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Biomedical subjects

L M Demers

Publications and source records attributed to L M Demers.

At least 19 recordsLinked to original sources
PubMed1992

Ovariectomy selectively reduces the concentration of transforming growth factor beta in rat bone: implications for estrogen deficiency-associated bone loss.

Previous work showed that production of transforming growth factor beta (TGF-beta) by osteoblast-like rat UMR 106 cells was increased by 17 beta-estradiol at physiological concentrations. To determine whether ovariectomy alters the concentration of TGF-beta in rat long bones, female Sprague-Dawley rats were either sham-operated (n = 19) or ovariectomized (n = 19), pair-fed a semisynthetic diet for 6 weeks, and sacrificed. Tibial and femoral diaphyses were removed and extracted by demineralization. Ovariectomy lowered serum estrogen; did not alter body weight, serum magnesium, or serum 1,25-dihydroxyvitamin D; and produced only modest differences in serum calcium and phosphate concentrations. Hydroxyproline was higher and extractable protein was lower in bones from ovariectomized rats than in bones from sham-operated rats; calcium content did not differ between the two groups of animals. Ovariectomy lowered the concentration of TGF-beta in bone but did not change the concentration of insulin-like growth factors I or II compared with values in bone from control animals. The reduction of bone TGF-beta was evident 6 weeks after surgery but not at 3 weeks. Treatment of ovariectomized rats with estrogen eliminated the TGF-beta deficit. To determine whether 17 beta-estradiol increased TGF-beta production by normal bone cells, mouse osteoblasts were treated for 2 days with 17 beta-estradiol. The production of TGF-beta was increased almost 2-fold by 1 nM 17 beta-estradiol, and short-term treatment stimulated the intracellular accumulation of TGF-beta 1 mRNA. We conclude that ovariectomy reduces deposition of TGF-beta in rat bone and that diminished skeletal TGF-beta could play a role in the pathogenesis of bone loss, fractures, and microfractures that occur in estrogen-deficient states. Our results support the possibility that estrogen and bone TGF-beta may be necessary for normal maintenance of the skeleton in female rats.

Animals↗
PubMed1992

Influence of mineral dust surface chemistry on eicosanoid production by the alveolar macrophage.

It has been suggested that radicals on the surface of dust particles are key chemical factors in the pathophysiology that results from the occupational inhalation of coal and silica dust. In addition, oxygenated derivatives of arachidonic acid (eicosanoids) have been implicated as important biochemical mediators of mineral dust-induced lung disease through their role in bronchial and vascular smooth muscle reactivity, inflammation, and fibrosis. Therefore, we assessed eicosanoid production by the rat alveolar macrophage (AM) exposed in vitro to mineral dusts with varying surface chemical characteristics in order to determine if radicals associated with the mineral dust could influence the production of proinflammatory mediators in the lung environment. Primary cultures of rat AM were exposed to freshly fractured or "stale" bituminous coal dust, as well as untreated silica or silica calcined to 500 and 1100 degrees C. Prostaglandin E2 (PGE2), thromboxane A2 (TXA2), and leukotriene B4 (LTB4) levels in incubation medium were determined by specific radioimmunoassay. When AM were exposed to freshly fractured coal dust, PGE2 production was markedly increased. In contrast, exposure of AM to "stale" dust significantly reduced PGE2 production. Exposure of AM to freshly fractured coal dust resulted in a significant increase in production by AM, while exposure to stale coal dust did not influence AM TXA2 production. Neither "fresh" nor "stale" coal dust had any effect on LTB4 production. In vitro exposure of AM to untreated silica resulted in a significant increase in TXA2 PGE2, TXA2, and LTB4 production compared with control. However, exposure of AM to silica calcined to 1100 degrees C resulted in eicosanoid levels that were not significantly different from control. These effects were still apparent 8 wk after calcination of the silica particles. Silica was a more potent activator of AM eicosanoid production than was coal, and amorphous fumed silica was a more potent activator of AM eicosanoid production than was crystalline silica. These findings suggest that radicals associated with respirable coal and silica particles may play a key role in the ability of mineral dust to activate AM eicosanoid production and therefore may be important in the pathophysiological consequences of occupational mineral dust inhalation.

