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Biomedical subjects

Z Hochberg

Publications and source records attributed to Z Hochberg.

At least 109 records · Page 6Linked to original sources
PubMed1989

Effect of thyroid hormone and growth hormone on recovery from hypothyroidism of epiphyseal growth plate cartilage and its adjacent bone.

Hypothyroidism was induced in young female Sprague-Dawley rats by the addition of methimazole (0.67 mg/ml) to drinking water for a period of 7 weeks (7-14 weeks of age). The responses of the articular cartilage, epiphyseal growth plate cartilage, epiphyseal trabecular bone, and metaphyseal trabecular bone in the proximal tibia were assessed by structural parameters. In addition, replacement therapies were introduced for the last 2 weeks of the experimental period. These included 0.7 U/kg BW human GH (hGH), 15 micrograms/kg BW L-T4 (T4), and a combination of hGH and T4 at the same doses. In the hypothyroid rats, the width of epiphyseal growth plate cartilage decreased by 27%, that of articular cartilage by 35%, epiphyseal trabecular bone volume by 30%, and metaphyseal trabecular bone volume by 66% relative to those in age-matched control tissues. T4 treatment led to a full restoration of the epiphyseal trabecular bone and surpassed by 40% the control value. The magnitude of the articular cartilage and the epiphyseal trabecular bone volume returned to control values, while that of metaphyseal trabecular bone was 68% of control values. Treatment with hGH did not improve the epiphyseal growth plate cartilage or articular cartilage. It did restore epiphyseal trabecular bone to almost normal values, but metaphyseal trabecular bone improved to only a small though significant level (45% of control value). The combination of T4 and hGH resulted in an additional enlargement in the width of the epiphyseal growth plate cartilage and an increase in metaphyseal trabecular bone volume compared to those in the T4 group. Qualitative examinations indicated that it was only in the T4 and T4 plus hGH groups that the lowest chondrocytes in the epiphyseal growth plate cartilage resumed their normal hypertrophied size. These results suggest that the change in the hypothyroid state do not rely solely on the lack of pituitary GH synthesis and secretion, as replacement by exogenous GH did not restore normal epiphyseal growth plate cartilage morphology or its remodeling into metaphyseal trabecular bone. Treatment with T4 (which restored endogenous pituitary GH to 30% of control levels) results in full recovery of the epiphyseal growth plate cartilage morphology along with its associated metaphyseal trabecular bone. In addition, it can also be concluded that the decrease in epiphyseal trabecular bone volume observed in the hypothyroid animals was due solely to the GH-deficient state that accompanied hypothyroidism.

Animals↗
PubMed1989

Effects of sex steroids on the response of cultured rat pituitary cells to growth hormone-releasing hormone and somatostatin.

In the male rat, GH secretion is characterized by high amplitude pulses that appear at regular intervals of 3-4 h, with low basal levels between such pulses. In the female, the pulses are irregular and more frequent, with lower amplitudes, while basal secretion is higher. The present study was designed to exclude the indirect effects of sex steroids on the pituitary, enabling investigation of the direct effects of sex steroids on the pituitary. Rats were gonadectomized at 22 days of age, and 12 days later their anterior pituitaries were trypsinized for cell dispersion. Testosterone (T) or 17 beta-estradiol (E2), 5 nM, was added to the medium for 6 days, and subsequently, GRF or somatostatin was added for 4 h. In a perifusion system, the male-derived cell response to GRF was augmented after pretreatment with T, but not with E2. The female-derived cell response to GRF was augmented by E2, but not by T. T increased the sensitivity of the cells to GRF from 3.0-0.03 nM and increased the maximal potency of GH secretion 3-fold. E2 had no significant effect on the sensitivity, but lowered the potency. Somatostatin (1 nM) inhibited GH secretion by 44% in T-treated cells. In E2-treated cells, somatostatin was ineffective. GRF increased the total amount of GH (medium plus cells) in both T- and E2-treated cells, but not in control pituitary cells. It is suggested that T has direct effects on the male somatotroph. By increasing the pituitary cell responses to GRF and somatostatin, T contributes to the high amplitude peak/low baseline pattern of the male. By decreasing the pituitary cell responses to GRF and somatostatin, E2 contributes to the low amplitude peak/high baseline pattern of the female.

Animals↗
PubMed1989

Human growth hormone enhances chondrogenesis and osteogenesis in a tissue culture system of chondroprogenitor cells.

