Biomedical subjects

M R Adams

Publications and source records attributed to M R Adams.

188 records · Page 11Linked to original sources

PubMedDate not supplied

Assessment of hormonally active agents in the reproductive tract of female nonhuman primates.

Using the ovariectomized macaque model of postmenopausal women's health, we investigated the effects of long-term treatments (5 weeks-3 years) with estradiol, conjugated equine estrogens (CEE), esterified estrogens, progestins such as medroxyprogesterone acetate (MPA) and nomegestrol acetate, CEE + MPA, tamoxifen, soybean phytoestrogens (SPEs), a variety of putative selective estrogen receptor modulators (SERMs), and androgens. Agents tested were selected on the basis of beneficial effects on arteries and/or bone. Doses were scaled on a caloric or serum-concentration basis to approximate human clinical doses. We evaluated endometrial and mammary gland histopathology and morphometry and used immunohistochemistry to evaluate cell proliferation and expression of estrogen receptor alpha and progesterone receptor (PR). Both estradiol and CEE induced endometrial hyperplasia. MPA antagonized epithelial proliferation induced by CEE in endometrium and induced pseudodecidual stromal hyperplasia in some animals. Tamoxifen induced endometrial polyps, cystic hyperplasia, stromal fibrosis, and PR expression but not Ki-67 expression. SPEs were not estrogenic at dietary doses and antagonized estrogen-induced proliferation in the endometrium and breast. Nandrolone induced mucometra and an adenomyosis-like change. The potential SERM 17 alpha dihydroequilenin did not have uterotrophic or mammotrophic effects. In general, experimental findings in macaques have been predictive of outcomes in human clinical trials of the same agents.

Animals↗

PubMedDate not supplied

Behaviorally elicited heart rate reactivity and atherosclerosis in female cynomolgus monkeys (Macaca fascicularis).

We previously reported that the coronary atherosclerosis of cholesterol-fed, male cynomolgus monkeys (Macaca fascicularis) was exacerbated among animals that exhibited the largest heart rate (HR) reactions to a standard laboratory stressor. Here we report a similar relationship between behaviorally induced HR reactivity and atherosclerosis in females of the same species. Twenty-one female monkeys were fed a moderately atherogenic diet for 30 months. Near the end of this period, animals were fitted with electrocardiogram telemetry devices and their HRs were recorded under baseline and stressed conditions. Stress period HR measurements were obtained during a standard challenge involving threatened capture and physical handling of the animals. At necropsy, sections taken from the left anterior descending, left circumflex, and right coronary arteries were examined histologically. Mean intimal area measurements were then compared between animals identified as High (n = 7) and Low (n = 7) HR reactors. High HR reactive animals were found to have significantly greater coronary artery atherosclerosis than Low reactors; atherosclerosis at the right carotid bifurcation also differed significantly between High and Low reactive monkeys. Groups did not differ in baseline HR, blood pressure, and total or HDL cholesterol concentrations. Relative to Low HR reactors, however, High reactive animals weighed less and were less ponderous, had greater heart weights (adjusted for differences in body weight), were behaviorally less aggressive, and had lower luteal phase progesterone concentrations. These relationships were corroborated in correlation analyses employing data of all 21 study animals.

Aggression↗

PubMedDate not supplied

Opioidergic inhibition of circulatory and endocrine stress responses in cynomolgus monkeys: a preliminary study.

Twenty-five female cynomolgus monkeys (Macaca fascicularis) were exposed to psychological stress (threat of capture) after blockade of endogenous opioids with naloxone and after saline control injections. Heart rates were monitored continuously and blood samples were obtained for determination of plasma levels of cortisol and beta-endorphin-like immunoreactivity. Results indicate that the stress manipulation resulted in increased heart rates as well as plasma cortisol levels in monkeys pretreated with saline. Blockade of opioid receptors with naloxone potentiated the stress-induced rise in plasma cortisol and stimulated release of beta-endorphin-like immunoreactivity. The drug effect on heart rate reactivity was significantly correlated with the drug effects on both cortisol and beta-endorphin. When saline-treated monkeys were divided into high and low heart rate reactivity groups, the effects of naloxone on heart rate, cortisol, and beta-endorphin-like immunoreactivity responsiveness were significantly greater in low heart rate reactors. These data suggest that monkeys with low heart rate responses to stress have an effective opioidergic inhibition of circulatory and pituitary-adrenocortical reactivity. Monkeys showing excessive heart rate reactivity during psychological stress have a less active opioidergic inhibitory mechanism. The potential pathophysiological consequences of impaired opioidergic inhibition are discussed in light of the relationship between exaggerated stress reactivity and atherosclerotic lesion formation.

Animals↗

PubMedDate not supplied

Psychosocial factors, sex differences, and atherosclerosis: lessons from animal models.

