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Biomedical subjects

K Kontula

Publications and source records attributed to K Kontula.

At least 163 records · Page 9Linked to original sources
PubMed1985

Cytochemical demonstration of estrogen binding sites in breast cancer by estradiol covalently linked to horseradish peroxidase.

17 beta-Estradiol-6-carboxymethyloxime was covalently linked to horseradish peroxidase for the cytochemical demonstration of estrogen binding sites in breast cancer tissue. The affinity of the 17 beta-estradiol-horseradish peroxidase (E2-HRP) conjugate for the estrogen receptor in a human myometrial cytosol preparation was reduced by a factor of about 16 relative to that of 17 beta-estradiol. The estradiol concentration of the E2-HRP conjugate used in the incubations was in the range 2 X 10(-9) -1 X 10(-7) mol/l which, when the reduced affinity of the conjugate is taken into account, corresponds to 1 X 10(-10) -7 X 10(-9) mol/l unbound estradiol. The cytochemical reaction was carried out on cytofuge preparations of cell suspensions of breast cancer tissue. The intensity of the cytochemical reaction was microscopically evaluated by scoring. The results were analyzed in a plot allowing the calculation of an apparent score-max and an apparent Kd value. The reaction intensity was reduced to 20-25% of the control level by a 20-fold excess of 17 beta-estradiol. The cytochemical results correlated positively with the content of estrogen receptors in the cytosol as measured by a validated radioligand method.

Breast Neoplasms↗
PubMed1985

Glucocorticoid receptors and responsiveness of normal and neoplastic human adrenal cortex.

Glucocorticoids have been postulated to directly inhibit adrenocortical steroid production in laboratory animals. To investigate this in the human, we measured specific [3H]dexamethasone-binding sites in cytosol samples from normal and neoplastic human adrenal tissues. All nine normal adrenocortical samples, six adenomas (four cortisol-producing and two aldosterone-producing), and two hyperplastic adrenocortical samples studied were devoid of measurable specific glucocorticoid-binding activity. In contrast, steroid binding with characteristics of the glucocorticoid receptor (concentration of binding sites, 32-146 fmol/mg cytosol protein; Kd, 1.7-3.1 X 10(-9) M) was readily detectable in cytosol of all three adrenocortical carcinomas and all three pheochromocytomas examined. To elucidate the in vivo role of glucocorticoids as direct regulators of adrenocortical function, five patients with hypopituitarism receiving varying oral maintenance doses of dexamethasone were given ACTH iv. Increasing the orally administered dexamethasone dose from 1 to 8 mg/day did not alter the plasma cortisol response to a 4-h infusion of 250 micrograms synthetic ACTH in these patients. Collectively, these data cast doubt on the proposal that synthetic glucocorticoids directly suppress adrenocortical function in the human. Whether glucocorticoid receptors in tumor tissue could mediate the dexamethasone-induced suppression of hypercortisolism occasionally reported in patients with adrenocortical neoplasia remains to be investigated.

Adolescent↗
PubMed1984

Development of Cushing's disease in a patient with anorexia nervosa.

A young woman developed clinical features of anorexia nervosa with a maximal loss of ideal body weight of 54 per cent at the age of 16 yr. A partial recovery from the anorectic symptoms was encountered six years later. At the age of 27 yr pituitary Cushing's disease was diagnosed and corticotroph cell pituitary adenoma subsequently removed by transsphenoidal surgery. Within two years after the operation the clinical and biochemical signs of hypercortisolism had disappeared but some of the anorectic features reappeared. Without neglecting the likelihood of a simple coincidence, the possibility of a common pathogenetic mechanism for anorexia nervosa and Cushing's disease, either affecting the function of the hypothalamic serotonergic pathways or concentration of glucocorticoid receptors, is discussed.

Adenoma↗
PubMed1983

Binding of progestins to the glucocorticoid receptor. Correlation to their glucocorticoid-like effects on in vitro functions of human mononuclear leukocytes.

