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Biomedical subjects

C M Foster

Publications and source records attributed to C M Foster.

At least 37 records · Page 2Linked to original sources
PubMed1991

Naloxone does not reverse the suppressive effects of testosterone infusion on luteinizing hormone secretion in pubertal boys.

In this study we wished to test whether, and if so when, the suppressive effects of testosterone on LH and, by inference, GnRH secretion are mediated via endogenous opioid pathways during male pubertal maturation. As a preliminary study, we evaluated the acute effects of a 24-h infusion of testosterone (T) in eight pubertal boys with constitutional delay of growth in order to determine the optimal time for administration of naloxone. Eight additional pubertal boys received a saline infusion, followed 1 week later by a similar T infusion starting at 1000 h and lasting for 33 h. After 2 h of infusion (both saline and T), four iv boluses of saline were given hourly, and after 26 h of infusion, four hourly iv boluses of naloxone were given. Blood was obtained every 15 min for LH and every 30 min for T measurements. T infusion increased the mean T concentration by 3.8-fold (P less than 0.001). Mean LH and LH pulse frequency were suppressed (P less than 0.01), and the sleep-associated increase in LH secretion was abolished. Naloxone administration during the infusion of T did not reverse the suppression of LH secretion. Compared to the saline control period, mean LH was significantly lower during T infusion during the time naloxone boluses were given (4.5 +/- 0.9 vs. 5.9 +/- 1.1 IU/L, T infusion and naloxone boluses vs. saline respectively, P less than 0.01). Although the suppression of LH pulse frequency remained significantly lower than that during the saline control period (0.23 +/- 0.04 pulses/boy.h during T infusion and saline boluses; 0.33 +/- 0.04 pulses/boy.h during T infusion plus naloxone boluses; 0.44 +/- 0.06 pulses/boy.h during saline infusion and saline boluses). Naloxone increased mean LH and LH pulse frequency only in the four older, more mature boys during the infusion of saline. Pituitary responsiveness to exogenous GnRH was not altered by infusion of T. We conclude that acute administration of T suppresses LH secretion and, by inference, GnRH secretion at all stages of pubertal maturation in boys. These negative feedback effects, however, cannot be reversed by coadministration of naloxone, even in mid- to late pubertal boys who respond to naloxone with increased pulsatile secretion of LH. These studies suggest that during pubertal maturation in boys, endogenous opioid pathways do not play a major role in the regulation of the negative feedback effects of T.

Adolescent↗
PubMed1990

Differential regulation of serum immunoreactive luteinizing hormone and bioactive follicle-stimulating hormone by testosterone in early pubertal boys.

The microheterogeneity and bioassayable activity of serum FSH (B-FSH) can be regulated by exogenous GnRH in boys with idiopathic hypogonadotropic hypogonadism and by estrogen in a women with gonadal dysgenesis, presumably via hormonally mediated changes in the degree of FSH glycosylation. To test the hypothesis that testosterone (T) regulates the circulating forms of B-FSH, we raised the serum T levels of early pubertal boys to adult levels. In this model, high dose T inhibits the pubertal nocturnal augmentation of LH secretion, apparently through decreased GnRH secretion. This model allowed us to test a second hypothesis, that B-FSH is a sensitive indicator of hypothalamic GnRH release. The boys were studied on two consecutive weekends, during which they received either saline (S) or T infusions. Beginning at noon on the study day, after an overnight acclimatization, the boys received either S or T at 33% or 100% of the adult male production rate. Blood was sampled from 2000-0800 at 10-min intervals for immunoactive LH and FSH (I-FSH) and for B-FSH, as determined by the in vitro Sertoli cell aromatase induction assay, and at 30-min intervals for T. Gonadotropin levels were analyzed as mean hourly or 3-h concentrations and as pulse profiles by two established objective peak detection programs, Cluster and Detect. During S treatment, mean LH increased after the onset of sleep (P = 0.0006) and, after plateauing for several hours, declined to baseline in the early morning hours. Mean levels of B-FSH were also minimally (but significantly) increased after the onset of sleep (P = 0.046) and paralleled the decline noted for LH. Mean levels of I-FSH did not demonstrate a diurnal rhythm. The effect of T was gonadotropin specific. High dose T abolished the nocturnal elevation in mean LH concentrations, but had no effect on the nocturnal elevation of B-FSH (P less than 0.05) or on I-FSH levels. The LH pulse frequency was greatest from 2300-0450 h, during S treatment (P = 0.016). The pulse frequency of B-FSH was also minimally increased after the onset of sleep (P = 0.045). The T infusion abolished the nocturnal increase in LH pulse frequency, without an effect on B-FSH pulse frequency. B-FSH pulse frequency exceeded LH pulse frequency during S treatment (8.0 +/- 0.7 pulses/12 h vs. 5.5 +/- 0.4), and B-FSH pulses persisted throughout the night. The pulse amplitudes of LH and B-FSH were not affected by T.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1989

