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Acute effects of steroids on immune complex profile of patients with systemic lupus erythematosus. Correlation of profile with development of target organ involvement.

Eleven patients with active systemic lupus erythematosus, previously untreated, were studied to 1) determine the acute effect of corticosteroids on circulating immune complex (CIC) levels and 2) correlate the initial CIC profile with the development of organ system involvement. Using serial measurements of CIC as detected by assays for cryoglobulins and binding to C1q, Raji cells, and rheumatoid factor, we found that levels of CIC change little during the first month of high dose daily steroid therapy, but they uniformly decrease to near normal by 6 to 12 months. High levels of CIC detected by Raji cell assay early in the course of systemic lupus erythematosus and before steroid therapy appear to be predictive of the development of chronic lupus nephritis (P less than 0.005).

Adult↗

Familial true hermaphorodism in three siblings: plasma hormonal profile and in vitro steroid biosynthesis in gonadal structures.

The in vitro biosynthesis of estrogens and androgens by gonadal tissues of the ovotestes was studied in three siblings with familial true hermaphrodism and correlated with daily steroid and gonadotropin plasma levels. The probands were 15, 13, and 11 years old with normal male phenotype and external genitalia, grade III hypospadias, bilateral scrotal ovotestes, gynecomastia, and no uterus or fallopian tubes. Their karyotypes were 46XX both in peripheral lymphocytes and in gonadal fibroblasts, and no Y chromosome fluorescence was observed. A fusiform biopsy of each gonad was obtained, and the testicular and ovarian structures were excised and incubated for five days at 37 C with 3.8 muCi of 7alpha3H dehydroepiandrosterone, in Eagle's growth media, 95% O2 and 5% CO2. After standard procedures, four extractions with methylene chloride were performed, and the residue was assayed using Sephadex LH no. 20 chromatography. Testosterone (T), delta4androstenedione (delta 4), 5alphadehydrotestosterone (5alphaDHT), estrone (E1), estradiol-17 beta (E2) and estriol (E3) were measured. Also, during 16 consecutive days daily venous samples were obtained, and FSH, LH, E2, progesterone (P), and testosterone (T) were determined. The predominant steroids formed in vitro were estrogens, mainly E1 by either the testicular or ovarian structures. In the 11-year-old subject, the ovotestes were less active than in his oldest siblings. The patterns of androgen production showed that T was the principal androgen formed, followed by delta4 and minimal amounts of 5alphaDHT. The daily plasma hormonal profile resembled more closely a female pattern, specially in the 15 and 13-year-old patients. It is suggested that the ovotestes of these siblings had the enzymatic mechanisms necessary for estrogen and androgen biosynthesis, mainly E1 and T using a preferential metabolic pathway via androstenedione. Furthermore, it seems that the testicular structures had a greater capability to synthesize estrogens than the ovary.

Adolescent↗

Sex steroid and growth factor profile of a meningioma associated with pregnancy.

BACKGROUND: Increased growth of meningiomas during pregnancy as well as postpartum clinical regression of symptoms have been reported but remain poorly understood. A better understanding of the factors that contribute to these observations, including potential factors associated with pregnancy, could enable design of more effective adjuvant therapies. METHODS: We describe the presentation of a meningioma during the immediate postpartum period. Serial imaging demonstrated subsequent rapid decrease in size of the tumour prior to any intervention. The lesion was resected, and the tissue was subjected to immunostaining for gene products associated with pregnancy, including estrogen receptor (ER), progesterone receptor (PR), platelet-derived growth factor receptor B (PDGFRB), fibroblastic growth factor receptor 2 (FGFR-2), epidermal growth factor receptor (EGFR) and human placental lactogen (hPL). RESULTS: The lesion proved to be an atypical fibroblastic meningioma grade II (WHO). Immunostaining demonstrated significant staining for PR, PDGFRB, and FGFR-2. No specific staining for ER, EGFR, or hPL was identified. CONCLUSION: Although clinical regression of meningioma following pregnancy is well-recognized, imaging data are much less abundant. This report provides clear clinical and imaging documentation of a meningioma associated with pregnancy. In addition, the growth factor profile of this tumour suggests the importance of PR, PDGFRB, and FGFR-2 as potential therapeutic targets.

Adult↗

Combined effect of tamoxifen or interferon-beta and 4-hydroxyphenylretinamide on the growth of breast cancer cell lines.

