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L Holloway

Publications and source records attributed to L Holloway.

At least 19 recordsLinked to original sources
PubMed2001

One year of insulin-like growth factor I treatment does not affect bone density, body composition, or psychological measures in postmenopausal women.

The activity of the hypothalamic-GH-insulin-like growth factor I (hypothalamic-GH-IGF-I) axis declines with age, and some of the catabolic changes of aging have been attributed to the somatopause. The purpose of this investigation was to determine the impact of 1 yr of IGF-I hormone replacement therapy on body composition, bone density, and psychological parameters in healthy, nonobese, postmenopausal women over 60 yr of age. Subjects (n = 16, 70.6 +/- 2.0 yr, 71.8 +/- 2.8 kg) were randomly assigned to either the self-injection IGF-I (15 microg/kg twice daily) or placebo group and were studied at baseline, at 6 months, and at 1 yr of treatment. There were no significant differences between the IGF-I and placebo groups in any of the measured variables at baseline. Fasting blood IGF-I levels were significantly elevated above baseline values (65.6 +/- 11.9 ng/mL) at 6 months (330.0 +/- 52.8) and 12 months (297.7 +/- 40.8) in the IGF-I treated group but did not change in the placebo subjects. Circulating levels of IGF-binding protein-1 and -3 were unaffected by the IGF-I treatment. Bone mineral density of the forearm, lumbar spine, hip, and whole body [as measured by dual-energy x-ray absorptiometry (DXA)] did not change in either group. Similarly, there was no difference in DXA-measured lean mass, fat mass, or percent body fat throughout the treatment intervention. Muscle strength values (grip, bench press, leg press), blood lipid parameters (cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides), and measures of postmeal glucose disposal were not altered by IGF-I treatment, although postmeal insulin levels were lower in the IGF-I subjects at 12 months. IGF-I did not affect bone turnover markers (osteocalcin and type I collagen N-teleopeptide), but subjects who were taking estrogen had significantly lower turnover markers than subjects who were not on estrogen at baseline, 6 months, and 12 months. Finally, the psychological measures of mood and memory were also not altered by the intervention. Despite the initial intent to recruit additional subjects, the study was discontinued after 16 subjects completed the protocol, because the preliminary analyses above indicated that no changes were occurring in any outcome variables, regardless of treatment regimen. Therefore, we conclude that 1 yr of IGF-I treatment, at a dose sufficient to elevate circulating IGF-I to young normal values, is not an effective means to alter body composition or blood parameters nor improve bone density, strength, mood, or memory in older women.

Affect↗
PubMed2000

UVA-Induced DNA single-strand cleavage by 1-hydroxypyrene and formation of covalent adducts between DNA and 1-hydroxypyrene.

1-Hydroxypyrene (HOP), a metabolite found in the urine of humans and laboratory animals exposed to polycyclic aromatic hydrocarbons (PAHs), is known to be both acutely toxic and genotoxic. It has been widely used as a biomarker for studying PAH exposure. In this research, we have found that, upon UVA irradiation, HOP causes DNA single-strand cleavages and forms HOP-DNA covalent adducts. The UVA-induced cleavage of supercoiled plasmid PhiX174 DNA is dependent upon both HOP concentration and UVA dosage. A longer irradiation time or higher HOP concentration induces more DNA cleavage. Results of the photocleavage experiments carried out in the presence of reactive oxygen species scavengers, histidine, sodium azide, mannitol, SOD, and desferal indicate that both the superoxide free radical and singlet oxygen are likely involved in causing DNA single-strand cleavage. The photocleavage is inhibited by the presence of an excited singlet-state quencher, KI, indicating that it is an excited-state reaction. Along with light-induced DNA cleavage, HOP also forms DNA covalent adducts while being degraded upon light irradiation. Light-induced degradation of 20 microM HOP follows first-order reaction kinetics in a 10% methanolic buffer (10 mM phosphate) solution in the absence or presence of 40 microM calf thymus DNA, with degradation half-lives of 20 or 15 min, respectively. The shorter degradation half-life in the presence of DNA is due to the formation of the HOP-DNA covalent adduct. The formation of the HOP-DNA covalent adduct is evidenced by comparing the UV-vis absorption and fluorescence emission spectra of the pure HOP with those of the HOP-DNA adduct. The covalent HOP-DNA adduct produced due to irradiation was purified by either extensive dialysis (3 x 500 mL buffer solutions), phenol and chloroform extraction followed by ethanol precipitation, or chloroform extraction alone. The isolated HOP-DNA adduct has an absorption peak at 353 nm, which is 8 nm red-shifted compared to that of free HOP. The fluorescence emission for HOP-DNA is at least 70 times weaker than that for free HOP in solution. In summary, the findings with HOP reveal that, in addition to metabolic activation that eventually leads to the formation of alkylated DNA adducts or other forms of DNA damage, HOP may be activated by light to produce DNA single-strand cleavage and covalent DNA adducts. These DNA lesions can be sources of toxicity.

