Biomedical subjects

L M Demers

Publications and source records attributed to L M Demers.

At least 145 records · Page 8Linked to original sources

PubMed1987

A stimulatory role for the protein kinase C pathway in ovarian prostaglandin synthesis: studies with cultured swine granulosa cells.

A calcium-sensitive, lipid-activated protein kinase is present in ovarian granulosa cells and may modulate granulosa cell function through an effect on granulosa cells prostaglandin F2 alpha biosynthesis. Phorbol-ester activation of this protein kinase elicits a dose- and time-dependent augmentation in the synthesis of PGF2 alpha by swine granulosa cells which can be inhibited by inhibitors of prostaglandin and protein synthesis. Our studies support a linkage between protein kinase C activation and prostaglandin F2 alpha synthesis by these cells.

Animals↗

PubMed1987

Aminoglutethimide therapy in breast cancer: relationship of blood levels to drug-related side effects.

Aminoglutethimide (AG) is now an established agent for producing a 'medical adrenalectomy' in patients with breast cancer. A number of annoying symptoms can occur in some patients placed on this medication. It has been suggested that the expression of symptoms may be related to the ability of the patient to acetylate AG to N-acetyl aminoglutethimide (NAG). Using high-pressure liquid chromatography (HPLC), we examined blood levels of AG and NAG in patients with breast cancer and compared the levels to the expression and frequency of drug symptoms. 43% of patients examined were judged to be slow acetylators in that 92% of the drug remained unacetylated irrespective of the dose administered. There was no significant correlation between acetylator status (rapid vs. slow) and the frequency of drug symptoms noted. In contrast, there was a significant correlation between the level of AG itself and the frequency of symptoms. 80% of patients with blood levels exceeding 12 mg/l had drug-related symptoms while only 36% of patients with levels below 8 mg/l showed symptoms (chi 2 p less than 0.05). 67% of patients with NAG levels in excess of 4 mg/l had symptoms. These findings indicate the presence of slow and rapid acetylators of AG in a breast cancer population and the importance of determining blood levels of the drug to minimize the onset of drug-related symptoms in some patients without losing drug efficacy.

Aminoglutethimide↗

PubMed1986

An inhibitory role for the protein kinase C pathway in ovarian steroidogenesis. Studies with cultured swine granulosa cells.

We have used primary cultures of swine granulosa cells to investigate the regulatory role of the protein kinase C pathway in the ovary. In this system, we observed the following. Swine granulosa cells bound [3H]phorbol 12,13-dibutyrate [( 3H]PDB) specifically with high affinity [apparent Ki for 12-O-tetradecanoylphorbol 13-acetate (TPA) = 3.1 (2.1-4.7) nM] and low capacity [0.68 (0.34-0.99) pmol/10(7) cells]. The cytosol of granulosa cells contained functionally active protein kinase C capable of phosphorylating distinct proteins in response to stimulation with active phorbol ester. TPA and PDB induced dose-dependent inhibition (greater than 85%) of follicle-stimulating-hormone (FSH)-stimulated progesterone production. Half-maximally inhibitory concentrations were 0.10 and 0.75 nM for TPA and PDB respectively, whereas phorbol analogues that do not activate protein kinase C were not inhibitory. TPA did not impede cyclic AMP generation in response to FSH, cholera toxin or forskolin acutely (within 48 h), but did inhibit the stimulatory effects of 8-bromo cyclic AMP, insulin and oestradiol on progesterone biosynthesis. In the presence of maximally effective concentrations of 25-hydroxy-, 20 alpha-hydroxy- or 22R-hydroxy-cholesterol as exogenous sterol substrates for cholesterol side-chain cleavage, treatment with TPA suppressed pregnenolone, progesterone and 20 alpha-hydroxypregn-4-en-3-one biosynthesis by more than 80%. The inhibitory effects of phorbol esters were not attributable to non-specific cytotoxicity, since prostaglandin F2 alpha production increased in the same cultures and aromatization of exogenously supplied testosterone to oestradiol was not suppressed. In intact granulosa cells, the effects of phorbol esters were mimicked by a synthetic non-diterpene diacylglycerol, 1-octanoyl-2-acetylglycerol, and the tumour promoter, mezerein, which specifically activates protein kinase C. We conclude that swine granulosa cells contain specific high-affinity receptors for phorbol esters that are functionally coupled to protein phosphorylation. Moreover, treatment with phorbol esters or non-phorbol activators of protein kinase C results in selective inhibition of cholesterol side-chain cleavage activity without impairing cyclic AMP generation or oestrogen biosynthesis.