Nocturnal serum growth hormone concentration is not augmented by short-term testosterone infusion in pubertal boys.

Chronic exposure to testosterone (T) increases growth hormone (GH) secretion. To determine whether acute exposure to T would also enhance GH secretion, we infused saline, followed 1 wk later by T, for 18-24 h at one-third the adult male production rate in 12 pubertal boys and at the adult male production rate in eight additional pubertal boys. Blood was obtained every 20 min for GH and every 30 min for T from 2000-0800 h. Though infusion significantly increased serum T concentrations in all 20 boys, mean GH concentration, GH pulse frequency, and GH pulse amplitude did not increase compared to the saline infusion night. The secretory dynamics of GH as a function of 3-h time blocks from 2000-0800 h were also determined in the eight boys who received the higher dose of T. The profile for mean GH concentration, pulse frequency, pulse amplitude, and peak area were not affected by acute infusion of T at concentrations sufficient to alter LH secretion. This suggests that, at least in pubertal boys, one must be exposed to T for a period longer than 12-18 h to induce increased GH secretion.

Adolescent↗
PubMed1989

Testosterone infusion reduces nocturnal luteinizing hormone pulse frequency in pubertal boys.

Administration of testosterone (T) can inhibit LH secretion in early pubertal boys. However, the GnRH pulse generator is relatively resistant to the effects of T, since T infusion beginning at 2100 h, 3 h before the usual nighttime increase in T, does not suppress the characteristic increase in LH pulse frequency or amplitude associated with the onset of sleep in early pubertal boys. To test the hypothesis that the hypothalamic-pituitary axis must be exposed to T for a longer duration to suppress the nocturnal rise in LH pulse frequency and amplitude, we infused saline or T at one third the adult male production rate (320 nmol/h), beginning at 1200 h on two consecutive weekends in each of eight early to midpubertal boys. Blood was obtained from 2000-0800 h every 10 min for LH and every 30 min for T measurements. T infusion increased the mean plasma T concentration from 6.9 +/- 1.7 to 11.8 +/- 1.4 nmol/L (P less than 0.01) between 2000-0800 h. Despite the T infusion, the nocturnal rise in mean LH concentration and LH pulse frequency persisted, suggesting that the nocturnal amplification of LH, and by inference GnRH, secretion is resistant to the negative feedback effects of T. A higher dose of T, approximating the adult male production rate (960 nmol/h), was given to eight additional boys beginning at 1200 h. The mean T concentration increased from 4.2 +/- 1.7 to 20.8 +/- 3.1 (P less than 0.001) nmol/L between 2000-0800 h. The mean plasma LH concentration was suppressed by T infusion from 5.2 +/- 0.5 to 2.9 +/- 0.4 IU/L, and LH pulse frequency decreased from 0.50 +/- 0.04 to 0.27 +/- 0.11 pulses/boy/h (P less than 0.01). There was no nocturnal amplification of LH secretion, but high amplitude LH pulses did occur during the night in six of the eight boys. The low dose T infusion had no effect on pituitary LH release by exogenous GnRH. With the high dose T infusion, however, the ability of GnRH, at 25 ng/kg but not at 250 ng/kg, to release pituitary LH was amplified. Thus, T supplementation at one third the adult male production rate does not blunt the sleep-associated nighttime rise in LH pulse frequency or LH concentration. T infusion approximating the adult male production rate suppresses the nocturnal increase in LH pulse frequency and mean LH concentration, and high amplitude, slow frequency LH pulses similar to patterns seen in adult men persist.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1988

Growth hormone promoted tyrosyl phosphorylation of growth hormone receptors in murine 3T3-F442A fibroblasts and adipocytes.