Animals↗
PubMed1999

Liarozole acts synergistically with 1alpha,25-dihydroxyvitamin D3 to inhibit growth of DU 145 human prostate cancer cells by blocking 24-hydroxylase activity.

1Alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] inhibits the proliferation of many cancer cells in culture, but not the aggressive human prostate cancer cell line DU 145. We postulated that the 1,25-(OH)2D3-resistant phenotype in DU 145 cells might result from the high levels of expression of 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) induced by treatment with 1,25-(OH)2D3. As this P450 enzyme initiates 1,25-(OH)2D3 catabolism, we presumed that a high level of enzyme induction could limit the effectiveness of the 1,25-(OH)2D3 antiproliferative action. To examine this hypothesis we explored combination therapy with liarozole fumarate (R85,246), an imidazole derivative currently in trials for prostate cancer therapy. As imidizole derivatives are known to inhibit P450 enzymes, we postulated that this drug would inhibit 24-hydroxylase activity, increasing the 1,25-(OH)2D3 half-life, thereby enhancing 1,25-(OH)2D3 antiproliferative effects on DU 145 cells. Cell growth was assessed by measurement of viable cells using the MTS assay. When used alone, neither 1,25-(OH)2D3 (1-10 nM) nor liarozole (1-10 microM) inhibited DU 145 cell growth. However, when added together, 1,25-(OH)2D3 (10 nM)/liarozole (1 microM) inhibited growth 65% after 4 days of culture. We used a TLC method to assess 24-hydroxylase activity and demonstrated that liarozole (1-100 microM) inhibited this P450 enzyme in a dose-dependent manner. Moreover, liarozole treatment caused a significant increase in 1,25-(OH)2D3 half-life from 11 to 31 h. In addition, 1,25-(OH)2D3 can cause homologous up-regulation of the vitamin D receptor (VDR), and in the presence of liarozole, this effect was amplified, thus enhancing 1,25-(OH)2D3 activity. Western blot analyses demonstrated that DU 145 cells treated with 1,25-(OH)2D3/liarozole showed greater VDR up-regulation than cells treated with either drug alone. In summary, our data demonstrate that liarozole augments the ability of 1,25-(OH)2D3 to inhibit DU 145 cell growth. The mechanism appears to be due to inhibition of 24-hydroxylase activity, leading to increased 1,25-(OH)2D3 half-life and augmentation of homologous up-regulation of VDR. We raise the possibility that combination therapy using 1,25-(OH)2D3 and liarozole or other inhibitors of 24-hydroxylase, both in nontoxic doses, might serve as an effective treatment for prostate cancer.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed1999

The relationship of biochemical markers of bone turnover to bone density changes in postmenopausal women: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial.

