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PubMed1981

Transport of steroid hormones: interaction of 70 drugs with testosterone-binding globulin and corticosteroid-binding globulin in human plasma.

This report describes the binding of 70 synthetic compounds to both testosterone-binding globulin (TeBG) and corticosteroid-binding globulin (CBG). The ability of each compound to displace [3H]testosterone from TeBG and [3H]cortisol from CBG adsorbed from a plasma pool onto a solid phase matrix of Concanavalin A-Sepharose was determined under equilibrium conditions at physiological pH and temperature. From these data, the association constants of the compounds for binding to both TeBG and CBG were calculated and used to predict whether endogenous steroid transport would be altered by the therapeutic administration of the drug. Computer simulation predicted that by interacting with TeBG, therapeutic levels of danazol, methyltestosterone, fluoxymesterone, and norgestrel could displace 83%, 48%, 43%, and 16%, respectively, of the concentration of testosterone bound to TeBG in a normal man. Similarly, by interacting with CBG, therapeutic levels of prednisolone could decrease the concentration of cortisol bound to CBG by approximately 32% in both men and women, and despite relatively low affinity binding to TeBG (5 X 10(5) M-1), prednisolone could also displace small amounts of testosterone from TeBG. These results indicate that binding to steroid transport proteins should be considered among the in vivo effects of drugs on endogenous steroid hormone levels.

Binding, Competitive↗

PubMed1986

Identification and measurement of sex hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG) in human saliva.

Sex hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG) were detected by specific immunoassays in mixed-saliva taken from normal men and women. The immunochemical identity of both proteins was demonstrated by parallelism between dose response curves generated by serial dilutions of saliva and standards in the immunoassays. In addition, the specific removal of both proteins by incubation with steroid affinity-chromatography gels demonstrated the integrity of their steroid binding activity. The mean +/- SD concentrations of SHBG (pmol/l) and CBG (microgram/l) in mixed-saliva taken from normal volunteers were as follows: men (n = 6) 19 +/- 10 and 38 +/- 18; women (n = 6) 63 +/- 60 and 72 +/- 71 and women during late pregnancy (n = 6) 282 +/- 168 and 92 +/- 80, respectively. The data indicate that the concentrations of SHBG and CBG in saliva represent approximately 0.1% of plasma concentrations. It is suggested that these proteins pass from the blood to saliva in a non-specific manner, and may influence the steroid content of saliva under certain physiological circumstances.

Chromatography, Affinity↗

PubMed1976

Prostatic distribution of sex hormone-binding globulin and cortisol-binding globulin in benign hyperplasia.

Sex hormone-binding globulin-(SHBG) and cortisol-binding globulin-(CBG) like proteins have been demonstrated in prostatic tissue surgically removed from patients with benign prostatic hyperplasia. These proteins are not easily removed by superfusion of tissue slices. Epithelial tissue was separated from stroma and found not to contain the SHBG- or CBG-like proteins. Substantial amounts of these proteins, however, remained associated with the stroma. It is suggested that they may be constituents of interstitial fluid in this tissue compartment. The possible significance of this in benign prostatic hyperplasia is discussed.

Binding Sites↗

PubMed1991

Patterns of plasma sex hormone-binding globulin, thyroxine and thyroxine-binding globulin in relation to reproductive state and hibernation in female little brown bats.

A sex hormone-binding globulin (SHBG), which bound both oestradiol and dihydrotestosterone, was studied in the plasma of adult female little brown bats throughout the annual reproductive cycle. This protein was present at low baseline levels from September to May inclusive, months which correspond to the periods of hibernation, ovulation and early pregnancy. During the second half of pregnancy in June, SHBG levels increased 15- to 30-fold and remained increased throughout lactation and anoestrus/prooestrus (July-August). Although SHBG was increased during late pregnancy, the fact that levels were also high during and after lactation indicates that this protein is not specific to pregnancy. Plasma concentrations of thyroxine (T4) and the percentage binding of T4 to thyroxine-binding globulin (TBG) also showed marked seasonal variations, with T4 levels exhibiting a biphasic seasonal pattern. A major peak in plasma concentrations of T4 occurred around the time of spring arousal from hibernation and subsequent ovulation, while a second peak of lesser magnitude was measured in August, corresponding to the time of pro-oestrus and the onset of mating. The percentage binding of T4 by TBG was increased during the summer months in parallel with the increase in SHBG concentrations. Electrophoretic analysis of plasma T4 binding revealed a single peak of TBG activity throughout most of the year; however, during the early lactational period TBG was resolved as a double peak, suggesting the presence of a molecular variant during this reproductive stage.

