Biomedical subjects

B C Nisula

Publications and source records attributed to B C Nisula.

At least 19 recordsLinked to original sources

PubMed1995

A potential novel mechanism for precocious puberty in juvenile hypothyroidism.

Some children with juvenile hypothyroidism exhibit unexplained precocious puberty. Interaction of TSH with the human FSH receptor (hFSH-R) is a possible pathophysiological mechanism for this syndrome that has not been explored due to the lack of hFSH-free TSH preparations and the scarcity of a suitable hFSH-R-based assay system. To devise an in vitro FSH bioassay suitable for exploring this mechanism, we expressed hFSH-R complementary DNA in COS-7 cells and stimulated them with recombinant hTSH (rec-hTSH). Rec-hTSH elicited a dose-dependent cAMP response in the in vitro hFSH-R bioassay; however, the concentration of rec-hTSH required for half-maximal stimulation was several logs greater than that of hFSH. Rec-hTSH acted as a competitive inhibitor of hFSH at the hFSH-R, indicating that hTSH and hFSH are acting through the same receptor, namely the hFSH-R. This provides a potential novel mechanism for the precocious puberty of juvenile hypothyroidism.

Biological Assay↗

PubMed1994

Site-directed mutagenesis defines the individual roles of the glycosylation sites on follicle-stimulating hormone.

To determine the specific role of each follicle-stimulating hormone (FSH) oligosaccharide, we mutated Asn to Gln at each glycosylation site (alpha Gln52, alpha Gln78, alpha Gln52-78, beta Gln7, beta Gln24, and beta Gln7-24) to selectively inhibit oligosaccharide attachment. For wild-type and mutant FSH, we determined the binding affinity to homogenized rat Sertoli cells and the signal-transducing activity in cultured rat granulosa cells. The binding affinity of FSH lacking any one of the oligosaccharides was increased over wild-type FSH, while the signal-transducing activity of FSH lacking the oligosaccharide at alpha Asn52 (alpha Gln52 FSH) was markedly reduced, and that of FSH lacking either beta oligosaccharide (beta Gln7 and beta Gln24 FSH) was slightly reduced. At each FSH beta glycosylation site, we made a second amino acid substitution to inhibit glycosylation (beta Tyr9 and beta Tyr26) and an amino acid substitution that preserved glycosylation (beta Ser9 and beta Ser26). The amino acid sequence of the second beta subunit glycosylation site was important for signal transduction, regardless of the presence or absence of the oligosaccharide. Thus, while each FSH oligosaccharide has a similar impact on binding affinity, the alpha 52 oligosaccharide has a disproportionate role in signal transduction, and the amino acid sequence at beta Asn24 functions in both binding and signal transduction.

Amino Acid Sequence↗

PubMed1994

Modulation of the expression of murine lupus by gonadotropin-releasing hormone analogs.

Recent studies have suggested that hypothalamic and pituitary hormones may directly influence the immune system. One such hormone with immunomodulatory properties is GnRH. We hypothesized that GnRH and/or the gonadotropins might alter the severity of autoimmune disease through mechanisms distinct from their effects on gonadal hormones. This possibility was tested in a murine model of lupus. We assessed disease severity over time in intact and castrated, male and female, lupus-prone (SWR x NZB) F1 hybrid mice during treatment with GnRH agonist, GnRH antagonist, or vehicle. Compared to vehicle administration, GnRH antagonist administration significantly decreased total serum immunoglobulin G and anti-DNA antibodies in castrated male and female mice and significantly improved survival. In contrast, GnRH agonist administration exerted reciprocal effects in castrated mice, leading to early increases in serum anti-DNA and total immunoglobulin G levels. We conclude that GnRH and/or the gonadotropins can modify the expression of murine lupus independently of their regulation of gonadal steroid secretion.

Animals↗

PubMed1994

Human chorionic gonadotropin stimulates thyroid hormone secretion, iodide uptake, organification, and adenosine 3',5'-monophosphate formation in cultured human thyrocytes.