We assessed the associations of eight bone turnover markers (BTMs) with baseline and 1-year percentage changes in lumbar spine and hip bone mineral density (BMD) of 293 postmenopausal women undergoing treatment with hormone replacement therapy (HRT) or placebo using squared correlation coefficients (R2). In 239 women assigned to treatment with estrogen alone or with with estrogen plus progestins (active treatment), mean percentage changes for all markers decreased significantly and remained below baseline values through 3 years of study, whereas mean percentage changes for 54 women assigned to the placebo group showed no significant change from baseline in any marker. At baseline, age and body mass index (BMI) together accounted for 16% and 25% of the variance in spine and hip BMD, respectively. The telopeptide resorption marker, cross-linked N-telopeptide of type I collagen (NTX), alone accounted for 12% and 8% of variance, respectively. Another telopeptide, carboxy-terminal telopeptide of type I collagen (Crosslaps), accounted for 8% and 7% of variance, respectively. A bone-specific alkaline phosphatase (BALP-2) accounted for 8% of variance at the spine and 5% at the hip. No other marker accounted for more than 5% of total variance at either site; adding either baseline NTX, Crosslaps, or BAP-2 to regressions containing age and BMI increased R2 values at the spine and hip to about 22% and 28%, respectively. In the placebo group, baseline spine BMD accounted for 4% of the variance in 1-year spine BMD percentage change, whereas baseline values for age and BMI accounted for 1% and 0% of the variance, respectively; none of the three accounted for more than 0% of hip BMD percentage change; Crosslaps and NTX contributed 5% and 4% to the variance in 1-year spine BMD percentage change, but other markers accounted for < 2% of variance at the spine. At the hip, another BALP (BALP-1) accounted for 4% of variance, but no other baseline marker except NTX accounted for more than 1% of variance. In the active treatment group, baseline values for age, BMI, and spine BMD together accounted for 13% of the percentage change in spine BMD and for 4% of the BMD change at the hip. No individual or pair of baseline markers significantly enhanced these R2 values, but addition of 1-year percentage changes in some individual markers did significantly increase it. The largest R2 value was obtained by adding the percentage change in BALP-2, which increased the R2 in spine BMD percentage change to 20% and that at the hip to 8%. Adding baseline and change variables for all eight markers to the regression increased R2 to 28% at the spine and 12% at the hip. Restricting the set of analyses to individuals who suppressed marker activity beyond the precision error for the measurement did not improve R2s for the regressions. When baseline marker values were stratified into quartiles, only NTX and osteocalcin showed significant relationships between quartile and change in spine BMD, and these did not reach significance at the hip. When the 1-year change in markers was stratified into quartiles, significant relationships with percentage change in spine BMD were observed only for BALP phosphatases. We conclude that BTMs are not a surrogate for BMD to identify women with low bone mass and that they offer little useful information for predicting BMD changes for individual untreated or HRT-treated postmenopausal women.

Alkaline Phosphatase↗
PubMed1999

Lack of association of anabolic hormone status and muscle strength with regional and whole body bone mineral density in healthy men aged 60-79 years.

This study investigated the capacity of muscle strength and anabolic hormone status to predict regional and whole body bone mineral density (BMD) in older men. Fifty-two healthy men aged 60-79 years served as subjects. BMD of the lumbar spine, proximal femur, upper and lower limbs, and whole body was assessed by dual X-ray absorptiometry. Dynamic muscle strength for several upper and lower body muscle groups was determined by the one-repetition maximum and isometric grip strength by dynamometry. Anabolic hormone status was assessed by the ratio of testosterone (T) to sex hormone binding globulin (SHBG), given as the free androgen index (FAI), and the ratio of insulin-like growth factor I (IGF-I) to IGF binding protein-3 (IGFBP-3). Age was associated with declines in dynamic strength and the log FAI. In stepwise regression analysis, only body mass was an independent predictor of whole body and upper limb BMD (R2 = 0.13), and hip adductor strength predicted the Ward's triangle (R2 = 0.14). For lumbar spine BMD, triceps extensor strength was significantly correlated (r = 0.36, p < 0.01), while no strength or hormonal variable was associated with the femoral neck, trochanter, or lower limb. The lack of association between muscle strength and BMD was generally unaltered after controlling for hormone status and body mass. There was no difference in BMD when analyzed by tertiles of log FAI or IGF-I/IGFBP-3 or by tertiles of muscle strength. These results suggest that in healthy community-dwelling men in the seventh and eighth decade, muscle strength and hormonal status are not significant contributors to regional or whole body BMD.