Because many growth factor receptors are ligand-activated tyrosine protein kinases, the possibility that growth hormone (GH), a hormone implicated in human growth, promotes tyrosyl phosphorylation of its receptor was investigated. 125I-Labeled human GH was covalently cross-linked to receptors in intact 3T3-F442A fibroblasts, a cell line which differentiates into adipocytes in response to GH. The cross-linked cells were solubilized and passed over a column of phosphotyrosyl binding antibody immobilized on protein A-Sepharose. Immunoadsorbed proteins were eluted with a hapten (p-nitrophenyl phosphate) and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. The eluate from the antibody column contained an Mr 134,000 125I-GH-receptor complex. A similar result was obtained when the adipocyte form of 3T3-F442A cells was used in place of the fibroblast form. O-Phosphotyrosine prevented 125I-GH-receptor complexes from binding to the antibody column, whereas O-phosphoserine and O-phosphothreonine did not. In studies of GH-promoted phosphorylation in 3T3-F442A fibroblasts labeled metabolically with [32P]Pi, GH was shown to stimulate formation of a 32P-labeled protein which bound to immobilized phosphotyrosyl binding antibodies. The molecular weight of 114,000 obtained for this protein is similar to that expected for non-cross-linked GH receptor. The Mr 114,000 phosphorylated protein could be immunoprecipitated with anti-GH antibody, indicating that GH remained noncovalently bound to this protein during absorption to and elution from the immobilized phosphotyrosyl binding antibody. Phosphoamino acid analysis after both limited acid hydrolysis and extensive base hydrolysis of the Mr 114,000 phosphoprotein confirmed the presence of phosphotyrosyl residues.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1988

Effects of human growth hormone on insulin-stimulated glucose metabolism in 3T3-F442A adipocytes.

GH is believed to play a role in promoting insulin resistance in patients with diabetes and with GH excess. The means by which GH produces insulin resistance may be through direct suppression of glucose metabolism in target cells (insulin-independent) or by interfering with the ability of insulin to stimulate glucose metabolism (insulin-dependent). In 3T3-F442A adipocytes, long term incubation (24-72 h) with GH directly inhibits glucose oxidation and lipid synthesis in the absence of insulin. To distinguish the insulin-independent effects of GH on glucose metabolism from the insulin-dependent effects of GH, we examined the effect of GH on insulin-stimulated lipid accumulation in cultured 3T3-F442A adipocytes. Cells were incubated for 48-72 h with GH and then treated with insulin. Insulin stimulated lipid accumulation in GH-pretreated and control cells. Compared to control, GH-treated cells had lower absolute levels of lipid accumulation in the absence of insulin and at each insulin concentration tested. Thus, GH directly suppresses basal lipid accumulation and lowers the response to insulin. In addition, a 10 times higher insulin concentration was required to reach maximum stimulation of lipid accumulation in GH-treated cells (50 ng/ml) than in control cells (5 ng/ml). When cells were exposed simultaneously to insulin and GH for 72 h, GH treatment inhibited the ability of insulin to stimulate lipid accumulation, and the degree of suppression by GH was related to the GH concentration present. These observations suggest that GH suppresses glucose metabolism not only in the absence but also in the presence of insulin. Since short term (4-h) incubation with GH increases glucose metabolism transiently in GH-deficient preparations, we also examined the influence of short term incubation with GH on insulin responses. Cells were incubated for 4 h with varying concentrations of insulin in the simultaneous presence or absence of GH. Insulin stimulated the conversion of glucose to lipid when tested alone or in the presence of GH. Short term exposure to GH alone also stimulated glucose metabolism. The stimulation of lipid accumulation at insulin concentrations less than 5 ng/ml was greater with GH, but responses were comparable above 5 ng/ml insulin. The ability of insulin to bind to its receptor was not affected by prior treatment with GH for either short or prolonged time periods.(ABSTRACT TRUNCATED AT 400 WORDS)

Adipose Tissue↗
PubMed1988

Increased luteinizing hormone pulse frequency during sleep in early to midpubertal boys: effects of testosterone infusion.

