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PubMedDate not supplied

Effect of high-dose intravenous steroid pulse therapy followed by 3-month oral steroid therapy for Graves' ophthalmopathy.

PURPOSE: To evaluate the effect of high-dose intravenous steroid pulse therapy followed by 3-month oral steroid therapy for Graves' ophthalmopathy. METHODS: We selected 41 Japanese patients (age range, 21-76 years; mean = 49 years) who had active Graves' ophthalmopathy among 205 consecutive patients examined at Sapporo Medical University Hospital between 1997 and 1999. In a prospective study, we investigated the effect on the 41 patients of high-dose intravenous methylprednisolone pulse therapy (1 g/day x 3 days x 3 times) followed by 3-month oral prednisone therapy. Coronal computed tomography (CT) of the orbit, exophthalmometry and monocular fixation field measured by Goldmann perimetry were carried out before the steroid pulse therapy, and 1 and 6 months after the steroid pulse therapy. The maximum coronal section area of the rectus muscle in each eye was measured using an orbital CT image. RESULTS: Extraocular muscle hypertrophy was significantly reduced 1 and 6 months after the pulse therapy (paired t-test, P <.01), and was not significantly different between 1 and 6 months after the pulse therapy. Proptosis was not significantly reduced by the pulse therapy. Monocular fixation fields were measured in 34 patients with diplopia, and limitation of eye movements was improved in 15 patients (44%) by the pulse therapy. In the other patients, improvement of the limitation was not detectable by the test of the monocular fixation field. CONCLUSIONS: The treatment in this study is effective for extraocular muscle hypertrophy, and relapse was minimum within 6 months. However, this treatment has limited effect on limitation of eye movements and less effect on proptosis.

Administration, Oral↗
PubMed2000

The sex steroid binding protein (SBP or SHBG) of human plasma: identification of Tyr-57 and Met-107 in the steroid binding site.

Tyrosine-57 (Y57) and methionine-107 (M107) have been identified in the binding site of the sex steroid binding protein (SBP) (or sex hormone binding globulin) of human plasma by replacing the two amino acids with a number of residues of varying structure. Replacement of Y57 with phenylalanine resulted in a fourfold increase in the K(d) of 5 alpha-dihydrotestosterone but left the K(d) of 17 beta-estradiol unchanged. Except in two cases, no further loss in binding took place when replacing Y57 with other residues, suggesting that the phenolic group of Y57 may form a hydrogen bond with the ligand. Replacement of M107 with isoleucine increased the 5 alpha-dihydrotestosterone K(d) fourfold to a value equal to that of rabbit SBP, which contains isoleucine at the corresponding position; however, the K(d) of 17 beta-estradiol remained unchanged. Replacement of M107 with threonine resulted in a tenfold decrease in 5 alpha-dihydrotestosterone binding affinity, whereas replacement with leucine left the K(d) unchanged. These data indicate that substitutions on the beta-carbon of the amino acid side-chain at position 107 causes significant loss of binding affinity but, as in the case of Y57, the activity was not totally eliminated. We conclude that Y57 and M107 form part of a structural motif within the steroid binding site and specifically contribute binding energy to ring A of 5 alpha-dihydrotestosterone but not to ring A of 17 beta-estradiol. We also propose that the integrated contribution of several side chains may be required to optimize the ligand affinity of the steroid binding site. This proposal may fit a 'lock and key' model where little movement of the side chains occurs during binding as might be expected for a rigid structure like the steroid nucleus.

Amino Acid Substitution↗
PubMed1979

"Affinity" chromatography of steroid-transforming enzymes with a non-steroidal ligand.