20-alpha-Dihydroprogesterone↗

PubMed1986

The effect of endogenous estrogen fluctuation on metabolism of 25-hydroxyvitamin D.

To test the hypothesis that estrogen modulates the metabolism of 25-hydroxyvitamin D (25(OH)D) to 1,25-dihydroxyvitamin D (1,25(OH)2D) and 24,25-dihydroxyvitamin D (24,25(OH)2D), we studied 20 normal premenopausal women at four consecutive weekly intervals during one menstrual cycle. Estrogen stimulation was semiquantitatively defined into baseline, low-grade, or medium-grade categories, based on endogenous estrone and estradiol concentrations. 1,25(OH)2D increased incrementally from baseline levels of 34 +/- 3(SE) pg/ml to 39 +/- 3 pg/ml (P = 0.2) with low-grade estrogen stimulation and to 43 +/- 3 pg/ml (P less than 0.05) with medium-grade estrogen stimulation, while 25(OH)D, 24,25(OH)2D, vitamin D binding protein, parathyroid hormone, calcium, and phosphate did not change. 24,25(OH)2D was correlated to 25(OH)D at baseline (r = 0.65, P less than 0.01) and with low-grade estrogen stimulation (r = 0.62, P less than 0.01), but not with medium-grade stimulation (r = 0.13); these relationships are consistent with the concepts that 25(OH)D is metabolized predominantly to 24,25(OH)2D at low estrogen levels, but not at higher estrogen levels. We conclude that endogenous estrogen elevation promotes formation of 1,25(OH)2D from 25(OH)D, and that it may reciprocally inhibit synthesis of 24,25(OH)2D.

24,25-Dihydroxyvitamin D 3↗

PubMed1986

Interaction between parathyroid hormone and endogenous estrogen in normal women.

It has been hypothesized that estrogens conserve bone substance by blocking the resorbing effect of parathyroid hormone (PTH). We evaluated this hypothesis by examining the relation of circulating PTH to endogenous estrogen fluctuation during four quarters of a single menstrual cycle in 20 normal women. The hypothesis predicts that PTH should vary directly with estrogen, since PTH should increase following estrogen elevation to satisfy physiologic demands for calcium. Contrary to the predicted direct variation, PTH remained constant throughout the menstrual cycle despite sharply fluctuating estrogen levels. Furthermore, PTH was negatively associated with estrone during the early follicular (r = -.65, P less than 0.005) and late follicular (r = -.84, P less than 0.0001) phases. We attempted to determine whether this unexpected relationship between estrone and PTH signified a direct physiologic link, by excluding factors which could have spuriously engendered the inverse correlation. Stepwise multiple regression and partial correlation showed that estrone contributed significantly to circulating PTH independent of the effects of dietary calcium, 25-hydroxyvitamin D, serum calcium, 1,25-dihydroxyvitamin D, phosphate, estradiol, progesterone, and body weight. Therefore, it is possible that the inverse correlation between estrone and PTH signified a direct physiologic link, as an artifactual cause for the relationship could not be identified. These data imply that estrone interacts with PTH, but not by blocking PTH-mediated bone resorption. We conclude that estrone is associated with reduced circulating PTH through an as yet undetermined mechanism.

Adult↗

PubMed1986

Peripheral plasma levels of prostaglandin metabolites, cortisol and prolactin in women undergoing falope ring application and tubal cautery.

The levels of 11-deoxy-13,14-dihydro-15-keto-11 beta, 16 xi-cyclo PGE2 (bicyclo PGEM), 13,14-dihydro-15-keto PGF 2 alpha (PGFM), cortisol and prolactin were measured by radioimmunoassays in five serial plasma samples collected from fourteen patients undergoing falope ring application and three patients undergoing tubal electrocautery. Bicyclo PGEM, PGFM and cortisol levels were unchanged regardless of the type of tubal occlusion procedure or the type of anesthesia administered (7 received general and 10 local anesthesia). Prolactin levels, on the other hand, markedly increased. The increase was greatest in women that received general anesthesia. The lack of change in bicyclo PGEM and PGFM in peripheral plasma would suggest a local transfer of PGs produced by injured tubal tissue to other parts of the tube and the uterus resulting in increased contractions and pelvic pain.

Dinoprost↗

PubMed1986

Absence of bile acid malabsorption as a late effect of pelvic irradiation.