Gonadotropin secretion is pulsatile in prepubertal and early pubertal boys, and the onset of puberty is characterized by a sleep-associated rise in LH pulse amplitude. To determine whether an augmentation in LH pulse frequency as well as amplitude occurs at the onset of puberty, we studied gonadotropin secretion in 21 early to midpubertal boys. Blood samples were taken every 20 min (every 15 min in 4 boys) for LH determinations. A 2-fold increase in LH pulse frequency occurred during the nighttime sampling period (2200-0400 h) compared to that in the hours when the boys were awake (1000-2200 h). The maximum frequency (0.7 pulses/h) occurred between 2400 and 0200 h. The mean plasma LH concentration increased during the night from 2.3 +/- 0.2 (+/- SE) mIU/mL (2.3 +/- 0.2 IU/L) between 2000-2200 h to a maximum of 6.2 +/- 0.4 (6.2 +/- 0.4 IU/L) between 0200-0400 h. The mean plasma LH decreased to 5.5 +/- 0.4 mIU/mL (5.5 +/- 0.4 IU/L) between 0400-0600 h and to 4.2 +/- 0.5 (4.2 +/- 0.5 IU/L) between 0600-0800 h. Plasma testosterone rose during the night to a mean maximum value of 2.4 +/- 0.5 (+/- SE) ng/mL (8.3 +/- 1.7 nmol/L). This finding suggested that the rise in testosterone might play a role in decreasing LH secretion during the later hours of sleep (after 0400 h). To address this question and to study further the effects of testosterone in early puberty, we measured plasma LH concentrations every 10 min from 2000-0800 h in 8 early to mid-pubertal boys before and during short term testosterone administration. Saline or testosterone at a concentration of 9.33 micrograms/mL (32 mumol/L) was infused at a rate of 10 mL/h from 2100-1200 h to shift the nighttime testosterone rise 3 h earlier than would occur spontaneously. Blood samples were obtained every 10 min for LH and every 30 min for testosterone determinations from 2000-0800 h. Pituitary responsiveness was assessed by administering sequential doses of synthetic GnRH (25 and 250 ng/kg) at 1000 and 1200 h, respectively. The nighttime increase in LH pulse frequency and mean plasma LH concentration occurred between 2300 and 0200 h despite testosterone infusion. However, testosterone infusion was associated with significantly lower mean plasma LH concentrations from 0200-0800 h compared to those on the night of the saline infusion. Pituitary responsiveness to synthetic GnRH was unaltered by testosterone administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1988

Bioactive follicle-stimulating hormone responses to intravenous gonadotropin-releasing hormone in boys with idiopathic hypogonadotropic hypogonadism.

To test the hypothesis that exogenous pulsatile administration of GnRH will increase serum bioactive FSH (bFSH) levels, we studied four boys with suspected idiopathic hypogonadotropic hypogonadism (IHH). These boys presumably secreted relatively little GnRH. By virtue of their low baseline serum gonadotropin levels yet responsive pituitary gonadotrophs, these boys with IHH proved to be an excellent clinical model to test this hypothesis. Administration of GnRH (0.025 microgram/kg.dose) iv at 1- or 2-h intervals for 3-5 days resulted in an increase in serum bFSH after 91% of the GnRH doses. Serum immunoreactive FSH (iFSH) and LH (iLH) levels increased after 42% and 64% of the GnRH doses, respectively. Ninety percent of the iLH responses were concordant with bFSH responses, but only 33% of the iLH responses were concordant with iFSH responses. The serum bFSH responses occurred consistently within 20 min after GnRH administration and resulted in an increased serum bioactive to immunoreactive FSH ratio. By 60 min, serum bFSH levels had returned to preinjection levels. Serum testosterone and estradiol levels did not change during the period of GnRH administration in three of the four boys. We conclude that pulsatile, low dose iv GnRH administration in boys with IHH elicits significant serum bFSH increases by 20 min; the newly secreted FSH is preferentially enriched with increased in vitro FSH bioactivity, and it is rapidly cleared from serum (60 min). Therefore, serum bFSH measurements may provide a sensitive index of GnRH effects on the gonadotrophs.

