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Thomas B Clarkson

Publications and source records attributed to Thomas B Clarkson.

34 records · Page 2Linked to original sources
PubMed2003

Effects of tibolone and conjugated equine estrogens with or without medroxyprogesterone acetate on body composition and fasting carbohydrate measures in surgically postmenopausal monkeys.

The effects of tibolone on body weight, body composition, and fasting carbohydrate measures in surgically postmenopausal cynomolgus monkeys were compared to those of conjugated equine estrogens (CEE) with and without medroxyprogesterone acetate (MPA). Monkeys were fed a moderately atherogenic diet with either no hormones (control n = 29), CEE (0.042 mg/kg, n = 27), CEE + MPA (0.167 mg/kg, n = 29), low-dose tibolone (LoTib, 0.05 mg/kg, n = 30), or high-dose tibolone (HiTib, 0.20 mg/kg, n = 31) daily for 2 years. Body weight (BW) was measured throughout the study, and dual-energy x-ray absorptiometry (DEXA) scans of the abdominal region (lumbar vertebrae 1 through 5) were performed at the end of the trial to assess abdominal body composition. Fasting carbohydrate measures (glucose, insulin, C-peptide, and fructosamine) were determined at baseline and after 2 years of treatment. Compared to controls, BW significantly increased and abdominal soft tissue mass was greater (analysis of variance [ANOVA], P <.001, P = 0.003, respectively) in all but the CEE-treated group (P =.78, P =.94, respectively). HiTib-treated monkeys had greater abdominal lean mass compared to controls (P =.008), while there was no significant treatment effect on abdominal fat mass (analysis of covariance [ANCOVA], P =.29). Fasting insulin concentrations and fasting insulin/glucose ratios were greater in CEE + MPA- (P =.002, P =.03, respectively) and HiTib-treated monkeys (P =.03, P =.02, respectively) compared to controls. There was a strong trend for a treatment effect on fasting blood glucose concentration (ANCOVA, P =.06) with CEE + MPA-treated animals having the greatest values, despite no difference in fructosamine concentration (ANCOVA, P =.57). Using these fasting measures, the homeostasis model assessment (HOMA-IR) revealed significant insulin resistance with CEE + MPA treatment compared to controls (P =.008), while the quantitative insulin sensitivity check index (QUICKI) showed significantly impaired insulin sensitivity in all hormone replacement therapy (HRT) groups (all P values <.03), except CEE (P =.12). In conclusion, HRT with CEE + MPA or tibolone results in greater BW, abdominal soft tissue, and insulin resistance (CEE + MPA and HiTib) compared to control-treated monkeys.

Animals↗
PubMed2003

MPA and postmenopausal coronary artery atherosclerosis revisited.

Whether progestins, particularly medroxyprogesterone acetate (MPA), attenuate the cardiovascular benefits of postmenopausal estrogen replacement therapy (ERT) has been controversial for over a decade. Concerns related first to findings that MPA attenuated increases of high density lipoprotein cholesterol (HDLC) concentrations of postmenopausal women compared to conjugated equine estrogen (CEE) alone. That observation was followed by early cynomolgus monkey studies that suggested MPA decreased estrogen's cardiovascular benefits (vascular reactivity and coronary artery atherosclerosis inhibition). In a more recent and larger trial with cynomolgus monkeys, no differences were seen in the coronary artery atherosclerosis protective effect of CEE when MPA was co-administered (HRT). The lack of attenuation of ERTs benefits by progestins has also been seen in at least three studies of carotid artery intima-media thickness (IMT) of postmenopausal women. Additionally, the majority of studies of vascular reactivity of postmenopausal women have not found differences when CEE is given alone or with MPA. Seven observational studies of cardiovascular outcomes of postmenopausal women permit separate consideration of ERT versus HRT use; there is no evidence of attenuation of ERTs benefits by progestin use. In conclusion, it is evident that the current experimental, clinical, and observational data do not provide evidence that progestins attenuate estrogen's cardiovascular benefits.

