Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A double-blind, placebo-controlled study on 21 postmenopausal osteoporotic women was performed in order to assess the effects of 1 year estrogen therapy (Premarin, 1.25 mg/day) on bone mass, intestinal calcium absorption, and mineral metabolism. Bone mineral content (BMC), measured by dual photon absorptiometry on the vertebral bodies and the femoral shaft, increased in both areas, but the changes were more evident at the former site, which is predominantly trabecular (+8.3%, P less than 0.05), than at the latter, which is mainly cortical (+2.6%, P less than 0.05). An improvement of intestinal calcium absorption was also detected at the end of the study (P less than 0.05) in the estrogen-treated group. Parameters of bone metabolism showed a decrease in hydroxyproline/creatinine ratio and osteocalcin, an increase in calcitonin, and no significant changes in parathyroid hormone (PTH) and alkaline phosphatase. Serum 1,25-dihydroxycholecalciferol (1,25(OH)2D3) levels increased after estrogen therapy, whereas 25-hydroxycholecalciferol (25OHD3) remained stable during the study period. Renal 25-hydroxyvitamin D 1 alpha-hydroxylase reserve, assessed by the PTH-stimulation test, showed a more rapid response in producing a 1,25(OH)2D3 peak in the estrogen-treated patients compared with the control subjects. However, estrogens did not induce an absolute improvement in the secretory reserve. This study demonstrates that 1 year treatment with estrogens improves both intestinal calcium absorption and BMC in postmenopausal osteoporotic women. The latter effect appears to be induced by an inhibition of bone resorption, associated to an increased secretion of calcitonin, whereas vitamin D metabolites do not seem to contribute substantially to the mediation of estrogen action on bone.
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PMID:Effects of one-year treatment with estrogens on bone mass, intestinal calcium absorption, and 25-hydroxyvitamin D-1 alpha-hydroxylase reserve in postmenopausal osteoporosis. 312 28

The effects of oral contraceptives of varied estrogen/progestin composition on clinical measurements of hepatic, thyroid, and renal function and carbohydrate metabolism were examined in 1,355 women in the Lipid Research Clinics Program Prevalence Study. In general, bilirubin and alkaline phosphatase levels are lower with both oral contraceptives and postmenopausal estrogen use, suggesting an estrogen effect. The least bilirubin reduction is seen with a progestin dominant oral contraceptive. A significant decrement in aspartate aminotransferase is observed in users of one high estrogen dose oral contraceptive and in postmenopausal Premarin users, while aspartate aminotransferase is higher in postmenopausal users of higher dose ethinyl estradiol. Globulins are slightly higher in all hormone use categories, suggesting an estrogen effect on hepatic secretion of this protein class into the circulation. Fasting glucose concentrations are generally slightly lower even in the progestin dominant oral contraceptives, where glucose intolerance has been described. Thyroxine concentrations are generally elevated in all women using oral contraceptives. A relationship to estrogen dose is seen in women with thyroxine concentrations greater than the 99th percentile and in postmenopausal estrogen users. Creatinine concentration is greater with the use of Ovral, a progestin dominant oral contraceptive, and lower with two estrogen dominant oral contraceptives and Premarin, suggesting a competitive effect of estrogen and progestin. Among the clinical laboratory tests considered here, oral contraceptive effects seem to be largely estrogen mediated with a suggestion of competitive effect of estrogen versus progestin only on bilirubin and creatinine levels. These observations differ from lipoproteins where opposing hormonal effects are more clearly reflected in changing lipoprotein concentrations.
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PMID:Effect of estrogen/progestin potency on clinical chemistry measures. The Lipid Research Clinics Program Prevalence Study. 394 98

Symptomatic post-menopausal women were treated with conjugated equine estrogens (Premarin; Ayerst International) 1.25 mg daily, continuously, adding either norethisterone (Primolut N; Schering Chemicals) 1, 2.5, 5 or 10 mg daily or D/L norgestrel (Wyeth Laboratories) 150 or 500 micrograms daily for 10 days each calendar month. Endometrial biopsies were obtained during estrogen therapy alone and on the 6th day of combined estrogen/progestin administration. Sensitive biochemical indices of estrogen and progestogenic activities were measured in th endometrial samples. These included measurements of DNA synthesis in epithelium and stroma by tritiated thymidine autoradiography; nuclear estradiol receptor content, and the activities of estradiol 17 beta and isocitric dehydrogenase and acid and alkaline phosphatase. Low dosages of progestins achieved maximal biochemical effects and the larger doses failed to enhance these responses. It is concluded that the dosages of progestins currently added in post-menopausal estrogen therapy are greatly in excess of those necessary to suppress endometrial proliferation effectively; lowering the daily progestin dosage is unlikely to result in any lessening of this protective effect and will probably reduce the incidence of side effects, as these appear to be dose-dependent.
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PMID:Dose-dependent effects of synthetic progestins on the biochemistry of the estrogenized post-menopausal endometrium. 628 30