GH is a systemic promoter of skeletal growth which increases the synthesis of insulin-like growth factor I in parenchymal tissues as well as in peripheral tissues such as the liver and growing cartilage. The present study was designed to examine whether GH possesses a direct effect on cellular proliferation and differentiation in mouse condylar cartilage. Cartilage progenitor cells were cultured in the form of a tissue culture on top of collagen sponges in medium containing 10% fetal calf serum and were treated with 50 ng/ml GH for 6 days. Three-day incubation with GH caused a marked increase in DNA synthesis and in the size of the culture, which developed into a nodule of differentiated chondrocytes and a well developed perichondrial layer around it. The effect of GH was even more pronounced after 6 days in culture; at which time a distinct network of trabeculae was noted throughout the extracellular matrix. The trabeculae contained osteocyte-like cells and were in close contact with both osteoblast-like and osteoclast-like cells. Using antibodies against bone-specific antigens, i.e. osteocalcin and osteopontin, provided further support for the notion that the newly formed trabecular formation was comprised of bone matrical components. Untreated control cultures lacked such structures, but contained hyaline-like cartilage. It, therefore, seems reasonable to suggest that GH induces a strong stimulatory effect on progenitor cell proliferation, cartilage differentiation, and extracellular mineralization, which supports de novo bone formation in vitro.

Alkaline Phosphatase↗
PubMed1989

Adaptation of liver membrane somatogenic and lactogenic growth hormone (GH) binding to the spontaneous pulsation of GH secretion in the male rat.

The secretory pattern of GH is pulsatile in both man and experimental animals. The present study was undertaken to investigate the effect of the endogenous pulsatility of serum GH on the dynamics of plasma membrane GH binding sites. In order to characterize somatogenic and total specific binding, male rats 45 days old were decapitated at 15-min intervals, and rat liver membranes were prepared. Binding studies were done in parallel with and without excess ovine PRL, 1 microgram/tube. Removal of endogenous ligand was performed by exposing the membranes to 3 M MgCl2. A composite picture of serum GH showed relatively good synchronization of the secretory episodes among the animals. Peak levels of the spontaneous secretion pulse of rat GH were followed by an immediate decrease in free somatogenic binding. Two hours later the binding activity returned to presecretion levels, essentially resetting the cell for another cycle. The kinetics of desaturated somatogenic binding were similar. The occupancy of liver GH somatogenic binding sites was maximal at the time of peak serum GH. High levels of the endogenous hormone caused an immediate sharp down-regulation of lactogenic desaturated binding. Up-regulation of the binding sites occurred about 90 min later. Scatchard analysis showed that binding activity of the membranes was a result of the altered number of binding sites, while the binding affinity remained fairly constant. Thus, the centrally regulated GH secretion in the male rat is complemented by appropriate dynamics of the GH receptor turnover, which in turn recognizes individual pulses and allows individual pulse-related responses to occur.

Activity Cycles↗
PubMed1989

The dynamics of somatogenic and lactogenic growth hormone binding: internalization to Golgi fractions in the male rat.

Rapid turnover of the GH receptor has previously been shown, and its turnover (t1/2) has been estimated to be 30-85 min. In a companion study, we found that lactogenic and somatogenic GH binding sites on rat liver membranes were down-regulated immediately after an episode of GH secretion and reappeared at the plasma membrane in time for the next secretory surge of the hormone. In the present in vivo study, we followed the fate of the down-regulated membrane GH binding sites in the Golgi membranes. Male rats were killed at 1000, 1100, and 1200 h, and their livers were removed for preparation of Golgi membranes. Lactogenic and somatogenic [125I]human GH binding to Golgi membranes was measured. The results of the present study show that Golgi receptors are related to the endogenous pulsation of serum GH. After the GH surge, an increase in the capacity of the lactogenic and somatogenic receptors in the Golgi membranes takes place. Most of these receptors were occupied by ligand and represent, therefore, internalized receptors. Two hours after the GH secretory peak, the occupied receptors had disappeared from the Golgi membranes and appeared in the plasma membrane, suggesting that receptors were recycled to the plasma membrane, awaiting the next GH surge. The following model is proposed: A surge of GH secretion causes immediate down-regulation of the plasma membrane receptors to GH. The receptors that disappear from the plasma membrane are internalized to the Golgi complex. A fraction of the Golgi receptors is recycled to the membrane, along with newly synthesized receptors, awaiting the next GH pulse.

Activity Cycles↗
PubMed1989

Abnormal binding of vitamin D receptors to deoxyribonucleic acid in a kindred with vitamin D-dependent rickets, type II.

