Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown that testosterone (T) deficiency per se is associated with marked catabolic effects on protein, calcium metabolism, and body composition in men independent of changes in GH or insulin-like growth factor I production. It is not clear,,however, whether estrogens have a major role in whole body anabolism in males. We investigated the metabolic effects of selective estrogen suppression in the male using a potent aromatase inhibitor, Arimidex (Anastrozole). First, a dose-response study of 12 males (mean age, 16.1 +/- 0.3 yr) was conducted, and blood withdrawn at baseline and after 10 days of oral Arimidex given as two different doses (either 0.5 or 1 mg) in random order with a 14-day washout in between. A sensitive estradiol (E2) assay showed an approximately 50% decrease in E2 concentrations with either of the two doses; hence, a 1-mg dose was selected for other studies. Subsequently, eight males (aged 15-22 yr; four adults and four late pubertal) had isotopic infusions of [(13)C]leucine and (42)Ca/(44)Ca, indirect calorimetry, dual energy x-ray absorptiometry, isokinetic dynamometry, and growth factors measurements performed before and after 10 weeks of daily doses of Arimidex. Contrary to the effects of T withdrawal, there were no significant changes in body composition (body mass index, fat mass, and fat-free mass) after estrogen suppression or in rates of protein synthesis or degradation; carbohydrate, lipid, or protein oxidation; muscle strength; calcium kinetics; or bone growth factors concentrations. However, E2 concentrations decreased 48% (P = 0.006), with no significant change in mean and peak GH concentrations, but with an 18% decrease in plasma insulin-like growth factor I concentrations. There was a 58% increase in serum T (P = 0.0001), sex hormone-binding globulin did not change, whereas LH and FSH concentrations increased (P < 0.02, both). Serum bone markers, osteocalcin and bone alkaline phosphatase concentrations, and rates of bone calcium deposition and resorption did not change. In conclusion, these data suggest that in the male 1) estrogens do not contribute significantly to the changes in body composition and protein synthesis observed with changing androgen levels; 2) estrogen is a main regulator of the gonadal-pituitary feedback for the gonadotropin axis; and 3) this level of aromatase inhibition does not negatively impact either kinetically measured rates of bone calcium turnover or indirect markers of bone calcium turnover, at least in the short term. Further studies will provide valuable information on whether timed aromatase inhibition can be useful in increasing the height potential of pubertal boys with profound growth retardation without the confounding negative effects of gonadal androgen suppression.
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PMID:Estrogen suppression in males: metabolic effects. 1129 27

Evidence for the role of estrogen in male bone metabolism has been confirmed by studies on a man with a genetic defect in the estrogen receptor as well as men with aromatase defects. All exhibited tall stature, delayed epiphysial closure, decreased bone density and increased bone turnover. Estrogen is likely to affect bone turnover in men throughout life; therefore, we hypothesized that older men would show decreased bone resorption in response to estrogen therapy. To test our hypothesis, fourteen community-dwelling men with osteopenia of the femoral neck were treated for 9 weeks with micronized estradiol, 1 mg/d, a dose which is effective in postmenopausal women. Each subject served as his own control. Markers of bone resorption, N-terminal collagen crosslinks (NTX) and C-terminal collagen crosslinks (CTX) and markers of bone formation, osteocalcin (OC) and bone specific alkaline phosphatase (BSAP) were measured every 3 weeks during a 9-week treatment period and 9 weeks post-treatment. Sex hormones, gonadotrophins and calciotropic hormones were measured at baseline, 9 weeks on treatment and 9 weeks post- treatment. After 9 weeks of treatment, estradiol and estrone levels increased significantly by greater than 6-fold and 15-fold, respectively. SHBG levels increased significantly by 17%. Testosterone and free testosterone levels decreased significantly by 27% and 34%, respectively. Markers of bone resorption showed wide variation at baseline and while on treatment. There was no correlation between changes in bone markers and changes in estrogen levels. During treatment, 11 patients showed a decrease of NTX or CTX, but three showed an increase. These three and one other subject had high initial levels of FSH and LH, suggesting some degree of primary gonadal failure, which decreased during estrogen therapy. Thus, the change in NTX (and CTX) after 9 weeks of E2 treatment was correlated with initial FSH (r= -.66, p= .01) and LH (r= -.73, p= .003) values. In addition, the largest decrease in free testosterone at 9 weeks was correlated with the higher values for NTX, CTX and BAP (r=-0.66, -0.68, -0.70 respectively; p< or =.01 for each of the markers). Treatment was generally well tolerated. Side effects of treatment were minimal, and included breast tenderness and decreased libido which reversed after treatment. We conclude that it is feasible to give low dose estrogen to healthy older men, but that the effects on bone turnover are not consistent. Changes in central feedback and in endogenous sex hormone production may alter the response of bone turnover to exogenous estrogen in this population.
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PMID:The effect of short-term treatment with micronized estradiol on bone turnover and gonadotrophins in older men. 1101 3