To improve the effectiveness of 4-hydroxyphenylretinamide (4-HPR), an analogue of retinoic acid used in chemoprevention and treatment of breast cancer, we investigated the effect of concomitant administration of 4-HPR (0.1, 1 microM) and tamoxifen (TAM, 0.1, 1 microM), or 4-HPR and interferon-beta (IFN-beta, 10, 100, 500 IU/ml) on the growth of four cell lines (MCF7, T47D, MDA-MB231 and BT20) characterized by a different steroid receptor profile. A high concentration of 4-HPR caused a significant inhibitory effect not only on the estrogen receptor-positive cell lines (MCF7 and T47D), but also on one (BT20) of the two estrogen receptor-negative cell lines. IFN-beta displayed a dose-dependent inhibitory effect in all cell lines, but it was most evident in MCF7 cells. In all cell lines, the combination of 4-HPR (0.1 microM) and TAM (1 microM) or IFN-beta (500 IU/ml) generally caused additive or synergistic effects. In particular, the finding that in estrogen receptor-negative MDA-MB231 cells 4-HPR (which at 1 microM was singly ineffective) in combination with TAM at 1 microM or any concentration of IFN-beta produced a synergistic effect suggests that the compound could act through a pathway independent of specific receptors for retinoids. Our results indicate that intrinsic characteristics of cells can influence responsiveness to 4-HPR, TAM and IFN-beta, singly or in association, ever within cell lines with similar steroid receptor profiles. Thus, more attention should be payed to the biological characteristics of the single tumor in order to help choose the best combination of drugs to be applied.

Antineoplastic Agents↗

Microbial transformations of steroids--XII. Progesterone hydroxylation profiles are modulated by post-translational modification of an electron transfer protein in Streptomyces roseochromogenes.

When Streptomyces roseochromogenes strain 10984 was incubated with exogenous progesterone for 25 h the major monohydroxylated metabolite, 16alpha-hydroxyprogesterone was produced in 3.6 fold excess to the minor metabolite 2beta,16alpha-dihydroxyprogesterone. In a reconstituted system containing highly purified progesterone 16alpha-hydroxylase cytochrome P-450, and electron transfer proteins ferredoxin-like redoxin (roseoredoxin) and redoxin reductase (roseoredoxin reductase), both metabolites were produced but in a 10:1 ratio. When S. roseochromogenes was pre-incubated for 8 h with 0.32 mM progesterone and the purified components of the hydroxylase system incubated as before, the ratio of 16alpha-hydroxyprogesterone to 2beta,16alpha-dihydroxyprogesterone produced decreased to 2.8:1, virtually identical to the ratio in whole cell transformations. Reconstitution assays containing all combinations of hydroxylase proteins purified from progesterone pre-incubated and control cells showed that the roseoredoxin was solely responsible for the observed changes in in vitro metabolite ratios. The fact that the lower 16alpha-hydroxyprogesterone to 2beta,16alpha-dihydroxyprogesterone ratio was also obtained when S. roseochromogenes was exposed to 0.335 mM cycloheximide for 8 h prior to the progesterone pre-incubation, pointed to post-translation modification of the roseoredoxin. Separation of two isoforms of roseoredoxin by isoelectric focusing supported this proposition.

Bacterial Proteins↗

Endometrial adenocarcinoma. A multiparameter clinicopathologic analysis including the DNA profile and the sex steroid hormone receptors.

With endometrial adenocarcinoma, several factors, such as stage and histologic grade, are well recognized as having prognostic significance. Other variables, e.g., nuclear grade, probably are also important clinically. A preliminary investigation of the prognostic value of the ploidy, cell cycle kinetics, and sex steroid receptor contents of these tumors has been conducted and compared with more conventional prognostic factors such as stage, grades, and depth of invasion. As analyzed by flow cytometry, the proliferative activities of the carcinomas were significantly associated with prognosis. Tumors with lower levels of proliferative activity were related to improved survivals. Two thirds of the carcinomas were diploid; ploidy did not carry prognostic weight in the series. Both the estrogen and progesterone receptor status were related to survival. Patients whose tumors were positive for these receptors had a better prognosis than did those in which the receptors were not present in significant quantities.

Adenocarcinoma↗

Effect of steroid hormones on membrane profiles of HeLa S3 cells.

