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Biomedical subjects

K M Menon

Publications and source records attributed to K M Menon.

At least 91 records · Page 5Linked to original sources
PubMed1981

Estrogenic and antiestrogenic effects of danazol administration in studies of estradiol receptor binding.

In order to study possible cellular estrogenic and/or antiestrogenic effects of danazol, immature female rats were treated with danazol (10 mg/kg/day) or propylene glycol (control) for 4 days (short-term study) and 14 days (long-term study). Estradiol receptor-binding assays were done on the cytosol fraction of the homogenized uterine tissue of each group. AT saturation levels of substrate, short-term danazol treatment was uterotropic and induced an increase in estradiol receptor concentration and binding (p less than 0.02). Long-term treatment, however, caused a marked decrease in estradiol receptor capacity (p less than 0.001). This disparity of the effect of danazol on estradiol receptors suggests a dose- or duration-dependent mechanism of action in the target tissue that may account for some of the clinical effects seen in patients receiving this drug.

Animals↗
PubMed1981

Receptor-mediated gonadotropin action in the ovary. Action of cytoskeletal element-disrupting agents on gonadotropin-induced steroidogenesis in rat luteal cells.

The role of the cellular cytoskeletal system of microtubules and microfilaments on gonadotropin-stimulated progesterone production by isolated rat luteal cells has been investigated. Exposure of luteal cells to human choriogonadotropin resulted in a stimulation of cyclic AMP (4-7-fold) and progesterone (3-4-fold) responses.l Incubation of cells with the microfilament modifier cytochalasin B inhibited the gonadotropin-induced steroidogenesis in a dose- and time-dependent manner. The effect of cytochalasin B on basal production of steroid was less pronounced. Cytochalasin B also inhibited the accumulation of progesterone in response to lutropin, cholera enterotoxin, dibutyryl cyclic AMP and 8-bromo cyclic AMP. The inhibition of steroidogenesis by cytochalasin B was not due to (a) inhibition of 125I-labelled human choriogonadotropin binding to luteal cells, (b) inhibition of gonadotropin-stimulated cyclic AMP formation or (c) a general cytotoxic effect and/or inhibition of protein biosynthesis. Cytochalasin D, like cytochalasin B, inhibited gonadotropin- and 8-bromo cyclic AMP-stimulated steroidogenesis. Although cytochalasin B also blocked the transport of 3-O-methyl-glucose into luteal cells, cytochalasin D was without such an effect. Increasing glucose concentration in the medium, or using pyruvate as an alternative energy source, failed to reverse the inhibitory effect of cytochalasin B. The anti-microtubular agent colchicine failed to modulate synthesis and release of progesterone by luteal cells in response to human choriogonadotropin. These studies suggest that the cellular microfilaments may be involved in the regulation of gonadotropin-induced steroidogenesis. In contrast, microtubules appear to be not directly involved in this process.

3-O-Methylglucose↗
PubMed1981

In vitro effect of danazol on luteinizing hormone-releasing hormone-stimulated luteinizing hormone release in rat anterior pituitary cell cultures in vitro.

Monolayer cultures of anterior pituitary glands from female rats were exposed to 5 X 10(-6) M danazol for 0, 4, 24, 48, and 72 h in Dulbecco's Modified Eagle's Medium supplemented with 10% horse serum and 2.5% fetal calf serum. After this treatment, the cell cultures were rinsed and challenged with 10(-8) M LHRH for 6 h. The media were collected and assayed for LH by a hormone-specific RIA using the double antibody precipitation technique. A control incubation was carried out by exposing cell cultures for the same length of time in the absence of danazol but in the presence of 0.5% ethanol in which danazol was dissolved, then challenging the culture with 10(-8) M LHRH, as was done in the experimental group, and assaying the LH released in the medium. The results showed that exposure of cell cultures to danazol caused a significant decrease in LH release in response to LHRH from 13,800 +/- 500 to 3,500 +/- 200 ng/ml. The inhibition of LH release was dependent on both the duration of danazol exposure and its concentration. Danazol exposure had, however, little effect on basal LH secretion by the pituitaries, which remained at about 600 ng/ml at all time points examined. Under the experimental conditions, danazol exerted no effect on the incorporation of amino acid into protein in the cell culture. These results suggest that one of the mechanisms of the antigonadotropic effect of danazol is inhibition of the responsiveness of the pituitary to LHRH-induced LH release.

Animals↗
PubMed1980

Evidence that danazol inhibits gonadotropin-induced ovarian steroidogenesis at a point distal to gonadotropin-receptor interaction and adenosine 3',5' cyclic monophosphate formation.