The pathophysiology of chronic radiation-induced diarrhea was evaluated in 28 patients who had undergone pelvic irradiation for gynecologic neoplasms 2 to 7 years previously. Twenty-seven patients undergoing radiotherapy with techniques that did not require abdominal or pelvic irradiation served as controls. The glycine conjugates of cholic acid (GC) were measured in serum by radioimmunoassay. Fasting and 2 hr. pp GC levels for the pelvic irradiated patients were 11.0 +/- 11.1 (mean +/- SD) and 24.8 +/- 17.3 micrograms/dl. Fasting and 2 hr. pp GC levels for controls were 12.6 +/- 7.4 and 28.0 +/- 14.7. There were no significant differences in the post-prandial increases in serum GC between pelvic irradiated patients and controls (p = .23, Type II error probability = .13). There was also no significant difference in the 2 hr. pp and fasting GC ratio (p = .39). There was significant difference between the stool frequency (p less than .01) and the prevalence of diarrhea (p less than .02) between pelvic irradiated patients and controls. The data suggest that bile acid malabsorption due to ileal dysfunction is not an inevitable late complication of pelvic irradiation and is not the major determinant in the pathophysiology of chronic radiation-induced diarrhea.

Aged↗

PubMed1986

Aortic pressure as a determinant of cardiac protein degradation.

Mechanical parameters and intracellular mediators that may control protein degradation were studied in isolated rat hearts subjected to increased aortic pressure. Elevation of aortic pressure from 60 to 120 mmHg in Langendorff preparations provided glucose or pyruvate as substrate decreased the rate of protein degradation during the second hour of perfusion. Intracellular contents of ATP or creatine phosphate or the creatine phosphate/creatine ratio did not indicate that energy depletion accounted for these effects. When ventricular pressure development was prevented by ventricular draining, and hearts were arrested with tetrodotoxin, protein degradation still decreased as aortic pressure was raised. The effect of elevated aortic pressure on proteolysis was unchanged when perfusate calcium concentrations were 0.6, 3.0, or 5.1 mM, or when indomethacin or meclofenamate was added to the perfusion buffer. These results provided no evidence to indicate that intraventricular pressure development or cardiac contraction was responsible for the inhibitory effect of increased aortic pressure on protein degradation. Instead, they suggested that stretch of the ventricular wall, as a consequence of increased aortic pressure, could be the mechanical parameter most closely related to the restraint on proteolysis. No evidence was obtained that the lower rate of degradation depended on energy or calcium availability or prostaglandin synthesis.

Adenosine Triphosphate↗

PubMed1985

Influence of ovarian steroids on prostaglandin- and leukotriene-induced uterine contractions.

The mammalian uterus is capable of metabolizing arachidonic acid via the lipoxygenase pathway, and the uterus responds to lipoxygenase products. We postulated that progesterone influences the production of leukotrienes in the uterus in a way similar to that in which estradiol influences prostaglandin production. Uterine contractions were measured in actively sensitized guinea pigs throughout the estrous cycle and in ovariectomized, hormonally primed, sensitized guinea pigs. Antigen challenge stimulated uterine contractions (caused by prostaglandins) that increased throughout the estrous cycle to a maximum in day 15, when estradiol is at its peak. Pretreatment with indomethacin abolished uterine contractions except on day 9 of the cycle, when progesterone levels are at their highest. Day 9 contractions were blocked by FPL 55712, a selective receptor antagonist of leukotrienes. These findings were confirmed in ovariectomized/sensitized guinea pigs. Our data suggest that endogenous synthesis of leukotrienes in the uterus may be directly related to the rise of progesterone.

Animals↗

PubMed1985

A role for somatomedin C as a differentiating hormone and amplifier of hormone action on ovarian cells: studies with synthetically pure human somatomedin C and swine granulosa cells.

Isolated swine granulosa cells incubated in chemically defined medium in vitro responded to synthetically pure human somatomedin C/IGF-I in a dose and time-dependent fashion with increased pregnenolone, progesterone and estradiol biosynthesis. These stimulatory actions were not mimicked by growth hormone, proinsulin, desoctapeptide insulin, epidermal growth factor, or fibroblast growth factor. Moreover, somatomedin C/IGF-I augmented the steroidogenic response of granulosa cells to exogenously supplied sterol substrate in the form of low-density lipoprotein, and amplified the stimulatory actions of the classical ovarian effector hormones, estradiol and follicle-stimulating hormone, in a synergistic fashion. The ability of somatomedin C/IGF-I to stimulate estradiol production on the one hand, and to act synergistically with estradiol to stimulate progesterone biosynthesis on the other hand, suggests a unique intrafollicular mechanism for amplifying progestin biosynthetic capacity in granulosa cells.