Adolescent↗
PubMed1986

Treatment of precocious puberty in the McCune-Albright syndrome with the aromatase inhibitor testolactone.

The McCune-Albright syndrome is characterized by café au lait spots, fibrous dysplasia of bones, and sexual precocity. Girls with precocious puberty due to this syndrome have episodic increases in serum estrogen levels together with the formation of large ovarian cysts. The serum gonadotropin levels are typically suppressed, and the precocious puberty has not responded to treatment with long-acting analogues of luteinizing hormone-releasing hormone (LHRH). Encouraged by our initial success in a pilot study of one patient, we have now treated five girls with the McCune-Albright syndrome with the aromatase inhibitor testolactone, which blocks the synthesis of estrogens. Testolactone decreased the levels of circulating estradiol (P less than 0.05) and the ovarian volume (P less than 0.05), and there was a return to pretreatment levels after testolactone was stopped. During treatment, the peak responses of luteinizing hormone and follicle-stimulating hormone to stimulation by LHRH rose above suppressed pretreatment levels--significantly above pretreatment levels for follicle-stimulating hormone (P less than 0.02)--and then returned to pretreatment levels after testolactone was discontinued. Growth rates fell in three patients during treatment but could not be assessed in the other two because of bone deformities. The mean rate of bone maturation decreased and menses stopped in three of the four girls who were menstruating regularly. We conclude that testolactone is an effective treatment of precocious puberty in the McCune-Albright syndrome.

Aromatase Inhibitors↗
PubMed1986

Limited dermal ossification: clinical features and natural history.

For 9 years we have observed a girl who has ossification in the dermis with a strikingly limited distribution. Recently a second girl with similar dermal ossification restricted to a single extremity was identified. The ectopic bone is histologically identical to normal membranous bone. These two patients have no obvious underlying cause for soft tissue bone formation, and no disorder of calcium or phosphate metabolism. Ossification first involved the dermal and subcutaneous connective tissue, and with time advanced locally in the affected areas to bridge joints and limit mobility. The ossification has now extended to involve muscle fascia but has not involved the muscle itself. This disease appears to represent a heretofore unrecognized disorder of mesenchymal differentiation.

Bone and Bones↗
PubMed1986

Ovarian function in girls with McCune-Albright syndrome.

We measured plasma estradiol levels and ovarian volumes in eight girls with precocious puberty due to McCune-Albright syndrome. Six girls had gonadotropin-independent ovarian estrogen secretion and two girls had pubertal gonadotropin levels. Mean ovarian volume in all patients was significantly greater than in normal prepubertal girls. Mean ovarian volumes of the girls with McCune-Albright syndrome overlapped the range found in girls with idiopathic central precocious puberty or central precocious puberty associated with central nervous system lesions. However, the degree of asymmetry between the right and left ovaries was significantly greater in girls with McCune-Albright syndrome. Asymmetry was due, for the most part, to the presence of large solitary cysts in the larger of the two ovaries. In the six girls with McCune-Albright syndrome and gonadotropin-independent precocious puberty, both mean ovarian volume and the degree of asymmetry between the right and left ovaries were significantly correlated with plasma estradiol. Serum follicle-stimulating hormone bioactivity was increased in two patients but did not vary with ovarian cyst size. Thyroid-stimulating hormone levels were normal but serum prolactin was slightly elevated in one of the six girls with gonadotropin-independent precocious puberty. Fluctuation in the size of unilateral ovarian cysts appears to result in changes in the plasma estradiol level, leading to advancement and spontaneous regression of secondary sexual characteristics and menses in girls with McCune-Albright syndrome. The cause of the cyst formation is unknown but may be related to periodic elevation of as yet undefined serum factors such as follicle-stimulating hormone bioactive substances.

Animals↗
PubMed1986

Pituitary and recombinant deoxyribonucleic acid-derived human growth hormones alter glucose metabolism in 3T3 adipocytes.