Aged↗
PubMed1998

Relationship of chronic endurance exercise to the somatotropic and sex hormone status of older men.

To investigate putative abrogating effects of habitual endurance exercise on age-related changes in endocrine function and body composition, we compared insulin-like growth factor-I (IGF-I), sex hormonal status and body composition in 15 Masters runners and 15 minimally exercising men (MEM) aged 60-70 years. A higher maximal oxygen uptake (VO2 max.) in the runners (41.4+/-1.6 compared with 27.3+/-1.4 ml/kg/min, P=0.0001; mean+/-S.E.M.) reflected our group allocations. Analysis of body composition and bone mineral density (BMD) by dual energy X-ray absorptiometry showed no group differences in lean tissue mass or in regional or whole body BMD, but MEM were heavier, reflecting greater adiposity. Of nine muscle groups tested, only quadriceps strength differed significantly, being greater in runners (60.3+/-2.8 compared with 51.1+/-2.3 kg, P=0.02). Total IGF-I (129+/-10 compared with 124+/-11 ng/ml, P=0.72) and IGF-binding protein-3 (2854+/-94 compared with 2623+/-128ng/ml, P=0.16), were similarly depressed compared with young adult norms in both groups. There was no relationship between total or bioavailable IGF-I and any body composition, BMD or muscle strength variable. In the runners, concentrations of total testosterone (19.1+/-0.8 compared with 15.0+/-0.9 nmol/l, P=0.002) and sex hormone binding globulin (SHBG) (124.4+/-21.6 compared with 67.7+/-11.6 nmol/l, P=0.03) were significantly greater, but the free androgen index was significantly lower (20.7+/-2.7 compared with 31.4+/-4.1, P=0.04). Directly measured free testosterone, however, was similar between the runners and MEM (47.9+/-1.8 compared with 47.1+/-2.0 nmol/l P=0.80). Therefore the group differences in total testosterone and free androgen index were due to their different SHBG concentrations. Although estrone concentration was higher in MEM (85.1+/-5.2 compared with 108+/-6.7 pmol/l, P=0.03), estradiol concentration was similar between groups (73.0+/-6.3 compared with 81.8+/-8.0 pmol/l, P=0.18), indicating that estrogens were not responsible for the increased SHBG in runners. These results indicate that even high levels of regular endurance exercise do not prevent the decline in the somatotropic axis that occurs with aging. Furthermore, the somatic effects of exercise in older men (reduced adiposity and increased regional muscle strength) occurred independently of somatotropic or androgen status. Although habitual exercise does not influence free testosterone concentrations in older men, it appears to enhance the age-associated increase in SHBG synthesis.

Aged↗
PubMed1997

Skeletal effects of cyclic recombinant human growth hormone and salmon calcitonin in osteopenic postmenopausal women.

