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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Long-term estrogen replacement therapy in postmenopausal women can bring relief to hot flushes and reduce loss of bone mass due to osteoporosis, however, such treatment often can cause uterine hyperplasia and other undesirable effects. This study compared changes in bone mineral content (BMC), uterine weight, pituitary weight and pituitary gonadotropin content in the ovariectomized rat model following treatment with estradiol (E2) or two levels of clomiphene citrate (CC), an estrogen agonist/antagonist. Groups (n = 8-12) of adult ovariectomized (OVX) rat were implanted with E2 pellets (5 micrograms/day) or injected subcutaneously with CC at 1 mg/kg body wt (CC-1) or 5 mg/kg body wt (CC-5) twice weekly for 12 months. Placebo implanted OVX and intact (INT) female rats served as negative and positive controls, respectively. Following treatment, the uterus, pituitary gland and right femur were collected from each animal. E2 treatment increased (P less than 0.05) uterine weight compared to all other treatment groups, while both CC doses increased uterine weight over the OVX group only (E2, 0.24 +/- 0.03; INT, 0.14 +/- 0.01; CC-1, 0.06 +/- 0.01; CC-5, 0.07 +/- 0.01; and OVX, 0.02 +/- 0.01 g per 100 g body wt). Pituitary weight was increased 15-fold (P less than 0.05) by E2 treatment over all other treatment groups (E2, 65.7 +/- 13.9; INT, 4.0 +/- 0.5; CC-1, 3.3 +/- 0.03; CC-5, 2.7 +/- 0.02; and OVX, 2.9 +/- 0.02 mg per 100 g body wt). Both E2 and CC treatments reduced pituitary luteinizing hormone and follicle stimulating hormone content (micrograms/pit) to INT levels and were lower (P less than 0.05) than OVX levels. Mean BMC of E2, CC-1- or CC-5-treated rats was greater (P less than 0.05) than that of either the INT or OVX groups, while INT animals had a higher BMC compared to OVX animals (E2, 0.027 +/- 0.003; CC-1, 0.026 +/- 0.001; CC-5, 0.028 +/- 0.001; INT, 0.021 +/- 0.001; and OVX, 0.017 +/- 0.001 g/cm per 100 g body wt). These data indicate that CC has the potential to reduce bone mineral loss without causing other undesirable effects, including uterine hyperstimulation, and thus needs to be further investigated.
J Steroid Biochem Mol Biol 1991
PMID:Effects of long-term treatment with estradiol or clomiphene citrate on bone maintenance, and pituitary and uterine weights in ovariectomized rats. 195 70

The secretion of dehydroepiandrosterone (DHEA) and its sulfate is known to decline gradually with advancing age. Furthermore DHEA is known to be significantly lower in osteoporotic subjects than in normals. Recently 11 beta-hydroxyandrostenedione (11-OHA) has been proposed as an important indicator of the adrenal source of hormone excess in different hyperandrogenic states. In the present study we measured 11-OHA in 224 normal women aged 20-79 yr and 130 osteoporotic women aged 40-79 yr. RIA of 11-OHA was performed with highly specific antiserum raised in rabbits. The mean 11-OHA serum concentration was 2.20 +/- 0.90 ng/ml in normal women and 1.75 +/- 0.58 ng/ml in osteoporotic women. In contrast to DHEA there was no age-related decrease in 11-OHA serum concentrations in normal and osteoporotic women. Osteoporotic subjects showed statistically significantly lower 11-OHA serum concentrations than normal women. Therefore low serum 11-OHA might represent a further risk factor for osteoporosis.
J Steroid Biochem Mol Biol 1991
PMID:Age-related changes in 11 beta-hydroxyandrostenedione concentration in normal and osteoporotic women. 195 71

The recent demonstration of estrogen receptors in bone derived cells has stimulated the study of direct effects of sex steroids on bone. We have shown direct stimulation of proliferation by 17 beta-estradiol (E2) of ROS 17/2.8 rat osteogenic osteosarcoma cells, and other bone-derived cells in culture, as well as sex-specific stimulation of diaphyseal bone in vivo by estrogen and testosterone, using [3H]thymidine incorporation into DNA and stimulation of the specific activity of creatine kinase as markers. ROS 17/2.8 cells were used as models of osteoblast-like cells to study the reciprocal modulation of stimulation of bone cell proliferation by sequential treatment by sex steroid and calciotrophic hormones. Pretreatment with 1,25(OH)2D3 and PTH augmented stimulation by E2, while pretreatment with PGE2 followed by E2 resulted in no additional stimulation. Reciprocally, pretreatment with E2 significantly reduced the response to PGE2 while showing an insignificant effect on the response to the other hormones. Gonadectomized Wistar-derived rats provided a useful model system for study of postmenopausal osteoporosis. In diaphyseal bone, [3H]thymidine incorporation and creatine kinase activity decreased 4 weeks after gonadectomy. At that time, a single i.p. injection of E2 in females, and testosterone in males, resulted in a highly significant increase in both these parameters within 24 h.
J Steroid Biochem Mol Biol 1990 Nov 20
PMID:Hormonal stimulation of bone cell proliferation. 225 46