Despite extensive studies, the issue of whether hCG possesses intrinsic thyrotropic activity remains unresolved. This is mainly because in the experimental systems used so far, the parameters measured did not include the thyroid-specific functions of iodine organification and the hormonal end-point response, T3 secretion, and cells of nonhuman origin were employed, constituting a major drawback in view of the wide variation in sensitivity of thyroid responsiveness to hCG in different species. We investigated the thyrotropic activity of hCG, using for this purpose a novel homologous assay system consisting of human thyroid follicles cultured suspended in collagen gel in serum-free medium. Under these conditions, the cells are organized as follicular three-dimensional structures with normal polarity, enabling enhanced responsiveness to hormonal stimulation. The parameters measured were the thyroid-specific functions of iodide uptake, organification, and T3 secretion, as well as formation of the second messenger, cAMP. Purified hCG (biological potency, 21,700 IU/mg; with no detectable TSH by immunoradiometric TSH assay) did indeed exhibit thyroid stimulatory activity. At doses ranging from 10-400 mg/L, hCG induced a dose-dependent increase in the parameters measured. The rise from basal to maximal levels achieved after hCG stimulation was 1.3 to 3.6 pmol/well for cAMP formation, 34 to 21,408 cpm/well for iodide uptake, 261 to 20,167 cpm/well for iodide organification, and 40 to 927 fmol/well for T3 secretion. Maximal levels elicited by hCG (200 mg/L) relative to maximal values achieved with bovine TSH were 49%, 56%, and 42% for iodide uptake, organification, and T3 secretion, respectively, and only 5% for cAMP. Iodide uptake proved to be the most sensitive indicator of the thyrotropic activity of hCG, with increases occurring at a concentration of 10 mg/L. Acting as a partial agonist, hCG was also capable of dose-dependently inhibiting TSH-stimulated cAMP formation. The free alpha- and beta- subunits of hCG, at doses as high as 200 mg/L, had no thyroid-stimulating effect. The present data thus clearly demonstrate that hCG is a human thyroid stimulator. Moreover, hCG managed to elicit substantial biological cell responses in human thyrocytes while evoking minimal amounts of cAMP, illustrating the concept of cAMP superfluity and highlighting the potential pitfalls of using cAMP as a reliable measure of hormonal bioactivity.

Cells, Cultured↗

PubMed1994

Increased biological activity due to basic isoforms in recombinant human follicle-stimulating hormone produced in a human cell line.

FSH has four asparagine-linked oligosaccharides with variable sialic acid contents, so that FSH is not a single molecule, but a heterogeneous group of isoforms. These isoforms differ in their biological properties and their distribution changes in various physiological states, allowing the modulation of FSH activity. Recombinant human (h) FSH has been produced in Chinese hamster ovary cells and has an isoform profile similar to those of both pituitary FSH standard and purified urinary FSH. These FSH preparations, however, do not contain the full spectrum of FSH isoforms found in the circulation. Production of recombinant hFSH in a cell line with a different pattern of glycosylation could broaden its isoform profile and potentially alter its biological activity. Thus, we transfected human embryonal kidney cells (293) with the human alpha and FSH beta genes to produce recombinant hFSH (hFSH-293) and determined its biological activity in a rat granulosa cell bioassay. Although hFSH-293 was immunologically indistinguishable from pituitary FSH standard, its biological potency was 3- to 6-fold higher than those of two different pituitary FSH standards. To investigate this increased potency, we separated the isoforms of hFSH-293 by chromatofocusing and determined their biological potencies in the rat granulosa cell bioassay. The isoform profile of hFSH-293 demonstrated a greater number of basic isoforms than that of pituitary FSH standard. Several of these basic isoforms exhibited enhanced in vitro biological potency, accounting for the increased biological potency of hFSH-293. This pattern of high in vitro biological activity and more basic isoforms is analogous to the FSH circulating during GnRH stimulation, pubertal induction, and ovulation.

Animals↗

PubMed1993

Oral gossypol in the treatment of metastatic adrenal cancer.

