION(S): Once-daily i.m. injections for 15 days as follows: vehicle or VCD doses of 80 mg/kg, 160 mg/kg, 250 mg/kg. Ovaries were removed 27 days after treatment, and pathological determinations were made at necropsy. MAIN OUTCOME MEASURE(S): Baseline and interim hematologic and biochemical measures, physical exams, and body weights. Follicle counts and organ evaluation at necropsy. RESULT(S): A nearly complete elimination of primordial, intermediate, primary and secondary follicles was achieved with 250 mg/kg VCD. A 50% reduction in primordial and primary follicles was observed with 160 mg/kg VCD. No effect of 80 mg/kg VCD per day was observed. Clinical health measures remained within normal range except for transient, mild increases in liver enzymes and an inflammatory response at the injection site with 250 mg/kg. Postmortem evaluations (9 months) revealed no gross or histological lesions in the organs studied. CONCLUSION(S): These results demonstrate that the monkey ovary is susceptible to VCD and that as in rodents, primordial and primary follicles are targeted selectively.

Animals↗
PubMed2006

Effects of high-dose soy isoflavones and equol on reproductive tissues in female cynomolgus monkeys.

Soy isoflavonoids have well-established estrogenic properties in cell culture and rodent models, raising concerns that high isoflavonoid intake may promote development of uterine and breast cancers. To address this concern we evaluated the effects of high-dose isoflavonoid supplements on reproductive tissues in a postmenopausal primate model. Thirty adult female ovariectomized monkeys (Macaca fascicularis) were randomized to receive a control diet 1) alone, 2) with 509 mg/day of the soy isoflavones genistein and daidzein (IF), or 3) with 1020 mg/day of racemic equol (EQ), an isoflavan, for approximately 1 mo. Doses are expressed in aglycone units as calorically scaled human equivalents. Total serum isoflavonoid levels 4 h postfeeding were <20 nmol/L, 2570.7 nmol/L, and 6944.8 nmol/L for control, IF, and EQ groups, respectively. Equol was the predominant serum isoflavonoid in both IF (72.5%) and EQ (99.7%) groups. Aglycones represented 0.9% (IF) and 0.5% (EQ) of total serum isoflavonoids. Histologically, uteri and mammary glands were diffusely atrophic in all groups. Uterine weight, endometrial thickness, glandular area, and epithelial proliferation in the uterus were not significantly different among treatment groups (ANOVA P > 0.1 for all). Endometrial progesterone receptor gene expression was significantly increased in the IF group (P = 0.02), while protein expression was not altered (ANOVA P > 0.1). Within the mammary gland, proliferation and indicators of estrogen exposure did not differ among treatment groups (ANOVA P > 0.1 for all). These findings indicate that high doses of dietary soy isoflavonoids have minimal uterotrophic or mammotrophic effects in an established primate model.

Animals↗
PubMed2006

Low dose estrogens inhibit coronary artery atherosclerosis in postmenopausal monkeys.

OBJECTIVES: To determine if low dose conjugated equine estrogens (CEE) result in a reduction of coronary artery atherosclerosis progression, and to relate these findings to previous studies using the traditional dose. METHODS: Adult female monkeys (Macaca fascicularis) were fed an atherogenic diet for 10 months, to induce fatty streaks and small plaques comparable to those present in early postmenopausal women, and then ovariectomized and treated orally with: CEE (0.30 mg/day women's equivalent dose, n=28) or placebo (n=25) daily for 24 months. Body weight and estradiol were measured at 3, 6, 12 and 18 months and plasma lipids were measured at baseline and every 6 months. RESULTS: Despite the lack of effect on plasma lipid profiles, monkeys treated with low dose CEE had marked reductions in coronary artery atherosclerosis plaque extent (intimal area) in all three main coronary arteries: left anterior descending artery (52% less, 0.044 mm(2) versus 0.091 mm(2), p=0.04); left circumflex artery (62% less, 0.045 mm(2) versus 0.119 mm(2), p=0.006) and right circumflex artery (42% less, 0.018 mm(2) versus 0.031 mm(2), p=0.20). The overall mean coronary atherosclerosis extent was 52% lower in CEE treated animals (0.042 mm(2) versus 0.088 mm(2), p=0.02). CONCLUSION: Low dose CEE (0.30 mg/woman/day equivalent) was effective in reducing coronary atherosclerosis and the magnitude of the protection was comparable to previously reported studies using doses equivalent to 0.625 mg/woman/day. This study provides an experimental basis for the assumption that low dose CEE may be as effective as the traditional dose in inhibiting coronary atherosclerosis progression in early postmenopausal subjects.