Osteoporosis is a growing disease, and attention should be directed to possible means of preventing and treating this disease. Osteoporosis may be caused by a number of diseases (secondary osteoporosis), but it most often occurs in otherwise healthy persons. The major risk factors are a low bone mass at skeletal maturity, and a rapid bone loss. Postmenopausal bone loss may be prevented by hormone replacement therapy. All types of oestrogens and all administration forms are effective, as long as a sufficient serum concentration is obtained. The greatest benefit of hormone replacement therapy is obtained if instituted right after the menopause, when the bone loss is most rapid. But oestrogen will also arrest the bone loss when instituted much later in life.
J Steroid Biochem Mol Biol 1990 Nov 20
PMID:Hormonal prevention and treatment of osteoporosis--state of the art 1990. 225 48

Estrogen deficiency following natural or surgical menopause, is thought to be the main factor leading to postmenopausal bone loss. Furthermore, after estrogen failure a significant reduction of intestinal calcium absorption and a negativization of calcium balance has been observed. The mechanism of estrogen effect on skeletal tissue is not yet fully elucidated. Recently, specific receptors for estrogens in osteoblastic cells have been described; however their low density does not give a full explanation about their functional role. Therefore estrogens act, at least in part, indirectly through calciotropic hormones. In order to further elucidate this issue, we performed some studies in postmenopausal osteoporotic patients and in fertile oophorectomized women. In the first double blind placebo controlled study, after a 1-year estrogen treatment period we observed an increase in bone mineral content in the hormone-treated patients. Furthermore, in all treated patients an improvement of intestinal calcium absorption was detected, while 1,25-dihydroxy-vitamin D serum levels did not show significant changes. To further analyse the relationship between estrogens (E) and calcitonin (CT) in postmenopausal osteoporosis, we performed a double blind placebo controlled study to evaluate the effects of 1-yr estro-progestative treatment on CT secretory reserve, evaluated by calcium infusion test. Blood levels of CT showed a progressive increase during the study period in the hormone-treated group, with a significant increase in the CT response to calcium stimulation test, suggesting a modulation of CT secretion by E. Recently, we performed two studies in fertile oophorectomized women. In the first, we followed longitudinally 24 fertile women for 1 yr. In these patients we measured, before and after oophorectomy, biochemical indexes of bone metabolism and bone mass. During the observation period a significant increase in bone resorption and a significant drop in intestinal calcium absorption was observed. In the second study, performed on 14 women before and 6 months after oophorectomy, a treatment with conjugated estrogens allowed the correction of the primary intestinal defect responsible for the reduced calcium absorption.(ABSTRACT TRUNCATED AT 400 WORDS)
J Steroid Biochem Mol Biol 1990 Nov 20
PMID:Calcitonin, estrogens and the bone. 225 49

Steroid 17 alpha-hydroxylase (cytochrome P-450(17)alpha) mediates both 17 alpha-hydroxylase and 17,20-lyase activities. A relatively rare disease, 17 alpha-hydroxylase deficiency is characterized by defects in either or both of these activities. The molecular basis for variability of the defect is not well understood. We have determined the exonic sequence of the mutant P-450(17)alpha gene from one Japanese patient with combined 17 alpha-hydroxylase/17,20-lyase deficiencies. A stop codon (TGA) due to a single point mutation was found at the position of amino acid 17 in exon 1 of the P-450(17)alpha gene. The presence of a stop codon in the N-terminal region of this gene leads to the absence of a functional P-450(17)alpha protein in adrenal cortex and ovary, and consequently hypertension, primary amenorrhea and osteoporosis in this patient.
Mol Cell Endocrinol 1988 Oct
PMID:Combined 17 alpha-hydroxylase/17,20-lyase deficiency due to a stop codon in the N-terminal region of 17 alpha-hydroxylase cytochrome P-450. 326 89