Animals↗

PubMed1995

Sex hormone-binding globulin and corticosteroid-binding globulin mRNA levels in infertile women with luteal phase deficiency.

This study was designed to investigate the biological significance in intracellular expression of sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) mRNA in uterine endometrium with luteal phase deficiency (designated as out-of-phase endometrium or low serum progesterone level). The levels of such mRNAs were measured by the quantitative reverse transcription-polymerase chain reaction. Under the normal serum 17 beta-estradiol and progesterone levels in the mid-luteal phase, the levels of SHBG and CBG mRNAs in the out-of-phase endometria were not significantly different from those in the normal endometria. On the other hand, SHBG and CBG mRNA levels in the endometria of low serum midluteal progesterone level were significantly (p < 0.05) reduced and raised, respectively, compared with normal levels. These findings suggest that the synthesis of endometrial steroid-binding proteins in the out-of-phase endometrium is conserved, as that in the in-phase endometrium, whereas the decreased progesterone level might up-regulate CBG expression with down-regulation of SHBG expression.

Adult↗

PubMed1999

Levels of sex hormone-binding globulin and corticosteroid-binding globulin mRNAs in corpus luteum of human subjects: correlation with serum steroid hormone levels.

To understand regulation of the function of human ovarian corpus luteum by sex steroid-binding proteins, the levels of luteal intracellular sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) mRNAs and serum steroid hormones were simultaneously determined. The expression of SHBG and CBG mRNAs was detected in all samples analyzed. SHBG mRNA level was positively correlated with serum estradiol-17 beta level (p < 0.05), but not with serum progesterone level. There was a positive correlation between SHBG mRNA level and serum estradiol-17 beta/progesterone ratio (p < 0.01). On the other hand, CBG mRNA level was positively correlated with serum estradiol-17 beta and progesterone level (p < 0.01 and p < 0.01, respectively). There was no correlation between CBG mRNA level and serum estradiol-17 beta/progesterone ratio. SHBG and CBG mRNA levels were not correlated with the levels of serum testosterone, free testosterone or cortisol. These findings suggest that the synthesis of luteal SHBG and CBG is complexly regulated by estrogen and progesterone, and that SHBG and CBG interact with estrogen and progesterone, respectively, for luteal steroidal activity.

Adult↗

PubMed1986

Concentrations of sex-hormone binding globulin and corticosteroid binding globulin in serum in relation to cardiovascular risk factors and to 12-year incidence of cardiovascular disease and overall mortality in postmenopausal women.

We determined sex-hormone binding globulin (SHBG) and corticosteroid binding globulin (CBG) by radioimmunoassay of serum samples from a group of 253 women, who were 54 or 60 years old when first studied in 1968-69. The SHBG concentration was highly significantly and inversely related to body mass, body mass index, waist-to-hip circumference ratio, and serum triglyceride concentration; CBG concentration was inversely related to body mass and body mass index. The concentration of neither protein was related to whether or not the subject smoked. Decrease in the concentration of SHBG, but not of CBG, was a significant risk factor for 12-year overall mortality. The plot of the 12-year incidence of myocardial infarction vs SHBG concentration was U-shaped. We recommend that SHBG be included when serum androgens or estrogens are being evaluated as risk factors for cardiovascular disease and death.

Adipose Tissue↗

PubMed1975

Lack of B lymphocyte depletion from murine spleen cell populations by a human gamma-globulin, anti-human gamma-globulin column system.

It has been reported previously that enriched populations of mouse thymus-dependent (T) lymphocytes could be prepared by the use of a column procedure that is believed to remove selectively cells with receptors for antigen-antibody complexes. In our hands, this procedure does not selectively remove B lymphocytes but rather masks the surface immunoglobulin. Analysis of the column-passed cells revealed an apparent decrease in the percentage of immunoglobulin-bearing cells but little decrease in either the percentage of complement receptor lymphocytes or the mitogenic response to lipopolysaccharide. Furthermore, rabbit immunoglobulin could be detected on the surface of 35 to 45% of the cells emerging from the columns prepared with rabbit anti-human gamma-globulin (HGG). After overnight incubation, 30 to 40% of the emerging cells reexpressed mouse immunoglobulin on their surfaces. Adsorption of the antisera used to make the columns with mouse gamma-globulin (MGG) diminished the depleting capacity of the columns. We conclude from these observations that antibodies in the anti-HGG sera, cross-reactive with mouse immunoglobulin, account for the spacious depletion of B lymphocytes observed when cells are passed over these antigen-antibody complex columns.

