Young female patient with testosterone-producing adrenocortical adenoma also showing signs of subclinical Cushing's syndrome.
(65/79)A 28-year old female patient with virilization due to left adrenocortical adenoma was studied. The patient had clinical features of hyperandrogenism such as hirsutism and a low pitched voice, but not of hypercorticoidism. Plasma testosterone and dehydroepiandrosterone-sulfate (DHEA-S) were high. Although the basal plasma cortisol concentration and urinary excretion of 17-hydroxycorticosteroids (17-OHCS) were within the normal range, the absence of diurnal variation in plasma cortisol and loss of suppressibility by dexamethasone suggested constitutive secretion of cortisol by the tumor. Inappropriate cortisol secretion was also supported by blunted ACTH response to provocative stimuli. After successful removal of the left adrenal tumor, such endocrinological abnormalities were all normalized. Immunohistochemical analysis revealed that tumor cells were positively stained for C21 hydroxylase cytochrome P-450 (P-450C21) and P-450(11) beta which convert 17-hydroxy (OH) progesterone to cortisol as well as P-450SCC, 3 beta-hydroxysteroid dehydrogenase and P-450(17) alpha which are involved in testosterone biosynthesis. These findings suggest that adrenocortical adenoma secretes predominantly testosterone and constitutively cortisol in a young woman patient with virilization. (+info)
Heparin-steroid conjugates: new angiogenesis inhibitors with antitumor activity in mice.
(66/79)Inhibitors of angiogenesis hold potential in the treatment of cancer and other diseases where the disease is caused or maintained by the inappropriate growth of blood vessels. In the present study, a novel inhibitor of angiogenesis was synthesized by covalently linking a nonanticoagulating derivative of heparin, heparin adipic hydrazide (HAH), by an acid-labile bond to the antiangiogenic steroid, cortisol. The rationale was that the heparin derivative, which binds to sulfated polyanion receptors on endothelial cells, should concentrate the steroid on the surface of vascular endothelial cells. Endocytosis of the conjugate and decomposition of the acid-labile linkage inside lysosomes and other acidic intracellular compartments should then lead to release of the cortisol and expression of its antiproliferative activity. Analysis of the stability of HAH-cortisol showed that it was stable at pH 7.4 and broke down rapidly (t1/2 15 min) at pH 4.8 at 37 degrees C. Treatment of murine pulmonary capillary endothelial cells with HAH-cortisol at 10(-5) M (with respect to cortisol) suppressed their DNA synthesis by 50% and inhibited their migration into wounded areas of confluent monolayers. HAH-cortisol at 10(-4) M (with respect to cortisol) did not suppress the DNA synthesis of Lewis lung carcinoma cells. Daily i.p. injections of HAH-cortisol into mice bearing s.c. sponge implants retarded vascularization of the sponge, and injections directly into the sponge abolished vascularization for as long as the injections were continued. Daily i.v. injections of HAH-cortisol at doses causing no apparent toxicity retarded the growth of solid s.c. Lewis lung carcinomas in mice by up to 65%. In all of these assays, equivalent treatments with a mixture of the HAH plus cortisol was significantly less effective. The antiproliferative effect of HAH-cortisol on endothelial cells appeared independent of the glucocorticoid activity of the steroid since HAH conjugated to 5 beta-pregnane-3 alpha,17 alpha,21-triol-20-one, a steroid lacking glucocorticoid or mineralocorticoid activity, was even more effective at inhibiting DNA synthesis by murine pulmonary capillary endothelial cells than was HAH-cortisol. In conclusion, HAH-cortisol represents the prototype of a new class of angiogenesis inhibitors for the treatment of cancer and other angiogenic diseases. (+info)
Reliability of hormonal levels for assessing the hypothalamic-pituitary-adrenocortical system in clinical pharmacology.