The chromatographic behaviour of an avian oestradiol-17 beta dehydrogenase, the 3(17) beta-hydroxy steroid dehydrogenase from Pseudomonas testosteroni and cortisone reductase from Streptomyces dehydrogenans was studied on columns of p-(phenoxypropoxy)aniline attached to CNBr-activated Sepharose. The ligand was effective in adsorbing the oestradiol dehydrogenase from a partially purified extract of chicken liver, and the cortisone reductase was perferentially retained when mixtures of the three dehydrogenases were applied to columns in 10mM-buffer. Under these conditions the 3(17)beta-hydroxy steroid dehydrogenase was eluted in the front, but was adsorbed in the presence of 3 M-KCl. beta-N-Acetylglucosaminidase present in the liver preparation was not retained by the ligand, whereas lactate dehydrogenase from rabbit muscle was adsorbed in a manner similar to the retention pattern found on affinity chromatography with 2',5'-ADP--Sepharose. The mean overall purification of the oestradiol dehydrogenase was 13-fold, with a mean recovery of 53%. p-(Phenoxypropoxy)aniline offers promise for the purification of steroid-transforming enzymes where elution with substrate or cofactor is not wanted. It is also suggested that the ligand may be of service in the purification of receptors of hormonal steroids.

17-Hydroxysteroid Dehydrogenases↗
PubMed2002

Azathioprine or methotrexate in the treatment of patients with steroid-dependent or steroid-resistant ulcerative colitis: results of an open-label study on efficacy and tolerability in inducing and maintaining remission.

BACKGROUND: The role of azathioprine and methotrexate in inducing and maintaining remission in patients with ulcerative colitis is still controversial. AIM: To evaluate the efficacy and tolerability of these two drugs in a series of patients with steroid-dependent or steroid-resistant active ulcerative colitis. METHODS: Forty-two patients were treated with a daily dose of azathioprine (2 mg/kg) and, if intolerant or not responding, with methotrexate (12.5 mg/week intramuscularly), and their efficacy was established by clinical, endoscopic and histological examinations at 6 months. Patients achieving clinical remission continued with treatment and were followed up. RESULTS: Of the 42 patients on azathioprine, 10 experienced early side-effects requiring withdrawal from treatment, 22 (69%) achieved complete remission, six (19%) achieved improvement and four (12%) obtained no substantial benefit. Methotrexate, administered to eight patients intolerant to and two patients resistant to azathioprine, induced complete remission in six patients (60%) and improvement in four (40%). During follow-up, a larger number of patients on azathioprine relapsed in comparison with patients on methotrexate [16/28 (57%) vs. 2/10 (20%), respectively; P < 0.05]. Only minor side-effects were observed on both treatments. CONCLUSIONS: Azathioprine is effective in patients with steroid-dependent or steroid-resistant ulcerative colitis. Methotrexate seems to be a good alternative in patients intolerant to or not responding to azathioprine.

Adult↗
PubMed1998

Ovarian steroid-independent diurnal rhythm in cyclic GMP/nitric oxide efflux in the medial preoptic area: possible role in preovulatory and ovarian steroid-induced LH surge.

The aim of this study was to evaluate the relationship between cyclic LH hypersecretion and nitric oxide (NO) release in the medial preoptic area (MPOA), the hypothalamic site implicated in induction of LH hypersecretion. The MPOA extracellular cyclic GMP (cGMP) efflux (an index of NO release), was monitored by microdialysis. Quite unexpectedly, we observed a daily afternoon rise in the MPOA cGMP efflux in cycling female rats on proestrus and diestrus II, in ovariectomized (ovx) rats and in ovx rats treated with ovarian steroids to induce the LH surge. The daily rise in cGMP efflux occurred earlier in diestrous and in estradiol benzoate (EB)-treated ovx rats than in ovx rats. Progesterone (P) injection to estrogen-primed ovx rats further advanced the onset of the rise close to the earliest time of rise as seen on proestrus. The afternoon increase in the cGMP efflux in proestrous rats was abolished by pentobarbital treatment that blocked the LH surge. Intracerebroventricular (i.c.v.) injection of 1 H-[1,2,4]oxadiazo[4,3-a]quinoxalin-one (ODQ), a selective inhibitor of soluble guanylyl cyclase, suppressed the P-induced LH surge in EB-primed ovx rats, but not basal LH secretion in unprimed ovx rats. Analysis of brain NOS (bNOS) levels in the POA by Western blotting showed that the morning bNOS levels were higher in the POA of EB-treated rats than in unprimed ovx rats. Further, with the exception of ovx rats treated with sequential EB and P treatment, the POA bNOS levels rose significantly in the afternoon in unprimed ovx and EB-treated ovx rats. Collectively, these findings reveal a diurnal rhythm in the MPOA cGMP/NO efflux that is ovarian steroid-independent. Ovarian steroids apparently shift the timing of the afternoon rise in cGMP/NO efflux to synchronize with the activation of steroid-dependent neuronal systems responsible for the LH surge.