Animals↗
PubMed2003

Treatment with antibiotics reduces plasma equol concentration in cynomolgus monkeys (Macaca fascicularis).

To explore the importance of equol on health outcomes in future studies, it was necessary to develop a method to reduce equol production. Female monkeys (n = 22) fed a soy diet were treated twice daily with vehicle (control; n = 4), doxycycline (2.5 mg/kg; n = 4), metronidazole (125 mg/d; n = 3), kanamycin (1000 mg/d; n = 4), vancomycin (100 mg/d; n = 3) or kanamycin+vancomycin (n = 4). Plasma samples were collected 4 h postfeeding at baseline, after 4 wk of treatment and 8 wk after the end of treatment and analyzed for isoflavonoid concentrations. Fecal swabs were collected at baseline and at the end of antibiotic treatment for analysis of Gram(+) and Gram(-) bacterial growth. Equol concentrations were reduced (P < 0.05) compared with baseline by 80, 93, 98 and 99% after treatment with metronidazole (955 +/- 164 vs. 193 +/- 53 nmol/L), kanamycin (545 +/- 211 vs. 37.1 +/- 17.6 nmol/L), vancomycin (607 +/- 163 vs. 8.9 +/- 8.2 nmol/L) and kanamycin+vancomycin (721 +/- 169 vs. 17.4 +/- 17.3 nmol/L), respectively. Daidzein concentrations were increased (P < 0.05) compared with baseline by treatment with doxycycline (336 +/- 87 vs. 576 +/- 76 nmol/L), kanamycin (168 +/- 67 vs. 374 +/- 15 nmol/L), and kanamycin+vancomycin (166 +/- 35 vs. 384 +/- 78 nmol/L). Similar increases (P < 0.05) in dihydrodaidzein were observed after treatment with kanamycin (31.2 +/- 6.2 vs. 479 +/- 188 nmol/L) and metronidazole (56.0 +/- 27.9 vs. 414 +/- 212 nmol/L). Isoflavonoid concentrations returned to baseline values after antibiotic treatment was terminated. Gram(+) bacterial growth was reduced by all treatments, including Control, compared with baseline. In conclusion, treatment with antibiotics resulted in a marked reduction in plasma equol concentrations and altered plasma isoflavonoid patterns in cynomolgus monkeys.

Administration, Oral↗
PubMed2002

Estrogen replacement therapy, atherosclerosis, and vascular function.

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.

Aged↗
PubMed2002

Use of the progestin challenge test in nonhuman primates (Macaca fascicularis).

OBJECTIVE: To determine whether the progestin challenge test (PCT) would provide a reliable, noninvasive indicator of endometrial stimulation in nonhuman primates. DESIGN; Randomized, 2x2, crossover study. SETTING; Nonhuman primates (Macaca fascicularis) in an academic research environment. PATIENT(S): Adult, surgically postmenopausal, female cynomolgous macaques (n = 27) were studied. INTERVENTION(S): Females were randomly assigned to receive estradiol (n = 14; 0.028 mg/kg body weight) or vehicle (n = 13) daily. All animals were administered two PCTs in a crossover study design using two doses (0.28 mg/kg or 0.56 mg/kg body weight) of medroxyprogesterone acetate (MPA). MAIN OUTCOME MEASURE(S): Incidence and severity of withdrawal bleeding and serum estradiol (E(2)) and progesterone (P(4)) levels were evaluated. RESULT(S): Estradiol treatment resulted in endometrial "withdrawal" bleeding in all but one instance. Females receiving daily doses of E(2) exhibited a significantly greater (P<.01) incidence, severity, and duration of withdrawal bleeding compared to control animals. Of the five positive responses observed in the control females, four occurred when the higher dose of MPA was administered. CONCLUSION(S): These results indicate that the PCT is a useful, noninvasive method for determining the presence of endometrial stimulation in nonhuman primates.

Animals↗
PubMed2002

Serum cholesterol efflux potential in postmenopausal monkeys treated with tibolone or conjugated estrogens.