Animals↗

PubMed1980

Subdermal estradiol pellets following hysterectomy and oophorectomy. Effect upon serum estrone, estradiol, luteinizing hormone, follicle-stimulating hormone, corticosteroid binding globulin-binding capacity, testosterone-estradiol binding globulin-binding capacity, lipids, and hot flushes.

Subderman estradiol (E2) pellets (25 mg) were inserted immediately after hysterectomy and oophorectomy in 22 menstruating women, ages 29 to 50 years. Serum samples were obtained daily for 7 days, weekly for 4 weeks, and at monthly intervals for 6 months. Although there was significant variation between patients, E2 levels remained within the follicular phase range, averaging 50 to 70 pg/ml for 3 months, and then slowly declining to a mean of 37 pg/ml at 6 months, when new pellets were inserted. Over the entire study period, the E2:estrone (E1) ratio was greater than unity. Subdermal E2 pellets limited the rise in luteinzing hormone (LH) and follicle-stimulating hormone (FSH) after gonadectomy and the levels of LH and FSH 6 months after the insertion of E2 pellets were significantly lower (p < 0.01) than in 20 postmenopausal women who had undergone oophorectomy and whose serum E2 levels were less than 20 pg/ml. Serum corticosteroid binding globulin-binding capacity (CBG-BC) and serum testosterone-estradiol binding globulin-binding capacity (TeBG-BC) remained unchanged with E2 pellets. Although high-density lipoprotein-cholesterol increased significantly (p < 0.05), low-density lipoprotein-cholesterol, total cholesterol, and triglycerides were unaffected, except for a rise in triglycerides in three older women with diabetes mellitus and hypertension. There were no complaints of severe hot flushes. Women who had vasomotor symptaoms had mild or moderate flushes that occurred at 5 or 6 months after replacements of the pellets. Thus, E2 pellets are an effective form of parenteral estrogen replacement therapy and offer both practical and theorteical advantages over other forms of estrogen.

Adult↗

PubMed1977

[Influence of combined application of antilymphocyte globulin and plasmatic alpha-globulin fraction on precipitin formation in rabbits (author's transl)].

In the experiments on rabbits immunized with human albumin the effect of combined application of both antilymphocyte globulin (ALG) and plasmatic alpha-globulin fraction (agf) on antibody formation was studied. The course of immune response had been compared to groups administered the above preparation alone, and to controls which had been applied saline. It was found that both ALG alone and AGF were capable to a certain extent of suppressing precipitin formation; a pronounced suppression appeared following the combined effect of both drugs. A strong suppression, however, was likewise attained when a high dose of AGF alone was applied. These findings are discussed in association with other statements that under given experimental conditions the combined application of both drugs, besides the immunosuppressive effect on the formation of antibodies against the antigen used (albumin) showed also an adverse side effect. The latter resulted in a considerably increased level of antibodies against ALG as compared to the group receiving ALG only. The authors point out the necessity of a further follow-up this interesting experience and, unless a more feasible pattern is found which would eliminate the side effects, warn against eventual clinical use of this drug combination under study.

Alpha-Globulins↗

PubMed2000

The cost of treating immune thrombocytopenic purpura using intravenous Rh immune globulin versus intravenous immune globulin.

Multiple factors, including efficacy, toxicity and cost, may influence the decision to treat immune thrombocytopenic purpura (ITP) with intravenous immune globulin (IVIG) or intravenous Rho (D) immune globulin (IV RhIG). We conducted a survey of 50 hospitals in 31 states to determine the costs for treating ITP using conventional doses for IVIG or IV RhIG, based on package insert recommendations. The average cost for a dose of IVIG ($2,771) was 71.7% ($1,157) more than that for a dose of IV RhIG ($1,614). In the absence of clearly defined differences in clinical outcomes when treating ITP with IVIG or IV RhIG, the difference in cost may be an important factor in selecting the treatment.

Data Collection↗

PubMed1983

The interaction of immune serum globulin and immune globulin intravenous with complement.