Animals↗
PubMed2004

Tumor necrosis factor-alpha suppresses the expression of steroid receptor coactivator-1 and -2: a possible mechanism contributing to changes in steroid hormone responsiveness.

Inflammation is associated in some tissues with diminished responsiveness to steroid hormone action. We hypothesized that proinflammatory cytokines alter steroid hormone sensitivity, in part, by reducing levels of key nuclear receptor coactivators. Treatment of cultured human uterine smooth muscle cells (UtSMC) with TNF-alpha significantly reduced mRNA for the coactivators, SRC-1 (42%, P<0.01) and 2 (47%, P<0.03), and diminished the respective protein levels, but did not significantly alter the mRNAs encoding SRC-3, CBP and the corepressors, NCoR and SMRT; or progesterone receptor protein levels. To assess TNF-alpha effects on steroid hormone-mediated transcriptional activity, UtSMC were transfected with progesterone receptor B (PR-B) and a model PRE2-luciferase reporter construct. Transfected UtSMC were treated with progesterone alone or in the presence of TNF-alpha, and assayed for luciferase activity. TNF-alpha (10 ng/ml) diminished progesterone-stimulated PR-B-mediated transactivation by approximately 60% (P<0.02). The TNF-alpha-dependent decrease in PRE-luciferase activity was fully prevented by cotransfection with SRC-2, and partially prevented with exogenous SRC-1. In conclusion, TNF-alpha impairs progesterone-stimulated PR-B-mediated transactivation, and these effects appear to be due, in part, to reduced expression of SRC-1 and -2, which is a novel mechanism by which inflammation can functionally block steroid hormone action.

Down-Regulation↗
PubMed2004

The allylic 7-ketone at the steroidal skeleton is crucial for the antileukemic potency of chlorambucil's active metabolite steroidal esters.

We have investigated the role of the allylic 7-ketone in oxidized Delta5-steroids on antileukemic activity. We synthesized and studied a series of oxidized and non-oxidized steroidal esters of p-N,N-bis(2-chloroethyl)aminophenylacetic acid (PHE), chlorambucil's active metabolite. In a comparative study of these 7-keto derivatives, on a molecular basis, regarding their ability to induce sister chromatid exchanges (SCEs) and to inhibit cell proliferation in normal human lymphocytes in vitro, the results with these 7-keto derivatives, on a molecular basis, correlated well with their antileukemic potency against leukemia P388- and L1210-bearing mice, which proved to be significantly increased compared to that of the non-oxidized derivatives. Our results indicate that the role of the steroidal skeleton it is not only for the transportation of the alkylating agent into the cell, but also contributes directly to the mechanism of antileukemic action, by an as-yet unknown way. The main conclusion from this study is that the existence of the allylic 7-keto group in the skeleton of the Delta5-steroidal esters impressively enhances their antileukemic activity, while the toxicity remains at clinically acceptable levels, suggesting that this structural modification should be further investigated.

Androstenes↗
PubMedDate not supplied

The hiccup reflex arc and persistent hiccups with high-dose anabolic steroids: is the brainstem the steroid-responsive locus?

Hiccups have been classified as a neurologic reaction triggered by a multitude of factors. There are only a few reports of persistent hiccups associated with oral and intravenous corticosteroid use in the medical literature. It has been proposed that corticosteroids lower the threshold for synaptic transmission in the midbrain and directly stimulate the hiccup reflex arc. There is a recent report of progesterone-induced hiccups, which were thought to occur secondary to the glucocorticoid-like effects of progesterone on the brainstem. We report the first case of anabolic steroid-induced hiccups occurring in an elite power lifter. The hiccups occurred within 12 hours of the individual increasing his doses of oral anabolic steroids and persisted for 12 consecutive hours until medical attention was sought. In this report the pathophysiology of anabolic steroid-induced hiccups is discussed, and the postulated relationships of steroids and the hiccup reflex arc reviewed.

Administration, Oral↗
PubMed1980

A steroid sparing effect of ketotifen in steroid-dependent asthmatics.