This paper presents a review of the significant body of literature liking dietary iron overload, not only to heart disease, but also to cancer, diabetes, osteoporosis, arthritis, and possibly other disorders. Following an analysis of our understanding of the mechanistic role iron plays in oxidative damage, an interpretation of the fact that plasma concentrations of several antioxidants are decreased in the presence of disease is offered. Evaluation of (1) age-related dietary trends over time and (2) factors involved in iron absorption leads to the hypothesis that the combination of citric acid and ascorbic acid (a synergistic pair of strong enhancers) is instrumental in causing a deleterious increase in iron load in aging populations. Iron overload may be the most important common etiologic factor in the development of the diseases mentioned; therefore, the synergistic combination of citric and ascorbic acids may play a major role in our worsening disease statistics. Evidence to support this hypothesis and possible experiments to test it are included. This combination needs further study, particularly because the iron overload produced may be correctable.
Biochem Mol Med 1995 Feb
PMID:Proposed role for a combination of citric acid and ascorbic acid in the production of dietary iron overload: a fundamental cause of disease. 755 10

Bone metabolism is regulated by a balance between bone resorption caused by osteoclasts and bone formation caused by osteoblasts. This balance is disturbed in postmenopausal women as a result of lower serum estrogen levels. Estrogen, which is used in hormone replacement therapy to prevent postmenopausal osteoporosis, downregulates expression of the interleukin 6 (IL-6) gene in osteoblasts and bone marrow stromal cells. IL-6 is directly involved in bone resorption by activating immature osteoclasts. We show here that NF-kappa B and C/EBP beta are important regulators of IL-6 gene expression in human osteoblasts. Importantly, the IL-6 promoter is inhibited by estrogen in the absence of a functional estrogen receptor (ER) binding site. This inhibition is mediated by the transcription factors NF-kappa B and C/EBP beta. Evidence is presented for a direct interaction between these two factors and ER. We characterized the protein sequence requirements for this association in vitro and in vivo. The physical and functional interaction depends in part on the DNA binding domain and region D of ER and on the Rel homology domain of NF-kappa B and the bZIP region of C/EBP beta. The cross-coupling between ER, NF-kappa B, and C/EBP beta also results in reduced activity of promoters with ER binding sites. We further show that the mechanism of IL-6 gene repression by estrogen is clearly different from that of activation of promoters with ER binding sites. Therefore, drugs that separate the transactivation and transrepression functions of ER will be very helpful for treatment of osteoporosis without causing undesirable side effects.
Mol Cell Biol 1995 Sep
PMID:Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. 765 15

The estrogen receptor has been successfully targeted with the anti-estrogen tamoxifen to treat all stages of breast cancer. Because tamoxifen is a partial agonist, it exhibits target-site specificity: it acts as an anti-estrogen in the breast to inhibit tumor growth, while exhibiting estrogenic effects on bones and lipid metabolism. Therefore, tamoxifen has the added benefit of maintaining bone density and reducing the risk of myocardial infarction in postmenopausal women. However, undesirable side effects of tamoxifen preclude its use as a hormone replacement therapy for otherwise healthy women. New anti-estrogens are currently being developed that may prevent osteoporosis, breast and endometrial cancer, and reduce the risk of myocardial infarction.
Mol Med Today 1996 May
PMID:Targeted anti-estrogens to treat and prevent diseases in women. 879 91

Corticosteroids have profound effects on bone metabolism, though the underlying mechanisms remain unclear. They are also known to alter glucose metabolism, in part by induction of insulin resistance. To determine whether corticosteroids impair glucose metabolism in bone cells, we have examined the actions of dexamethasone (DEX) on glucose transport and insulin receptor expression using osteoblast-like UMR 106-01 cells. DEX was shown to inhibit basal 2-deoxyglucose uptake by up to 30% in a time- and dose-dependent manner. It inhibited insulin-stimulated glucose transport by 13%. By Northern and Western blot analysis, DEX was shown to stimulate insulin receptor mRNA and protein by up to 5.6-fold, but it had no effect on expression of the glucose transporter GLUT 1 mRNA or protein under basal conditions. However, DEX augmented insulin-stimulated GLUT 1 mRNA and protein levels. By Scatchard analysis of labelled insulin binding, DEX increased insulin receptor number per cell by 54%. Subcellular fractionation and Western blot analysis demonstrated that DEX caused a redistribution of immunoreactive GLUT 1 from plasma membrane to intracellular microsomes, resulting in a 21% decrease in GLUT 1 at the plasma membrane. These data suggest that (i) DEX impairs basal glucose transport by post-translational mechanisms in UMR 106-01 cells, (ii) DEX increases insulin receptor mRNA, protein and insulin binding and (iii) the inhibition of glucose transport by DEX dominates its effects on the insulin receptor. It is possible that DEX inhibition of glucose transport in osteoblasts may contribute to steroid-induced osteoporosis.
J Mol Endocrinol 1996 Aug
PMID:Dexamethasone modulates insulin receptor expression and subcellular distribution of the glucose transporter GLUT 1 in UMR 106-01, a clonal osteogenic sarcoma cell line. 886 82


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