Aminoglutethimide↗

PubMed1985

Effects of triiodothyronine and propylthiouracil on regeneration of catecholaminergic nerve terminals in the paraventricular hypothalamic nucleus of the adult rat.

Effects of triiodothyronine and the antithyroid drug, propylthiouracil, on regeneration of catecholaminergic nerve terminals in the paraventricular hypothalamic nucleus of adult rats were studied. Lesions were produced by 6-hydroxydopamine neurotoxin and then the animals were treated with triiodothyronine or propylthiouracil inducing hyperthyroidism or hypothyroidism, respectively, as determined by radioimmunoassay. Although catecholaminergic varicosities increased with time in the paraventricular hypothalamic nucleus of rats after lesion, fluorescent microscopic quantitation showed no statistical difference in their number between rats treated with triiodothyronine and the vehicle for as long as 56 days. Furthermore, electron microscopic quantitation at 56 days postlesion showed no significant difference between the triiodothyronine-treated and control rats in terms of the density, proportion, size, types of synapses, and synaptic frequency of catecholaminergic nerve terminals. There were growth cones in the paraventricular hypothalamic nucleus, suggesting growth activity after lesion. However, we found that exogenous administration of large doses of triiodothyronine at 25 micrograms/kg had little effect on the enhancement of regeneration of central catecholaminergic terminals after their destruction by 6-hydroxydopamine.

Animals↗

PubMed1985

Tissue production of androgens in women with acne.

Precursor and target tissue-produced androgens were measured in the plasma of eighteen women with mild to moderate acne. Mean plasma levels of the precursor androgens (total testosterone, free testosterone, androstenedione, and dehydroepiandrosterone sulfate) wer similar to levels in a group of carefully selected acne-free and hirsute-free, age-matched female controls. In contrast, plasma 3 alpha-androstanediol glucuronide (3 alpha-diol G) values were elevated in 13 of the patients, with a mean value for the entire group nearly threefold that of the normal controls (117 vs 43 ng/dl; p less than 0.001). These results support the concept that target tissue androgen production plays an important hormonal role in the pathogenesis of acne in women and that plasma 3 alpha-diol G may be the most sensitive marker of this process.

Acne Vulgaris↗

PubMed1985

Maternal plasma prostaglandin E2 metabolite levels during human pregnancy and parturition.

Because of methodological problems associated with the measurement in biological fluids of both prostaglandin E2 (PGE2) and its unstable principal circulating metabolite 13,14-dihydro-15-keto-PGE2 (PGEM), there is little reliable information on these prostaglandins in human pregnancy and parturition. The recent discovery of a stable PGEM degradation product 11-deoxy-13,14-dihydro-15-keto-11 beta, 16 epsilon-cyclo-PGE2 (bicyclo-PGEM) has provided a means of studying endogenous plasma levels of PGEM which circumvents the problems encountered with direct measurements of PGE2 and PGEM. Using a radioimmunoassay for bicyclo-PGEM we have therefore determined maternal peripheral plasma PGE2 metabolite levels during human gestation. PGE2 metabolite levels did not alter significantly during the second or third trimesters nor during labour. This contrasts with maternal peripheral plasma levels of the principal circulating metabolite of PGF2 alpha 13,14-dihydro-15-keto-PGF2 alpha (PGFM) which increases several fold during labour. Compared to PGE2 therefore, PGF2 alpha may be quantitatively the more significant prostaglandin associated with human parturition.

Dinoprostone↗

PubMed1985

Response of the prepubertal ovary to acute chorionic gonadotropin administration: absence of modulation by growth hormone.

Twenty-five short term hCG stimulation tests were performed in seven prepubertal girls, aged 3-11 yr, who were being evaluated for short stature. Provocative testing revealed GH deficiency in all patients, but reevaluation of one girl at a later date showed normal somatotropin levels. The study protocol lasted 18 months and included testing before, during, and after 1 yr of GH therapy. Delta 4-Androstenedione, testosterone, estrone, and estradiol were determined 0, 24, 48, and 72 h after initiation of a two-injection course of CG. Significant responses (approximately 2-fold over baseline) to the stimulation tests occurred for all steroids except testosterone, though no augmented effects were found in the presence of human GH. The results indicate functional capability of the prepubertal ovary when exposed acutely to a LH-like material, but no role for somatotropin in gonadal steroid production in the prepubertal female.