Animals↗
PubMed1992

Determinants of bone density in young women. I. Relationships among pubertal development, total body bone mass, and total body bone density in premenarchal females.

Bone mass accretion during puberty appears to be critical in the development of peak bone mass, which, in turn, is believed to be a major determinant of osteoporosis risk. Although genetics may be the primary determinant of peak bone mass, modifiable secondary factors, such as nutrition and hormone exposure, may significantly affect bone mass accretion during the second decade of life. As part of a longitudinal study of major determinants of bone development during puberty, we obtained cross-sectional measurements from 112 premenarchal caucasian females (mean +/- SD age, 11.9 +/- 0.49 yr at study entry). Total body bone mineral density (TBBMD) and total body bone mineral content (TBBMC) were measured by dual energy x-ray absorptiometry and compared to anthropometric, pubertal development, urinary steroid and gonadotropin levels, and nutrient intake. An integrated estrogen exposure index was developed and used to evaluate the cumulative effect of circulating estrogen levels on both development. Compared to normative reference data for adults, our subjects possessed 90% of adult height, 68% of adult weight, 83% of adult TBBMD, and 53% of TBBMC. The strongest combined predictors of prepubertal TBBMD and TBBMC were body weight, followed by height and pubertal development. Urinary estradiol levels were positively correlated with dietary intake of iron and vitamin B6.

Adolescent↗
PubMed1992

CA-549 is not diagnostically useful as an immunohistochemical marker for breast carcinoma.

We evaluated BC4E549, a monoclonal antibody to CA-549, for use as an immunohistochemical marker to determine (1) differences in staining patterns between breast carcinoma and nonmalignant breast tissue specimens, (2) sensitivity and specificity of staining patterns for CA-549 in breast carcinoma vs other carcinomas, and (3) conservation of primary staining patterns in tumor metastases. We studied paraffin-embedded tissue specimens from 382 cases including nonmalignant breast tissue, endometrium, lung, pancreas, and thyroid gland; breast carcinoma; and adenocarcinomas of the colon, endometrium, lung, ovary, pancreas, and thyroid gland. Membranous staining was present in all nonmalignant breast tissue specimens and in most breast carcinoma tissue specimens. Diffuse cytoplasmic staining was more extensive in breast carcinomas than in benign processes. However, similar staining was also seen in normal and neoplastic tissue specimens obtained from a variety of other sites. Sensitivity and specificity of diffuse cytoplasmic staining for CA-549 in breast carcinoma relative to carcinomas from other sites studied were 78.6% and 77.4%, respectively. Staining patterns were not preserved from primary tumor to metastases in 67.4% of cases evaluated. We conclude that BC4E549 antibody to CA-549 is not a sufficiently sensitive or specific immunohistochemical marker in routinely processed tissue specimens to be useful in the clinical-diagnostic laboratory setting.

Antibodies, Monoclonal↗
PubMed1991

Endocrine effects in female weight lifters who self-administer testosterone and anabolic steroids.

It appears that the self-administration of testosterone and anabolic steroids is increasingly practiced by women in sports where strength and endurance are important. We recently evaluated endocrine parameters in nine female weight lifters using steroids and seven not using these agents. Of the nine anabolic steroid users, seven took multiple anabolic steroids simultaneously. Thirty-fold elevations of serum testosterone were noted in the women injecting testosterone. In three of these women serum testosterone levels exceeded the upper limits for normal male testosterone concentrations. A significant compensatory decrease in sex hormone-binding globulin and a decrease in thyroid-binding proteins were noted in the women steroid users. Also, a 39% decrease in high-density lipoprotein cholesterol was noted in the steroid-using weight lifters. Most of the subjects in this study used anabolic steroids continuously, which raises concern about premature atherosclerosis and other disease processes developing in these women.