A number of physiological and synthetic progestins were tested for their ability to compete with [3H]dexamethasone for the binding to the glucocorticoid receptor of human mononuclear leukocytes and their ability to elicit glucocorticoid-like effects on the same cells. As compared to the reference compound dexamethasone (relative receptor binding affinity defined as 100%), two potent synthetic progestins with a pregnane-type structure, megestrol acetate and medroxyprogesterone acetate, were found to display a considerable binding affinity towards the receptor (46 and 42%, respectively). The relative binding affinity of the naturally occurring ligand, cortisol, to the receptor was clearly lower (25%). The effective binding of medroxyprogesterone acetate to the glucocorticoid receptor was confirmed by direct binding studies utilizing a tritiated derivative of this steroid. No evidence for the existence of a specific progesterone receptor in human mononuclear leukocytes was obtained as judged by the results of competition experiments where a progesterone receptor-specific ligand [3H]Org 2058 was used. Medroxyprogesterone acetate and megestrol acetate also induced glucocorticoid-like effects on the lymphocyte functions. These included inhibition of the proliferative responses to the T-cell mitogens concanavalin A and phytohaemagglutinin and an enhanced accumulation of immunoglobulin secreting cells in pokeweed mitogen-stimulated cultures. The progestin effect appears to be mediated through a radiosensitive (suppressor) subpopulation of T lymphocytes. In contrast, the synthetic progestins related structurally to 19-nortestosterone, norethisterone and d-norgestrel, were virtually devoid of binding affinity towards the glucocorticoid receptor nor did they measurably influence the in vitro lymphocyte functions. These studies demonstrate that certain progestins in common clinical use probably possess inherent glucocorticoid activity and suggest that side effects attributable to this character (e.g. suppression of the pituitary-adrenal axis) might be expected when these compounds are used in pharmacological doses.

DNA Replication↗
PubMed1982

Glucocorticoid receptors in hairy-cell leukemia.

Glucocorticoid receptors were measured from leukemic cells of five patients with hairy-cell leukemia as well as a cell line (JOK-1) derived from one of the patients studied and grown in continuous culture in vitro. Receptor analyses were accomplished using a whole-cell binding assay with [3H]dexamethasone as the ligand. Glucocorticoid receptor sites in the leukemic hairy cells ranged from 5,710 to 11,400 sites/cell, and the mean dissociation constant (KD) between the receptor sites and [3H]dexamethasone was 0.67 +/- 0.03 X 10(-8) M. The glucocorticoid receptor nature of the binding activity was verified by demonstration of an appropriate order of competing ability for a selected group of ligands. The cell line JOK-1 contained 9830 receptor sites/cell with a KD of 0.78 X 10(-8) M. The in vitro growth pattern of this cell line was characterized by an almost complete insensitivity to glucocorticoids. We conclude that the postulated general presence of glucocorticoid receptors in various types of normal and malignant leukocytes extends to hairy-cell leukemia, a disease often characterized by resistance to antileukemic drugs, including corticosteroids. The sole presence of the glucocorticoid receptor thus does not seem to signify steroid responsiveness.

Binding, Competitive↗
PubMed1982

Effect of acute ethanol intake on thromboxane and prostacyclin in human.

To investigate the effects of acute ethanol administration on the production of proaggregatory thromboxane A2 (TxA2) and antiaggregatory prostacyclin (PGI2), ethanol (1.5 g/kilogram body weight) was given to eight healthy nonsmoking men, and the stable metabolites thromboxane B2 (TxB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), respectively, measured by radioimmunoassay from serial blood samples before drinking and during the ensuing 18 hours. Each subject was studied as his own control on another occasion when only an equivalent volume of water was given. Serum TxB2 level decreased (p less than 0.01) from 206 +/- 31 ng/ml (mean +/- S.E.) to 167 +/- 24 and 161 +/- 23 ng/ml (two and four hours after beginning of the drinking, respectively) concomitantly with the attainment of maximal blood ethanol concentrations (about 120 mg/100 ml), whereas no changes occurred in plasma 6-keto-PGF1 alpha concentrations. Our results may provide an explanation for known effects of ethanol on platelet aggregation. They also raise speculation whether TxA2-inhibition and the antiatherogenic effect of alcohol intake are somehow related.