The action of danazol on 125I-human chorionic gonadotropin (hCG) binding, gonadotropin-stimulated adenosine 3',5' cyclic monophosphate (cAMP) accumulation and progesterone production has been investigated in luteinized rat ovaries. Preincubation of luteal cells for short periods of time with increasing concentrations of danazol caused a significant inhibition of gonadotropin-stimulated steroidogenesis. The inhibitory effect of danazol was both concentration and time dependent. Danazol also reduced progesterone production in response to cholera enterotoxin and 8 bromo-adenosine-cAMP, but it had no effect on hCG, luteinizing hormone, and cholera enterotoxin stimulated cAMP formation. Similarly danazol did not affect 125I-hCG binding as assessed by the equilibrium dissociation constant (Kd) and number of hormone-binding sites on the luteal cell surface. These results suggest that in intact luteal cells danazol inhibits steroidogenesis at a point distal to hormone-receptor interaction and cAMP formation.

Animals↗
PubMed1980

Multiple inhibitory actions of luteinizing hormone-releasing hormone agonist on luteinizing hormone/human chorionic gonadotropin receptor-mediated ovarian responses.

The administration to female rats of the LHRH agonist, [des-GlyNH2(10)]LHRH ethylamide, as either a single dose or repeated injections resulted in a decrease in the binding of 125I-labeled hCG to ovarian plasma membranes. An ovarian cell suspension prepared from the agonist-injected group of rats also responded to hCG with a decreased ability to accumulate cAMP and progesterone compared with the saline-treated controls. The receptor loss was due to a decreased number of hormone-binding sites rather than to a change in the affinity of the receptor for the hormone. Preincubation of ovarian cells with the agonistic analog in vitro also caused an inhibition of progesterone synthesis in response to hCG, cholera toxin, and 8-Bromo-cAMP, suggesting a direct inhibitory effect of the analog on ovarian steroidogenesis. Prior exposure to the agonistic analog, however, had no effect on cAMP accumulation by the ovarian cells in response to either hCG or cholera enterotoxin, further suggesting that the site of inhibitory action lies at a point after cAMP accumulation. In summary, the present study demonstrates that 1) the inhibition of ovarian steroidogenesis observed in response to the injection of the LHRH agonist is primarily due to down-regulation of ovarian hCG/LH receptors with a resultant decrease in cAMP accumulation, and this effect may be caused by the pulses of LH release from the pituitary, and 2) the direct inhibitory effect on steroidogenesis observed under in vitro conditions is independent of gonadotropin receptor, and the site of this inhibitory action lies at a point after cAMP accumulation.

Animals↗
PubMed1979

A radioreceptor assay for human chorionic gonadotropin in normal and abnormal pregnancies: a clinical evaluation.

The human chorionic gonadotropin-radioreceptor assay (hCG-RRA) offers a rapid and accurate method of diagnosing early and abnormal pregnancies. Such a method is described along with clinical correlations in 139 assays done on 122 patients with amenorrhea, normal pregnancies, infertility, trophoblastic disease, ectopic pregnancies, and missed or incomplete abortions. The accuracy of the test is correlated with weeks of amenorrhea, weeks after ovulation, and clinical diagnoses. The overall accuracy of the assay was 95%. Those performed more than 28 days after the last menstrual period had an accuracy of 96.4%. There were no errors in the diagnosis of eight ectopic pregnancies among 33 suspected cases. Three patients are described who had serial changes from negative to positive early in pregnancy, providing data on precise timing of a positive result. Cases of missed abortion sometimes demonstrate a positive hCG-RRA after documented fetal loss. Recommendations for the most appropriate use of the hCG-RRA are presented based on the clinical experience at one referral center during the period January, 1977, to June, 1978.

Abortion, Incomplete↗
PubMed1979

Receptor-mediated gonadotropin action in the ovary. Regulatory role of cyclic nucleotide phosphodiesterase(s) in intracellular adenosine 3':5'-cyclic monophosphate turnover and gonadotropin-stimulated progesterone production by rat ovarian cells.