The cervical carcinoma cell line, HeLa S3, was exposed to oestradiol and progesterone separately and combined in ratios similar to those of the luteal and follicular phases of the menstrual cycle. After 48 h of exposure, membrane proteins were extracted from the plasma membrane and analyzed. The lipid composition of the cells and lectin binding patterns to the cells were also assessed. The hormones had a profound effect on the HeLa S3 membrane protein profiles. Progesterone inhibited the synthesis of a wide variety of proteins while oestradiol negated this effect. Less variation between lipid profiles was noted although progesterone reduced the amount of cholesterol present. Differences in lectin binding profiles between the various treatments were noted, indicating an hormonal effect on glycosylation. Such hormonal effects on membrane composition may have implications in cervical susceptible to microbial infections.

Cell Membrane↗

Anticonvulsant profile of an anesthetic steroid.

The synthetic steroids alphaxalone and alphadolone are combined for use as a veterinary anesthetic and marked under the trade name Saffan. This study evaluated the anticonvulsant activity of Saffan in 2 rat models of epilepsy: maximal electroshock and subcutaneous pentylenetetrazol seizures. Neurological deficit was tested in each animal just prior to the seizure test to differentiate selective antiepileptic effects from nonselective anticonvulsant or anesthetic activity. In both seizure models Saffan induced anticonvulsant activity only at doses associated with neurological deficit.

Anesthetics↗

Changes in profiles of serum sex steroids of male buffaloes from birth to maturity.

Age-related changes in testosterone, progesterone and estradiol 17-beta were determined by radioimmunoassay (RIA) in the serum of 155 male buffalo calves of varying ages. The calves were classified into 17 age groups. The mean weight of calves increased from 33.6+/-9.6 kg at one week of age to 531+/-41.4 kg at 42 months. The testosterone levels were less than 100 pg/ml from birth until 15 months of age, followed by peak concentrations of 422+/-79 pg/ml at 24 to 30 months and 793+/-193 pg/ml at 42 to 48 months (corresponding to puberty and maturity, respectively). The progesterone levels were higher in newly born calves and mature bulls. Otherwise, the levels continued to be low throughout the period of growth and development. Estradiol 17-beta was significantly higher in postnatal calves up to two months of age. The testosterone revealed a positive correlation with weight and age while E2 17-beta showed a negative correlation with age. These results do not support a direct role of peripheral progesterone and estradiol 17-beta in the onset of puberty and sexual maturity of buffalo bulls.

Journal Article↗

Altered profiles of serum neuroactive steroids in premenopausal women treated for alcohol addiction.

Long-term alcohol consumption results in menstrual irregularities due to the inhibition of progesterone secretion. Some progesterone metabolites, including three pregnanolone isomers (PI), abate, while pregnenolone sulfate (PregS) and dehydroepiandrosterone sulfate (DHEAS) increase, alcohol tolerance. The rationale of this study was to evaluate how the neuroactive steroids reflect the impaired progesterone formation in premenopausal women treated for alcohol addiction, and whether detoxification therapy could restore female reproductive functions and psychosomatic stability by reinstatement of the steroid biosynthesis. Accordingly, serum allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one (P3alpha5alpha)), pregnanolone (P3alpha5beta), isopregnanolone (P3beta5alpha) and epipregnanolone (P3beta5beta), progesterone, PregS, pregnenolone, 17alpha-hydroxy-pregnenolone (Preg17), 17alpha-hydroxy-progesterone (Prog17), DHEA, DHEAS, cortisol and estradiol were measured in 20 women during the therapy (start, 3 days, 14 days, 1 month, 4 months), and in 17 controls, using GC-MS or RIA and evaluated by age-adjusted ANCOVA with status and phase of the menstrual cycle (PMC) as factors, and status-PMC interaction. The patients exhibited depressed progesterone, Prog17, PI, and estradiol, a decreased progesterone/pregnenolone ratio, a decreased ratio of neuroinhibiting P3alpha5alpha to neuroactivating PregS, and an elevated PregS and PregS/pregnenolone ratio. The treatment mostly restored the indices. The reduction of neuroinhibiting pregnanolone isomers in the patients is primarily associated with the impairment in ovarian steroid biosynthesis. Nevertheless, changes in enzyme activities connected with the formation of PI and the influence of altered physiological requirements on the balance between endogenous neuroinhibiting and neuroactivating steroids are also likely. The reinstatement of serum estradiol, progesterone, and PI during the therapy demonstrates its favorable effect on both reproductive functions and the psychosomatic stability of the patients.