Adult↗
PubMed1982

Reduced level of cellular glucocorticoid receptors in patients with anorexia nervosa.

Specific glucocorticoid receptors were measured in circulating mononuclear leukocytes from 12 patients with anorexia nervosa and 21 healthy control subjects. Cells from patients were found to contain a significantly (p less than 0.01) lower level of glucocorticoid receptor (3830 +/- 210 sites/cell, mean +/- SE) than those from controls (4930 +/- 250 sites/cell). A partial glucocorticoid receptor defect may well explain the abnormal cortisol metabolism and glucocorticoid resistance commonly found in patients with anorexia nervosa.

Adolescent↗
PubMed1981

Glucocorticoid receptors in human polymorphonuclear and mononuclear leucocytes. Concentrations and binding characteristics.

Both polymorphonuclear (PMN) and mononuclear (MN) leucocytes constitute targets for glucocorticoid hormones. In order to comparatively characterize the earliest steps of steroid action in these cell populations, we investigated the concentrations and specificities of glucocorticoid receptors in purified human PMNs and MNs by a whole-cell binding assay using (3H)dexamethasone as the ligand. PMNs and MNs were found to contain the same amounts of glucocorticoid receptors (4720 and 4900 receptor sites/cell, respectively). The equilibrium dissociation constant (KD) of the interaction between the cellular receptor and (3H)dexamethasone was about the same (1 x 10(-8)M) in both cell populations. No significant difference in the specificities of the steroid binding sites in PMNs and MNs were found; competition studies revealed the following order of relative binding affinities for a number of compounds: betamethasone greater than dexamethasone greater than prednisolone greater than cortisol greater than deoxycorticosterone = progesterone greater than aldosterone greater than testosterone greater than estradiol-17 beta. We conclude that known differences in the sensitivities of PMNs and MNs to glucocorticoids are apparently not caused by differences in the concentrations or characteristics of their glucocorticoid receptors.

Betamethasone↗
PubMed1980

Serum progesterone, estradiol, and estriol before and during induced labor.

To investigate the association of serum levels of progesterone (P), estradiol (E2), and estriol (E3) with the initiation of regular contractions, venous blood samples were taken prior to and 3 hours after the successful induction of labor in 83 parturients by means of low amniotomy and intravenous oxytocin infusion. The serum P level and P/E2 ratio decreased and serum E2 level increased after induction in healthy primigravidas and in parturients with an initial P dominance (serum P/E2 ratio more than 5). There was also a decrease in the serum P level and P/E2 ratio in postterm patients and parturients with a ripe cervical state. Cholestasis of pregnancy was associated with a rise in the serum level of E2 and a decrease in the P/E2 ratio. In an unfavorable cervical state there was a rise in the serum E2 level; patients with an initial E2 dominance (serum P/E2 ratio 5 or less) showed a rise in the serum P level and P/E2 ratio. Healthy multigravidas and patients with pre-eclampsia did not show any hormonal changes. The onset of induced labor seems to be associated with a rise in serum E2 concentration and/or with a drop in P concentration. The increase in serum E2 level is thought to be due to the activation of the anterior pituitary--adrenal axis. The lower P level is supposedly a result of diminished uteroplacental circulation.

Cervix Uteri↗
PubMed1980

Glucocorticoid receptors and glucocorticoid sensitivity of human leukemic cells.