3T3-F442A adipocytes were used to compare the effects on glucose metabolism of pituitary human (h) GH and methionyl-hGH produced by recombinant DNA techniques (met-hGH 22K). Pituitary hGH and met-hGH 22K were similar in their ability to inhibit glucose oxidation and lipid accumulation after 48 h. After 4 h of incubation, both forms of hGH stimulated glucose oxidation transiently in 3T3 adipocytes. A bacterially produced form of the 20,000-dalton variant of hGH (met-hGH 20K) also stimulated glucose oxidation at 4 h and inhibited glucose oxidation and lipid synthesis after 48 h. All three forms of hGH had a similar ability to inhibit [125I]iodo-met-hGH 22K binding to 3T3-adipocytes. Thus, met-hGH 22K and 20K directly produce in 3T3 adipocytes the transient stimulation and delayed inhibition of glucose metabolism attributed to pituitary hGH, indicating that these metabolic effects are intrinsic to the hGH molecule.

Adipose Tissue↗
PubMed1986

Glucocorticoid receptors in Epstein-Barr virus-transformed lymphocytes from patients with glucocorticoid resistance and a glucocorticoid-resistant New World primate species.

Members of a previously reported family with glucocorticoid resistance and several New World primates have high plasma cortisol concentrations without any signs of glucocorticoid excess. The glucocorticoid receptor in circulating leukocytes and cultured skin fibroblasts from these patients and the animals is characterized by a decreased affinity for dexamethasone. On the other hand, the cell content of receptor is similar to that of corresponding tissues of normal humans. Detailed biochemical-biophysical studies of the glucocorticoid receptor in this familial syndrome and animal model became possible with the use of Epstein-Barr virus-transformed lymphocyte lines. Cell lines from patients with this syndrome and from the marmoset (Saguinus oedipus) contained decreased amounts of glucocorticoid receptors with concomitant decreases in nuclear receptor content compared to cultured Epstein-Barr virus-transformed lymphocytes from normal human subjects. This may reflect diminished induction of glucocorticoid receptor during viral transformation of cells from the patients and the animal model. Receptors from a severely affected glucocorticoid-resistant patient and the marmoset had decreased affinity for dexamethasone. Evidence for a mild affinity defect of the glucocorticoid receptor in a patient with asymptomatic glucocorticoid resistance was obtained by increased hormone-receptor dissociation at an elevated temperature. Thermal stability, mero-receptor formation, thermal activation of cytosolic receptor, and mol wt of receptors from all cell lines were normal. Only the receptors of the severely affected patient had a discernible defect in temperature-induced activation of intact cells. We conclude that the major detectable change in the receptor in both the patients and the animal model is the decreased affinity for glucocorticoid. Viral receptor induction is decreased in both patient and marmoset cells. The physiological relevance of this phenomenon is not known. Gross receptor molecule changes or changes in its stability at higher temperatures were not found. Mixing studies did not show involvement of cytosolic modifiers or inhibitors. Mutation(s) of the receptor molecule leading to low affinity for the hormone is the most likely explanation of the isolated glucocorticoid resistance in the patients. The glucocorticoid resistance of the New World primate, which is part of generalized steroid hormone resistance, appears to be a result of more complex changes.

Animals↗
PubMed1985

Glucocorticoid receptors in Epstein-Barr virus-transformed human lymphocytes.

Glucocorticoid receptors were studied in cultured human lymphocytes from normal donors after transformation with the Epstein-Barr Virus (EBV) and compared to those of circulating human mononuclear leukocytes. Both whole cell and cytosol fractions were examined for [3H]-dexamethasone binding. The concentration and absolute number of glucocorticoid binding sites were increased five-fold in the transformed cells when compared to the non-transformed human mononuclear leukocytes. However, the affinity (Kd) of the glucocorticoid receptor for dexamethasone was the same in both types of cells. The denatured glucocorticoid receptor, covalently labelled with [3H]-dexamethasone-21-mesylate, was identified by SDS polyacrylamide gel electrophoresis as a protein moiety with Mr approximately equal to 92,000, similar to that obtained from human non-transformed mononuclear leukocytes. The pattern of the activation of the hormone-receptor complexes, analyzed by phosphocellulose chromatography, was similar in both types of cells, and also the time-courses of loss of specific binding during thermal activation were similar. These results suggest that viral transformation is associated with increases in the concentration and the absolute number of glucocorticoid receptors whereas other qualitative receptor characteristics remain similar. Thus, transformation of cells with EB virus can provide a constant source of glucocorticoid receptors for study.