The objective of the present study was to assess the toxicology of melatonin (10 mg), administered for 28 days to 40 volunteers randomly assigned to groups receiving either melatonin (N = 30) or placebo (N = 10) in a double-blind fashion. The following measurements were performed: polysomnography (PSG), laboratory examinations, including complete blood count, urinalysis, sodium, potassium and calcium levels, total protein levels, albumin, blood glucose, triglycerides, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL), urea, creatinine, uric acid, glutamic-oxalacetic transaminase (GOT), glutamic-pyruvate transaminase (GPT), bilirubin, alkaline phosphatase, gama-glutamic transaminase (GGT), T3, T4, TSH, LH/FSH, cortisol, and melatonin serum concentrations. In addition, the Epworth Somnolence Scale (ESS) and a sleep diary (SD) were also applied to the volunteers 1 wk before each PSG. In addition, the volunteers were asked about possible side effects (SE) that appeared during the treatment. The study was carried out according to the following timetable: Visit 0, filling out the term of consent and inclusion criteria; Visit 1, PSG, laboratory examinations, ESS, SD, melatonin serum concentrations; Visit 2, SD, melatonin serum concentrations, SE; Visit 3, melatonin serum concentrations, PSG, ESS, SE; Visit 4, laboratory examinations, SE, melatonin serum concentrations, SD; and Visit 5, PSG, ESS, SE. Analysis of the PSG showed a statistically significant reduction of stage 1 of sleep in the melatonin group. No other differences between the placebo and melatonin groups were obtained. In the present study we did not observe, according to the parameters analyzed, any toxicological effect that might compromise the use of melatonin at a dose of 10 mg for the period of time utilized in this study.
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PMID:Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. 1106 41

Carbamate insecticides are widely used in industry, agriculture and for public health purposes. Numerous incidents of acute carbamate poisoning have resulted from inhalation of sprays or contamination of crops or food. This work was conducted to study the effect of chronic exposure to methomyl on hormonal, histopathological and histochemical changes in rat testes. The treated group received methomyl orally (17 mg kg(-1)in saline) daily for 2 months, while the control group received saline. A significant decrease in the level of testosterone was observed in the intoxicated animals, while the levels of FSH, LH and prolactin were significantly increased. Histopathological studies of the intoxicated rat testes revealed variable degrees of degenerative changes in the seminiferous tubules up to total cellular destruction. As regards the histochemical results, it was found that both acid phosphatase and alpha esterase enzyme activity was significantly increased compared to the control group. On the other hand succinic dehydrogenase enzyme activity was significantly reduced. No significant change was observed in alkaline phosphatase enzyme activity. The hormonal changes and testicular damage continued for 30 days after withdrawal of the insecticide indicating a persistent effect. From the above-mentioned findings, it has been concluded that chronic exposure to methomyl insecticide has deleterious effects on rat testes. Therefore application of such insecticide should be limited to a designed program with special care in handling to limit or minimize its hazards.
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PMID:Evaluation of chronic exposure of the male rat reproductive system to the insecticide methomyl. 1151 54

Cytokines and nitric oxide (NO) have been implicated in bone loss caused by estrogen deficiency. Here we evaluated the effect of nitric oxide synthase (NOS) inhibitors on the bone particle resorbing activity and TNF-alpha release of cultured peripheral blood monocytes (PBM) obtained from 10 premenopausal (PreM) and 10 postmenopausal (PostM) women. Gonadal status (menopause < 3 yr) was assessed by FSH and estradiol. Bone alkaline phosphatase and N-Telopeptide were significantly increased in PostM. Significant differences between PreM and PostM women were observed in bone mineral density of lumbar spine. The bone particle resorbing activity of PBM cultured in the presence of L-arginine-methyl ester (NAME) or aminoguanidine, NOS inhibitors, was determined by (45)Ca release from rat bone labeled particles. TNF-alpha release was assayed in supernatants by ELISA. (45)Ca release was higher in PostM (p < 0.01) and was enhanced by NAME (p < 0.02). Furthermore, TNF-alpha release from PBM was significantly higher in PostM (p < 0.01). Aminoguanidine significantly increased TNF-alpha release in PreM. Based on these findings and on the evidence that estrogen stimulates NOS, we suggest that estrogen withdrawal may reduce the inhibitory effect of NO on TNF-alpha release. Thus, this increased production of TNF-alpha could contribute to the increased postmenopausal bone turnover.
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PMID:Estrogenic status influences nitric oxide-regulated TNF-alpha release from human peripheral blood monocytes. 1157 73

