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Biomedical subjects

M E Geffner

Publications and source records attributed to M E Geffner.

At least 19 recordsLinked to original sources
PubMed1997

Impact of overnight dexamethasone suppression on the adrenal androgen response to an oral glucose tolerance test in women with and without polycystic ovary syndrome.

In order to test the hypothesis that adrenocortical overactivity, possibly related to the stress of testing, may impact on the measurement of circulating androgen concentrations during glucose-induced hyperinsulinaemia, we prospectively screened 10 patients with the polycystic ovary syndrome (PCOS) and nine healthy control women with an oral glucose tolerance test (OGTT), before and after the administration of dexamethasone. Blood sampling was performed at 0, 30, 60, 90, and 120 min following the oral ingestion of 75 g of glucose, before and after the administration of 1.0 mg dexamethasone on the evening prior to testing. Total and free testosterone, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulphate (DHEAS), cortisol, glucose and insulin were assessed during the 2 h OGTT. Women with PCOS had increased basal concentrations of free testosterone, total testosterone, androstenedione, and insulin compared to control women. In women with PCOS an acute decline in circulating concentrations of DHEAS occurred during the OGTT. In PCOS women there were no changes in other ovarian or adrenal androgens during OGTT before or following dexamethasone administration. In control women DHEA concentrations declined during the OGTT. Following overnight dexamethasone suppression in control women, circulating concentrations of DHEAS and testosterone also declined. It is concluded that: (i) in PCOS women only the concentration of circulating DHEAS decreased during glucose-induced hyperinsulinaemia and dexamethasone administration did not further alter androgen responses to an OGTT; (ii) it is possible that, in these hyperandrogenic patients, the insulin-related suppression of adrenocortical testosterone and DHEA is negated by their much greater ovarian secretion of these androgens; (iii) in control women DHEA concentrations acutely declined during the OGTT and the administration of dexamethasone resulted in the acute decline of DHEA, DHEAS, and testosterone; (iv) it appears that the stress related to testing impacts on the androgen response to OGTT, at least in healthy women.

Adrenal Cortex↗
PubMed1996

IGF-I resistance in virus-transformed B-lymphocytes from African Efe Pygmies.

To investigate IGF-I resistance in African Efe Pygmies, we examined clonal responsiveness to IGF-I in Epstein-Barr virus-transformed B-lymphocytes from three Efe Pygmies and three American control subjects. The Efe B-lymphoblasts did not increase clonal responsiveness when incubated with IGF-I (as high as 250 micrograms/liter) in contrast to the control B-lymphoblasts which showed a bimodal dose-response with a maximal stimulation of 50% above baseline. The proliferative response of Efe B-lymphoblasts was similar to that of control B-lymphoblasts when incubated with another growth factor, phorbol 12-myristate 13-acetate, which does not activate the IGF-I receptor. These findings indicate that Efe Pygmy B-lymphoblasts are resistant to IGF-I as measured by in vitro clonal proliferation assays. Coupled with our previous report of IGF-I unresponsiveness in Efe Pygmy HTLV-II-transformed T-lymphocytes, these data suggest that IGF-I resistance is generalized and may play a central role in the etiology of short stature in this population.

Adult↗
PubMed1996

IGF-I does not mediate T-lymphoblast colony formation in response to estradiol, testosterone, 1,25(OH)2 vitamin D3, and triiodothyronine: studies in control and pygmy T-cell lines.