Adult↗
PubMed1991

Hirsutism: metabolic effects of two commonly used oral contraceptives and spironolactone.

Fifty-one hirsute women were randomly treated for nine months with ethinyl estradiol 35 ug plus norethindrone 0.4 mg or 30 ug ethinyl estradiol plus 1.5 mg norethindrone acetate if they needed contraception or spironolactone 200 mg daily if they did not. Metabolic evaluations in response to therapy demonstrated triglyceride elevations with the two oral contraceptives but not with spironolactone. While systolic blood pressure was lower with spironolactone, fasting insulin levels were higher as opposed to either low-dose oral contraceptive preparation. Ethinyl estradiol 30 ug plus 1.5 mg norethindrone acetate lowered 3-alpha-diol glucuronide levels, yet ethinyl estradiol 35 ug plus norethindrone 0.4 mg and spironolactone were more effective in lowering Ferriman-Gallwey Scores. Treatment strategies for hirsute women need to consider metabolic consequences as well as efficacy.

Analysis of Variance↗
PubMed1991

Urinary hormonal concentrations and spinal bone densities of premenopausal vegetarian and nonvegetarian women.

We evaluated the relationships among nutrition, hormone concentrations, and bone density of the spine in 27 vegetarian and 37 nonvegetarian premenopausal women. The two groups were indistinguishable with respect to age, height, weight, menarche, years of formal education, and medical histories. The frequency of menstrual irregularity was significantly higher in the vegetarian group. The bone densities of the vegetarians and the nonvegetarians were not significantly different. Caffeine intake in both groups had a positive effect on urinary calcium excretion, but no association was observed between bone density and caffeine intake. Total fat, monosaturated fat, and oleic acid intake were positively associated with luteinizing hormone concentrations of the vegetarians only. Overall, the differences in dietary practices of these premenopausal vegetarian and nonvegetarian women did not appear to have major effects on bone biology or reproductive history.

Adult↗
PubMed1991

Ovarian actions of tumor necrosis factor-alpha (TNF alpha): pleiotropic effects of TNF alpha on differentiated functions of untransformed swine granulosa cells.

We have examined interactions between tumor necrosis factor-alpha (TNF alpha), a product of the immune system, and ovarian cells using serum-free monolayer cultures of untransformed swine granulosa cells. Recombinant human TNF alpha, a potent cytoactive product of activated macrophages, bound specifically and with high affinity to intact granulosa cells. Binding sites had an apparent Kd of 0.17 nM (95% confidence interval, 0.065-0.31), and a binding capacity of 80 nmol/micrograms DNA (95% confidence interval, 52-110). The binding capacity of granulosa cells for TNF alpha (but not the binding affinity) was increased approximately 2-fold by treatment with FSH and insulin. The biological effects of TNF alpha on pig granulosa cells were expressed after 48 and 96 h in culture. At the latter time, TNF alpha significantly suppressed insulin- and insulin- plus FSH-stimulated progesterone accumulation, with respective ID50 values of 0.08 +/- 0.008 and 0.06 +/- 0.014 nM, but did not affect basal progesterone accumulation or DNA content. TNF alpha also significantly attenuated the stimulatory effect of combined treatment with FSH and insulin on cAMP generation during 48-96 h of culture. TNF alpha inhibited the stimulatory effects of forskolin, cholera toxin, and the cAMP analog 8-bromo-cAMP on progesterone accumulation, indicating multiple sites of action of this immune modulator. Inhibition of progestin biosynthesis was observed even in the presence of 25-hydroxycholesterol, a soluble oxygenated sterol substrate for the cholesterol side-chain cleavage reaction, and was accompanied by decreased concentrations of specific cellular mRNA encoding cholesterol side-chain cleavage enzyme. There were no changes in the amounts of a constitutively expressed enzyme, phosphoglyceraldehyde dehydrogenase. Inhibitory actions of TNF alpha were specific to de novo steroid hormone biosynthesis, since nanomolar concentrations of this cytokine stimulated accumulation of prostaglandin E2 and prostaglandin F2 alpha basally and during treatment with FSH, cholera toxin, or 8-bromo-cAMP. In contrast, prostaglandin accumulation was not enhanced by interferon-gamma or interleukin-2. In summary, untransformed porcine granulosa cells exhibit specific, high affinity, low capacity saturable binding sites for TNF alpha, and the number of such binding sites can be regulated by combined treatment with insulin and FSH. Granulosa cells are susceptible to the inhibitory actions of TNF alpha on FSH- and insulin-supported progesterone biosynthesis and cAMP accumulation. One important locus of TNF alpha action is blockade of hormonally stimulated increases in specific mRNA encoding the cholesterol side-chain cleavage cytochrome P450 enzyme.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Clinical and biochemical parameters of androgen action in normal healthy Caucasian versus Chinese subjects.