B-Lymphocytes↗
PubMed1985

Growth hormone and insulin-like growth factors I and II produce distinct alterations in glucose metabolism in 3T3-F442A adipocytes.

In 3T3-F442A adipocytes, human growth hormone (hGH) stimulates glucose oxidation in 4 hr. A maximal increase is evident at hGH concentrations of 50-100 ng/ml and rarely exceeds 50% above control. The stimulation is transient; after 48 hr of incubation with GH, glucose oxidation is significantly suppressed to 35% below control values. In view of the concept that insulin-like growth factors (IGF) may mediate the effects of GH, we compared the effects of hGH (500 ng/ml) and several preparations of IGF on glucose metabolism in 3T3 adipocytes. After 4 hr of incubation, IGF-I from human plasma stimulated glucose oxidation in a dose-related manner, producing a 10-fold increase at 50 ng/ml. Methionyl-IGF-I produced by recombinant DNA techniques was 85-88% as effective as IGF-I. IGF-II stimulated glucose oxidation 3-fold at 50 ng/ml after 4 hr of incubation. In contrast to the suppression observed with hGH after 48 hr, all three of the IGF preparations stimulated glucose oxidation after 48 hr of incubation and were as effective as they were after 4 hr. When each of the IGF preparations was tested (at 5 ng/ml) in combination with hGH, both the stimulatory and suppressive effects of GH were superimposed on the stimulation by the IGFs. Thus, the stimulatory properties of IGF differed from those of GH in that the maximum extent to which IGF increased glucose oxidation, compared with hGH, was as much as 20-fold greater. Furthermore, all of the IGF preparations stimulated glucose oxidation after 48 hr under conditions in which hGH suppressed glucose metabolism. Thus, it is unlikely that extracellular IGFs mediate the effects of hGH on glucose metabolism in 3T3-F442A adipocytes.

Adipose Tissue↗
PubMed1985

Testolactone treatment of precocious puberty in McCune-Albright syndrome.

Current medical and surgical therapies of precocious puberty in McCune-Albright syndrome are often unsatisfactory. We used an aromatase inhibitor, testolactone, to treat precocious puberty in a girl with McCune-Albright syndrome. This child was unresponsive to 28 weeks of treatment with the long-acting agonist of LRH, D-trp6-pro9-NEt-LRH. During testolactone therapy, menses ceased, bone age advancement and height velocity diminished, and plasma oestradiol levels were suppressed. Serum gonadotrophin levels remained in the prepubertal range. Testolactone may be an effective therapy of precocious puberty in girls with McCune-Albright syndrome.

Androstenedione↗
PubMed1984

Limited proteolysis of covalently labeled glucocorticoid receptors as a probe of receptor structure.

[3H]Dexamethasone 21-mesylate affinity-labeled glucocorticoid receptors were subjected to controlled proteolysis by trypsin, chymotrypsin, and Staphylococcus aureus V8 protease and then analyzed on denaturing constant percentage or gradient polyacrylamide gels. The molecular weights (Mr congruent to 98 000) and cleavage patterns for rat liver and HTC cell receptors indicated extensive homology between the glucocorticoid receptors from normal rat liver and a transformed rat liver cell line. The major DNA-binding species generated by chymotrypsin treatment was found to be a 42K fragment that was accompanied by several unresolved, slightly lower molecular weight fragments. The meroreceptors obtained after trypsinization were comprised of two species of Mr 30 000 and 28 000. Each of the three proteases, despite their differing specificities, generated fragments with molecular weights close to 42 500, 30 500, and 27 000. Nevertheless, each of the three proteases gave rise to a distinctive "ladder" of labeled fragments. No differences could be detected in the digestion patterns of unactivated and activated HTC cell complexes for all three proteases. Also, native and denatured receptor-steroid complexes yielded surprisingly similar digestion patterns with each enzyme. Digestion of denatured complexes readily generated large amounts of a fragment of Mr congruent to 15 000 that was much smaller than the protease-resistant meroreceptors formed from native complexes. The presence of these approximately 15K fragments suggested that the [3H]dexamethasone 21-mesylate labeling of the steroid-binding cavity is restricted to a relatively small segment of the receptor.

Animals↗