The mechanism by which estradiol, testosterone, 1,25(OH)2 vitamin D3, and triiodothyronine promote tissue growth is unknown, although, in some tissues, a role for local IGF-I has been suggested. We previously showed that HTLV-II-transformed T-cell lines from healthy adults augmented basal colony formation in response to peptide (growth hormone, parathormone, and adrenocorticotrophin) and glycoprotein (thyroid-stimulating hormone) hormones through stimulation of local IGF-I. T-cell lines from African Efe Pygmies, however, were resistant to the direct growth-promoting action of IGF-I, as well as to the growth-promoting action of growth hormone, parathormone, adrenocorticotrophin, and thyroid-stimulating hormone. We, therefore, used these cell lines to determine the mechanism of T-cell growth in response to steroid and thyroid hormones. We quantified colony formation of American control T-cell lines in the presence and absence of alpha IR-3 antibody against the type 1 IGF receptor and Pygmy T-cell lines in response to estradiol (36.7-1835 pmol/ liter), testosterone (34.7-17,350 pmol/liter), 1,25(OH)2 vitamin D3 (2.4-24,000 pmol/liter), and triiodothyronine (1536-192,000 pmol/liter). There were no statistically significant differences by ANOVA in overall response curves for any of the four hormones comparing control clonal responses in the presence or absence of alpha IR-3 and no statistically significant difference in overall responsiveness between control and Pygmy T-cell lines. From these data, we conclude that (i) normal T-cell lines grow in response to estradiol, testosterone, 1,25(OH)2 vitamin D3, and triiodothyronine; (ii) these responses are not mediated through local IGF-I since they are not blocked by pretreatment with antibody to the type 1 IGF receptor; and (iii) Pygmy T-cell lines, which are genetically resistant to IGF-I, grow equivalently to control T-cell lines in response to estradiol, testosterone, 1,25(OH)2 vitamin D3, and triiodothyronine, further underscoring the IGF-I independence of this stimulation in our system.

Analysis of Variance↗
PubMed1996

The growth without growth hormone syndrome.

The phenomenon of growth without GH has been recognized for over a quarter of a century in various physiologic or near-physiologic situations, including the fetal state and obesity, and in various obviously pathologic states, including postsurgical resection of suprasellar/hypothalamic tumors, most notably craniopharyngiomas, and in acromegaloidism. The mechanism or mechanisms responsible for this fascinating clinical syndrome are unknown. The available data implicate, at least in some of these subjects, a role for hypothalamic injury leading to obesity and insulin resistance which, in turn, leads to elevated circulating concentrations of insulin to which the body retains mitogenic sensitivity. Alternatively, in other subjects with this syndrome, evidence exists to support the presence of a circulating as yet incompletely characterized potent growth-promoting factor which appears in the serum. Further studies of this syndrome should help to enhance our knowledge of the mechanisms governing both normal and abnormal human growth.

Adult↗
PubMed1996

Decreased insulin-like growth factor I receptor expression and function in immortalized African Pygmy T cells.

Efe Pygmies of northeast Zaire have the shortest mean adult stature of any population on earth. Although various alterations in the GH/insulin-like growth factor I (IGF-I) axis have been suggested, the basis for short stature in the Pygmy is unknown. We previously described IGF-I unresponsiveness in a T lymphoblast cell line derived from an Efe Pygmy, and studies in five additional lines have confirmed severe IGF-I resistance in these cells. We have now performed experiments to determine the molecular basis for the IGF-I resistance in these cells. We found markedly decreased cell surface expression of IGF-I receptors with normal ligand binding affinity. The Pygmy IGF-I receptors were not autophosphorylated and did not transmit a signal in response to physiological concentrations of IGF-I. There was a substantially decreased level of IGF-I receptor messenger ribonucleic acid in the Pygmy cells with a normal messenger ribonucleic acid half-life. The nucleotide sequence of the full-length IGF receptor complementary DNA in Pygmy 1 showed no significant variation. These results indicate decreased IGF-I receptor gene transcription and IGF-I receptor signaling as the primary variation in the Pygmy cell lines. The findings point to the IGF-I receptor as the locus governing short stature in the African Pygmy and suggest that human stature may be genetically controlled by expression of the IGF-I receptor.

Base Sequence↗
PubMed1995

Characterization of heterogeneous mutations causing constitutive activation of the luteinizing hormone receptor in familial male precocious puberty.