Vitamin D-dependent rickets, type II, is a hereditary disease that results from target organ resistance to the action of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. We describe here a family (designated G) with a defect in the DNA-binding domain of the 1,25-(OH)2D receptor (VDR) manifested by normal steroid binding and decreased VDR affinity for DNA. The phenotypically normal parents are heterozygous, expressing both normal and defective forms of VDR. The affected children in this family had early-onset rickets, alopecia, hypocalcemia, and elevated serum 1,25-(OH)2D3 levels. The VDR of cultured skin fibroblasts of the affected children (G1 and G2) as well as the parents (G3 and G4) bound [3H]1,25-(OH)2D3 normally (Kd = 2-3 X 10(-11) mol/L; maximal number of binding sites = 20-40 fmol/mg protein). The cells from G1 and G2 were resistant to 1,25-(OH)2D3 action, as measured by induction of 24-hydroxylase activity, while the cells from G3 and G4 responded normally. Western blot analysis using the anti-VDR monoclonal antibody 9A7 showed that hypertonic extracts of fibroblasts from both affected children (G1 and G2) and their parents (G3 and G4) had immunoreactive bands of 48K, identical to the size of the VDR in normal cells. The VDR from G1 and G2 eluted as a single peak from DNA-cellulose columns at a lower salt concentration (0.1 mol/L) than that from normal subjects (0.2 mol/L), indicating an apparent decreased affinity for DNA. Fibroblast VDR from G3 and G4 each eluted from DNA-cellulose columns as two peaks, the normal peak (0.2 mol/L) and the abnormal peak (0.1 mol/L), which was found in G1 and G2. Western blot analysis of the 0.1 and 0.2 mol/L KCl peak fractions also confirmed that VDR was present in only the 0.1 mol/L fraction and not the 0.2 mol/L fraction from G1. However, VDR was present in both fractions from G3. In summary, this vitamin D-dependent rickets, type II, kindred has a defect in the DNA-binding domain of VDR. The parents are phenotypically normal and express both the normal and defective VDR alleles, as demonstrated by both DNA-cellulose chromatography and Western blot analysis. The affected children are resistant to 1,25-(OH)2D3 action and are homozygous for the defective VDR.

Blotting, Western↗
PubMed1989

Growth hormone stimulates the growth of mouse neonatal condylar cartilage in vitro.

This study used an organ culture system of neonatal condylar cartilage to study the in vitro effects of recombinant human growth hormone on the growth of cartilage and its inherent cell populations: progenitor cells, chondroblasts and early hypertrophic chondrocytes. Growth hormone at a dose of 2.5 nmol/l enhanced the overall growth of cartilage explant and stimulated the differentiation of its cells. Hence, growth hormone-treated explants revealed a substantial increase in the number of chondroblasts and young hypertrophic chondrocytes. Along with its effects upon cartilage the hormone also stimulated new bone formation adjacent to mineralized hypertrophic chondrocytes. These results provide support to the notion that growth hormone stimulates cartilage growth which in turn is followed by endochondral ossification. In spite of its in vitro effect it is not as yet clear whether the effect of growth hormone is indeed a direct one or is mediated via the local production of IGF-I.

Age Factors↗
PubMed1989

The role of catecholamines in estradiol and progesterone secretion by cultured explants and cells of human term placentae.

The effects of physiological concentrations of the native catecholamines norepinephrine and epinephrine upon term placental hormonal function were examined by measuring estradiol and progesterone secretion by organ and cell culture systems. Results show that, in explants, both catecholamines caused a significant increase in the secretion of both sex steroids, p less than 0.05. Estradiol secretion was blocked by the alpha and beta adrenergic receptors antagonists, phenoxybenzamine and propranolol, respectively, p less than 0.05. Norepinephrine but not epinephrine dependent progesterone secretion was blocked by propranolol. In cells, epinephrine stimulated cyclic AMP generation and caused a 30% increase in estradiol secretion, p less than 0.05. Both were abrogated by propranolol. Norepinephrine increased secretion by 25%, p less than 0.05. This was inhibited by yohimbin and prazosin, alpha-1 and -2 receptors antagonists, respectively. In conclusion, the placenta in vitro is a target organ for catecholamines. The marked response of the explant system as compared with the marginal response of the cell culture system indicates that cell to cell contact/communication is required for full expression of catecholamine effect.

Adrenergic alpha-Antagonists↗
PubMed1989

Short-term efficacy of thyroid hormone supplementation for patients with Down syndrome and low-borderline thyroid function.