The efficacy of commercially available progestin preparations were investigated with a view toward determining the optimum type, dose, duration, and route of administration required to protect the endometrium. Biochemical indices of estrogen and progestin action in endometria from postmenopausal women receiving various hormone therapies were monitored. The premenopausal samples obtained during the proliferative and secretory phases of the cycle can be compared with physiologically normal activities. Estrogen effects were monitored by nuclear estradiol receptor (REN) and soluble progesterone receptor (RP) content and DNA synthesis by autoradiography after [3-H]-thymidine labelling. Progestin action was assayed by inhibition of estrogen-induced REN and DNA synthesis by induction of isocritic and estradiol dehydrogenases and by morphological criteria. Postmenopausal patients were attending the menopause clinics at King's College Hospital or the Chelsea Hospital for Women in London for symptoms associated with the climacteric. Premenopausal samples were obtained from women attending the above hospitals as well as St. Thomas Hospital in London. There are no differences in REN or estradiol receptor content (RET) between epithelium and stroma for any of the groups. Progestins, regardless of whether they are derived from exogenous (postmenopausal) or endogenous (premenopausal sources, decrease REN and RET in both fractions. Progestins also decreased DNA synthesis in both cell types and this suppression correlates with the fall in REN. The RP content of epithelium is greater than stroma, but the 2 enzymes are markedly stimulated by progestins in epithelium but not stroma. The lower RP content of the stromal fraction could be because of cellular heterogeneity, differential loss of receptor during processing, or to genuine differences between epithelium and stroma. Estrogen induced DNA synthesis is inhibited by progestins in both epithelium ans stroma but the induction of some enzymes is dissimilar in the 2 cell populations. Marked increases in activity of isocitric and estradiol dehydrogenases take place in epithelium but not stroma under the influence of progestins. Enzymes such as acid and alkaline phosphatase do not exhibit this uneven cellular distribution. For the clinical studies on progestin effects, it was decided to analyze DNA synthesis, REN, and estradiol and isocritric dehydrogenase activities. All estrogenic medications in clinical use in the U.K. produce levels of REN and RP that are at least equivalent to those found in the proliferative phase of the premenopausal endometrium. No differences in REN, RP, or DNA synthesis were observed between the 0.625 and 1.25 mg doses of Premarin so it appears that even the low dose of estrogen is maximally stimulating the endometrium. The study results strongly indicate that the addition of a progestin to estrogen medication is efficacious in preventing continued cell multiplication of both epithelium and stroma. They also show that unnecessarily high doses of progestin are in current use.
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PMID:Assessment of oestrogen and progestin effects on epithelium and stroma from pre- and postmenopausal endometria. 733 44

Estrogen replacement therapy (ERT) prevents bone loss and fracture in early postmenopausal women, but its benefit for women over 70 yr of age has not been determined. We have examined the effect of a short course of ERT on biochemical markers of bone turnover in older women. Eleven women (mean age, 77 yr) were given conjugated estrogen (Premarin; 0.625 mg/day) for 6 weeks. Biochemical markers were measured on serum and urine collected at baseline (two samples), after 5 and 6 weeks of ERT, and 5 and 6 weeks post-ERT. Markers of bone formation were osteocalcin, bone alkaline phosphatase, and type I procollagen peptide. Markers of bone resorption were total urinary hydroxyproline, total and free pyridinoline and deoxypyridinoline cross-links, type I collagen cross-linked N-telopeptides, and serum C-terminal cross-linked telopeptide. Data were analyzed by repeated measures multivariate analysis of variance to estimate the overall effect of ERT on the biochemical markers. Markers of bone resorption decreased during ERT and returned to baseline after ERT (P < 0.05). Markers of bone formation declined less during ERT and continued to decline after ERT (P < 0.05). We conclude that ERT reduces bone turnover in older women and that markers of bone turnover may be useful in assessing the response to treatment in this age group.
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PMID:The short-term effects of conjugated estrogen on bone turnover in older women. 804 49