Familial male precocious puberty (FMPP) is a gonadotropin-independent disorder that is inherited in an autosomal dominant, male-limited pattern. A heterozygous mutation encoding substitution of Asp578 with Gly in transmembrane helix 6 of the G protein-coupled receptor for luteinizing hormone (LHR) has been found in affected males from nine American FMPP families. Cells expressing the mutant LHR exhibit markedly increased cyclic adenosine monophosphate (cAMP) production in the absence of agonist, suggesting that autonomous Leydig cell activity in FMPP is caused by a constitutively activated LHR. We have now analyzed genomic DNA from affected males from six additional FMPP families. PCR was used to amplify a fragment of the LHR gene encoding amino acid residues 441-594. None of the six new samples contained the Asp578-->Gly mutation, as indicated by absence of digestion with MspI. PCR products were then screened for heterozygous mutations using temperature-gradient gel electrophoresis. DNA fragments from two of the patients migrated abnormally. Direct sequencing of PCR product from one affected German male revealed a heterozygous mutation (ATG-->ATA) encoding Met571-->Ile at the cytoplasmic end of helix 6, the same mutation that has been reported in another European FMPP kindred. Affected males in the second family had a novel Thr577-->Ile mutation (ACC-->ATC). Mutations in different portions of the LHR or in a different gene may be responsible for disease in the other FMPP kindreds. Agonist binding and functional coupling of the mutant receptors to the cAMP and inositol phosphate pathways were studied by transiently expressing them in COS-7 cells. Agonist affinity was unaffected by the mutations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Growth-promoting actions of parathyroid hormone, adrenocorticotrophic hormone, and thyroid-stimulating hormone: in vitro studies in normal and pygmy T-lymphoblast cell lines.

We used an in vitro T-lymphoblast clonal proliferation assay to quantify human IGF-I (hIGF-I)-, human PTH (hPTH)-, human ACTH (hACTH)-, and human TSH (hTSH)-stimulated growth of human T-cell leukemia virus-II-transformed T-lymphoblast cell lines from normal individuals and to elucidate the role of IGF-I as the mediator of hPTH-, hACTH-, and hTSH-induced T-cell growth. Normal T-lymphoblast cell lines respond to hIGF-I in a bimodal fashion. The mean first peak response was 143 +/- 9.8% above baseline (defined as 100%) occurring at 8 micrograms/L, and the mean second peak response was 154 +/- 14.4% occurring at 100 micrograms/L. Both responses were completely blocked after incubation with alpha IR-3, an MAb to the IGF-I receptor (by analysis of variance, p = 0.015 between full response curves). After stimulation with hPTH, the mean peak clonal response of normal T-lymphoblast cell lines was 189 +/- 7.0%; after incubation with alpha IR-3, the mean peak clonal response was 108 +/- 7.9% (p = 0.0015 between full response curves). The mean peak clonal response of normal T-lymphoblast cell lines after hACTH stimulation was 192 +/- 8.6%; preincubation with alpha IR-3 reduced the mean peak clonal response to 94 +/- 1.2% (p < 0.0001 between full response curves). With hTSH stimulation, the mean peak clonal response of normal T-lymphoblast cell lines was 167 +/- 7.0%; after incubation with alpha IR-3, the mean peak clonal response was 94 +/- 8.2% (p = 0.003 between full response curves).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1995

Insulin-like growth factor I resistance in immortalized T cell lines from African Efe Pygmies.

Previous investigations suggested that resistance to GH was the cause of short stature of African Pygmies. Because many of the actions of GH are mediated by insulin-like growth factor I (IGF-I), we sought to determine whether Pygmy tissue was responsive to IGF-I. An initial effort to obtain HTLV-II-transformed T lymphoblast cell lines resulted in a single cell line that showed complete resistance to both IGF-I and GH in a clonal proliferation assay as well as decreased IGF-I binding. In the current study, we examined T cell lines from seven Efe Pygmy subjects, three neighboring Lese farmers, and six American controls and quantified clonal responses to IGF-I, GH, and insulin. The T cell lines from the Efe Pygmies were all completely resistant to the growth-promoting actions of IGF-I concentrations less than 250 micrograms/L and GH concentrations less than 500 micrograms/L. The Lese population, with whom there is admixture with the Efe population, showed heights and clonal responses to IGF-I and GH intermediate between those of Pygmies and American controls. The Pygmy T cell lines showed reduced clonal proliferation in response to high insulin concentrations known to act through the IGF-I receptor. These findings indicate that genetic IGF-I resistance is present in the T cell lines of Efe Pygmies and suggest that unresponsiveness to IGF-I may be responsible for their short stature.