The regulatory role of cyclic nucleotide phosphodiesterase(s) and cyclic AMP metabolism in relation to progesterone production by gonadotropins has been studied in isolated rat ovarian cells. Low concentrations of choriogonadotropin (0.4-5ng/ml) increased steroid production without any detectable increase in cyclic AMP, when experiments were carried out in the absence of phosphodiesterase inhibitors. The concentration of choriogonadotropin (10ng/ml) that stimulated progesterone synthesis maximally resulted in a minimal increase in cyclic AMP accumulation and choriogonadotropin binding. Choriogonadotropin at a concentration of 10ng/ml and higher, however, significantly stimulated protein kinase activity and reached a maximum between 250 and 1000ng of hormone/ml. Higher concentrations (50-2500ng/ml) of choriogonadotropin caused an increase in endogenous cyclic AMP, and this increase preceded the increase in steroid synthesis. Analysis of dose-response relationships of gonadotropin-stimulated cyclic AMP accumulation, progesterone production and protein kinase activity revealed a correlation between these responses over a wide concentration range when experiments were performed in the presence of 3-isobutyl-1-methylxanthine. The phosphodiesterase inhibitors papaverine, theophylline and 3-isobutyl-1-methylxanthine each stimulated steroid production in a dose-dependent manner. Incubation of ovarian cells with dibutyryl cyclic AMP or 8-bromo cyclic AMP mimicked the steroidogenic action of gonadotropins and this effect was dependent on both incubation time and nucleotide concentration. Maximum stimulation was obtained with 2mm-dibutyryl cyclic AMP and 8-bromo cyclic AMP, and this increase was close to that produced by a maximally stimulating dose of choriogonadotropin. Other 8-substituted derivatives such as 8-hydroxy cyclic AMP and 8-isopropylthio cyclic AMP, which were less susceptible to phosphodiesterase action, also effectively stimulated steroidogenesis. The uptake and metabolism of cyclic [(3)H]AMP in ovarian cells was also studied in relation to steroidogenesis. When ovarian cells were incubated for 2h in the presence of increasing concentrations of cyclic [(3)H]AMP, the radioactivity associated with the cells increased almost linearly up to 250mum-cyclic [(3)H]AMP concentration in the incubation medium. The (3)H label in the cellular extract was recovered mainly in the forms ATP, ADP, AMP, adenosine and inosine, with cyclic AMP accounting for less than 1% of the total tissue radioactivity. Incubation of cyclic AMP in vitro with ovarian cells resulted in a rapid breakdown of the nucleotide in the medium. The degradation products in the medium have been identified as AMP, adenosine and inosine. The rapid degradation of cyclic AMP by phosphodiesterase(s) makes it difficult to correlate changes in cyclic AMP concentrations with steroidogenesis. These observations thus provide an explanation for the previously observed lack of cyclic AMP accumulation under conditions in which low doses of choriogonadotropin stimulated steroidogenesis without any detectable changes in cyclic AMP accumulation.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1979

Progesterone binding by human endometrial tissue during the proliferative and secretory phases of the menstrual cycle and by hyperplastic and carcinomatous endometrium.

Cytosol receptors for progesterone were assayed in human endometrial tissue during the proliferative and secretory phases of the menstrual cycle and in the hyperplastic and carcinomatous endometrium. The assays were performed utilizing a technique involving prior treatment of the cytosol extract with dextran-coated charcoal to remove endogenous progesterone. The results showed that the progesterone receptor activity was higher during the later proliferative and early secretory phases of the menstrual cycle. Hyperplastic and carcinomatous endometrium also contained specific cytosol receptor for progesterone, and the binding activity of the hyperplastic endometria and endometrial polyps was comparable to that found during the later proliferative phase of the menstrual cycle. No apparent correlation between the progesterone receptor level and the morphologic degree of differentiation in Grades 1 and 2 adenocarcinomas of the endometrium was observed.

Adenocarcinoma↗
PubMed1979

Evidence for the involvement of an energy-dependent process in gonadotropin-releasing hormone-stimulated luteinizing hormone release by rat anterior pituitary.

The involvement of an energy-dependent process in gonadotropin-releasing hormone-(GnRH) stimulated LH release in the anterior pituitary has been examined. Inhibitors of both glycolysis and oxidative phosphorylation inhibited stimulation by GnRH of LH release in a time- and dose-dependent manner. Iodoacetate and 2-deoxyglucose inhibited GnRH-stimulated LH release, and this inhibition was not overcome by the addition of pyruvate. Similarly carbonyl cyanide m-chlorophenylhydrazine, an uncoupler of oxidative phosphorylation, and sodium azide, an inhibitor of electron transport, decreased ATP levels, enhanced lactate accumulation, and inhibited GnRH-stimulated LH release. These studies demonstrate that inhibition of glycolysis and oxidative phosphorylation with metabolic inhibitors lead to inhibition of GnRH-stimulated LH release. Based on these results, it is postulated that GnRH-stimuoated LH release is dependent on an energy-dependent process.

Adenosine Triphosphate↗