Medical treatment of metastatic adrenal cancer is largely unsuccessful and has considerable toxicity. We previously demonstrated the activity of the plant toxin gossypol against human adrenal cancers in nude mice. We therefore examined the efficacy and toxicity of oral gossypol as a treatment for adrenal cancer in humans. Twenty-one patients with metastatic adrenal cancer received oral gossypol at doses of 30-70 mg/day. Patients were monitored for side effects of gossypol, changes in hormone secretion, and tumor response. Eighteen patients completed at least 6 weeks of gossypol treatment. Three of these patients, whose tumors were refractory to other chemotherapeutic agents, had partial tumor responses (> or = 50% decrease in tumor volume) that lasted from several months to over 1 yr. One patient had a minor response followed by resection of her remaining disease, 1 patient had stable disease, and 13 patients had disease progression. Three patients died of their disease without receiving sufficient gossypol to achieve detectable drug levels, and were eliminated from the final analysis. The side effects of gossypol were generally well tolerated; the only serious side effect was abdominal ileus that resolved when the drug was temporarily withheld and restarted at a lower dose. We conclude that oral gossypol can be used relatively safely on an outpatient basis for the treatment of metastatic adrenal cancer. The response rate is similar to the other agents currently available for adrenal cancer, and responses were seen in patients who had failed other chemotherapeutic regimens. This study provides the first indication that gossypol may have activity against cancer in humans, suggesting the need for further investigation of gossypol as an antitumor agent.

Adolescent↗

PubMed1993

Measurement of human chorion gonadotropin by biological methods.

The clinically significant biological activities of hCG result from its interaction with LH and TSH receptors. In vivo bioassays for measurement of these hCG activities have many disadvantages including complexity, expense, labor-intensity, and insensitivity. In vitro bioassays based on animal Leydig cell responses are widely used in research studies, but since they are based on animal receptors, their relevance to human biology remains uncertain. Visible on the horizon are in vitro bioassays constructed with human receptor genes transfected into cell systems by modern molecular techniques.

Animals↗

PubMed1992

Nocturnal thyrotropin surge in growth hormone-deficient children.

Because some patients with growth hormone (GH) deficiency are found to be hypothyroid after initiation of treatment with GH, we assessed the predictive value of the nocturnal thyrotropin surge (a sensitive test for central hypothyroidism) in 56 untreated GH-deficient children and adolescents. Eighteen patients had a subnormal thyrotropin surge (mean 18% (range -30% to 46%)), significantly less than that of 96 normal control subjects (mean 124%; 95% confidence limits, 47% to 300%; p less than 0.01); 13 of the 18 had a subnormal total thyroxine (T4) level or a subnormal free T4 level, or both. These 18 patients were given thyroid hormone replacement therapy; GH deficiency was confirmed during treatment with thyroxine. Of the remaining 38 patients, who had no initial evidence of dysfunction of the hypothalamic-pituitary-thyroid axis, 23 were re-examined while they were receiving GH treatment. Hypothyroidism developed in none of those 23 children during GH therapy. The nocturnal thyrotropin surge test and determination of iodothyronine levels were repeated in 14 of these euthyroid patients. There was no significant change in mean thyrotropin surge (129% (range +49% to +300) vs 125% (range +51% to +222%)), mean serum level of total T4 (111 +/- 4 vs 103 +/- 3 nmol/L), mean serum level of free T4 (19 +/- 0.7 vs 18 +/- 0.8 pmol/L), mean serum level of triiodothyronine (2.5 +/- 0.1 vs 2.5 +/- 0.1 nmol/L), or mean serum level of thyrotropin (2.9 +/- 0.3 vs 2.9 +/- 0.5 mU/L (mean +/- SEM)). We conclude that GH treatment does not appreciably alter thyroid function in GH-deficient patients who have no evidence of thyroid axis dysfunction before GH treatment.

Adolescent↗

PubMed1992

Glycosylation changes in human chorionic gonadotropin and free alpha subunit as gestation progresses.