Tibolone is a synthetic steroid used for the treatment of climacteric symptoms and the prevention of osteoporosis, but the effect on the cardiovascular system is unclear since tibolone lowers high-density lipoprotein (HDL) levels. We investigated if long-term treatment with tibolone or conventional hormone replacement therapy (HRT) in cynomolgus monkeys could affect their serum cholesterol efflux potential. Surgically postmenopausal cynomolgus monkeys were treated for 2 years with conjugated equine estrogens (CEE), CEE plus medroxyprogesterone acetate (MPA), low-dose tibolone, or high-dose tibolone. Plasma lipid, lipoprotein, and apolipoprotein levels were monitored during the study. The cholesterol efflux potential of the serum from each animal was determined in (3)H-cholesterol-labeled Fu5AH cells and skin fibroblasts in culture. Tibolone induced a dose-dependent 30% to 52% reduction in HDL levels. When HDL concentrations were reduced by 30%, as seen in women, there was no reduction in the serum cholesterol efflux potential in Fu5AH cells. With a 52% reduction in HDL, there was a 14% reduction in cholesterol efflux. Although CEE or CEE+MPA had no significant effect on HDL levels, CEE treatment increased serum cholesterol efflux potential by 7%. With the same sera, no changes in cholesterol efflux were seen with fibroblasts. Although our findings suggest that HDL concentration is correlated with cholesterol efflux potential of serum, this relationship is weak, explaining only 16% of the variability. This is emphasized by the fact that despite a 30% lowering of HDL with tibolone, there was no indication of an adverse effect on cellular cholesterol efflux. Other changes in the serum not measured in this study must contribute significantly to the cholesterol efflux potential of serum. Because changes in cholesterol efflux potential of serum were seen only in Fu5AH cells, a cell line rich in SR-B1 receptors, this implies that the changes seen in this study were mediated largely by the SR-B1 pathway.

Analysis of Variance↗
PubMed2002

Dietary soy and soy isoflavones have gender-specific effects on plasma lipids and isoflavones in golden Syrian f(1)b hybrid hamsters.

The specific components of soy responsible for its beneficial effects on plasma lipids are unknown. Golden Syrian F(1)B Hybrid hamsters (75 male, 74 female) were evaluated for the effect of dietary soy and soy isoflavones on plasma lipids. They were fed the following diets for 16 wk: casein/lactalbumin (C/L), soy protein with isoflavones [Soy(+)], soy protein with isoflavones removed [Soy(-)], Soy(-) plus isoflavone extract (IF), and C/L + IF. At necropsy, plasma total cholesterol, HDL cholesterol (HDLC), LDL + VLDL cholesterol (LDL + VLDLC), isoflavones, and uterine and accessory gland weights were measured. Male hamsters fed the three soy-containing diets had lower LDL + VLDLC concentrations than those fed the two C/L diets (P < 0.01), and those fed Soy(-) + IF did not differ from those fed Soy(+). In females, diet did not affect plasma LDL + VLDLC concentration. Females fed Soy(+) or Soy(-) had higher HDLC (P < 0.05) than those fed C/L. HDLC was not affected by diet in males. Due to higher equol production (P < 0.01), males had greater plasma isoflavone concentrations (P < 0.01) than females. There was a positive association between plasma total isoflavones and LDL + VLDLC (r = 0.65, P < 0.05) in females. These data suggest gender differences in plasma lipid and isoflavone responses to soy- based diets in Syrian F(1)B Hybrid hamsters, which offer an opportunity to explore effects of sex hormones on isoflavone metabolism and the effects of isoflavones on lipid metabolism.

Animals↗
PubMed2002

Soy, soy phytoestrogens and cardiovascular disease.

Dietary soy protein has been shown to have several beneficial effects on cardiovascular health. The best-documented effect is on plasma lipid and lipoprotein concentrations, with reductions of approximately 10% in LDL cholesterol concentrations (somewhat greater for individuals with high pretreatment LDL cholesterol concentrations) and small increases in HDL cholesterol concentrations. Dietary soy protein improves flow-mediated arterial dilation of postmenopausal women but worsens that of men. Soy isoflavone extracts improve systemic arterial compliance, an indicator of atherosclerosis extent. Complete soy protein but not alcohol-washed soy protein reduces atherosclerosis of postmenopausal monkeys. No definite experimental evidence exists currently to establish that the cardiovascular benefits of soy protein are accounted for by its isoflavones.

