Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00627 (MAP)
 15,705 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of sex steroid hormones on the responsiveness of the neural mechanism responsible for the secretion of LH-RF have been examined in the female rat. Responsiveness was determined at pro-oestrus by measuring the increments in immunoreactive LH-RF of pituitary stalk blood produced by electrical stimulation of the medial preoptic area or median eminence. Ovariectomy on the morning of dioestrus reduced the LH-RF response to preoptic stimulation while oestradiol benzoate (OB) or testosterone propionate (TP) administered immediately after ovariectomy significantly augmented the response. The facilitatory effect of TP was possibly due to its conversion to an aromatized derivative since 5alpha-dihydrotestosterone monobenzoate was ineffective. Progesterone did not facilitate preoptic responsiveness, and, when administered to animals ovariectomized at 12.00 h of pro-oestrus, reduced the LH-RF response at 18.00 h the same day. Stimulation of the median eminence produced a significantly greater increment in LH-RF than stimulation of the preoptic area. The facilitatory action of OB on the LH-RF response was less marked for median eminence compared with preoptic stimulation. The administration of ICI 46474 at 17.00 h of dioestrus did not reduce preoptic responsiveness on the morning of the next day, suggesting that this compound does not act as an 'antioestrogen' at the level of the preoptic area.
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PMID:Immunoreactive luteinizing hormone releasing factor in pituitary stalk blood from female rats: sex steroid modulation of response to electrical stimulation of preoptic area or median eminence. 78 4

GnRH analogues are widely used for the reduction of uterine fibroids. This case report describes the therapy of a 27-year-old woman, whose uterus had a diameter of about 13 cm. After 7 injections of Zoladex Depot (ICI Pharma, Heidelberg, Germany), the uterus was reduced to normal size carrying dorsally a myoma of the same size. After only 7 weeks of medroxyprogesterone acetate (5 mg twice daily, Clinofem, Upjohn, Heppenheim, Germany) the uterus had grown again, so that therapy was changed to Zoladex Depot for another 3 months. On the 27th day of the first spontaneous cycle, the patient ovulated and conceived. Up to the 29th week of gestation (Aug '91), the foetal growth and development was normal, the uterus was normal in size, a childhead sized myoma being situated unproblematically behind the foetus.
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PMID:[Intrauterine pregnancy with uterine myoma after downregulation with GnRH analogs]. 131 57

Most oral contraceptives (OC) contain a progestin in combination with an estrogen, and the progestin component in OC includes one of the following 19-nortestosterone derivatives: norethynodrel; norethindrone; or norgestrel (levonorgestrel). It is well known that estrogens promote the growth of breast cancer. However, progestins have recently also been implicated in the development of breast cancer. We have compared and contrasted the ability of synthetic progestins to stimulate the proliferation of cultured human breast cancer cells and examined their possible mechanism of action. We found that some progestins used in OC were able to stimulate the growth of estrogen receptor-positive (ER+) MCF-7 and T47DA18 human breast cancer cells but not ER- MDA-MB-231, BT-20, and T47DC4 human breast cancer cells. However, two other progestins, MPA and R5020, which are not used in OC, were either not able to stimulate or only slightly stimulated growth. The potency of norethynodrel [median effective dose (EC50) = 4 x 10(-8) M] and norethindrone (EC50 = 3 x 10(-8) M) was greater than norgestrel (EC50 = 2 x 10(-7) M) in MCF-7 cells. E2 (EC50 = 8 x 10(-13) M) was an even more potent stimulator of growth. More importantly, the progestin-induced growth stimulation was blocked by the antiestrogens 4-hydroxytamoxifen and ICI 164,384 but not the antiprogestin 17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)-17 alpha-(1-propynyl)-estra-4, 9-dien-3-one (RU486). To determine whether the proliferative action of progestins was mediated through the ER, cells were transfected with a chloramphenicol acetyltransferase reporter gene containing an estrogen response element derived from vitellogenin 2A gene. The progestins which stimulated the growth of breast cancer cells also increased chloramphenicol acetyltransferase activity. The induction of chloramphenicol acetyltransferase activity was blocked by the addition of the antiestrogens 4-hydroxytamoxifen and ICI 164,384 but not the antiprogestin RU486. This study provides direct evidence that the 19-nortestosterone derivatives in OC have estrogenic properties and suggests that activation of ER, but not progesterone receptor, is the growth-stimulatory mechanism for these synthetic progestins. Our results may help to explain the conflicting evidence linking OC and breast cancer risk. A rigorous evaluation of the "total" estrogenic potential of OC might produce a better correlation with breast cancer risk.
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PMID:Estrogenic potential of progestins in oral contraceptives to stimulate human breast cancer cell proliferation. 142