We have established optimal conditions for the measurement of glucocorticoid receptors (GR) in human white cells using a whole-cell binding assay with [3H]dexamethasone as the ligand, and the subsequent determination of the GR content in normal human lymphocytes and in leukemic cells of patients with various forms of acute and chronic leukemia. A number of leukemia cell lines in continuous culture were also subjected to the GR assay, and the results were correlated with the sensitivity of these cell lines to glucocorticoid steroids in vitro. The GR content of normal human lymphocytes amounted to 4,850 +/- 1,340 (mean +/- SD) receptors/cell. The mean equilibrium dissociation constant (KD) of the interaction of [3H]dexamethasone with the GR was 1.2 x 10(-8) M. Steroidal compounds with a known glucocorticoid potency effectively competed for the binding, whereas steroids devoid of glucocorticoid activity (e.g. estradiol-17 beta and testosterone) were ineffective. The GR content of the blast cells obtained from eight patients suffering from acute leukemia and four patients with a blast crisis of chronic myelocytic leukemia was found to be highly variable (3,230-29,900 receptors/cell), while the lymphocytes of six patients with chronic lymphatic leukemia contained a rather stable GR content (2,930-5,120 receptors/cell), which was comparable with that of normal lymphocytes. GR was identified in all the 12 malignant continuous white cell lines studied. Large cells contained more GR than the smaller ones. There was no apparent correlation between the GR concentration and the sensitivity of the cells in vitro to glucocorticoids as judged by [3H]thymidine incorporation studies. Distribution of the surface markers in the leukemic cell lines did not relate to the GR concentration. We conclude that the presence of GR is probably a universal feature of the leukemic cells, and, from a clinical standpoint, probably does not alone imply steroid responsiveness.

Adolescent↗
PubMed1980

Amenorrhea with low normal thyroid function and thyroxine treatment.

The effect of thyroxine treatment in cases of functional amenorrhea accompanied by low normally thyroid function was studied. During six months of follow-up, regular or single menstrual cycles were restored in ten of the 17 patients with thyroxine treatment and in four of the 11 patients without thyroxine treatment. During thyroxine treatment, thyroxine and free thyroxine index levels were elevated and serum testosterone levels decreased, but no significant changes were observed in serum estradiol, prolactin, follicle-stimulating hormone or luteinizing hormone levels. In the thyroid-releasing hormone/luteinizing-releasing hormone test, the thyroid-stimulating hormone response was markedly suppressed, but there were no changes in follicle-stimulating hormone, luteinizing hormone or prolactin responses. In one patient with primary hypothyroidism, regular menstrual cycles were restored and serum prolactin and thyroid-stimulating hormone levels normalized during thyroxine treatment. Thyroxine treatment seems to have benefits in some amenorrheic patients with low normal thyroid function.

Adult↗
PubMed1980

Glucocorticoid receptors in adrenocorticoid disorders.

Circulating human lymphocytes contain glucocorticoid receptors (GR). To see if adrenocortical imbalance is associated with changes in the level of GR, several patients with hypo- and hypercortisolism were studied. Peripheral lymphocytes were prepared by Ficoll-Hypaque gradients and were then subjected to a whole cell-binding assay measuring the total cellular receptor pool, with [3H]dexamethasone as the ligand. There were no significant differences in the cellular content of GR among healthy controls, 10 patients with Cushing's syndrome, and 3 patients suffering from Addison's disease; the absolute levels of GR were 4850 +/- 1340, 4900 +/- 2160, and 5640 +/- 1110 (mean +/- SD) receptors/cell, respectively. The mean equilibrium dissociation constants of the interaction of [3H]dexamethasone with the receptor were also about the same in the 3 groups (1-2 X 10(-8) M). Thus, aberrations in glucocorticoid balance strong enough to produce clear-cut clinical symptoms do not result in major alterations in the level of the peripheral GR. We also studied an additional patient who had hypercortisolism due to an adrenal adenoma but only slight clinical signs of hypercortisolism; interestingly, her cellular GR level was only 30% of normal. The lymphocytic GR content was also below normal in 2 patients with anorexia nervosa.

Addison Disease↗
PubMed1980

Lack of correlation between the glucocorticoid receptor density and the in vitro growth-inhibitory effect of dexamethasone in human leukemia cell lines.

We have developed a whole cell binding assay with [3H]dexamethasone as the ligand for the measurement of the glucocorticoid receptor (GR) content of normal and malignant human leukocytes. A panel of eleven phenotypically well-defined human leukemia cell lines were investigated for their GR expression and in vitro sensitivity to glucocorticoids. There were great variations in the GR contents of different cell lines (2200-18100 sites/cell) while no marked differences in the binding affinities of the GRs were seen. No obvious correlation was found between the GR content and the phenotype of the cell line nor between the GR content and the in vitro growth inhibition by glucocorticoids.

Animals↗