Animals↗
PubMed2002

Comparison of tibolone and conjugated equine estrogens effects on carotid artery atherosclerosis of postmenopausal monkeys.

BACKGROUND AND PURPOSE: Tibolone is a tissue-specific compound that has favorable effects on bone and menopausal symptoms without stimulating endometrium or breast, but lowers concentrations of plasma high-density lipoprotein (HDL) cholesterol (HDLC). This study was designed to determine whether the HDL lowering with tibolone exacerbated common or internal carotid artery atherosclerosis and to evaluate tibolone treatment relative to conjugated equine estrogens (CEE) alone or in combination with medroxyprogesterone acetate (MPA). METHODS: Carotid artery atherosclerosis was compared in groups of surgically postmenopausal cynomolgus monkeys treated with CEE, CEE+MPA, or either of 2 doses of tibolone versus untreated monkeys. RESULTS: Despite a 30% to 52% lowering of HDLC with tibolone, there was no significant effect on carotid artery atherosclerosis. CEE and CEE+MPA, however, inhibited carotid artery atherosclerosis by approximately 60%. CONCLUSIONS: In surgically postmenopausal cynomolgus monkeys, CEE and CEE+MPA inhibited common and internal carotid artery atherosclerosis. Despite the potentially adverse effects of tibolone on HDLC, tibolone did not exacerbate atherosclerosis.

Animals↗
PubMedDate not supplied

A comparison of tibolone and hormone replacement therapy on coronary artery and myocardial function in ovariectomized atherosclerotic monkeys.

OBJECTIVE: Tibolone is used to prevent osteoporosis and to treat climacteric symptoms. The objectives of these studies were to measure and compare the effects of tibolone with hormone replacement therapy on coronary artery vascular reactivity and myocardial function and to relate these outcomes to treatment-induced plasma lipid/lipoprotein concentrations and atherosclerosis. DESIGN: One hundred forty-eight adult ovariectomized cynomolgus monkeys were fed an atherogenic diet for 24 months while receiving one of five oral treatments: no treatment (control, n = 31); conjugated equine estrogens (CEE), given at the equivalent of 0.625 mg/day ( n = 27); CEE (same dose) plus medroxyprogesterone acetate (MPA), given at the equivalent of 2.5 mg/day ( n = 29); low-dose tibolone (LoTib; 0.625 mg/day equivalent, n = 30); or high-dose tibolone (HiTib; 2.5 mg/day equivalent, n = 31). RESULTS: Quantitative coronary angiography showed that endothelium-mediated dilation was enhanced (17.5 +/- 5%, p = 0.002) in the CEE-treated group (but not other treatment groups) compared with the control. Both doses of tibolone and CEE reduced the incidence of dobutamine-induced ST-segment depression (LoTib: 33%, HiTib 25%, and CEE: 23%) compared to the control (79%) ( p = <0.05). Neither vascular reactivity nor dobutamine-induced myocardial ischemia were associated with treatment-induced changes in atherosclerosis or plasma lipid/lipoprotein concentrations. CONCLUSIONS: Tibolone, unlike CEE, has no benefit for endothelium-mediated dilation. Despite these differences, both tibolone and CEE reduced the incidence of myocardial ischemia, whereas CEE+MPA had no effect. It is speculated that tibolone may have direct effects on the myocardium that protect against myocardial ischemia.

Animals↗
PubMedDate not supplied

Comparative effects of tibolone and conjugated equine estrogens with and without medroxyprogesterone acetate on the reproductive tract of female cynomolgus monkeys.