The thyroid function of 44 subjects with Down syndrome who were between 2 and 51 years of age was assessed. Three patients (7%) had hypothyroidism, and in 2 of them high titers of antimicrosomal antibody were detected. Seven additional subjects (16%) had low-borderline thyroid function, 6 with elevated thyroid stimulating hormone. These 7 subjects constituted the cohort for an evaluation of the short-term benefits of thyroid hormone supplementation in the low-borderline thyroid functional state. A double-blind crossover drug placebo trial failed to document any cognitive, social, response time, or physical changes attributable to the 8- to 14-week drug treatment period compared to an untreated matched control group. Results provided no evidence for the efficacy of short-term thyroid hormone therapy for this population.

Adolescent↗
PubMed1988

The human placenta as a target tissue for glucagon.

Glucagon's effect on the placenta was studied in cultured human term trophoblast and in homogenized term and first-trimester placentas. In studies with cultured term trophoblast, glucagon stimulated the generation of cyclic AMP and estradiol secretion and inhibited placental lactogen secretion. Incubation of homogenates of term and of first-trimester placenta with 0.5 mM dibutyryl cAMP revealed a marked decrease of pyruvate kinase activity. Glucagon produced a similar decrease in first-trimester homogenates, but failed to affect term placentas. The present demonstration of the placenta as a target tissue for glucagon suggests an active contribution of the trophoblast to energy metabolism during pregnancy.

Bucladesine↗
PubMed1988

Two pathways of placental lactogen secretion by cultured human trophoblast.

To assess the relative importance of regulated and of constitutive secretion of placental lactogen, a cell culture model of term human trophoblast was utilized. Time courses of secretion revealed a constant secretion rate over 9 days of culture, with relatively small constant intracellular hormone concentration. Potassium, 21 mM, produced a slight but significant increase in hormone secretion into the medium. Growth hormone-releasing hormone (5 X 10(-10)-5 X 10(-9)) stimulated a 27-48% increase in placental lactogen secretion. The data suggest a major process of constitutive secretion and a minor role for regulated secretion from a storage pool.

Cells, Cultured↗
PubMed1988

Enhancement of erythropoiesis in vitro by human growth hormone is mediated by insulin-like growth factor I.

Insulin-like growth factor I (IGF-I) is the presumed paracrine or autocrine growth-promoting mediator of growth hormone in peripheral tissues. In order to evaluate the role of IGF-I as mediator of human growth hormone (hGH) in erythropoiesis, we compared the effects of both peptides upon in vitro colony formation by primitive (BFU-E) and relatively mature (CFU-E) human erythroid precursors. Biosynthetic IGF-I (2 ng/ml) and hGH (25 ng/ml) induced a significant increase in the growth of both BFU-E and CFU-E. BFU-E growth was maximally enhanced by 6 ng/ml IGF-I and by 50 ng/ml hGH, resulting in an increase in burst numbers of 62 +/- 12% and 52 +/- 12%, respectively. Maximal enhancement of CFU-E growth was detected at higher concentrations of IGF-I (20 ng/ml) and hGH (150 ng/ml), with respective increases of 121 +/- 35% and 137 +/- 18% in colony numbers. Enhancement of bone marrow and peripheral blood erythroid progenitor cell growth by hGH required the presence of monocytes and was abrogated by specific monoclonal antibodies directed against IGF-I membrane receptors. The in vitro growth-promoting effect of hGH upon human erythroid precursors thus appears to be mediated by paracrine IGF-I.

Colony-Forming Units Assay↗
PubMed1988

Enhancement of human granulopoiesis in vitro by biosynthetic insulin-like growth factor I/somatomedin C and human growth hormone.

The effect of biosynthetic recombinant insulin-like growth factor I/somatomedin C (IGF-I/Sm-C) and human growth hormone (hGH) on the in vitro growth and maturation of human marrow myeloid progenitors was investigated. Myeloid colony formation was maximally enhanced by 60 ng/ml IGF-I/Sm-C and by 250 ng/ml hGH, resulting in an increase in colony numbers of 41 +/- 7 and 38 +/- 4%, respectively (P less than 0.001). Both peptides induced a 1.5-2.5-fold increase in the frequency of colonies composed of granulocytes alone, but did not alter the numbers of monocyte/macrophage or mixed granulocyte/macrophage colonies. IGF-I/Sm-C and hGH were also found to enhance myeloid maturation towards mature granulocytes in suspension cultures of human marrow cells. The effect of both peptides on human marrow granulopoiesis was similarly demonstrable in serum-free cultures stimulated with human recombinant granulocyte/macrophage colony-stimulating factor. Enhancement of human marrow granulopoiesis in vitro by hGH required the presence of marrow adherent cells and was abrogated by specific monoclonal antibodies directed against IGF-I/Sm-C receptors. The effect of hGH on marrow myeloid progenitors thus appears to be mediated by paracrine IGF-I/Sm-C.