Animals↗
PubMed2006

Metabolic phenotype of isoflavones differ among female rats, pigs, monkeys, and women.

Various physiologic effects of soy food consumption have been attributed to the estrogenic actions of isoflavones. The order of estrogen receptor binding potency of soy-derived isoflavone aglycones is equol > genistein > daidzein, and their conjugates are less potent. Because the metabolic profile may be an important determinant of bioactivity after soy intake, we studied the serum and urine isoflavone concentrations in 3 animal models and compared them with isoflavone profiles in women. Female Sprague-Dawley rats, Hampshire/Duroc Cross pigs, cynomolgus monkeys, and women were fed diets containing soy protein isolate. Isoflavones and their metabolites were measured by LC-MS or electrochemical detection. Equol represented approximately 77 and 52% (molar ratio) of summed serum isoflavones (isoflavones plus metabolites) in rats and cynomolgus monkeys, respectively. Equol was undetectable in pig serum and human plasma, but daidzein and genistein contributed >88% of summed circulating isoflavones. Monkey and rat urine contained high levels of aglycones (>85% and >32%, respectively), whereas pigs and women excreted isoflavone mainly in the form of glucuronides (>80%), with <10% as aglycones. Isoflavones in human plasma were predominantly glucuronides (75%) with 24% as sulfates and <1% as aglycones; in monkey serum, however, 64% of isoflavones were sulfates, 30% glucuronides, and 6% aglycones. Equol was also a major serum metabolite of 6-mo-old rhesus monkeys (80% of summed isoflavones). Thus, there were significant interspecies differences in isoflavone metabolism, and the overall metabolic profile of pigs was closer to that of women than that of rats or monkeys.

Animals↗
PubMed2006

Effects of soybean glyceollins and estradiol in postmenopausal female monkeys.

Glyceollins are a novel class of soybean phytoalexins with potential cancer-protective antiestrogenic effects. The purpose of this study was to evaluate the estrogen-antagonist effects of glyceollin-enriched soy protein on biomarkers for breast cancer risk. Thirty female postmenopausal cynomolgus macaques were randomized to one of three dietary treatments for 3 wk: 1) estradiol (E2, 1 mg/day) + casein/lactalbumin (control); 2) E2 + soy protein isolate (SPI) containing 194 mg/day isoflavonoids; and 3) E2 + glyceollin-enriched soy protein (GLY) containing 189 mg/day isoflavonoids + 134 mg/day glyceollins. Doses are expressed in calorically scaled human equivalents. Mean serum glyceollin concentrations at 4 h postfeeding were 134.2 +/- 34.6 nmol/L in the GLY group and negligible in the SPI group (P = 0.0007). Breast proliferation was significantly increased in the control group (+237%, P = 0.01) but not in the SPI group (+198%, P = 0.08) or GLY group (+36%, P = 0.18). Gene expression of trefoil factor 1 and progesterone receptor, two markers of estrogen receptor activity in breast epithelium, were also significantly higher in the control (P < 0.05 for both) but not in the GLY group. These preliminary findings suggest that soybean glyceollins are natural compounds with potential estrogen-modulating properties in the breast.

Animals↗
PubMed2005

Determination of plasma genistein fatty acid esters following administration of genistein or genistein 4'7-O-dioleate in monkeys.