Alcoholism↗

Automated qualitative and quantitative metabolic profiling analysis of urinary steroids by a gas chromatography-mass spectrometry-data system.

A computer system (MSSMET), using methylene unit retention indices for an off-line reverse library search analysis of selected ion chromatograms from gas chromatography-mass spectrometry data, has been applied to the qualitative and quantitative determination of urinary steroids. Several published methods for the isolation and derivatization of urinary steroids were evaluated for reproducibility using fused silica capillary column gas chromatography. Using a procedure that gave the greatest reproducibility, MSSMET analyses of urinary steroids were evaluated with packed (3-m 3% OV-101) and capillary (50-m OV-101 WCOT fused silica) columns. Most urinary steroids could be accurately quantitated using the packed column. However, urinary steroids with similar mass spectra and retention behavior on a packed column (i.e., androsterone and etiocholanolone, or 3 alpha, 11 beta, 17 alpha, 21-tetrahydroxy-5 beta-pregnane-20-one and 3 alpha, 11 beta, 17 alpha, 21-tetrahydroxy-5 alpha-pregnane-20-one) were completely separated using the capillary column and could be reproducibly quantitated with a 2-sec scan cycle time (10-15 data points across a peak) but not with a longer scan cycle time. Overloading was the major problem encountered with the fused silica capillary column.

Female↗

Developmental profiles of TSH, sex steroids, and their receptors in the thyroid and their relevance to thyroid growth in immature rats.

Sex steroids are reported to influence thyroid pathogenesis in human and experimental animals. However, there is no report on this phenomenon during the early developmental period. The mitotic activity of thyrocytes in rats reaches its peak by day 10 postpartum. Thyrocytes actively proliferate in immature rats during the first three postnatal weeks, during which the pre-pubertal rise in serum titers of testosterone and estradiol has been recorded. The aim of the present study was to analyze whether there is a physiological relevance between thyroid growth and sex steroids during the postnatal period. Serum and thyroid tissue hormones (TSH, testosterone, and estradiol) were assayed by liquid phase RIA, and receptors for these hormones were also quantified. The peak rate of thyrocyte proliferation was observed during the second postnatal week in rats. Since the concentrations of sex steroids and their receptors also reached a peak around this period, it is suggested that elevated sex steroids and their receptors in the thyroid might enhance thyrocyte proliferation. A positive correlation between thyroid growth indices and sex steroids and their receptors further strengthens this suggestion. This is a preliminary study, and further experimental study may strengthen this proposal. This is the first report to show the availability of sex steroids and their receptors in the thyroid glands of immature rats under normal conditions.

Age Factors↗

[Effect of sex steroids on the lipoprotein profile].

Hyperandrogenemia is associated with relatively high LDL- and low HDL-cholesterol levels, increasing the risk of the development of arteriosclerotic disease. In three women suffering from androgen producing ovarian tumors, this observation could be confirmed. After surgical removal of the ovaries, lipoprotein profiles returned to normal. In contrast, androgens did not affect lipoproteins in two testicular feminized individuals. Despite elevated testosterone levels, the lipoprotein profiles were absolutely normal. This observation indicates that the affects on the lipoprotein profile is receptor mediated.

Adolescent↗

[Effects of sex steroids on the lipoprotein profile].

Plasma testosterone levels were measured pre- and postoperatively as well as during estrogen substitution in a 47-year-old woman with excessive hyperandrogenaemia due to a Leydig-cell tumour of the left ovary. In addition, the lipoprotein profile was determined before and 14 days after removal of the tumour and four weeks later during estrogen substitution. The preoperative plasma testosterone level was between 6.25 and 8.50 ng/ml; at the same time there was a hypercholesterolaemia with increased beta-lipoprotein and decreased alpha-lipoprotein fractions: the ratio of beta- to alpha-lipoprotein cholesterol was 3.0, a type IIa hyperlipoproteinaemia. After the testosterone concentration had returned to normal both the beta- and pre-beta cholesterol fell significantly, while the alpha-lipoprotein fraction remained unaltered. The alpha-cholesterol fraction increased significantly after estrogen substitution, the beta- to alpha-lipoprotein ratio being 1.20. It is concluded from these results that hyperandrogenaemia goes together with raised peripheral beta and pre-beta-cholesterol concentration, while estrogens cause a rise in the alpha-fraction.

Cholesterol↗

Experimentally induced subnormal or normal luteal phases in sheep: reproductive hormone profiles and uterine sex steroid receptor expression.