OBJECTIVE: To measure the effects of 2 years' treatment with tibolone on the reproductive tract of female monkeys (Macaca fascicularis) in comparison with conventional hormone replacement therapy. DESIGN: Ovariectomized adult female monkeys were randomized for 2 years of treatment into five groups: controls (n = 31); tibolone at 0.05 mg/kg (LoTIB group; n = 30); tibolone at 0.2 mg/kg (HiTIB group; n = 31); conjugated equine estrogens (CEE) at 0.042 mg/kg (CEE group; n = 28); or CEE + medroxyprogesterone acetate (MPA) at 0.167 mg/kg (CEE + MPA group; n = 29). Endpoints included vaginal cytology; uterine weight; histopathologic evaluation of the uterus, vagina, and cervix; histomorphometry of the endometrium; and immunohistochemical detection of the proliferation marker Ki67 and progesterone receptor in endometrial tissue. RESULTS: Endometrial atrophy was found in 29 of 30 and 23 of 31 animals in the LoTIB and HiTIB groups, respectively, compared with 0 of 28 and 11 of 29 in the CEE and CEE + MPA groups, respectively. All ovariectomized control animals had atrophic endometria. No complex or atypical hyperplasia was seen. Simple endometrial hyperplasia of a significant degree was seen in 3 of 31 HiTIB-treated animals, 1 of 30 LoTIB-treated animals, 26 of 28 CEE-treated animals, and 16 of 29 CEE + MPA-treated animals, and in none of the control animals. Marked simple endometrial hyperplasia and Ki-67 expression was induced by CEE and partially antagonized by MPA. LoTIB and HiTIB slightly increased endometrial thickness, whereas CEE and CEE + MPA induced a marked increase of 350% and 200%, respectively. Neither LoTIB nor HiTIB increased endometrial proliferation (Ki67 labeling) or induced vaginal keratinization. Endometrial bleeding was not seen in tibolone-treated animals but was present in 10 of 29 animals given CEE + MPA. CONCLUSIONS: The effect of tibolone on the uterus and lower reproductive tract was minimal. The lack of a proliferative response of the endometrium to tibolone, coupled with the lower incidence of endometrial bleeding, suggests that tibolone may have advantages over CEE and CEE + MPA regarding endometrial safety and efficacy.

Analysis of Variance↗
PubMedDate not supplied

Effects of tibolone and conventional hormone replacement therapies on arterial and hepatic cholesterol accumulation and on circulating endothelin-1, vascular cell adhesion molecule-1, and E-selectin in surgically menopausal monkeys.

OBJECTIVE: Menopause and aging are associated with a marked increase in the incidence of coronary heart disease as well as reductions in circulating estrogen, progestogen, and androgen levels. The synthetic compound tibolone and its metabolites have estrogenic, progestogenic, and androgenic characteristics. In the present study, we compared the effects of tibolone, estrogen replacement therapy, and estrogen plus progestogen replacement therapy on arterial and hepatic lipid accumulation and on circulating soluble adhesion molecule and endothelin-1 concentrations in surgically postmenopausal cynomolgus monkeys. DESIGN: Animals were fed an atherogenic diet for 2 years while receiving either no hormone treatment (control, n = 31) or the following treatments at doses designed to mimic the human dose on a daily caloric intake basis: tibolone at 2.5 mg/day (HiTib, n = 31), tibolone at 0.625 mg/day (LoTib, n = 29), conjugated equine estrogens (CEE) alone at 0.625 mg/day (CEE, n = 29), or CEE plus continuous medroxyprogesterone acetate (MPA) at 2.5 mg MPA/day (CEE + MPA, n = 30). RESULTS: Relative to the control group, iliac artery total cholesterol content was not different in the HiTib, LoTib, and CEE + MPA groups but was significantly lower in the group receiving CEE only (P < 0.05). In contrast, hepatic free cholesterol content was reduced in all treatment groups [HiTib (P < 0.01), LoTib (P < 0.05), CEE (P < 0.01), and CEE + MPA (P < 0.05)], whereas hepatic total and esterified cholesterol content were reduced in the HiTib, CEE, and CEE + MPA groups (all P < 0.05). HiTib and CEE groups had lower hepatic triglyceride levels per milligram of protein (P < 0.05). Iliac arterial cholesterol content was highly correlated with hepatic cholesterol content and with previously published histomorphometrically determined coronary artery atherosclerosis, supporting the use of the iliac artery as a surrogate for the coronary artery in the monkey. Circulating levels of soluble vascular cell adhesion molecule-1 were significantly reduced in the HiTib (P < 0.02) and CEE (P < 0.05) groups, whereas soluble E-selectin was reduced in the CEE group only (P < 0.01). Plasma endothelin-1 was significantly reduced in the LoTib (P < 0.05), CEE (P < 0.01), and CEE + MPA (P < 0.01) groups. CONCLUSIONS: These results suggest that while tibolone caused marked depression of high-density lipoprotein cholesterol and a resultant twofold increase in the total plasma cholesterol/high-density lipoprotein cholesterol ratio, those effects did not result in exacerbation of iliac artery atherosclerosis, perhaps because of beneficial effects on vascular biology or hepatic metabolism.