The in vitro anticomplementary activity of untreated and heat-aggregated (63 degrees C, 10 min) immune serum globulin (ISG) and immune globulin intravenous (IGIV) prepared by partial reduction and alkylation have been evaluated by three assays, C3 activation, binding to C1q and enhancement of alternative pathway lysis of rabbit erythrocytes. Crossed immunoelectrophoresis was used to quantitatively measure the ability of ISG and IGIV to activate endogenous C3 in normal serum. Binding to C1q was determined according to the ability to inhibit binding of 125I-C1q to solid phase IgG. ISG and IGIV enhancement of lysis of rabbit erythrocytes by normal human serum adsorbed with rabbit erythrocytes in the presence of MgEGTA was used to determine activity in the alternative complement pathway. Unheated IGIV at 10 mg/ml only marginally activated endogenous C3 in normal serum, had about a 5-fold lower affinity for 125I-C1q (Ki = 138 to 356 microM vs Ki = 62.5 microM for ISG), but was very similar in ability to ISG on a weight basis in enhancing complement alternative pathway activity (RCH50 = 0.23 to 0.40 mg for IGIV vs 0.17 mg for ISG). Heat-aggregated IGIV at 5 mg/ml in normal human serum was about 2-fold less effective than heat-aggregated ISG in the activation of C3 in normal serum and had approximately 2- to 3-fold lower affinity in the C1q binding assay (Ki = 45 to 83 nM for heat-aggregated IGIV vs Ki = 14.6 nM for heat-aggregated ISG). These data suggest that IGIV prepared by chemical modification retains sufficient specific receptor activity to allow in vivo efficacy in complement-mediated amplification of host defense reactions, but is safe for intravenous use due to a lower capacity to initiate nonspecific complement activation.

Complement Activating Enzymes↗

PubMed1984

Comparison of varicella zoster antibody titers in patients given intravenous immune serum globulin or varicella zoster immune globulin.

We compared the VZV IgG antibody titers after administration of varicella zoster immune globulin and serum immune globulin intravenously (IGIV) in VZV seronegative pediatric patients with cancer. Four patients received VZIG at standard doses; four received IGIV at 4 ml/kg every 4 weeks for four doses; and five received IGIV at 6 ml/kg every 6 weeks for two to four doses. VZV antibody titers were measured by radiommunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), indirect fluorescent antibody assay (IFA), and neutralizing antibody assay. The mean peak and trough VZV titers by RIA were comparable in all three groups: 1:724 at 4 weeks after VZIG, 1:2048 at 4 weeks after 4 ml/kg IGIV, and 1:776 at 6 weeks after 6 ml/kg IGIV. The titers measured by ELISA, IFA, and neutralizing antibody were comparable after VZIG or IGIV. The VZV titers by RIA were maintained at greater than or equal to 1:1024 after subsequent doses of 4 ml/kg IGIV, and at greater than or equal to 1:256 after subsequent doses of 6 ml/kg IGIV. Adverse effects were rare. The VZV antibody titers assessed 4 to 6 weeks after IGIV administration were equivalent to the titers measured 4 weeks after administration of VZIG.

Adolescent↗

PubMed1996

Cadaveric kidney transplantation under prophylactic polyclonal antibody immunosuppression with anti-lymphoblast globulin versus anti-thymocyte globulin.

OBJECTIVES: This retrospective study was undertaken to evaluate and compare the clinical and immunologic outcomes following prophylactic induction treatment with Minnesota anti-lymphoblast globulin (MALG) and Upjohn anti-thymocyte globulin (ATGAM) in cadaver renal transplantation. METHODS: From 1990 to 1994, 63 patients with renal transplants from cadavers received MALG and 77 patients received ATGAM for induction treatment. Most pretransplant parameters were equivalent in both groups. There was no significant difference in the total dose and mean duration of MALG/ATGAM administration. The post-transplant outcome in these groups was compared. RESULTS: There was no difference between the MALG and ATGAM groups with respect to the overall number of rejection episodes, median days to rejection, or the number of steroid-resistant rejection episodes. However, MALG-treated patients experienced a greater number of rejections in the first 60 days postoperatively (P = 0.06). There was no difference in the nadir serum creatinine level in the first 20 postoperative days in the two groups; however, it took fewer days to reach the nadir in the ATGAM group (P = 0.03). The incidence of delayed graft function was higher in the MALG group than in the ATGAM group (38% versus 31%) but not statistically significant. Graft survival at 12 and 24 months was comparable in both groups. However, patient survival was superior at 12 and 24 months in ATGAM-treated transplant recipients (P = 0.03). The mean serum creatinine at 6, 12, and 24 months was similar in both the MALG and ATGAM groups. The mean fall and recovery of CD3, CD4, and CD8 T-lymphocyte subsets while on MALG/ATGAM were similar in both groups. The incidence of infectious complications was greater in the MALG group. CONCLUSIONS: MALG and ATGAM have comparable clinical immunosuppressive effects. Patients receiving ATGAM experienced fewer rejections in the first 2 months, fewer infections, and better survival.

Antilymphocyte Serum↗

PubMed2004

A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes.