The objectives of this study were to determine whether cyclic administration of recombinant human GH, with or without the antiresorptive agent, salmon calcitonin (CT), provides clinically meaningful increases in bone mineral density (BMD) at the lumbar spine and proximal femur in postmenopausal osteopenic women. The design of the study was a randomized clinical trial consisting of 12 56-day treatment cycles. Each cycle was initiated by a 12-day period of hormone administration, followed by 44 days of supplemental calcium only. Cycles of hormone administration consisted of 7 daily injections of recombinant GH (20 micrograms/kg.day) or its placebo, followed by 5 daily injections of salmon CT (100 U/day) or its placebo. The study was performed at the Palo Alto Veterans Affairs medical center. The patients were 84 healthy women with lumbar spine BMD more than 1 SD below the average value for a healthy 25-yr-old Caucasian woman. BMD was measured at the lumbar spine and proximal femur by dual energy x-ray absorptiometry. Biochemical markers of bone turnover and circulating insulin-like growth factor I were also measured. GH treatment increased insulin-like growth factor I concentrations from low values at baseline (112 +/- 56 ng/mL) to the young normal range (approximately 430 +/- 125 ng/mL). Groups receiving GH plus CT or GH plus placebo increased lumbar spine BMD at 2 yr by 2.70 +/- 0.81% (P < 0.01) and 1.72 +/- 0.74% (P < 0.05; intention to treat analysis). No significant change occurred in women receiving placebo plus CT or combined placebo. Significant increases in total hip BMD of 1-2% were observed for the GH plus placebo and placebo plus CT groups, with a nonsignificant trend in the GH plus CT group. For the femoral trochanter, significant increases were observed in the GH plus CT and placebo plus CT groups only. No significant change in femoral neck BMD was observed in any group. Women taking replacement estrogen had the same BMD response as those who were estrogen deficient. No significant increase in BMD was observed between 24 and 36 months in the 62 women who returned for a 3 yr measurement. In response to GH, short term increases in resorption and formation markers were observed, but these had decreased before the next treatment cycle. No long term changes in resorption markers were observed, but women in the GH groups showed a sustained rise in circulating osteocalcin over the entire 2-yr protocol. GH given cyclically with or without CT for 2 yr achieved statistically significant increases in BMD of the lumbar spine and selected areas of the hip in postmenopausal women. These gains were less marked than those achieved with estrogen or bisphosphonates and were associated with a relatively high incidence of adverse experiences. Therefore, it is unlikely that cyclic GH with or without CT will prove clinically useful in the treatment of postmenopausal women with osteoporosis.

Aged↗
PubMed1996

Cellular infiltration of the airways in asthma of varying severity.

We have tested the hypothesis that airway infiltration by inflammatory cells reflects the severity of asthma by comparing the inflammatory cell infiltrates in fatal severe asthma and in subjects with mild to moderate asthma who died of unrelated causes. Sections of lung tissue from 25 fatal asthma cases and eight asthmatics who died of unrelated causes were immunostained by monoclonal antibodies (mAbs) using streptavidin-biotin peroxidase technique. The following cells were identified: mast cells (AA1:tryptase), eosinophils (EG1:stored cationic protein and EG2: secretory form of cationic protein), monocytes/macrophages (CD68), neutrophils (elastase), CD3+ and CD8+ T cells (CD3 polyclonal Ab and CD8+ mAb, respectively). Positive cells were counted in the epithelium and airway wall. The airways were divided into two groups: larger airways with internal perimeter (Pi) > 2 mm and smaller airways with Pi < 2 mm. All airways together were studied first, followed by larger and smaller airways examined separately. The numbers of intraepithelial CD3+ T cells were significantly lower in fatal asthma than in mild-moderate asthma both when all airways were considered (0.35 versus 0.86 cells/mm, p = 0.034) and in the larger airways alone (0.08 versus 1.05 cells/mm, p = 0.039). The numbers of EG1- and EG2-positive eosinophils infiltrating the airway wall of the larger airways were greater in fatal asthma than in mild-moderate asthma (78.2 versus 22.8 cells/mm2, p = 0.012 and 138.1 versus 31.7 cells/mm2, p = 0.022). In the smaller airways no significant difference was found between the two groups. We conclude that in fatal asthma there is a redistribution of CD3+ T cells away from the epithelium and proximal enhancement of the eosinophil inflammatory infiltrate. These findings have implications for the pathophysiology of asthma that results in death.

Adolescent↗
PubMed1996

Immunopathology of fatal soybean dust-induced asthma.