In a multicentre, double-blind trial, the steroid sparing effect of a new anti-anaphylactic agent ketotifen was assessed against placebo in eighty-six steroid-dependent asthmatics. Mean reduction in total daily prednisolone dosage in patients on ketotifen was 4.0 +/- 3.6 mg compared to 1.7 +/- 2.8 mg on placebo, a result significantly in favour of the active drug (P < 0.01). This suggests that ketotifen has a place similar to that of disodium cromoglycate or steroid aerosols in the managment of steroid-dependent asthmatics. It has the advantage of requiring only twice-daily oral administration.

Adult↗
PubMed1997

Secondary structure and shape of plasma sex steroid-binding protein--comparison with domain G of laminin results in a structural model of plasma sex steroid-binding protein.

We have analyzed the secondary structure, shape and dimensions of plasma sex steroid-binding protein (SBP) by CD, size-exclusion chromatography and electron microscopy. CD spectra show extrema at 186 nm and 216 nm characteristic for beta-sheet structures. Analysis with different algorithms indicates 15% alpha-helix, 43% beta-sheet and 10-16% beta-turn structures. An irreversible structural change is observed upon heating above 60 degrees C, which correlates with the loss of steroid-binding activity. As the SBP sequence shows similarity with domains of several multidomain proteins, including laminins, we evaluated the structure of domain G of laminin-1. The CD spectrum shows extrema at 200 nm and 216 nm. Deconvolution results in 13% alpha-helix, 32% beta-sheet and 15% beta-turn structures. Steroid-binding assays indicate that laminin and fragments thereof have no activity. Size-exclusion chromatography reveals that SBP has an extended shape and can be modeled as a cylinder with a length and diameter of 23 nm and 3 nm, respectively. This shape and the dimensions are in agreement with the appearance on electron micrographs. We propose a model for the structure of SBP in which two monomers assemble head to head with the steroid-binding site located in the center of the rod-like particle.

Amino Acid Sequence↗
PubMed2004

Effectiveness of high trough levels of cyclosporine for 5 months in a case of steroid-dependent nephrotic syndrome with severe steroid toxicity.

Glucocorticoid treatment for steroid-dependent nephrotic syndrome (NS) is associated with severe adverse effects, such as bone fractures and epidural lipomatosis. Furthermore, a high trough level of cyclosporine (CsA) over an extended period of time is known to induce CsA nephropathy. We present a girl with steroid-dependent NS and steroid-induced vertebral compression fractures and epidural lipomatosis who was treated with a high-dose of prednisolone after experiencing several relapses. A high CsA trough level (between 147 and 225 ng/mL) over a period of only 5 months was effective in improving the vertebral compression fractures, alleviating the epidural lipomatosis by enabling the discontinuation of prednisolone treatment. Thus, high trough levels of CsA over a short period of time may enable prednisolone to be discontinued in cases of steroid-dependent NS without causing any clinical, histological, serum and/or urinary CsA-related adverse effects.

Child, Preschool↗
PubMed1991

Topical indometacin, a prostaglandin inhibitor, in acute anterior uveitis. A controlled clinical trial of non-steroid versus steroid anti-inflammatory treatment.

Forty-nine patients were included in a controlled clinical trial comparing the effect of topical non-steroid versus potent steroid preparation in acute anterior non-granulomatous uveitis. Twenty-five patients were randomized to 1% Indometacin and 24 patients to 0.1% Dexametason treatment 6 times a day. There was no difference between the two groups initially. After 7 days of treatment we found significantly less inflammation in the steroid treated group, this significant difference disappearing on day 14. We conclude that whenever adverse reactions to corticosteroid eye drops are suspected or proven, Indometacin eye drops make up a useful alternative to even strong solutions of steroids. The study was carried out in the following practices: L. Ahrendt, L. Damgård-Jensen, P. Eldrup-Jørgensen, J. Elmeros, H. Heuer, S. Jensen, M.H. Kjeldsen, P. Nellemann Sørensen, H. Petersen, N. Vedel-Jensen.

Acute Disease↗
PubMed2001

Switch from systemic steroids to budesonide in steroid dependent patients with inactive Crohn's disease.