Stimulation of androgen-sensitive hair follicles is mediated by dihydrotestosterone (DHT), which is formed in these tissues by 5 alpha-reduction of testosterone. A possible mechanism for increased body hair in some human populations might, therefore, be an increase in 5 alpha-reductase activity, resulting in elevated tissue levels of DHT. If present, this finding could have other important clinical implications, since the 5 alpha-reductase enzyme is pivotal in the pathophysiology of prostatic disease. To explore differences in clinical and biochemical parameters of androgen action, we conducted a study of 184 caucasian and Chinese subjects in whom we evaluated chest hair density and serum levels of androgen precursors and 5 alpha-reduced androgen metabolites. Differences in chest hair density were most notable in the men, in whom comparative mean chest hair scores (using a scale of 0-4) were 3.0 vs. 0.8 (P less than 0.0001), caucasian vs. Chinese. Levels of 5 alpha-reduced androgen products were also strikingly higher in the caucasian vs. Chinese subjects. Serum 3 alpha-androstanediol glucuronide levels (nanomoles per L) were 34.7 +/- 2.4 vs. 19.7 +/- 0.9 (P less than 0.001) for the men and 21.5 +/- 3.2 vs. 9.4 +/- 0.6 (P less than 0.001) for the women, and serum levels of androsterone glucuronide (nanomoles per L) were 179 +/- 26 vs. 107 +/- 7 (P less than 0.01) for the caucasian vs. Chinese men and 173 +/- 23 vs. 81 +/- 9 (P less than 0.001) for the women. Serum levels of total and bioavailable testosterone did not differ between the racial groups, but serum levels of the precursor androgens, dehydroepiandrosterone sulfate and androstenedione, were significantly higher in the caucasian vs. Chinese men, but not in the women. We conclude that increased serum levels of 5 alpha-reduced androgen metabolites in caucasians vs. Chinese subjects provide circumstantial evidence for a racial difference in 5 alpha-reductase activity and suggest a mechanism for the increased body hair observed in the caucasian men. Increased levels of precursor androgens may also play a role.

Adolescent↗
PubMed1991

Specificity of low dose fadrozole hydrochloride (CGS 16949A) as an aromatase inhibitor.