The aim of the current work was to investigate the role of gonadotropins and female sex hormones on interrenal activity in soft-shelled turtles, Lissemys punctata punctata. 1) FSH treatment (3 microg/100 g body wt daily for 10 days) caused interrenal hypertrophy with increased nuclear diameter, raises of acid phosphatase and alkaline phosphatase concentrations, and depletions of cholesterol (except the free fraction) and ascorbic acid levels from the interrenal gland. However, LH treatment (3 microg/100 g body wt daily for 10 days) failed to produce any perceptible change in the interrenal activity. The combined treatments of FSH and LH (3 microg each/100 gm body wt daily for 10 days) produced no further change beyond that of FSH alone. 2) Estrogen treatment with the low dose (25 microg/100 g body wt daily for 10 days) had no effect, but with higher doses (50 microg or 100 microg/100 gm body wt daily for 10 days) is caused interrenal stimulation by inducing the same manifestations to those of FSH. The degree of manifestations was higher with the higher dose (100 microg daily) than that of the moderate dose (50 microg daily). Progesterone treatment with the low dose (25 microg /100 g body wt daily for 10 days) had no significant effect, but with the moderate (50 microg daily) and higher (100 microg daily) doses suppressed interrenal activity by showing the reverse changes to those of estrogen. The degree of manifestations was higher with the higher dose than that of the moderate one. The combined treatments of estrogen and progesterone (100 microg each/100 g body wt daily for 10 days) caused interrenal stimulation but to a lesser extent than that of estrogen alone. The findings are briefly discussed.
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PMID:Gonadotropins and sex hormones modulate interrenal function in soft-shelled turtle. 1272 56

This multicenter, double-blind, placebo-controlled, randomized study of 45 patients evaluated the short-term effects of an oral contraceptive [Ortho Tri-Cyclen, 180-250 micro g of norgestimate (NGM) and 35 microg of ethinyl estradiol (EE)] on biochemical markers of bone resorption, formation, and osteoprotegerin in young women (mean age +/- SD, 26.5 +/- 6.3 yr) with hypothalamic amenorrhea and osteopenia. Body fat, endocrine, and cognitive function were evaluated as secondary endpoints. Biomarkers of bone metabolism were measured at baseline and after three cycles of NGM/EE or placebo. There were significant decreases in mean values of N-telopeptide [mean (SD), -13.4 (13.4) vs. 1.2 (23.8) nmol bone collagen equivalents (BCE)/mmol creatinine (Cr); P = 0.001] and deoxypyridinoline [-1.2 (2.9) vs. -0.5 (1.5) nmol deoxypyridinoline/mmol Cr; P = 0.021] as well as significant decreases in bone specific alkaline phosphatase [-5.1 (3.5) vs. 0.4 (3.1) ng/ml; P < 0.001], osteocalcin [-5.9 (3.6) vs. -2.9 (3.7); P = 0.016], and procollagen of type I propeptide [-35.2 (44.6) vs. -0.2 (30.0) ng/ml; P = 0.025], but not osteoprotegerin [0.39 (1.46) vs. -0.2 (0.49) pmol/liter; P = 0.397] in the NGM/EE vs. placebo group. There were no significant differences between groups with respect to changes in cognitive function, mood, body weight, body mass index, body fat, percentage of body fat, and all endocrine levels except FSH, [-3.7 (3.8) vs. -0.6 (2.1) IU/liter; P < 0.001, NGM/EE vs. placebo]. No serious adverse events were reported in either group. These results suggest that NGM/EE decreases bone turnover in osteopenic premenopausal women with hypothalamic amenorrhea. Further studies are needed to determine whether estrogen will increase bone density in this population.
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PMID:Effects of a triphasic combination oral contraceptive containing norgestimate/ethinyl estradiol on biochemical markers of bone metabolism in young women with osteopenia secondary to hypothalamic amenorrhea. 1291 50

Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are widely used for the treatment of hyperlipidemia, and recent studies and animal data suggest that statins promote osteogenesis and increase bone strength. However, little is known about the effects of statins delivered by sustained delivery system to a target site of a defect and segmental bone fractures on certain biochemical markers including reproductive hormones. The purpose of this study was to develop a targeted statin delivery system using Tricalcium Phosphate Lysine (TCPL) for defect and segmental femoral injuries and evaluate the effects on alkaline phosphatase, total protein, malinodialdehyde, glutathione, total cholesterol, testosterone, luteinizing hormone, statins, and follicle-stimulating hormone. Because of the influence oral intake of statins might have on certain body organs, we also examine the histomorphology of the vital and reproductive organs of the animals receiving statins for a period of 30 days and 12 weeks post surgery. Simvastatin used in this study significantly increased fracture healing and without significant influence on the body weights and the weights and morphology of the vital and reproductive organs. There was a significant reduction in the cholesterol levels on the 3rd week in both phases of the study and at the conclusion of the study the difference in the cholesterol levels was no more significant in both phases. Other biochemical markers including plasma LH, FSH and testosterone levels were not affected by active treatment with simvastatin. In conclusion, short and long-term simvastatin treatment delivered at a fracture target site did not influence vital and reproductive organs, the systemic levels of the biochemical markers studied, but was able to effectively stimulate bone formation in simple and complicated segmental fractures.
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PMID:Effects of sustained release of statin by means of tricalcium phosphate lysine delivery system in defect and segmental femoral injuries on certain biochemical markers in vivo. 1681 97