BACKGROUND: Steroid dependent patients with Crohn's disease are at high risk of developing glucocorticosteroid induced side effects. AIMS: We evaluated the possibility of switching from systemic steroids to budesonide (Entocort) in prednisolone/prednisone dependent patients with inactive Crohn's disease affecting the ileum and/or ascending colon. PATIENTS: Steroid dependent patients with a Crohn's disease activity index </=200 were included. METHODS: In a double blind multicentre trial, 120 patients were randomly assigned to receive budesonide 6 mg once daily or placebo. Prednisolone was tapered to zero during the first 4-10 weeks and budesonide or placebo was given concomitantly and for a further 12 weeks. Relapse was defined as an index >200 and an increase of 60 points from baseline or withdrawal due to disease deterioration. RESULTS: After one and 13 weeks without prednisolone, relapse rates were 17% and 32%, respectively, in the budesonide group, and 41% and 65% in the placebo group (95% confidence intervals for the difference in percentages -41%, -8% and -51%, -16%; p=0.004 and p<0.001, respectively). The number of glucocorticosteroid side effects was reduced by 50% by switching from prednisolone and was similar in the budesonide and placebo groups. Basal plasma cortisol increased in both groups. CONCLUSIONS: The majority of patients with steroid dependent ileocaecal Crohn's disease may be switched to budesonide controlled ileal release capsules 6 mg without relapse, resulting in a sharp decrease in glucocorticosteroid side effects similar to placebo, and with an increase in plasma cortisol levels.

Adolescent↗
PubMed2004

Expression of glucocorticoid receptors alpha and beta in steroid sensitive and steroid insensitive interstitial lung diseases.

BACKGROUND: Sensitivity to glucocorticoids may be related to the concentration of glucocorticoid receptors alpha (GRalpha) and beta (GRbeta). A study was undertaken to assess GRalpha and GRbeta expression in steroid insensitive interstitial lung disease (idiopathic pulmonary fibrosis (IPF)) and steroid sensitive interstitial lung diseases (sarcoidosis and cryptogenic organising pneumonia (COP)). METHODS: Lung tissue was obtained from control subjects and from patients with IPF, sarcoidosis, and COP. Pulmonary function tests were carried out at the time of lung biopsy and every 3 months. GRalpha and GRbeta expression was evaluated by both competitive RT-PCR and immunohistochemistry. Data are presented as median and 25-75th percentile. RESULTS: GRalpha mRNA expression (10(5) cDNA copies/ micro g total RNA) was higher in patients with steroid sensitive interstitial lung diseases (10.0; 7.8-14.9; n = 11) than in patients with IPF (4.4; 3.2-6.6; n = 19; p<0.001). GRbeta expression was at least 1000 times lower than that of GRalpha and did not differ between the three groups. A negative correlation was found between GRalpha mRNA levels and the fibrotic pathology score of the tissue (r = -0.484, p<0.01) and a positive correlation was found between GRalpha mRNA levels and improvement in forced vital capacity (r = 0.633; p<0.01) after treatment of patients with glucocorticoids. Immunoreactivity for GR protein was also higher in patients with sarcoidosis and COP than in those with IPF. CONCLUSION: The variable response of some interstitial lung diseases to steroid treatment may be the result of differences in the expression of GRalpha.

Adult↗
PubMed2005

Steroid receptor regulation of epidermal growth factor signaling through Src in breast and prostate cancer cells: steroid antagonist action.

Under conditions of short-term hormone deprivation, epidermal growth factor (EGF) induces DNA synthesis, cytoskeletal changes, and Src activation in MCF-7 and LNCaP cells. These effects are drastically inhibited by pure estradiol or androgen antagonists, implicating a role of the steroid receptors in these findings. Interestingly, EGF triggers rapid association of Src with androgen receptor (AR) and estradiol receptor alpha (ERalpha) in MCF-7 cells or ERbeta in LNCaP cells. Here, we show that, through EGF receptor (EGFR) and erb-B2, EGF induces tyrosine phosphorylation of ER preassociated with AR, thereby triggering the assembly of ER/AR with Src and EGFR. Remarkably, experiments in Cos cells show that this complex stimulates EGF-triggered EGFR tyrosine phosphorylation. In turn, estradiol and androgen antagonists, through the Src-associated receptors, prevent Src activation by EGF and heavily reduce EGFR tyrosine phosphorylation and the subsequent multiple effects, including DNA synthesis and cytoskeletal changes in MCF-7 cells. In addition, knockdown of ERalpha or AR gene by small interfering RNA (siRNA) almost abolishes EGFR tyrosine phosphorylation and DNA synthesis in EGF-treated MCF-7 cells. The present findings reveal that steroid receptors have a key role in EGF signaling. EGFR tyrosine phosphorylation, depending on Src, is a part of this mechanism. Understanding of EGF-triggered growth and invasiveness of mammary and prostate cancer cells expressing steroid receptors is enhanced by this report, which reveals novel aspects of steroid receptor action.