Peak III phosphodiesterase (PDE) inhibitors have combined positive inotropic and vasodilator effects. We studied 10 patients with chronic heart failure during and after infusion of intravenous (i.v.) ICI 153,110, an investigational peak III PDE inhibitor. Maximum hemodynamic response for the group occurred after cessation of infusion at a lower plasma drug concentration. At maximum hemodynamic response, cardiac index (CI) increased (2.4 +/- 0.5 vs. 3.2 +/- 0.37 L/min/m2, p less than 0.05) with a decrease in mean arterial pressure (MAP 91 +/- 5 vs. 80 +/- 3 mm Hg, p less than 0.05), pulmonary capillary wedge pressure (PCWP 25 +/- 2 vs. 17 +/- 3.1 mm Hg, p less than 0.01), systemic vascular resistance (SVR 1,422 +/- 106 vs. 983 +/- 97 dynes.s.cm-5, p less than 0.05) and pulmonary vascular resistance (PVR 227 +/- 39 vs. 16 +/- 31 dynes.s.cm-5, p less than 0.05). During the infusion, plasma renin activity (PRA) decreased from 6.34 +/- 2.53 to 3.6 +/- 3 ng/ml/h (NS). The five patients with high baseline PRA had a significant decrease (11.2 +/- 2.5 vs. 5.4 +/- 1.67 ng/ml/h, p less than 0.01) that preceded changes in CI and SVR by 1-2 h. These data suggest that reduction in PRA may have contributed to the hemodynamic effects of this peak III PDE inhibitor.
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PMID:Acute neurohormonal and hemodynamic response to a new peak III phosphodiesterase inhibitor (ICI 153,110) in patients with chronic heart failure. 170 Feb 5

The biological response of the anti-estrogens, ICI 164,384, 4-hydroxytamoxifen and tamoxifen were studied in isolated cells of the vagina and uterus of fetal guinea pig in culture. ICI 164,384 in these two cell lines provokes a significant stimulatory effect on the progesterone receptor levels. This is in opposition to available information where this compound is considered to have full anti-estrogenic properties. At the concentration of 10(-8) mol/l ICI 164,384 stimulates progesterone receptor 2-3 times in relation to the non-treated cells. 4-hydroxytamoxifen acts as an agonist in the vaginal cells, but as an antagonist in the uterine cells, in which it can block the stimulatory effect provoked by ICI 164,384. Progesterone, which inhibits progesterone receptor, can block in both cells the stimulatory action of ICI 164,384. No effect of the different compounds tested was found in proliferation or [3H] thymidine incorporation. The agonistic effect of the anti-estrogen ICI 164,384 adds new information about the complexity of the mechanism of anti-estrogen action and gives additional models to explore the biological responses of these compounds.
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PMID:Biological responses of ICI 164,384 and other anti-estrogens in vaginal and uterine cells of fetal guinea pig in culture. 195 58

Different estrogen-3-sulfates (estrone-3-sulfate, estradiol-3-sulfate, and estriol-3-sulfate) can provoke important biologic responses in different mammary cancer cell lines; there is a significant increase in progesterone receptor. However, no significant effect was observed with estrogen-17-sulfates. The reason for the biologic response of estrogen-3-sulfates is that these sulfates are hydrolyzed, and no sulfatase activity for C17-sulfates is present in these cell lines. [3H]-Estrone sulfate is converted in a very high percentage to estradiol (E2) in different hormone-dependent mammary cancer cell lines (MCF-7, R-27, and T47D), but very little or no conversion was found in hormone-independent mammary cancer cell lines (MDA-MB-231 and MDA-MB-436). Different antiestrogens (tamoxifen and its derivatives) and another potent antiestrogen, ICI 164,384, significantly decrease the concentration of estradiol after incubation of estrone sulfate with the different hormone-dependent mammary cancer cell lines. No significant effect in the uptake and conversion of estrone sulfate was observed in hormone-independent mammary cancer cell lines. The data indicate that sulfatase activity for estrone sulfate is very low in the hormone-independent cell lines; however, comparative kinetic studies carried out after homogenization of MCF-7 and MDA-MB-436 cells show that sulfatase activity is similar, suggesting different mechanisms in the hydrolysis of estrone sulfate in hormone-dependent and hormone-independent cell lines. Progesterone also provokes a significant decrease in uptake and in estradiol levels after incubation of [3H]-estrone sulfate with the MCF-7 cell line. It is concluded that estrogen sulfates can play an important role in the biologic response of estrogens in breast cancer and that control of sulfatase and 17-hydroxysteroid dehydrogenase activities are key steps in the concentration and ability of estradiol in the mammary cancer cell line.
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PMID:Metabolism and biologic response of estrogen sulfates in hormone-dependent and hormone-independent mammary cancer cell lines. Effect of antiestrogens. 237