Antibodies, Monoclonal↗
PubMed1988

11 Beta-hydroxylase deficiency congenital adrenal hyperplasia: update of prenatal diagnosis.

Hormonal measurements in maternal urine and amniotic fluid (AF) during pregnancy and/or at delivery correctly predicted the postnatal diagnosis of 11 beta-hydroxylase deficiency congenital adrenal hyperplasia (11 beta-OH deficiency CAH) in 7 fetuses at risk. In the 4 affected ones, maternal urinary tetrahydro-11-deoxycortisol (THS) excretion was high during the first trimester [0.3-2.2 mg/day (1.1-7.7 mumol/day)] and rose further during the third trimester [0.5-3.5 mg/day (1.8-12.3 mumol/day)] compared to urinary THS excretion in 20 normal pregnancies of the same gestational age (P less than 0.01). In 1 mother, dexamethasone administration (2 mg/day for 72 h) greatly reduced urinary THS excretion (and plasma steroid levels). Urinary THS excretion was low after delivery in these mothers, in normal pregnancies, and in parents of affected individuals [less than 0.05 mg/day (less than 0.08 mumol/day); P = NS]. However, 2 of the 3 heterozygous mothers who carried nonaffected fetuses excreted moderately increased amounts of THS during pregnancy, ranging from 0.15-0.26 mg/day (0.53-0.91 mumol/day), significantly higher than normal (P less than 0.01). Although urinary THS excretion in these mothers was similar to that in 2 mothers with affected fetuses early in pregnancy, urinary THS excretion was higher in mothers with affected compared to those with nonaffected fetuses after the first trimester (P less than 0.01). AF THS and 11-deoxycortisol concentrations were markedly elevated in pregnancies with affected fetuses (P less than 0.01), but normal in nonaffected ones. AF delta 4-androstenedione levels were high in 2 pregnancies and borderline elevated in a third. Although the AF tetrahydrocortisol and tetrahydrocortisone levels were always within the normal range, the AF THS to tetrahydrocortisol plus tetrahydrocortisone ratio was significantly elevated in all pregnancies with affected fetuses (2.8-5.5; P less than 0.01) and normal in nonaffected ones (0.48-1.2; P = NS) compared to that in 160 normal pregnancies [0.64 +/- 0.34 (+/- SD)]. AF 17-hydroxyprogesterone, testosterone, and 11-deoxycorticosterone levels were normal in all pregnancies. Maternal plasma 11-deoxycortisol and delta 4-androstenedione concentrations, determined sequentially throughout gestation, were variable and did not contribute to prenatal diagnosis. All affected infants were born hyperpigmented, 2 were large for gestational age, and the female was severely virilized. In the first week of life 2 males developed severe hypertension with seizures and adrenal insufficiency, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Hyperplasia, Congenital↗
PubMed1988

Normal response of factor VIII and von Willebrand factor to 1-deamino-8D-arginine vasopressin in nephrogenic diabetes insipidus.

The effects of 1-deamino-8D-arginine vasopressin (DDAVP) on plasma factor VIII and von Willebrand factor (vWF) levels were studied in four patients with nephrogenic diabetes insipidus (NDI) from two unrelated families. While the urine osmolality remained low, the plasma levels of factor VIII and vWF rose 2- to 3-fold after infusion of 0.3 micrograms/kg DDAVP, compared to preinfusion levels. The degree of increase was similar in both NDI patients and normal subjects. We conclude that in NDI patients the end-organ resistance to DDAVP is confined to the kidneys and does not involve the sites from which factor VIII and vWF are released.

Adult↗
PubMed1988

Androgen therapy in hypogonadotrophic hypogonadism: time course of erotosexual functions.

This study was designed to assess the duration of androgen's effects on male sexuality to recommend an optimal therapeutic regime. Nine young men with hypogonadotrophic hypogonadism were repeatedly tested for 9 weeks after an i.m. dose of a Depo-testosterone preparation. Testing included self-rating of sexuality and recording of penile tumescence during sleep and during pornographic film, slides, and self-induced fantasy. Although serum testosterone decreased to subnormal levels by the fourth week, erectile strength, according to self-report, became subnormal by the eighth week, whereas other reported parameters remained unchanged. Erectile response to erotic stimulations remained unchanged for the entire 9 weeks. Nocturnal erections were supranormal for the first 2-4 weeks and normalized thereafter. Testosterone's effect on male sexuality seems to persist beyond the period of normal serum testosterone. Treatment can, therefore, be given bimonthly.

Adolescent↗