Carbohydrate is important to the structure, function, and circulatory survival of the glycoprotein hormones. Human CG (hCG) and the related free alpha-molecule of pregnancy contain four and two asparagine-linked oligosaccharides, respectively. The present study analyzes changes in the glycosylation patterns of hCG and free alpha in early vs. late gestation. Five volunteers provided 24-h urine samples, weekly, throughout their pregnancies. Extracts of early pregnancy (weeks 7-12) and late pregnancy (weeks 28-32) urines were pooled. Early and late samples from each patient were subjected to gel filtration to separate hCG and free alpha, and the populations thus obtained were analyzed by lectin affinity chromatography on Concanavalin A-Sepharose (Con A) and Lens culinaris-agarose (Lch). Using Con A, free alpha and hCG were separated into an unbound fraction (eluted with Con A buffer), a weakly bound fraction (eluted with 10 mmol alpha-methyl-D-glucoside) and a tightly bound fraction (eluted with 500 mmol alpha-methyl-D-mannoside). For free alpha-molecule, a significant decrease in tightly bound Con A forms, was noted from early to late pregnancy with a mean difference of 17.0 +/- 2.4% (P less than 0.01). Concomitantly, in late pregnancy, an increase in Con A unbound forms of free alpha was noted with mean difference of 12.5 +/- 1.7% (P less than 0.01). These changes indicate the presence of more highly branched oligosaccharides on free alpha as gestation advances. No changes were noted in the Con A binding of intact hCG; nearly all hCG bound in both early and late pregnancy. Using Lch, free alpha and hCG were separated into an unbound fraction (eluted with Lch buffer) and a bound fraction (eluted with 500 mmol alpha-methyl-D-mannose). Both free alpha and intact hCG in late pregnancy exhibited increased binding to Lch, with mean differences from early to late pregnancy of 30.2 +/- 4.8% (P less than 0.01) and 11.4 +/- 4.5% (P less than 0.05), respectively. These data indicate increased incorporation of fucose into the carbohydrate moieties in late pregnancy. Taken together, these data derived by analysis using lectin specificity imply the presence of more highly branched, fucosylated oligosaccharides as gestation progresses.

Chorionic Gonadotropin↗

PubMed1991

Uptake of erythrocyte-associated component of blood testosterone and corticosterone to rat brain.

To study transport of steroids by erythrocytes, the tissue uptake of erythrocyte-associated testosterone and corticosterone was studied in vivo using a single injection technique into the carotid artery of rats. A brain uptake index (BUI) was calculated by dividing the ratio of [3H]steroid to [14C]butanol (internal reference) in the brain tissue by that in the injection material, and multiplying by 100%. BUIs of testosterone and corticosterone in an erythrocyte suspension were 131 +/- 3% (mean +/- SE, n = 6) and 57.0 +/- 2.7% (n = 6), respectively, which were greater than those in buffer (100 +/- 4%; n = 4, P less than 0.01 and 39.8 +/- 4.6%; n = 4, P less than 0.01, respectively). The erythrocyte accounted for 83.9% and 76.7% of the total testosterone and corticosterone delivered to the tissues, respectively, when calculated on the assumption that the BUIs of steroid in buffer and in the supernatant of an erythrocyte suspension are the same. BUIs of corticosterone in hemolysate and in a suspension of erythrocyte plasma membranes (60.8 +/- 7.0%; n = 4 and 69.5 +/- 3.7%; n = 4, respectively) were also greater than those in buffer (P less than 0.05 and P less than 0.01, respectively). Our results suggest that the erythrocyte-associated component of testosterone and corticosterone are delivered to the tissue of rat brain, and that their membranes may play a major role in their capacity to transport steroids to the tissues.

Animals↗

PubMed1991

Subtle primary hypothyroidism in patients treated for acute lymphoblastic leukemia.