Adult↗
PubMed1994

Continuous insulin infusions in neonates: pharmacologic availability of insulin in intravenous solutions.

Continuous insulin infusion is sometimes used in very low birth weight infants with glucose intolerance. We studied the availability of insulin to the neonate by means of a laboratory-simulated clinical infusion under both flushed and non-flushed conditions. Although loss of insulin was noted with both solutions (0.5 U/ml), under the nonflushed condition only 55.9% of the prescribed dose for the first 2 hours was delivered before the delivery rate of the flushed system, 71.4%, was approached. These findings have implications for neonatal insulin administration.

Adsorption↗
PubMed1994

Divergent dimerization properties of mutant beta 1 thyroid hormone receptors are associated with different dominant negative activities.

Syndromes of resistance to thyroid hormones are caused by mutations in the T3-binding domain of the c-erbA beta thyroid hormone receptor gene. The S receptor (deletion of THR332) is a potent dominant negative protein cloned from a kindred with generalized resistance to thyroid hormones. The G-H receptor (ARG311HIS) has compromised dominant negative function and was found in both normal individuals and in a patient with severe pituitary resistance to thyroid hormones. We have investigated the mechanism responsible for the difference in receptor phenotypes by analyzing the binding of S and G-H receptors to thyroid hormone response elements with electrophoretic mobility shift analysis. Wild-type human c-erbA beta 1 (WT), S, and G-H receptors were synthesized in reticulocyte lysate, reacted with a thyroid hormone response element consisting of a direct repeat with 4 base pairs (DR+4; AGGTCA CAGG AGGTCA), and the products analyzed by gel shift. G-H receptor homodimerization was greatly impaired; G-H formed predominantly monomeric complex compared with monomeric and homodimeric WT complexes. The G-H receptor was able to form heterodimeric complexes with cellular thyroid hormone receptor auxiliary protein (TRAP) factors including the human retinoid X receptor-alpha. When TRAP was limiting, the levels of G-H heterodimeric complex were 2- to 3-fold reduced compared with WT receptor. In contrast to the WT and G-H receptors, the S receptor formed almost exclusively homodimeric complex with DR+4; the approximate ratio of S:WT:G-H homodimeric complexes at equivalent concentrations of receptors was 60:20:1. A measurable increase (1.2- to 2.6-fold) in heterodimeric complex formation was observed with the S receptor relative to WT when TRAP was at limiting concentration. As reported previously by others, thyroid hormone significantly reduced the WT homodimeric complex with DR+4. There was no effect on the S homodimeric complex. Finally, the WT, S, and G-H receptors formed different complexes with the element consisting of an inverted repeat with 5 base pairs (IR+5; AGGTCA ACAGT TGACCT) and the IR element (AGGTCA TGACCT), which were differently regulated by thyroid hormone. The S receptor bound as a homodimer with IR+5, whereas the WT receptor bound as a homodimer only with thyroid hormone. No homodimeric complex formed with IR+5 and the G-H receptor. Qualitatively similar results were observed with the IR element. We conclude that the ARG311HIS mutation severely perturbs the homodimerization and, to a much less degree, heterodimerization functions of the c-erbA beta 1 receptor. Furthermore, the THR332 deletion mutation augments homodimerization of the c-erbA beta 1 receptor. These results indicate that different mutations in the c-erbA beta 1 thyroid hormone receptor have divergently affected dimerization activities which seem to influence the level of dominant negative activity in man.