A hypothesis was postulated that the characteristic clinical course of fatal soybean asthma may be reflected by specific immunopathological findings. Seven cases of fatal soybean dust-induced asthma from Barcelona, Spain were compared with 25 fatal asthma cases from New Zealand. Sections of lung tissue were stained by monoclonal antibodies using standard streptavidin-biotin peroxidase technique. The following cell types were identified: mast cells, "activated" eosinophils, neutrophils, monocytes/macrophages, CD3+ T-cells and CD8+ T-cells. The positively staining cells were counted in the epithelium and the submucosa and their numbers expressed per mm and mm2, respectively. The airways were divided into larger (internal perimeter (Pi) > 2 mm) and smaller (Pi < 2 mm). Firstly, all airways were studied together; and subsequently, larger and smaller airways were studied separately. Differences in the numbers of mast cells, eosinophils, neutrophils and monocytes/macrophages between the two groups were not significant. The numbers of CD3+ and CD8+ T-cells were significantly reduced in fatal soybean asthma when all airways were taken together. In larger airways, the difference was not significant in the epithelium, but was significant in the submucosa for CD3+ cells. CD8+ cells were significantly reduced in fatal soybean asthma both in the epithelium and the submucosa. The cell counts in smaller airways were not significantly different either in the epithelium or in the submucosa for CD3+ cells. The numbers of CD8+ cells were not different in the epithelium, but were significantly reduced in the submucosa of fatal soybean asthma cases. We conclude that the numbers of CD3+ and CD8+ T-cells are substantially reduced in fatal soybean asthma. These data together with the clinical features of the fatal attack suggest a different mechanism(s) from that described for most asthma deaths, probably involving anaphylaxis.

Adult↗
PubMed1995

Effects of recombinant insulin-like growth factor-I and growth hormone on bone turnover in elderly women.

We evaluated the effects of recombinant insulin-like growth factor-I (IGF-I) and growth hormone (GH) on calciotropic hormones and bone turnover markers in 16 healthy elderly women 71.9 +/- 1.3 years of age (mean +/- SEM). Subjects consumed a fixed diet providing 1000 mg of calcium and 0.9 g/kg of protein for 10 days before starting baseline 24-h urine and blood collections. Specimens were collected for 6 consecutive days before initiating subcutaneous injections of GH (25 micrograms/kg/day, n = 5) and IGF-I at 60 micrograms/kg b.i.d. (high-dose, n = 5) or at 15 micrograms/kg b.i.d. (low-dose, n = 6) for 28 days. Resorption markers included urine hydroxyproline (OHP), total pyridinolines (PYD), and N-telopeptide; formation markers include osteocalcin, skeletal alkaline phosphatase (sALP), and type I procollagen carboxy-terminal extension peptide (CICP). For each subject, baseline daily turnover markers varied substantially (DV = 16-22%). With GH and high-dose IGF-I, resorption and formation markers increased progressively to maximum levels at day 21. For GH, the increase in day 21 PYD, N-telopeptide, osteocalcin, and CICP was 143, 111, 53, and 81%, respectively (p < 0.96-0.02). For high-dose IGF-I, these increases were 108, 81, 77, and 111% (p < 0.02-0.002). However, with low-dose IGF-I no change was observed in resorption markers while osteocalcin and CICP increased progressively (day 21, % increases = 88 +/- 51, 36 +/- 14). Twenty-four hour urine collections during the last days of baseline and of study drug were taken as six 4 h aliquots. When deoxyPYD was measured on these samples in the low-dose IGF-I group, a significant increase was observed only on the 0800-1200 h aliquot. Serum phosphorus concentrations increased with GH (21.2 +/- 3.3%) and high-dose IGF-I (8.8 +/- 3.6%) by day 21 but actually decreased by day 28 (-9.7 +/- 2.7, p < 0.02) with low-dose IGF-I. Urinary phosphorus excretion decreased with high-dose IGF-I only. Twenty-four hour calcium excretion increased with all treatments. These results indicate that both GH and high-dose IGF-I activate remodeling osteons. By contrast, low-dose IGF-I may directly increase osteoblastic function with only a minimal increase in bone resorption and may therefore provide a useful means to increase bone mass. The results also suggest some of the GH action on renal phosphorus handling represents a direct action of GH on the nephron which does not involve the intermediacy of IGF-I. Finally, even under controlled conditions bone turnover markers exhibit substantial daily variation so that a very large treatment effect will be required for these markers to have clinical utility.