Soy-derived isoflavone phytoestrogens, such as genistein (4',5,7-trihydroxyisoflavone), have been shown to protect low-density lipoprotein from oxidation. In addition, human plasma was previously shown to be capable of converting genistein into lipophilic fatty acid esters that accumulate in lipoproteins in vitro. We developed a method for the quantitation of genistein fatty acid esters in plasma. Furthermore, the method was utilized to measure genistein ester concentrations in monkey plasma following administration of genistein or genistein 4',7-O-dioleate. After extraction from plasma, genistein fatty acid esters were separated from unesterified genistein by Sephadex LH-20 column chromatography. The genistein ester fraction was hydrolyzed by saponification and purified by a second chromatography on Sephadex LH-20. The hydrolyzed genistein esters were measured by time-resolved fluoroimmunoassay. Adult female rhesus monkeys (n=10) received a subcutaneous injection of genistein (24 mg, n=2) or genistein 4',7-O-dioleate (71 mg, n=3) or an oral dose of genistein (24 mg, n=2) or genistein 4',7-O-dioleate (71 mg, n=3). Plasma was collected at 4, 8, and 24 h post-dosing. Following subcutaneous administration of genistein 4',7-O-dioleate, the plasma concentrations of genistein esters became elevated in two out of three monkeys with 8-h values exceeding 7.5 nmol/L and 24-h values above 12 nmol/L. Other treatments resulted in lower plasma values ranging between 2.7 and 6.1 nmol/L. The lower limit of detection for the method was 1.44 nmol/L. Subcutaneously administered genistein 4',7-O-dioleate was also converted to water-soluble conjugates, but oral administration did not elevate plasma genistein fatty acid ester levels. The results suggest that it may be possible to introduce intact genistein ester molecules into plasma by parenteral but not oral administration.

Administration, Oral↗
PubMed2005

Effects of tibolone on bone quality in ovariectomized monkeys.

OBJECTIVE: The purpose of this report is to examine the effects of two doses of tibolone on bone quality (bone biomarkers, bone density, and bone strength) in ovariectomized cynomolgus monkeys fed high-fat diets. DESIGN: Ovariectomized cynomolgus monkeys were randomized into one of five treatment groups: placebo-treated control, tibolone (0.2 mg/kg/day), tibolone (0.05 mg/kg/day), conjugated equine estrogens (Premarin, 0.042 mg/kg/day), and conjugated equine estrogens plus medroxyprogesterone acetate (0.042 and 0.167 mg/kg/day, respectively). Bone quality was assessed by determining bone strength and density in vertebrae and femora collected after 24 months of treatment. RESULTS: Monkeys treated for 24 months with tibolone had increased bone mineral density in the distal femur and improved biomechanical properties in the midshaft femur compared with placebo-treated ovariectomized monkeys, as did monkeys treated with conjugated equine estrogens with or without medroxyprogesterone acetate. No treatment effects were seen in lumbar vertebra bone density or strength. There was no significant difference between tibolone and estrogen on biomechanical properties of the femur. CONCLUSION: These data show that tibolone is comparable to conjugated equine estrogens with or without medroxyprogesterone acetate in decreasing bone turnover and increasing bone strength in ovariectomized monkeys.

Alkaline Phosphatase↗
PubMed2005

Controversies about HRT--lessons from monkey models.

Lessons from monkey models contribute significantly to a better understanding of the controversies in reconciling the differences in postmenopausal hormone treatment outcomes between observational and randomized trial data. Monkey studies brought attention to premenopausal estrogen deficiency with resulting premature coronary artery atherosclerosis. Recently, those monkey studies were confirmed for premenopausal women in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) Study. Monkey studies have provided convincing evidence for the primary prevention of coronary artery atherosclerosis when estrogens are administered soon after the development of estrogen deficiency. Equally convincing are the data from monkey studies indicating the total loss of these estrogens beneficial effects if treatment is delayed for a period equal to six postmenopausal years for women. An attempt has been made using the monkey model to identify the hormone treatment regimen most effective in preventing the progression of coronary artery atherosclerosis. By a substantial margin, the most effective approach is that of using estrogen containing oral contraceptive during the perimenopausal transition, followed directly by hormone replacement therapy postmenopausally. Because of similarities between human and nonhuman breast, monkeys have had a major role in clarifying controversies surrounding the breast cancer risk of estrogen only versus estrogen plus progestin therapies. The results of monkey studies suggest little or no effects of estrogen only treatment; whereas, estrogen+progestin clearly increases breast cancer risk.

Animals↗
PubMed2005

The applicability of hormonal effects on atherosclerosis in animals to heart disease in postmenopausal women.