Amino Acid Sequence↗
PubMed1994

Growth hormone induces resistance to the mitogenic action of insulin through local IGF-I. Studies in normal and Pygmy T-cell lines.

Growth hormone (GH) and insulin have both mitogenic and metabolic actions. The growth-promoting effects of GH in vivo are thought to be mediated by insulin-like growth factor-I (IGF-I), whereas the metabolic effects of GH are thought to be either direct or mediated by factors other than IGF-I. In previous studies using HTLV-II-transformed T-lymphoblast cell lines established from normal individuals, we have shown that GH preincubation induces resistance to the growth-promoting (mitogenic) action of insulin. In this study, using T-cell lines from 3 American control subjects, 1 African control subject, and 1 African Pygmy (the latter previously shown to be resistant to the growth-promoting actions of both IGF-I and GH), we examined the role of local IGF-I in the mediation of GH-induced resistance to the mitogenic action of insulin. In these studies, we quantified the stimulation of T-cell colony formation in response to insulin in the presence and absence of either GH or IGF-I.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Insulin-like growth factor-I unresponsiveness in an Efe Pygmy.

The cause of short stature in African Pygmies is unknown, but some evidence suggests that they are GH resistant. Since IGF-I mediates many actions of GH, we sought to determine if Pygmy tissue is responsive to IGF-I. We established HTLV-II-transformed cell lines from 1 Efe Pygmy, 1 African control, and 3 American controls, and quantified in vitro colony formation in response to IGF-I, GH, and insulin, and assessed IGF-I receptor binding. The Pygmy T-cell line showed no clonal responsiveness following stimulation with physiologic concentrations of IGF-I or any concentration of GH, but responded normally to insulin. IGF-I binding studies showed no binding to the Pygmy T-cell line with normal binding to control cells. The primary abnormality in this Pygmy T-cell line is IGF-I resistance at the receptor level with secondary GH resistance.

Adult↗
PubMed1993

The influence of luteinizing hormone and insulin on sex steroids and sex hormone-binding globulin in the polycystic ovarian syndrome.

OBJECTIVE: To examine the relationship between hyperinsulinemia, sex hormone-binding globulin (SHBG), and body mass index (BMI) on LH-induced hyperandrogenemia in patients with polycystic ovarian syndrome (PCOS). DESIGN: Insulin responses during an oral glucose tolerance test (OGTT) were assessed in 25 consecutive women with PCOS and 20 control women matched for BMI. Insulin responses and sensitivity (SI) were also determined using a frequently sampled intravenous glucose tolerance test (IVGTT). SETTING: The clinical research center at a university medical center. MAIN OUTCOME MEASURES: Serum LH, SI, and basal, peak, and area under the curve (AUC-insulin responses) were determined and correlated with SHBG, androstenedione (A), T, and free T concentrations. RESULTS: Compared with controls, the AUC-insulin response during OGTT was greater in PCOS, with an average increase of 44%. During IVGTT, AUC-insulin response was also significantly higher in PCOS versus controls, with an average increase of 53%. In addition, SI was reduced in PCOS versus controls with an average decrease of 53%. The average differences in oral- and intravenous-glucose-induced hyperinsulinemia and in insulin sensitivity between PCOS and controls were relatively constant across the entire physiological range of BMI. In PCOS, baseline LH showed strong positive correlations with baseline A and T. However, there were no significant correlations between either basal, peak, or AUC-insulin response during OGTT and IVGTT with basal T or A concentrations or between insulin and androgen levels measured at 30-minute intervals throughout the OGTT. However, basal, peak, and AUC-insulin responses during OGTT were strongly correlated with fasting SHBG binding capacity. CONCLUSIONS: These data are consistent with the hypothesis that hyperinsulinemia in PCOS influences the biologically active component of T by lowering SHBG concentrations while having little apparent impact on LH-induced secretion of androgens in vivo.

Administration, Oral↗