Androgen Antagonists↗
PubMed1997

Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma.

The anti-asthmatic effects of theophylline may supplement those of inhaled steroids in asthma. The aim of the present trial was to study how the addition of theophylline compares to doubling the dose of inhaled steroid in asthmatics who remain symptomatic on beclomethasone dipropionate (BDP) 400 microg x day(-1). The trial was designed as a randomized, double-blind, parallel-group study in several European countries. Sixty nine patients were treated for 6 weeks with theophylline plus BDP 400 microg x day(-1), compared to 64 patients treated with BDP 800 micro x day(-1). The mean+/-SD serum theophylline concentration was 10.1+/-4.2 mg x L(-1). Lung function measurements were made throughout the study and patients kept daily records of peak expiratory flow (PEF), symptoms and salbutamol usage. Forced expiratory volume in one second and PEF at week 6 were significantly increased by both treatments (p<0.01). PEF variability was reduced by about 30% in both groups. There were significant improvements in asthma symptoms and rescue medication use (p<0.001). There were no significant differences between the treatment groups. The study demonstrated clinical equivalence of theophylline plus beclomethasone dipropionate 400 microg x day(-1) and beclomethasone dipropionate 800 microg x day(-1) in patients whose asthma is not controlled on beclomethasone dipropionate 400 microg x day(-1). The results support the use of theophylline as a steroid-sparing agent. The combination of low-dose inhaled steroid plus theophylline is a suitable treatment for moderate asthma.

Administration, Inhalation↗
PubMed1981

Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma.

This report describes a model of steroid transport in human plasma. The binding affinities of 21 endogenous steroids for both testosterone-binding globulin (TeBG) and corticosteroid-binding globulin (CBG) were determined under equilibrium conditions using a solid phase method at physiological pH and temperature. A computer program was used to solve the complex equilibrium interactions between these steroids and TeBG, CBG, and albumin. In this manner, we calculated the plasma distribution of each steroid into TeBG-bound, CBG-bound, albumin-bound, and unbound fractions in normal men, normal women during both the follicular and luteal phases of the ovarian cycle, and women during the third trimester of a normal pregnancy.

Adrenal Cortex Hormones↗
PubMed1989

Conjugates of ovarian steroids, including 17 alpha,20 beta-dihydroxy-4-pregnen-3-one (maturation-inducing steroid), accumulate in the urine of a marine teleost (plaice; Pleuronectes platessa).

Free and conjugated 17 alpha,20 beta-dihydroxy-4-pregnen-3-one (17,20 beta-P), 17 alpha,21-dihydroxy-4-pregnene-3,20-dione (11-deoxycortisol) and 3 alpha,17 alpha,21-trihydroxy-5 beta-pregnan-20-one (3 alpha,17,21-P-5 beta) were measured by radioimmunoassay in matching blood plasma and urine samples from plaice (Pleuronectes platessa) females at several ovarian maturity stages: post-vitellogenesis (IV), final oocyte maturation (V), and ovulation (VI). Free steroids were generally low in all samples. Conjugated steroids were up to 2 orders of magnitude higher in urine than in plasma samples. Conjugated 17,20 beta-P was higher in stage V than in stage IV or VI females. Conjugated 11-deoxycortisol was higher in stage IV and V females. Conjugated 3 alpha,17,21-P-5 beta was higher in stage V and VI females. These results support earlier studies which indicated that 17,20 beta-P was the most likely maturation-inducing steroid (MIS) in plaice, and that the urine might be a vehicle for steroid pheromones synthesized by the gonads.

Animals↗