Immunosuppression has recently been proposed for low-risk myelodysplastic syndromes (MDS) to reverse bone marrow failure by inhibiting intramedullary secretion of proapoptotic cytokines. We treated 35 MDS patients (24 refractory anaemia (RA), 10 RA with excess blasts and one chronic myelomonocytic leukaemia) with either horse antithymocyte globulin 15 mg/kg/day or rabbit antithymocyte globulin 3.75 mg/kg/day, each for 5 days. Median age was 63 years (range: 41-75). After 1 to 34+ months of follow-up (mean: 15+), four patients experienced complete haematological responses (CR), six good responses (GR) and two minor responses. All CRs and GRs occurred in patients with RA, in whom both horse and rabbit ATG yielded five responses out of 12 (42%). Time to response varied between 1 and 10 (mean: 3) months. The median duration of response was 9+ (1-17+) months; five patients are in continuing response. In all, 23 patients suffered side effects > degrees II WHO (the degree of toxicity encountered according to the internationally accepted WHO toxicity grading); one patient died 2 weeks after rabbit ATG from rhinocerebral mucormycosis. Parameters that correlated with response were duration of disease and RA subgroup. In our experience, immune-modulating therapy with either horse or rabbit ATG is feasible in patients with RA and short duration of disease.

Adult↗

PubMed1992

Anti-tetanus toxoid antibodies in intravenous gamma globulin: an alternative to tetanus immune globulin.

The levels of anti-tetanus toxoid IgG antibodies were measured in 29 lots of intravenous gamma globulin (IVIG). The antibody levels varied from 4 to 90 IU/mL (geometric mean, 18.6; 90% confidence interval, 9.7-35.7). The variation from manufacturer to manufacturer accounted for most of the observed differences among lots; there was relatively little variability among multiple lots from a single manufacturer. IVIG may be an acceptable alternative to horse or human tetanus immune globulin.

Antibodies, Bacterial↗

PubMed1991

Characterization of the 12S globulin complex of Brassica napus. Evolutionary relationship to other 11-12S storage globulins.

Cruciferin (12S globulin) is the major seed protein in Brassica napus (oil seed rape). It is synthesized during seed development and consists of six subunit pairs. Each of these pairs is synthesized as a precursor containing one alpha and one beta chain. At least three different precursors exist (P1-3), giving rise to four different mature subunits (cru1-4). Several cruciferin clones were isolated from a seed mRNA cDNA library. Comparison of the deduced amino acid sequences of these clones to amino acid sequences of purified cruciferin chains and peptides identified them as coding for cru2/3 and cru4 subunits. From the amino acid sequences deduced from two overlapping cDNA clones, the precursor of the cru4 subunit was shown to consist of 465 amino acid residues. Comparison of cruciferin and cruciferin-related sequences from B. napus and Arabidopsis thaliana, respectively, suggested that early during evolution the Brassicaceae family only possessed two types of 11-12S globulin genes, like the present-day Fabaceae.

Allergens↗

PubMed1989

Studies on the role of glycosylation for human corticosteroid-binding globulin: comparison with that for thyroxine-binding globulin.

The role of glycosylation on the secretion and the stability of human corticosteroid binding globulin (CBG) was studied. Cells of the human hepatoma line were labeled by [35S]methionine in presence of or absence of tunicamycin (TM). Media or cells were harvested at 0, 3, 6, and 20 h after the addition of excess unlabeled methionine. Media and cell lysates were incubated with anti-CBG serum and immune complexes were precipitated with Staphylococcus aureus protein A (Pansorbin). Immunoprecipitates were analyzed by fluorography after sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Immunoprecipitation of T4-binding globulin (TBG) was also carried out with anti-TBG serum. Fluorographic analysis revealed three forms of CBG: CBG1, a glycosylated, mature, and secretory form with apparent mol wt of 70 K; CBG2, a glycosylated precursor which due to incomplete carbohydrate processing has an apparent mol wt of 54 K; and CBG3, a nonglycosylated form consisting of the 40 K core protein. In absence of TM, CBG1 was observed in media and CBG2 was detected in cell lysates. The proportion of CBG1 increased during the chase, whereas that of CBG2 decreased, indicating that CBG was secreted after processing of the oligosaccharides on CBG2. In presence of TM, CBG3 was found both in media and cell lysates. The sum of CBG3 in the medium and the cell lysate decreased during the chase, whereas that of CBG1 and CBG2 remained unchanged. Similar to CBG, TBG1 (mature form, 60 K) and TBG2 (partially processed glycosylated form, 54 K) were observed in media and cell lysates, respectively, in absence of TM. However, TBG3 (nonglycosylated, 44 K) was not detected in medium. These results indicate that glycosylation is not a key factor for the secretion of CBG but is important for its stability. On the other hand the glycosylation is indispensable for the secretion of TBG.

Cell Line↗