Aged↗
PubMed1995

Effects of a gonadotropin-releasing hormone agonist on the calcium-parathyroid axis and bone turnover in women with endometriosis.

OBJECTIVE: Our purpose was to investigate the effects of nafarelin on bone turnover and mass (bone mineral density, in grams per square centimeter) in women with endometriosis. STUDY DESIGN: We monitored 22 young women with endometriosis during and 6 months after 6 months of nafarelin treatment. We compared the bone mineral density status of these women with that of healthy controls undergoing sequential bone mineral density measurement. RESULTS: Subjects had a 2.2% loss in L2-4 bone mineral density by 6 months, increasing 3 months later to 3% and returning toward baseline by 6 months after treatment. Radius bone mineral density did not change in the treatment group. Bone mineral density did not change in controls. Serum and urinary calcium levels rose during treatment. Hydroxyproline excretion increased and remained elevated 6 months after treatment. A rise in serum osteocalcin persisted 3 months after therapy but normalized by 6 months. CONCLUSIONS: Bone mineral density deficits with nafarelin are reversible. Increased bone turnover persists 6 months beyond treatment, demonstrating the need for careful monitoring of women receiving prolonged or repeated treatment.

Adult↗
PubMed1994

Interactions of growth hormone and parathyroid hormone in renal phosphate, calcium, and calcitriol metabolism and bone remodeling in postmenopausal women.

The mechanisms underlying the effects of recombinant human growth hormone (rhGH) on vitamin D, mineral, and bone metabolism are not known. We examined whether these effects are mediated by parathyroid hormone (PTH) by measuring renal phosphorus (P) and calcium (Ca) handling, serum calcitriol, and markers of bone turnover for 24 h before and 72 h after an infusion of hPTH(1-34) in eight healthy postmenopausal women at baseline and following short-term (1 week) and sustained (5 weeks) rhGH treatment. On short-term rhGH, serum phosphorus and basal TmP/GFR were unaffected, but the fall in TmP/GFR after hPTH infusion was exaggerated (integrated response: -99.2 +/- 22.3 versus -144.1 +/- 15.0 minute-mg/dl, P = 0.0021). Basal calcitriol levels rose from 115 +/- 17 to 163 +/- 16 pM (P = 0.0002), but the increase in calcitriol following hPTH infusion was unaffected by short-term rhGH. The basal Ca excretion index (CEI) rose from 0.054 +/- 0.005 to 0.073 +/- 0.007 mM (P = 0.0095), but markers of bone turnover were unaffected. With sustained rhGH treatment, serum P (1.47 +/- 0.05 mM), basal TmP/GFR (4.29 +/- 0.24 mg/dl), and basal CEI (0.067 +/- 0.005 mM) were elevated compared with control values, and the PTH-induced lowering of TmP/GFR was again enhanced (-158.7 +/- 22.8 minute-mg/dl, P = 0.0021). Basal calcitriol concentrations returned to control levels (108 +/- 10 pM), but the calcitriol response to hPTH remained unchanged. Markers of bone remodeling were elevated with sustained rhGH treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1994

Effects of recombinant human growth hormone on metabolic indices, body composition, and bone turnover in healthy elderly women.