(67/79)Few data are available on the reliability of measurements of adrenocortical and corticotroph hormones for use in clinical pharmacology. Two placebo controlled cross-over trials in 20 normal healthy male subjects offered the opportunity to perform three repeat samplings of adrenocortical and corticotroph hormones at 1 to 5 week intervals during the placebo periods. Measurements of baseline levels of plasma, salivary and urinary cortisol, plasma adrenocorticotroph hormone (ACTH), lipotrophic hormone (LPH), beta-endorphin, post tetracosactrin levels of plasma and salivary cortisol, post corticotrophin releasing hormone (CRH)-lysine vasopressine (LVP) levels of plasma cortisol, ACTH and LPH; and post metyrapone levels of plasma cortisol and 11-deoxycortisol (compound S), ACTH, LPH, beta-endorphin were performed in the same laboratory. The reliability of the measurements was estimated by computing the intraclass correlation coefficient (R) and by using Altman-Bland graphical method. The Rs of baseline parameters varied from 0.18 (for 08.00 h salivary cortisol) to 0.55 (for 08.00 h plasma cortisol and nocturnal urinary cortisol). In contrast, parameters obtained after direct stimulation or inhibition of the producing targets were much more reliable: Rs were above 0.80 for post tetracosactrin levels of plasma and salivary cortisol, post CRH-LVP levels of plasma ACTH and LPH. The Rs were below 0.50 for post metyrapone levels of plasma 11-deoxycortisol, ACTH, LPH and beta-endorphin. The interval between sampling did not affect R estimates. These data show that peak levels of plasma cortisol and ACTH after direct stimulation are highly reliable whereas baseline and main post-metyrapone levels are not.(ABSTRACT TRUNCATED AT 250 WORDS) (+info)
Adrenal steroids in serum during danazol therapy, taking into account cross-reactions between danazol metabolites and serum androgens.
(68/79)To investigate the changes in the serum androgen concentrations and the Free Androgen Index (FAI) in women during danazol therapy, we measured the serum concentrations of adrenal steroids and danazol metabolites, and then examined the effects of danazol metabolites on assays for serum androgens. Thirteen women who had endometriosis were treated with danazol (300 or 400 mg/day) for 8 to 16 weeks. Blood samples were taken before, during, and after the medication. During the danazol therapy, serum testosterone (T), cortisol (F), and sex-hormone binding globulin (SHBG) significantly decreased (P < 0.05); but serum dehydroepiandrosterone-sulfate (DHEAS) and FAI increased (P < 0.05). The serum concentrations of danazol metabolites were: danazol, 209.0 +/- 28.3 (ng/mL, mean +/- SEM); delta 1-2-hydroxymethyl ethisterone, 114.4 +/- 8.4; and 2-hydroxymethyl ethisterone, 660.0 +/- 54.2. There was considerable cross-reaction between danazol metabolites and androgens [T, androstenedione (A), and dehydroepiandrosterone (DHEA)] in the direct assays. As for the ratios of adrenal steroids in serum, the DHEAS/F, DHEAS/DHEA, and 11-deoxycortisol (S)/F ratios increased (P < 0.05). We conclude that the increase in FAI and DHEAS represents increased native androgenic activity with danazol, and the changes in adrenal steroid ratios in serum indicate the inhibition of 11 beta-hydroxylase and sulfatase activities during danazol therapy. (+info)
Hirsutism and acne in women: coordinated radioimmunoassays for eight relevant plasma steroids.
(69/79)We developed and validated a coordinated set of RIAs for the following eight steroids in single small aliquots (< or = 1 mL) of plasma: androstenedione, dehydroepiandrosterone, 11-deoxycortisol, 21-deoxycortisol (21-DF), 11 beta-hydroxyandrostenedione, 17 alpha-hydroxypregnenolone (17-Hpreg), 17 alpha-hydroxyprogesterone, and testosterone. Samples were extracted and then chromatographed on celite microcolumns. Radioiodinated tracers were used for two of the assays (17-Hpreg and 21-DF). Tritiated tracers and scintillation proximity assay counting were used to give separation-free procedures for the other six assays, which considerably improved their practicability and reproducibility. The basal and postadrenocorticotropic hormone plasma values for these steroids in normal women sampled in the follicular phase are presented. Finally, the measurement of the eight steroids as a diagnostic method is evaluated with reference to data from 203 patients with hirsutism and (or) acne. (+info)
Human papillomavirus (HPV) type 18 E7 protein is a short-lived steroid-inducible phosphoprotein in HPV-transformed cell lines.