We evaluated serum thyroid hormone and thyroid antibody levels, the serum TSH response to TRH, and the circadian pattern of serum TSH in 10 children and adolescents after radiation therapy for acute lymphoblastic leukemia. Four patients had received central nervous system preventive cranial irradiation and intrathecal chemotherapy, and the remaining 6 patients were treated with craniospinal irradiation for central nervous system relapse. Serum total T4 and T3 concentrations were within the normal range and thyroid antibodies were negative in all patients. Four patients who had received craniospinal irradiation had low free T4 levels. Prior to TRH administration, the overall mean serum TSH concentration was 5.4 +/- 1.3 mU/l, and the mean peak response to TRH was 33 +/- 6.5 mU/l. Both were significantly increased when compared to the levels observed in our control population (p less than 0.05 and less than 0.025, respectively). The overall mean nadir diurnal TSH was 3.6 +/- 0.8 mU/l, and the mean peak nocturnal TSH was 6.9 +/- 1.3 mU/l, both significantly elevated when compared to normal children (p less than 0.025). The mean nocturnal TSH surge, however, was not significantly different from normal. Four of 6 children treated with craniospinal irradiation, and one of four children treated with cranial irradiation had increased basal and peak serum TSH concentrations in response to TRH. One of the patients treated with cranial irradiation had an abnormal nocturnal TSH surge. We conclude that subtle primary hypothyroidism is relatively common in patients with acute lymphoblastic leukemia, particularly in those who have been treated with craniospinal irradiation.

Adolescent↗

PubMed1990

The binding properties of pyrethroids to human skin fibroblast androgen receptors and to sex hormone binding globulin.

The pyrethroids are a class of natural and synthetic pesticides which were associated with an epidemic of gynecomastia in Haitian men in 1981. In the present study we tested several pyrethroids for their ability to interact with androgen binding sites in dispersed, intact human genital skin fibroblasts and in human plasma to sex hormone binding globulin (SHBG). All the pyrethroids tested inhibited fibroblast binding of [3H]methyltrienolone (R1881) at 22 degrees C with the following rank order of potency:pyrethrins greater than bioallethrin greater than fenvalerate greater than fenothrin greater than fluvalinate greater than permethrin greater than resmethrin. 50% displacement of [3H]R1881 binding to fibroblast androgen receptors was achieved by 1.5-44 x 10(-5) M concentrations of the competitors, respectively. Previous studies with cimetidine, a known inhibitor of androgen receptor binding, showed 50% competition at a concentration of 1.4 x 10(-4) M in this system. Scatchard analysis of binding experiments performed with increasing concentrations of [3H]R1881 in the presence of the pyrethroids indicated that the binding inhibition was competitive. On the other hand, of the pyrethroids examined only the pyrethrins (50% inhibition) and bioallethrin (43% inhibition) were able to displace [3H]testosterone from SHBG when tested at a concentration of 10(-4) M. These data indicate that a novel class of non-steroidal compounds, the pyrethroids, can interact competitively with human androgen receptors and SHBG. These findings provide a mechanism by which chronic exposure of humans or animals to pesticides containing these compounds may result in disturbances in endocrine effects relating to androgen action.

Fibroblasts↗

PubMed1990

Disparity between beta-core levels in pregnancy urine and serum: implications for the origin of urinary beta-core.

We used a highly purified preparation of the naturally occurring core fragment of hCG beta (beta-core) and a new RIA for beta-core to investigate the concentrations and behavior of beta-core in serum and urine. We collected serum and 24-h urine specimens from healthy pregnant women during the first trimester of pregnancy. The concentrations of beta-core in serum were determined by analysis of fractions eluted from Sephadex G-100. Serum concentrations of beta-core immunoreactivity were very low (0.13-1.25 micrograms/L), while large amounts of beta-core were excreted in urine during pregnancy (as much as 4-5 mg/day). Interference with measurement by serum factors did not account for the low levels of beta-core immunoreactivity in pregnancy serum. Based on the known urinary clearance rate of beta-core in healthy nonpregnant subjects, we calculated that urinary clearance of serum beta-core accounts for only about 1% of the beta-core in pregnancy urine. We conclude that during pregnancy, the concentrations of beta-core in plasma are measurable, but extremely low, and that most of the beta-core in urine is derived by mechanisms other than urinary clearance of serum beta-core; most likely, these mechanisms involve nephrogenous production of beta-core from precursor molecules such as hCG and hCG beta.