The discrepancy between estrogen's beneficial cardiovascular effects found in animal studies and observational studies in women compared with the recently published randomized clinical trials have stimulated a great deal of controversy. Possibilities for the discrepancy include the age of the women, number of years postmenopausal, and amount of atherosclerotic complication (necrosis and inflammation) present when hormone therapy is initiated. Many of the previous benefits of estrogens noted in both animal studies and observational studies were found in primary prevention studies that experimentally refer to a decrease in the progression of atherosclerosis extent rather than prevention of clinical events, which often occur in women with undiagnosed atherosclerotic plaques. In support of this notion, animal studies in which artery damage was present prior to hormone treatment, due to either consumption of an atherogenic diet or balloon injury of the endothelium, found no benefit with estrogen treatment. These animal studies are consistent with the lack of protection found in secondary prevention studies in women. Other areas of concern deal with the route of hormone delivery or dose of hormones used. Higher doses of oral estrogens may result in increased risk of inflammation and thrombosis. Future studies should be directed at studying hormone therapy in relevant ages of women (perimenopausal women) using the lowest effective doses of hormones and comparing oral and parenteral forms of delivery.

Adult↗
PubMed2004

Effects of soy isoflavones and conjugated equine estrogens on inflammatory markers in atherosclerotic, ovariectomized monkeys.

The effects of dietary soy isoflavones (IF) and conjugated equine estrogens (CEE) on circulating inflammatory markers were determined at the end of a 3-yr study of ovariectomized monkeys consuming a moderately atherogenic diet. Treatments were: 1) control, receiving alcohol-extracted soy-protein-based diet with low IF content (comparable to approximately 5 mg/d); 2) CEE, added to the control diet at a dose comparable to 0.625 mg/d; and 3) IF, consumed as a part of unextracted soy protein isolate at a dose comparable to 129 mg/d. Serum soluble vascular cell adhesion molecule-1 (sVCAM-1) was reduced by both IF (P < 0.006) and CEE (P < 0.0001) relative to controls. Serum monocyte chemoattractant protein (MCP)-1 was reduced by CEE (P < 0.0001) but not by IF (P = 1.00). Treatments did not affect serum IL-6 (P = 0.40), soluble E-selectin (P = 0.17), or C-reactive protein (P = 0.15). Serum MCP-1 and, to a lesser extent, IL-6 significantly correlated with atherosclerosis (plaque area) in the iliac and carotid arteries (all P < 0.05). Serum MCP-1 was also strongly associated with coronary artery atherosclerosis and with indices of plaque inflammation and matrix remodeling (matrix metalloproteinase-9) in the coronary artery intima (all P < 0.01). We conclude that, in this well-established nonhuman primate model of atherosclerosis, this dose of soy IF provided an antiinflammatory effect specific for sVCAM-1, whereas the effects of CEE extended to both sVCAM-1 and MCP1. It is possible that the atheroprotective effects of IF and CEE are mediated, at least in part, by effects on VCAM-1. The sites of IF inhibitory effects on sVCAM-1 production are not known, but likely candidates include the liver and/or the cardiovascular system.

Animals↗
PubMed2004

Lessons to be learned from animal studies on hormones and the breast.

The relation of hormone use by postmenopausal women to breast cancer risk has been controversial and unclear. A recent large randomized trial, the Women's Health Initiative (WHI) and a large observational study (Million Women Study) provided somewhat conflicting answers. The WHI found an increased incidence of breast cancer among women given hormone therapy (conjugated equine estrogen plus medroxyprogesterone acetate) but no increase in those given estrogen only therapy (conjugated equine estrogen alone). Whereas, the Million Women Study found an increased breast cancer risk among the estrogen plus progestin and the estrogen only users. This review brings comparative perspective to the issue of the effects of estrogen plus progestin versus estrogen only effects on breast cancer and is focused particularly on nonhuman primates. Although data from rodents is mixed, studies of monkeys suggest that estrogen only treatment has little or no effect on breast cell proliferation, and by inference, on breast cancer risk. On the other hand, data from both mouse and monkey studies strongly support the conclusion that the co-administration of a progestogen with an estrogen markedly increases breast cell proliferation and the potential for breast cancer promotion.

Animals↗
PubMed2004

The Women's Health Initiative could not have detected cardioprotective effects of starting hormone therapy during the menopausal transition.