CGS 16949A (fadrozole hydrochloride), a potent cytochrome P450-mediated steroidogenesis inhibitor, blocks aromatase at low doses, but other biosynthetic steps at higher concentrations. Recent studies demonstrated inhibition of C11-hydroxylase, corticosterone methyloxidase-II, and deoxycorticosterone to corticosterone conversion with this agent at some-what higher concentrations than those required for blockade of aromatase. Based upon phase I studies, we postulated that relatively selective inhibition of aromatase might be possible if sufficiently low doses of CGS 16949A were used. A phase II study in 54 postmenopausal women with metastatic breast cancer examined the effects of low dose CGS 16949A on estrogen, mineralocorticoid, and glucocorticoid secretion. Two dose schedules and two dose levels were chosen based upon our prior dose escalation protocol study. Plasma estrone, estradiol, and estrone sulfate as well as urinary estrone and estradiol fell equally with 1.8-4 mg CGS 16949A given either on a twice daily or three times daily dose schedule. Isotopic kinetic studies demonstrated an 84% decrease in the rate of conversion of androstenedione to estrone to 0.40 +/- 0.07% (patients receiving 1.8-4 mg CGS 16949A daily). With these three regimens, basal levels of aldosterone and cortisol did not change significantly over a 12-week period of observation. Clinical examination, plasma electrolytes, and urinary sodium/potassium ratios suggested no biological evidence of mineralo-corticoid deficiency. ACTH-stimulated cortisol concentrations, however, were blunted at each dose level compared to pretreatment values. Nonetheless, peak responses exceeded 550 nmol/L, or a basal to peak difference of 190 nmol/L or greater, in 97% of instances. This probably reflected inhibition of C11-hydroxylase, since basal and ACTH-stimulated levels of 11-deoxycortisol were increased in response to CGS 16949A. Androstenedione and 17 alpha-hydroxyprogesterone also exhibited an upward trend in response to drug treatment. ACTH-stimulated aldosterone levels were blunted to a greater extent than those of cortisol, probably as a reflection of corticosterone methyloxidase type II blockade. Overall, the results suggest that CGS 16949A, at doses of 1.8-2 mg daily, blocks aromatase effectively and does not produce clinically important inhibition of cortisol or aldosterone biosynthesis. Thus, this agent can probably be used safely without glucocorticoid or mineralocorticoid supplementation.

17-alpha-Hydroxyprogesterone↗
PubMed1991

Endometrial antibodies versus CA-125 for the detection of endometriosis.

Detection of endometrial antibodies using an indirect immunofluorescence method along with a well-established human endometrial carcinoma cell line was evaluated and compared with CA-125 for detecting endometriosis. Two hundred two patient sera from the infertility, gynecological, and gynecological oncology services were evaluated. The sensitivity for antibody testing was 83.1% with a specificity of 78.8%, in contrast to a sensitivity of 27.3% and a specificity of 82.6% for CA-125. These preliminary findings offer promise that antibody detection methods may be a useful adjunct in the diagnosis of endometriosis.

Adult↗
PubMed1990

Somatostatin analogues in the treatment of breast and prostate cancer.

Newly developed somatostatin analogues may be useful agents in the treatment of breast and prostate cancer. Potential mechanisms of antitumor action include suppression of circulating levels of trophic hormones and growth factors as well as direct effects at the tumor level, potentially involving autocrine/paracrine mechanisms. Pilot clinical trials conducted in heavily pretreated women with advanced breast cancer indicate that SMS 201-995 (Sandostatin R) has minimal toxicity and moderately suppresses stimulated growth hormone secretion and basal somatomedin-C level. Somatostatin analogues have also been found to retard the growth of experimental prostate cancer, particularly when used in combination with LHRH analogues. The therapeutic efficacy of these compounds used alone or in combination with other agents in the treatment of breast and prostate cancer remains to be established in larger clinical trials involving less heavily pretreated patients.

Antineoplastic Agents↗
PubMed1990

A phase I trial of CGS 16949A. A new aromatase inhibitor.

CGS 16949A is a new, nonsteroidal competitive inhibitor of the aromatase enzyme. In this Phase I trial, 16 heavily pretreated postmenopausal patients with metastatic breast cancer were treated with escalating doses of CGS 16949A from 0.6 to 16 mg total daily oral dose. No hematologic, biochemical, or significant clinical toxicity was encountered. Endocrinologic and pharmacologic data were available from 12 of these patients. Maximum inhibition of estrogen biosynthesis was observed at a dose of 2 mg CGS 16949A daily. At this dose, the inhibition of estrogen biosynthesis was equivalent to 1000 mg aminoglutethimide (AG). The fall in plasma and urinary estrogens without a concomitant drop in androgens confirmed the specific blockade of aromatase activity. At doses of 4 to 16 mg daily, CGS 16949A appeared to inhibit the C21-hydroxylase enzyme as well. The t1/2 of CGS 16949A in the circulation was 10.5 hours. Of 16 evaluable patients there were two partial responses and seven patients with stable disease.

Adult↗