OBJECTIVE: Premenopausal women, compared with men, are relatively spared from coronary heart disease and the underlying atherosclerosis. Our purpose has been to elucidate the reason for this difference and to explore the role of behavioral factors in this phenomenon. METHODS: Studies employed socially housed cynomolgus macaques (Macaca fascicularis) fed an atherogenic diet and subjected to behavioral observations. Ovariectomy, with or without hormone replacement, was used to test specific hypotheses about estrogen's role in the protection of females from atherosclerosis and coronary heart disease. RESULTS: Female macaques, like women, are resistant to atherosclerosis. However, this resistance is modified by social status-dominant monkeys develop little atherosclerosis, whereas subordinates resemble males in the amount of lesion that occurs. Subordinate females also are characterized by hypercortisolemia, behavioral dysfunction, and impaired ovarian function; the resulting low concentrations of circulating estrogen perhaps explain their accelerated atherosclerosis. Notably, atherosclerosis is exacerbated in ovariectomized monkeys but is suppressed in association with pregnancy, a hyperestrogenic state. Moreover, exogenous estrogen (an oral contraceptive) inhibits atherosclerosis in premenopausal social subordinates. CONCLUSIONS: To the extent that our results apply to women, they highlight the potential importance of behavioral stressors and their effects on estrogen activity in the premenopausal development of atherosclerosis. The triad of hypercortisolism, ovarian impairment, and psychiatric morbidity found in monkeys also occurs in women and may represent a high-risk state for disorders of the cardiovascular system and perhaps, other estrogen-sensitive tissues.

Adrenocortical Hyperfunction↗

PubMedDate not supplied

Staining intensities in the fluorescent treponemal antibody-absorption (FTA-Abs) test: association with the diagnosis of syphilis.

In 1984 the reporting system for the fluorescent treponemal antibody-absorption (FTA-Abs) test was changed by the Centers for Disease Control (CDC; Atlanta, GA) to eliminate the borderline report. Factors influencing the reliability of the FTA-Abs test results, i.e., sensitivity, specificity, prevalence of syphilis, prescreening of sera with nontreponemal tests, and reproducibility, were considered before the change in the reporting system was recommended and are reported here. The borderline report, when associated with syphilis, was most frequently also associated with the diagnosis of early primary, dark-field-positive, nontreponemal test-nonreactive syphilis. Whereas elimination of the borderline report decreased the sensitivity of the FTA-Abs test as a confirmatory test from 100% to 99.5%, the specificity increased from 82.5% to 88.7%. The 1+ staining intensity had an association of approximately 5% with the diagnosis of syphilis. The changes in the reporting system were designed to assist the clinician in interpreting the results of the FTA-Abs test in those cases that present diagnostic dilemmas.

Fluorescent Antibody Technique↗

PubMedDate not supplied

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

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.

Animals↗

PubMedDate not supplied

Ovariectomy, social status, and atherosclerosis in cynomolgus monkeys.

Evidence is contradictory regarding the effects of natural or surgical menopause on "female protection" against coronary artery atherosclerosis. We evaluated atherosclerosis, plasma lipids, blood pressure, and carbohydrate tolerance in 21 ovariectomized and 23 intact female cynomolgus macaques fed a moderately atherogenic diet for 30 months. We also evaluated the influence of social dominance status, with particular emphasis on a possible relationship with ovarian endocrine function. Atherosclerosis was two to 10 times as extensive in coronary, carotid, and iliaco-femoral arteries of the ovariectomized females; this could be explained, in part, by 15% to 20% increases in total plasma and LDL cholesterol concentrations. Socially dominant intact females were protected against advanced atherosclerotic lesions (plaques) of the coronary arteries, while subordinate females and ovariectomized females were not. Increased susceptibility to advanced coronary artery atherosclerosis in subordinate intact females may have been related in some way to chronic ovarian dysfunction observed in seven of 12 of these individuals. As a group, subordinate intact females also had enlarged adrenal glands, suggestive of mechanisms that may influence atherogenesis independently. The results indicate that, in this species, ovariectomy and chronic ovarian dysfunction related to subordinate social status are associated with a more atherogenic plasma lipid pattern and abolish "female protection" against coronary artery atherosclerosis.

Adrenal Glands↗

PubMedDate not supplied

Pregnancy-associated inhibition of coronary artery atherosclerosis in monkeys. Evidence of a relationship with endogenous estrogen.

We investigated the influence of repeated pregnancy on diet-induced atherosclerosis in cynomolgus monkeys and sought to determine if circulating endogenous reproductive steroid levels were associated with the extent of coronary artery atherosclerosis. At necropsy, females which were pregnant one or more times were found to have coronary artery atherosclerosis which was one-fourth as extensive as that of intact females which had not been pregnant. Extent of coronary artery atherosclerosis correlated positively with mean total plasma cholesterol (Rho = 0.52, p less than 0.01) and inversely with high density lipoprotein (HDL) cholesterol (Rho = -0.48, p less than 0.01) concentrations; both decreased during pregnancy. Additionally, the extent of coronary artery atherosclerosis was found to have a strong inverse association (Rho = -0.66, p less than 0.001) with an index (area-under-the-curve) of magnitude and duration of the pregnancy-induced elevation in plasma 17-beta estradiol concentration. This association could not be explained by an interrelationship between estradiol area-under-the-curve and either plasma total or HDL cholesterol concentrations. There was no relationship between atherosclerosis extent and a similar index of plasma progesterone concentrations. These findings provide evidence for an inhibitory effect of endogenous estrogen on the progression of coronary artery atherosclerosis.

Animals↗