Recently, we have reported that a Prophet of Pit-1 homeodomain factor, Prop-1, is a novel transcription factor for the porcine follicle-stimulating hormone beta subunit (FSHbeta) gene. This study subsequently aimed to examine the role of Prop-1 in the gene expression of two other porcine gonadotropin subunits, pituitary glycoprotein hormone alpha subunit (alphaGSU), and luteinizing hormone beta subunit (LHbeta). A series of deletion mutants of the porcine alphaGSU (up to -1059 bp) and LHbeta (up to -1277 bp) promoters were constructed in the reporter vector, fused with the secreted alkaline phosphatase gene (pSEAP2-Basic). Transient transfection studies using GH3 cells were carried out to estimate the activation of the porcine alphaGSU and LHbeta promoters by Prop-1, which was found to activate the alphaGSU promoter of -1059/+12 bp up to 11.7-fold but not the LHbeta promoter. Electrophoretic mobility shift assay and DNase I footprinting analysis revealed that Prop-1 binds to six positions, -1038/-1026, -942/-928, -495/-479, -338/-326, -153/-146, and -131/-124 bp, that comprise the A/T cluster. Oligonucleotides of six Prop-1 binding sites were directly connected to the minimum promoter of alphaGSU, fused in the pSEAP2-Basic vector, followed by transfecting GH3 cells to determine the cis-acting activity. Finally, we concluded that at least five Prop-1 binding sites are the cis-acting elements for alphaGSU gene expression. The present results revealed a notable feature of the proximal region, where three Prop-1-binding sites are close to and/or overlap the pituitary glycoprotein hormone basal element, GATA-binding element, and junctional regulatory element. To our knowledge, this is the first demonstration of the role of Prop-1 in the regulation of alphaGSU gene expression. These results, taken together with our previous finding that Prop-1 is a transcription factor for FSHbeta gene, confirm that Prop-1 modulates the synthesis of FSH at the transcriptional level. On the other hand, the defects of Prop-1 are known to cause dwarfism and combined pituitary hormone deficiency accompanying hypogonadism. Accordingly, the present observations provide a novel view to understand the hypogonadism caused by Prop-1 defects at the molecular level through the regulatory mechanism of alphaGSU and FSHbeta gene expressions.
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PMID:Pituitary transcription factor Prop-1 stimulates porcine pituitary glycoprotein hormone alpha subunit gene expression. 1703 49

To our knowledge anorexia nervosa (AN) adversely influences bone density, but whether qualitative characteristics of bone are also affected is not known. For this reason we investigated prospectively the changes in skeletal status in a population of 18 adolescent girls with AN aged 11.5-18.1 years (mean 15.9+/-1.9 years) using both dual-photon X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) measurements, bone turnover markers (osteocalcin, bone alkaline phosphatase - bALP, carboxy-terminal cross-linked telopeptide of type I collagen - ICTP), and laboratory investigations (serum total and ionised calcium, serum phosphate, urine calcium/creatinine ratio, luteinizing hormone - LH, follicle-stimulating hormone - FSH, estradiol). Measurements of bone mineral density at the spine (s-BMD) and total body (TB-BMD) and amplitude-dependent speed of sound (Ad-SOS) of the hand phalanges were performed at baseline, 7.8+/-2.4 and 19.4+/-5.6 months of follow-up. The mean values of TB-BMD, s-BMD and Ad-SOS measurements did not change during the period of observation. The mean Z-scores for TB-BMD and Ad-SOS were significantly lower after 19.4 months of observation vs. baseline (-1.06+/-1.00 vs. -0.67+/-0.98 vs. and -0.50+/-0.88 vs. 0.26+/-1.75, respectively). Z-scores for s-BMD decreased non-significantly (p=0.08). Among bone turnover markers, we observed a significant increase in bALP and a non-significant increase in osteocalcin serum concentrations which were below normal ranges for age, sex and Tanner stage at baseline. High baseline serum ICTP concentration decreased non-significantly, reaching normal ranges during the observation. We conclude that anorexia nervosa seriously affects skeletal status in adolescent girls. Bone turnover markers analysed together with densitometric parameters suggest that AN influences both bone formation and resorption processes. QUS measurements at hand phalanges may be an appropriate method in the evaluation of skeletal status in patients with AN.
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PMID:Skeletal status and laboratory investigations in adolescent girls with anorexia nervosa. 1749 87


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