(70/79)We used a capture ELISA to quantify the E7 protein of human papillomavirus type 18 (HPV-18). In HeLa cells, which express low levels of immunoreactive E7 protein (iE7), iE7 had a mean half-life of 13.5 min. In HPV-18 E7 recombinant baculovirus (E7rec BV)-infected Sf21 cells, which express higher levels of E7, the half-life of iE7 was much longer (90 min and > 24 h, with two different E7rec BVs). For two transformed human cervical cell lines expressing HPV-18 E7, exposure of the cells to hydrocortisone resulted in a twofold increase in steady-state levels of the E7 protein: no similar effect was observed with progesterone, oestrogen or testosterone. The half-life of iE7 was unaltered by hydrocortisone or progesterone exposure. An immunoassay which distinguished Ser33-phosphorylated E7 from E7 not phosphorylated at this residue (Ser33dephospho-E7), showed that in HeLa and Sf21 cells the majority of E7 was phosphorylated: the half-life of both species of E7 was similar in HeLa cells, but the half-life of Ser33dephospho-E7 was much shorter (90 min) in Sf21 cells than that of Ser33phospho-E7 (> 24 h). A HeLa-fibroblast fusion cell line with tumorigenic potential (CGL-1) had a similar ratio of dephospho-E7 to total E7 (0.06), as a similar fusion cell line (CGL-4) with no tumorigenic potential (0.03). We conclude that E7 is a labile phosphoprotein, and that the expression and steady-state level of the E7 protein in eukaryotic cells may be influenced by the hormonal environment of the cells. (+info)
Hypothalamic-pituitary functions in patients with idiopathic pituitary dwarfism.
(71/79)To investigate hypothalamic-pituitary functions and the primary site of the lesion in idiopathic pituitary dwarfism, various pituitary function tests, especially the pituitary hormone responses to the hypophysiotropic hormones were studied in 23 patients with idiopathic pituitary dwarfism. A few cases showed slight responses of GH to GH stimulation tests. Gonadotropin deficiencies were most frequently noted among pituitary hormones. The basal levels and the responses of plasma LH and FSH to LH-RH test were diminished markedly in all of the cases except in 5 cases with isolated GH deficiency. Responses of LH and FSH to LH-RH improved markedly after a long term administration of LH-RH for a period of one month in 2 patients with gonadotropin deficiency. As to TSH axis, half of the cases accompanied hypothyroidism. However, the responses of TSH to TRH were normal in all of the cases regardless of the thyroid function. The basal levels and the responses of plasma cortisol and 11-deoxycortisol to the rapid metopirone test were also impaired in about half of the cases. Basal levels of plasma prolactin were normal in all of the cases and the responses of prolactin to TRH were normal in cases with normal thyroid function, but slightly delayed in cases with hypothyroidism. It is concluded from the above observations that the incidences of various pituitary hormone deficiencies were quite high in this disorder and hypophysiotropic hormone deficiencies may cause pituitary hormone deficiencies. Therefore, it is suggested that the primary site of the lesion in this disorder might be at the hypothalamus. (+info)
Cortisol is transported by the multidrug resistance gene product P-glycoprotein.
(72/79)The physiology of the multidrug transporter P-glycoprotein (Pgp) is still poorly understood. We now show evidence that cell lines with a high expression of Pgp display a reduced accumulation of cortisol and an ATP-dependent outward transport of the hormone. Cortisol efflux from Pgp negative cells does not have such an active component. Further we show that the steroid hormones cortisol, testosterone, and progesterone cause an immediate, dose-dependent increase of daunorubicin accumulation in Pgp overexpressing cells. These effects are particularly apparent for the more lipophilic steroids. These results demonstrate that Pgp may function as a transporter for cortisol and suggest a physiological role of the protein in steroid handling by organs such as the adrenal. (+info)