The Women's Health Initiative (WHI) randomized controlled trial failed to show cardioprotection by estrogen plus progestin treatment of postmenopausal women. But by design, the WHI population was 10-fold underpowered to show cardioprotection of women starting hormone treatment during the menopausal transition. Thus, observational studies that showed cardioprotection in such women remain the only applicable clinical guide to this issue. Randomized controlled trials are urgently needed to test cardioprotection in women starting treatment during the menopausal transition.

Cardiovascular Diseases↗
PubMed2004

Postmenopausal hormone therapy before and after the women's health initiative study: what consequences?

This review focuses on the question of whether the Women's Health Initiative (WHI) was a test of primary versus secondary cardiovascular benefits of postmenopausal hormone therapy. Evidence is presented to support the conclusion that the WHI was a secondary intervention trial and that primary cardiovascular benefits of hormone therapy are rational, likely, but not yet proven. The review makes clear that hormone therapy is not a 'cardiovascular drug' for the treatment of coronary heart disease; but rather that the public health debate is whether hormone therapy, used for the treatment of menopausal symptoms, provides any cardiovascular benefits that might offset its risk.

Age Factors↗
PubMed2003

Value of the micropig model of menopause in the assessment of benefits and risks of postmenopausal therapies for cardiovascular and reproductive tissues.

OBJECTIVE: To extend the comparative database demonstrating the cardioprotective benefits of estrogen therapy to an additional relevant species and to assess the usefulness of this model for studies designed to assess benefits and risks of postmenopausal therapies. DESIGN: Prospective, randomized, controlled periclinical trial. SETTING: Medical university animal facility. ANIMAL(S): Fifteen sexually mature Yucatan micropigs and 15 ovariectomized micropigs. INTERVENTION(S): Oral conjugated equine estrogens (CEE), 0.625 mg/d, or levormeloxifene, 37.5 mg/d, for 182 days. MAIN OUTCOME MEASURE(S): Coronary artery atherosclerosis was measured by digitization, uteri were weighed, and uterine and mammary tissues were evaluated histologically and morphometrically. Mean blood pressure was measured by oscillometry, C-reactive protein by enzyme-linked immunosorbent assay, and serum lipids by enzymatic methods. RESULT(S): Coronary artery atherosclerosis was reduced 51% in animals that received CEE compared with controls. Levels of C-reactive protein increased by 12% with both treatments. Serum lipid levels and mean blood pressure did not differ among groups. Levormeloxifene produced a 5.9-fold increase in the uterine-to-body weight ratio. Histologic and morphometric data indicate that levormeloxifene has uterotrophic and mammotrophic effects. CONCLUSION(S): The micropig model extends the comparative evidence for cardioprotection provided by estrogen therapy to an additional highly relevant species, thus supporting the rationale for a clinically beneficial role of estrogen for the heart. The marked uterine effects of levormeloxifene detected by this model are probably highly predictive of the adverse events that would be encountered in clinical trials.

Animals↗
PubMed2003

Serum cholesterol efflux potential is an independent predictor of coronary artery atherosclerosis.

The efflux of cholesterol from cells and its incorporation into HDL is believed to be the initial step in reverse cholesterol transport. This report addresses the question of whether there is a relationship between the ability of serum to promote efflux of cholesterol from cells in culture and the severity of coronary artery atherosclerosis (CAA). Surgically postmenopausal cynomolgus monkeys (n=142) were treated for 2-years with conjugated equine estrogens (CEE), CEE plus medroxyprogesterone acetate, or two different doses of tibolone, a synthetic steroid. CAA was determined at necropsy, and the cholesterol efflux potential of serum from each animal was determined using 3H-cholesterol-labeled Fu5AH cells and human skin fibroblasts in culture. A significant negative correlation was seen between CAA and cholesterol efflux from Fu5AH cells (r=-0.44, P< or =0.0001), but not skin fibroblasts. Although there was a wide range of plasma HDL cholesterol concentrations in these animals (10-81 mg/dl), using multiple regression analysis, LDL+VLDL cholesterol and the serum cholesterol efflux potential were the only significant independent predictors of CAA, explaining 41.6 and 10.7% of the variability (P<0.0001), respectively. Thus, the potential of serum to promote cholesterol efflux from Fu5AH cells may represent a useful independent measure for improving the assessment of CAA risk.

Animals↗