This randomized, double-blind, placebo-controlled, multicenter, 8-week study evaluated short-term effects of raloxifene on bone turnover, serum lipids, and endometrium in healthy, postmenopausal women. A total of 251 women received either placebo, raloxifene HCl 200 or 600 mg/day, or conjugated estrogens (Premarin, 0.625 mg/day). Bone turnover (serum alkaline phosphatase, serum osteocalcin, urinary pyridinoline cross-links, urinary calcium excretion, urinary hydroxyproline) and serum lipids (total serum cholesterol, high- and low-density lipoprotein cholesterol [HDL-C and LDL-C]) were evaluated at weeks 0, 2, 4, and 8. Endometrial biopsies were performed at weeks 0 and 8. Treatment groups were compared for each parameter for baseline-to-endpoint changes. The estrogen and raloxifene groups experienced similar decreases in serum alkaline phosphatase (range 10-11%), serum osteocalcin (range 21-26%), urinary pyridinoline cross-links (range 20-26%), and urinary calcium excretion (range 45-72%). These decreases differed significantly compared with placebo-treated subjects for all markers except serum osteocalcin, the raloxifene HCl 200 mg group. LDL-C decreased significantly in the estrogen and both raloxifene groups (range 5-9%) compared with placebo-treated subjects. HDL-C increased significantly in the estrogen group (16%) but was unchanged in the raloxifene groups. HDL-C:LDL-C ratios increased significantly in the estrogen and raloxifene groups (range 9-29%). Serum cholesterol decreased significantly in both raloxifene groups (range 4-8%) but was unchanged in the estrogen group. Uterine biopsies of raloxifene-treated subjects showed no change in the endometrium during this short-term treatment. Biopsies of the estrogen group showed significant endometrial stimulation. The only adverse event possibly related to raloxifene was vasodilatation (hot flashes) which was most common in the raloxifene HCl 600 mg group. Study results indicate that raloxifene may provide beneficial effects to bone and serum lipids in humans without uterine stimulatory effects.
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PMID:A controlled trial of raloxifene (LY139481) HCl: impact on bone turnover and serum lipid profile in healthy postmenopausal women. 872 81

The aim of this study was to investigate the effects of tibolone in the prevention of postmenopausal bone loss over 3 years, and to compare these with the effects of sequential hormone replacement therapy. Forty early postmenopausal women were randomized to a 21-day regimen of conjugated equine estrogens (CEE, Premarin) plus sequential medroxyprogesterone acetate (MPA, Prodafem), or tibolone (Livial) daily. In total, 36 women completed 12 months and were considered for the intent-to-treat analysis, 34 completed 24 months and 23 completed 36 months. Main drop-out reasons were: lost to follow-up (n = 9) and minor side-effects (n = 4). Bone mineral density was measured at baseline and after 6, 12, 24 and 36 months, using dual-energy X-ray absorptiometry at the lumbar spine and the upper femur (neck, trochanter, total hip). In both groups, bone loss was prevented. Treatment with tibolone demonstrated significant increases in bone density at the spine (+4.6%; p < 0.01), at the total hip (+3.2%; p < 0.01) and at the trochanter (+4.5%; p < 0.01), whereas the CEE/MPA group showed a non-significant increase of bone mineral density at the lumbar spine (+2.6%) but no increases at the hip. Between-group differences in bone mineral density changes were significant (p < 0.05) for the total hip and the trochanter at 36 months. This increase of bone mineral density was not accompanied by changes in insulin-like growth factor-I (IGF-I) or insulin-like growth factor binding protein-3 (IGFBP-3) in either group. Osteocalcin, alkaline phosphatase and urinary ratios of hydroxyproline/creatinine and calcium/creatinine significantly decreased in both groups. In conclusion, sequential CEE/MPA prevented cortical and trabecular bone loss, with a transient increase of bone mineral density only during the first 6 months. Tibolone not only prevented cortical and trabecular bone loss, but further increased bone mineral density at the lumbar spine and at the hip throughout the 3 years of treatment, suggesting a sustained positive effect on bone mass.
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PMID:A 3-year study of prevention of postmenopausal bone loss: conjugated equine estrogens plus medroxyprogesterone acetate versus tibolone. 1190 45

Estrogen replacement therapy has been correlated with an increased risk for developing breast and endometrial cancers. One potential mechanism of estrogen carcinogenesis involves metabolism of estrogens to 2- and 4-hydroxylated catechols, which are further oxidized to electrophilic/redox active o-quinones that have the potential to both initiate and promote the carcinogenic process. Previously, we showed that the equine estrogens, equilin and equilenin, which are major components of the estrogen replacement formulation Premarin (Wyeth-Ayerst), are primarily metabolized to the catechol, 4-hydroxyequilenin. This catechol was found to autoxidize to an o-quinone causing oxidation and alkylation of DNA in vitro and in vivo. To block catechol formation from equilenin, 4-halogenated equilenin derivatives were synthesized. These derivatives were tested for their ability to bind to the estrogen receptor, induce estrogen sensitive genes, and their potential to form catechol metabolites. We found that the 4-fluoro derivatives were more estrogenic than the 4-chloro and 4-bromo derivatives as demonstrated by a higher binding affinity for estrogen receptors alpha and beta, an enhanced induction of alkaline phosphatase activity in Ishikawa cells, pS2 expression in S30 cells, and PR expression in Ishikawa cells. Incubation of these compounds with tyrosinase in the presence of GSH showed that the halogenated equilenin compounds formed less catechol GSH conjugates than the parent compounds, equilenin and 17beta-hydroxyequilenin. In addition, these halogenated compounds showed less cytotoxicity in the presence of tyrosinase than the parent compounds in S30 cells. Also, as stated above, the 4-fluoro derivatives showed similar estrogenic effects as compared with parent compounds; however, they were less toxic in S30 cells as compared to equilenin and 17beta-equilenin. Because 17beta-hydroxy-4-halogenated equilenin derivatives showed higher estrogenic effects than the halogenated equilenin derivatives in vitro, we studied the relative ability of the 17beta-hydroxy-4-halogenated equilenin derivatives to induce estrogenic effects in the ovariectomized rat model. The 4-fluoro derivative showed higher activity than 4-chloro and 4-bromo derivatives as demonstrated by inducing higher vaginal cellular differentiation, uterine growth, and mammary gland branching. However, 17beta-hydroxy-4-fluoroequilenin showed a lower estrogenic activity than 17beta-hydroxyequilenin and estradiol, which could be due to alternative pharmacokinetic properties for these compounds. These data suggest that the 4-fluoroequilenin derivatives have promise as alternatives to traditional estrogen replacement therapy due to their similar estrogenic properties with less overall toxicity.
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PMID:Effect of halogenated substituents on the metabolism and estrogenic effects of the equine estrogen, equilenin. 1280 57