Androstenedione↗

PubMed1985

Altered neuroendocrine regulation of gonadotropin secretion in women distance runners.

We tested the hypothesis that the neuroendocrine control of gonadotropin secretion is altered in certain women distance runners with secondary amenorrhea. To this end, we quantitated the frequency and amplitude of spontaneous pulsatile LH secretion during a 24-h interval in nine such women. The ability of the pituitary gland to release LH normally was assessed by administration of graded bolus doses of GnRH during the subsequent 8 h. Compared to normally menstruating women, six of nine amenorrheic distance runners had a distinct reduction in spontaneous LH pulse frequency, with one, three, six, five, four, or two pulses per 24 h (normal, 8-15 pulses/24 h). This reduction in LH pulse frequency occurred without any significant alterations in plasma concentrations of estradiol and free testosterone or 24-h integrated serum concentrations of LH, FSH, or PRL. Moreover, in long-distance runners, the capacity of the pituitary gland to release LH was normal or accentuated in response to exogenous pulses of GnRH. In the six women athletes with diminished spontaneous LH pulsatility, acute ovarian responsiveness also was normal, since serum estradiol concentrations increased normally in response to the GnRH-induced LH pulses. Although long-distance runners had significantly lower estimated percent body fat compared to control women, specific changes in pulsatile gonadotropin release did not correlate with degree of body leanness. In summary, certain long-distance runners with secondary amenorrhea or severe oligomenorrhea have unambiguously decreased spontaneous LH pulse frequency with intact pituitary responsiveness to GnRH. This neuroendocrine disturbance may be relevant to exercise-associated amenorrhea, since pulsatile LH release is a prerequisite for cyclic ovarian function. We speculate that such alterations in pulsatile LH release in exercising women reflect an adaptive response of the hypothalamic pulse generator controlling the intermittent GnRH signal to the pituitary gland. The basis for amenorrhea in the remaining runners who have normal pulsatile properties of LH release is not known.

Adolescent↗

PubMed1984

Evaluation of commercial immunoperoxidase kits in diagnosis of prostate carcinoma.

Comparison of one commercial immunoperoxidase kit for prostate specific acid phosphatase (PSAP) and two for prostate specific antigen (PA) with an unlabelled antibody peroxidase-antiperoxidase (PAP) technique using rabbit antihuman PSAP revealed generally good reproducibility of results on formalin-fixed, paraffin-embedded sections of primary and metastatic prostatic carcinoma. Frequency of positivity was 92 per cent with both our noncommercial PAP and the kit method for PSAP, and 82 per cent and 89 per cent with kits for PA. Thus, sensitivity with the PA kits was less than with our noncommercial PAP and the kit PSAP, with less intense immunostain and occasional false negatives. Specificity was good with all three kits, and no false positive results were obtained. Commercial immunoperoxidase kits provide a relatively easy and inexpensive means for practicing pathologists in a service-oriented setting to make more precise diagnoses in cases of poorly differentiated or metastatic carcinoma of prostatic origin.

Acid Phosphatase↗

PubMed1984

Preparation of prostaglandin E2 vaginal gel for preinduction ripening of the cervix.

Low dose prostaglandin E2 (PGE2) vaginal gel has been shown to be an effective method for preinduction ripening of the cervix. A method for preparation of this gel from commercially available reagents is described. A twenty milligram PGE2 vaginal suppository ( Prostin , Upjohn) is added to 100 cc's of hydroxyethyl cellulose gel (K-Y Jelly, Johnson and Johnson), heated to 85 degrees C. Samples of this preparation were stored at a 4 degrees Centigrade (C) or 28 degrees C for one, six, or twenty-four hours. After storage, analysis by radioimmunoassay demonstrated there was no appreciable decrease in concentration of PGE2. A clinical useful prostaglandin E2 vaginal gel may be prepared from commercially available reagents under the conditions described.

Cervix Uteri↗

PubMed1984

Arachidonic acid metabolism by the non-pregnant human uterus.

Arachidonic acid metabolism in the non-pregnant human uterus was studied using short term incubations of human endometrium and myometrium with [14C] arachidonic acid followed by HPLC separation of the arachidonic acid metabolites formed. Lipoxygenase as well as cyclooxygenase activity was found in both the endometrium and myometrium although the endometrium predominated in arachidonic acid product formation. The lipoxygenase products formed by these tissues included the monohydroxy acids 5-HETE and 12-HETE.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