We conducted a controlled trial of recombinant human GH (rhGH) in 27 healthy elderly women (66.7 +/- 3.0 yr), of whom 8 took a stable dose of replacement estrogen throughout the study (plus estrogen group). Hormone or placebo was given as a single daily injection. A total of 19 women were assigned to receive rhGH at an initial daily dose of 0.043 mg/kg BW. After several weeks, 50% dose reductions were necessitated by side-effects. The last 7 subjects to be enrolled began treatment at this reduced level. A total of 13 women assigned to rhGH and 14 women assigned to placebo completed 6 months of drug treatment. In the rhGH group, 6 women took estrogen; thus, the effects of rhGH were assessed separately by estrogen status. Circulating insulin-like growth factor-I (IGF-I) levels were similar at baseline (rhGH, 133 +/- 40.4 micrograms/L; placebo, 128 +/- 13). rhGH increased IGF-I and IGF-I-binding protein-3 (IGFBP-3) in all subjects [6 month IGF-I in plus estrogen women, 230 +/- 25.4 micrograms/L; in those not receiving estrogen (minus estrogen), 308 +/- 21.3]. No changes in IGF-I or IGFBP-3 occurred with placebo (IGF-I, 144 +/- 21.3 micrograms/L). Skinfold thickness measurements showed an 11% decrease in fat mass (P < 0.005) and a 9% decrease in percent fat after 6 months of rhGH treatment. No significant difference in nitrogen balance was seen in either group at 6 months, but rhGH increased creatinine clearance by 9.2% (P < 0.05). rhGH dramatically increased markers of bone turnover, with more pronounced effects in minus estrogen women. Hydroxyproline excretion increased by 20% and 80%, and pyridinoline excretion increased by 44% and 75% in plus and minus estrogen subgroups, respectively. Osteocalcin concentrations increased by more than 60% in minus estrogen women (P < 0.05), but did not change in the plus estrogen group. No changes were observed in circulating type I procollagen extension peptide in either group, and no change in any turnover marker was seen in the placebo group. rhGH did not alter blood pressure or circulating L-T4 levels, but a transient increase in serum T3 was observed in the minus estrogen group at 3 months. rhGH decreased low density lipoprotein cholesterol in the minus estrogen group, but otherwise no significant changes in circulating lipoproteins or fibrinogen were observed. Eight women assigned to rhGH and 14 placebo-treated women remained on blinded treatment through 12 months.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1994

The relationship between pulmonary interstitial emphysema and clinical features in fatal asthma.

Using retrospective histological material and clinical data from the New Zealand National Asthma Mortality Study, we investigated whether there was a relationship between the presence of pulmonary interstitial emphysema (PIE) and different clinical features in fatal asthma, in particular precipitous asthma death. Histological evidence of PIE was determined in sections from 12 of the 60 patients who had died from asthma who fulfilled the pathological criteria for inclusion in the study. No significant correlation was found between the presence of PIE and the different clinical features examined. For example, of the 13 cases with precipitous fatal asthma (i.e., death occurred within 10 min of the onset of the attack), only two had PIE. This suggests that PIE is not an uncommon histological feature of fatal asthma and may, in fact, significantly contribute to an asthma death, but its presence does not appear to be associated with the specific clinical subgroups studied here.

Asthma↗
PubMed1993

Clinical uses of growth hormone in older people.

Many of the age-related changes in body composition resemble those associated with growth hormone deficiency, and growth hormone secretion decreases with normal human ageing. With the availability of recombinant human growth hormone (rhGH), it is now possible to test the metabolic and structural effects of growth hormone administration to adults. Administration of rhGH to healthy elderly people acutely promotes nitrogen retention and activates bone remodelling. Chronic administration may increase lean mass in men, but appears to give less impressive results in women. Changes in bone remodelling are not accompanied by dramatic increases in bone mass. Thus, it is not likely that daily administration of rhGH as a single agent will prove to be an effective means for regaining deficits in bone, but it may be possible to incorporate rhGH into a multi-agent strategy. In healthy older humans growth hormone can be given without obvious adverse effects on cardiovascular risk factors.

Aged↗