Chorionic Gonadotropin↗

PubMed1990

Hypothyroidism and deficiency of the nocturnal thyrotropin surge in children with hypothalamic-pituitary disorders.

The circadian pattern of serum TSH in normal children, aged 5-18 yr, is characterized by a nocturnal surge and is presumably related in some way to a biological clock within the central nervous system. To look for patients deficient in the nocturnal TSH surge, we studied 52 children with hypothalamic-pituitary disorders. Thirteen of the children were hypothyroid, as judged by subnormal serum free T4 (FT4). The hypothyroid patients had a mean nocturnal TSH surge of 22% (range, -30% to +114%), significantly less than that of normal controls (mean, 124%; 95% confidence limits, 47-300%; n = 96; P less than 0.01). Only 1 of the hypothyroid children had a value for the nocturnal TSH surge (114%) that was within the normal range. Nineteen of the 52 patients with hypothalamic-pituitary disorders had subnormal nocturnal TSH surges; their mean iodothyronine values were significantly less than those of the 33 patients with normal surges [total T4, 73 +/- 4 (mean +/- SE) vs. 109 +/- 3 nmol/L (P less than 0.01); FT4, 13 +/- 1.0 vs. 19 +/- 0.5 pmol/L (P less than 0.01)]. These data demonstrate a clear association of a deficient nocturnal TSH surge and low iodothyronine concentration in children with hypothalamic-pituitary disorders. We performed both TRH tests and nocturnal TSH surge tests in 11 of the children with central hypothyroidism; TRH was abnormal in only 2, while the nocturnal surge test was abnormal in 10 of the 11. We suggest that the nocturnal surge of TSH is important for maintenance of thyroid function and conclude that the nocturnal TSH surge is a much more sensitive test than the TSH response to TRH for the diagnosis of central hypothyroidism.

Adolescent↗

PubMed1990

Thyroid abnormalities in the McCune-Albright syndrome: ultrasonography and hormonal studies.

Hyperthyroidism and goiter have been reported frequently in association with the McCune-Albright syndrome (MAS). To assess the prevalence and extent of thyroid abnormalities in girls with MAS, we studied 19 patients [mean age, 6.6 +/- 1 (+/- SE) yr; mean bone age, 9.5 +/- 1 yr] and 18 normal control girls (mean age, 10.3 +/- 0.5 yr). All patients appeared euthyroid when examined; 1 was taking antithyroid medication. Ultrasonography revealed thyroid abnormalities in 7 patients, including generalized inhomogeneity, small (2-4 mm) and large (greater than 10 mm) hypoechoic regions, and echogenic nodule-like regions. Repeat ultrasonography after intervals of 9-18 months showed enlargement of large hypoechoic regions in 2 patients. In the patients with abnormal ultrasound findings, serum TSH was uniformly low or suppressed both at baseline and after administration of 7 micrograms/kg TRH. The mean serum T3 level in this group was significantly higher than that in controls (2.9 +/- 0.2 vs. 2.3 +/- 0.1 nmol/L; P less than 0.05), whereas mean serum T4, free T4, and T4-binding globulin levels did not differ from those of controls. In the remaining 11 patients, thyroid ultrasonography was normal, and the serum levels of T3, T4, free T4, and TSH were normal. Bioassay showed no detectable thyroid-stimulating activity in the plasma of the MAS patients with suppressed TSH levels. None of the patients became overtly thyrotoxic over 3-6 yr of observation, and their serum iodothyronine levels remained stable. We conclude that thyroid dysfunction is common in girls with MAS, but that it may be clinically occult and not rapidly progressive. The thyroid dysfunction, like that of the ovaries, is associated with structural abnormalities in the gland itself, together with suppressed levels of the respective stimulating hormones.