The putative skeletal effects of dietary soy phytoestrogens (SPE) were examined in comparison with those of conjugated equine estrogens (CEE; Premarin) in a 3-yr longitudinal study in ovariectomized female monkeys. Controls received alcohol-extracted soy protein with low phytoestrogen content, and treatment groups received either CEE (admixed into the control diet) or unextracted soy protein isolate containing SPE. The acknowledged bone protective effect of CEE was reflected by higher bone mass (by dual energy x-ray absorptiometry) and lower bone turnover marker levels. In contrast, control and SPE groups lost significant lumbar spine bone mineral content and density and whole body bone mineral content within the first year, resulting in reduced bone mass for both groups compared with CEE (P < 0.0005). No effect of SPE was observed for any bone mass measure (P > 0.44), although transient, estrogen-like effects of SPE on serum alkaline phosphatase, calcium, and C-terminal cross-link of type I collagen were observed at 3 months (P < 0.02). These results suggest that SPE may be poor substitutes for mammalian estrogens in protecting against bone loss resulting from estrogen deficiency.
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PMID:Soy phytoestrogens do not prevent bone loss in postmenopausal monkeys. 1297 Mar 11

Raloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), increases bone mineral density (BMD), decreases biochemical markers of bone turnover, and prevents incident vertebral fractures in postmenopausal women, while sparing the breast and endometrium from the undesirable stimulation caused by estrogen. How the long-term beneficial effects of raloxifene on bone turnover, as assessed by bone histomorphometry, compare with hormone replacement therapy (HRT) and placebo are not known. We studied 66 healthy postmenopausal women (age 55 to 75 years, mean 63 years) who were randomized to either raloxifene 150 mg/day, HRT (Premarin 0.625 mg/day, and Provera 2.5 mg/day), or placebo for 1 year. All women received 1-1.5 g of calcium/day. Following double tetracycline labeling, transiliac bone biopsies were obtained at baseline and 1 year and analyzed for changes in histologic indexes of bone remodeling on the cancellous surface as well as at the endocortical subdivision of the endosteal envelope, the location of the greatest fraction of postmenopausal bone loss. BMD and biochemical markers of bone turnover were also determined at baseline and 1 year. Four paired biopsies were obtained in the HRT group, six in the raloxifene group, and five in the placebo group. The frequency of remodeling events on cancellous bone and rate of bone formation in both cancellous and endocortical bone increased in the placebo group, while these measurements decreased in both drug treatment groups. Using analysis of mean percentage changes, when compared with the placebo group, these changes were significantly different for both raloxifene and HRT treatment groups (p<0.02). In all subjects, the bone was lamellar with discrete tetracycline labels and there was no evidence of marrow fibrosis or abnormal bone cells. BMD increased from baseline at the lumbar spine (p<0.05 in the HRT group) and in the total body (p<0.05 for both raloxifene and HRT). Compared with that of the raloxifene group, the increase in BMD was greater in the HRT group at the lumbar spine but not in the total body. Serum bone alkaline phosphatase, serum osteocalcin, and urine C-terminal cross-linking telopeptide of type I collagen significantly decreased (p<0.05) in both active treatment groups, changes significantly different from those seen with placebo. Overall, these results support the hypothesis that raloxifene preserves bone mass by reducing the elevated bone turnover found in postmenopausal women receiving placebo, by mechanisms similar to those operative in postmenopausal women receiving HRT.
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PMID:Effects of raloxifene, hormone replacement therapy, and placebo on bone turnover in postmenopausal women. 1461 Jun 42


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