Androgen Antagonists↗
PubMedDate not supplied

Effects of tibolone and hormone replacement therapy on the breast of cynomolgus monkeys.

OBJECTIVE: To measure the effects of 2 years of treatment with tibolone on the breasts of cynomolgus macaques (Macaca fascicularis) in comparison with conventional hormone replacement therapy. DESIGN: Ovariectomized cynomolgus macaques were randomized into five groups and treated for 2 years. Groups included controls (n = 31) and four drug treatments, including tibolone at 0.05 mg/kg (LoTIB, n = 30) or 0.2 mg/kg (HiTIB, n = 31), conjugated equine estrogens at 0.042 mg/kg (CEE, n = 28), or CEE + medroxyprogesterone acetate (MPA) at 0.167 mg/kg (CEE + MPA, n = 29). Endpoints included histologic, histomorphometric, and immunohistochemical assessment of the mammary gland. RESULTS: Tibolone did not cause stimulation of the breast in contrast to distinct proliferative responses of the breast to CEE and CEE + MPA, as measured by increases in breast epithelial tissue area and expression of the proliferation marker Ki67 in breast epithelial cells. Tibolone at the higher dose increased progesterone receptor expression in the breast relative to controls, indicating partial estrogen-agonist activity, but without induction of proliferation. Progesterone receptor expression was also induced by CEE. CONCLUSIONS: Tibolone may have an advantage over conventional hormone replacement therapy because it does not stimulate proliferation in the breast. This lack of mammotrophic effect may reflect a lower risk for promotion of breast cancer.

Animals↗
PubMedDate not supplied

The new conundrum: do estrogens have any cardiovascular benefits?

Clearly, a new era has begun, with increasing numbers of the scientific/medical community asking whether estrogens have any cardiovascular benefits. Doubts have arisen from two randomized prospective trials. The Heart and Estrogen/progestin Replacement Study (women who were generally beyond 65 years of age with preexisting coronary heart disease) found no benefit in reducing coronary events by a combination of estrogens and a progestin. Later, the Estrogen Replacement Atherosclerosis Trial reported that no benefit could be shown for either conjugated equine estrogens only or the combined therapy group for women with preexisting coronary artery stenosis. There are lessons to be taken from monkey models about the new conundrum. Estrogens have beneficial effects in the early stages of atherogenesis, but have little or no beneficial effects in the final stages of plaque complications, instability and coronary heart disease events. Using the monkey model, we have addressed the question of when "primary prevention" should begin. We examined the effect of contraceptive steroid treatment of stressed animals at high risk to progressing atherosclerosis due to their estrogen deficiency and subsequently examined the effect of estrogen replacement therapy or no estrogen replacement therapy following surgical menopause. The most robust inhibition of atherosclerosis progression was found in those animals given contraceptive steroids premenopausally and subsequently estrogen replacement postmenopausally. The notion of starting contraceptive therapy during the perimenopausal period to be followed immediately with estrogen replacement postmenopausally is likely to be the most favorable approach to the inhibition of atherosclerosis progression.

Animals↗