This study investigated if ewes expected to have subnormal luteal phases (SNLP) present a different pattern of uterine oestrogen receptor (ER) and progesterone receptor (PR) expression at the expected time of premature luteolysis. The concentrations of uterine ER, PR and ERalpha mRNA, and the steroid ovarian hormone were determined in anoestrous ewes treated with either gonadotrophin-releasing hormone (GnRH) to develop a SNLP (n = 16), or progesterone + GnRH to develop a normal luteal phase (NLP; n = 16). The ER, PR and ERalpha mRNA concentrations were measured using binding and solution hybridisation assays, while the hormone level concentration was measured by radioimmunoassay. In all ewes, a luteinising hormone- and follicle-stimulating hormone-synchronised surge was found. The SNLP group had lower preovulatory oestradiol levels than the NLP group. On Day 5, the SNLP group had lower progesterone levels, and higher uterine ER, PR and ERalpha mRNA concentrations than the NLP group. While in the SNLP group the receptor expression increased from Days 1 to 5, in the NLP group the receptor expression decreased. The results suggest that the induction of steroid receptor expression in the uterus and the hormonal environment found in the experimental SNLP group at the expected time of premature luteolysis may be involved in the mechanisms causing SNLP.

Animals↗

Nutritional status and lipid profiles of trained steroid-using bodybuilders.

Fourteen trained male anabolic steroid-using bodybuilders (SBBs) (19-41 years) were recruited for the study. Three-day diet records were obtained from SBBs and analyzed. A resting venous blood sample was drawn, and serum/plasma was subsequently analyzed for various nutritionally related factors. Results showed that mean dietary energy (4,469 +/- 1,406 kcal), protein 252 +/- 109 g), and vitamin and mineral intakes of SBBs greatly exceeded U.S. Recommended Dietary Allowances. Dietary cholesterol intake was 2.8 times the recommended levels. Mean serum/plasma nutrient concentrations of SBBs were within normal range. However, individual SBBs had a number of serum/plasma values outside of the normal or recommended range, the most notable of which was hypercalcemia, which was present in 42% of SBBs. Serum/plasma lipids were such as to increase the risk of cardiovascular disease in these subjects.

Adult↗

Gym and tonic: a profile of 100 male steroid users.

OBJECTIVE: To identify unsupervised anabolic steroid regimens used by athletes. METHODS: 100 athletes attending four gymnasia were surveyed using an anonymous self administered questionnaire. RESULTS: Anabolic steroid doses ranged from 250 to 3200 mg per week and users combined different drugs to achieve these doses. Injectable and oral preparations were used in cycles lasting four to 12 weeks. Eighty six per cent of users admitted to the regular use of drugs other than steroids for various reasons, including additional anabolic effects, the minimisation of steroid related side effects, and withdrawal symptoms. Acne, striae, and gynaecomastia were the most commonly reported subjective side effects. CONCLUSIONS: Multiple steroids are combined in megadoses and self administered in a cyclical fashion. Polypharmacy is practised by over 80% of steroid users. Skeletal muscle hypertrophy along with acne, striae, and gynaecomastia are frequent physical signs associated with steroid use.

Acne Vulgaris↗

The changing gastrointestinal side effect profile of non-steroidal anti-inflammatory drugs. A new approach for the prevention of a new problem.

The most serious side effects of non-steroidal anti-inflammatory drugs (NSAIDs) involve gastroduodenal perforations and massive haemorrhage. It is becoming increasingly clear, however, that it is the small intestine that bears the main brunt of NSAID-related gastrointestinal toxicity. Hence 70% of patients receiving NSAIDs in the long term have evidence of small-intestinal inflammation, and the same patients lose blood and protein as a consequence. Many patients have asymptomatic ileal dysfunction and occasionally may develop unique small-intestinal strictures necesitating surgery. The pathogenesis of the intestinal inflammation is beginning to emerge. There are data to support that an imbalance between prostaglandins and leukotrienes is important in disrupting small-intestinal integrity during drug absorption. Furthermore, a simple mixture of glucose and citrate with indomethacin appears to minimize the damage. Whether this overcomes a metabolic block caused by NSAIDs and replenishes ATP levels or acts by scavenging oxygen free radicals is unknown, but our further understanding of the mechanism may revolutionize our approach to prevention of the gastrointestinal toxicity of NSAIDs.

Anti-Inflammatory Agents, Non-Steroidal↗