Adolescent↗

PubMed1990

Human chorionic gonadotrophin-like and beta-core-like materials in postmenopausal urine.

In addition to human chorionic gonadotrophin (hCG), the urine of pregnant women contains a small molecular weight form of the hCG-beta subunit known as beta-core. Human CG-like material has been described in tissues, serum and urine of normal man, particularly in postmenopausal women. We examined different urine preparations from postmenopausal women to determine whether beta-core-like material, as well as hCG-like material, could be detected. We studied an acetone extract of a pool of 11 litres of postmenopausal urine, three different commercial preparations of human menopausal gonadotrophins and two commercial preparations of 'pure' FSH. After Sephadex G-100 chromatography of these various postmenopausal urine extracts, fractions were assayed using four assay systems to detect hCG, beta-core, LH and FSH immunoreactivities. Human CG immunoreactivity was readily detected in all urinary extracts and it eluted in a position indistinguishable from that of purified hCG. In addition to this hCG-like material, all urinary extracts, except the commercial 'pure' FSH preparations, contained material which reacted in the beta-core radioimmunoassay. This beta-core immunoreactive material eluted from Sephadex G-100 in a position corresponding to that of purified pregnancy-derived beta-core. We conclude that the urine of postmenopausal women contains material resembling the beta-core molecule found in pregnancy urine. The origin of this beta-core-like material remains to be determined, and its presence will have an impact on the application of urinary beta-core as a tumour marker.

Chorionic Gonadotropin↗

PubMed1989

Reduced metabolic clearance of acidic variants of human choriogonadotropin from patients with testicular cancer.

We investigated the plasma disappearance of purified urinary human choriogonadotropin (hCG) and acidic variants of hCG (AV-hCG) that are excreted in the urine of patients with testicular cancer to determine if there are differences in their disappearance rates. All cancer patients had relatively increased fractions (10% to 46%) of AV-hCG in their serum when compared with hCG from pregnant control subjects (less than 4% present as AV-hCG). After initiation of therapy in 12 patients with nonseminomatous testicular tumors, the proportion of hCG present as acidic variants in serum rose despite lower serum total hCG concentrations. Samples of highly purified AV-hCG (pI, 3.3 to 4.0) obtained from three patients by concentration from urine and isoelectric focusing were evaluated for their disappearance from serum after injection into rats. All AV-hCG samples had decreased clearance rates when compared with that of highly purified hCG (CR123). These data indicate that acidic forms of hCG have a delayed clearance that contributes to the increased proportion of AV-hCG in the serum of patients with hCG-producing neoplasia after therapy.

Adult↗

PubMed1989

Effect of alcohol on the interaction of cortisol with plasma proteins, glucocorticoid receptors and erythrocytes.

Alcohol ingestion stimulates glucocorticoid secretion in animals and normal men. It is generally believed that this effect is mediated through the pituitary-adrenal axis. To investigate its mechanism, we focussed on the effects of ethanol on cortisol binding to plasma proteins and to glucocorticoid receptors, and on cortisol uptake by erythrocytes. Addition of ethanol (up to 800 mg/dl) decreased cortisol binding to albumin and corticosteroid-binding globulin (CBG), causing an increase in the plasma unbound component. Ethanol also decreased cortisol binding to glucocorticoid receptors in normal human peripheral lymphocytes. The uptake of cortisol by erythrocytes was not affected at ethanol concentrations as high as 2000 mg/dl. These results provide new insight to ethanol effects in vivo. The stimulatory effect of ethanol on the pituitary-adrenal axis appears to be attributable in part to a relative ineffectiveness of cortisol in cortisol-responsive cells consequent to ethanol's ability to diminish cortisol binding to glucocorticoid receptors. A compensatory increase in ACTH secretion in response to the relative hypoglucocorticoid state perceived by corticotrophs would result in maintenance of elevated plasma unbound cortisol and cytosol cortisol levels. We conclude that altered interactions of cortisol with its receptors and transport proteins could be pathophysiological components of the changes in adrenocortical function induced by ethanol ingestion.

Blood Proteins↗