Estrogen sulfates are quantitatively the most important form of circulating estrogens during the menstrual cycle and in the post-menopausal period. Huge quantities of estrone sulfate and estradiol sulfate are found in the breast tissues of patients with mammary carcinoma. It has been demonstrated that different estrogen-3-sulfates (estrone-3-sulfate, estradiol-3-sulfate, estriol-3-sulfate) can provoke important biological responses in different mammary cancer cell lines: there is a significant increase in progesterone receptor. On the other hand, no significant effect was observed with estrogen-17-sulfates. The reason for the biological response of estrogen-3-sulfates is that these sulfates are hydrolyzed, and no sulfatase activity for C17-sulfates is present in these cell lines. [3H]Estrone sulfate is converted in a very high percentage to estradiol (E2) in different hormone-dependent mammary cancer cell lines (MCF-7, R-27, T-47D), but very little or no conversion was found in the hormone-independent mammary cancer cell lines (MDA-MB-231, MDA-MB-436). Different anti-estrogens (tamoxifen and derivatives) and another potent anti-estrogen: ICI 164,384, decrease the concentration of estradiol very significantly after incubation of estrone sulfate with the different hormone-dependent mammary cancer cell lines. No significant effect was observed for the uptake and conversion of estrone sulfate in the hormone-independent mammary cancer cell lines. Progesterone provokes an important decrease in the uptake and in estradiol levels after incubation of [3H]estrone sulfate with the MCF-7 cells. It is concluded that in breast cancer: (1) Estrogen sulfates can play an important role in the biological response of estrogens; (2) Anti-estrogens and progesterone significantly decrease the uptake and estradiol levels in hormone-dependent mammary cancer cell lines; (3) The control of the sulfatase and 17 beta-hydroxysteroid dehydrogenase activities, which are key steps in the formation of estradiol in the breast, can open new possibilities in the treatment of hormone-dependent mammary cancer.
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PMID:Importance of estrogen sulfates in breast cancer. 256 May 11

Both alpha- and beta-adrenergic receptors have been identified in the human myometrium by radioligand binding. Both adrenergic receptor subclasses have been shown to mediate the contractile response of the uterus upon catecholamine stimulation: alpha-adrenergic receptors cause uterine contraction while beta-adrenergic receptors induce relaxation. We have identified alpha 1- and alpha 2-adrenergic receptors in myometrial membranes using the newly developed radiolabelled specific antagonists [3H]-prazosin and [3H]-rauwolscine. This enabled us to characterize both receptor subclasses individually. Beta adrenergic receptors were identified using the radiolabelled antagonist (-)-[3H]-dihydroalprenolol. Binding of radioligands to the myometrial membrane receptors was rapid, readily reversible, of high affinity and stereoselective. The total number of alpha 1-, alpha 2- and beta-receptors was determined by Scatchard analysis of radioligand saturation binding and the beta/beta 2-receptor ratio was determined by computer analysis of the beta 2-selective antagonist ICI 118 551) (-)-[3H]-dihydroalprenolol competition binding curves. This enabled us to study the regulation of both alpha- and beta-receptor subclasses under various physiological and pharmacological conditions in the human, i.e., during different phases of the menstrual cycle, in postmenopausal women and during depo-progestin (Medroxyprogesterone acetate) therapy. Only the alpha 2- and beta 1-adrenergic receptor concentrations were found to be subjected to gonadal steroid regulation. The number of alpha 2- and beta 1-adrenergic receptors increased concomitantly with circulating plasma oestradiol levels. This effect was counteracted by progesterone. The number of alpha 1- and beta 2-adrenergic receptors was unaffected by the gonadal steroid environment. These results are an example of the heteroregulation of membrane receptors by oestrogens and progesterone and cast new light on the regulatory mechanisms involved in uterine contractility in the human.
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PMID:Regulation of alpha- and beta-adrenergic receptor subclasses by gonadal steroids in human myometrium. 299 Jan 61

The ultrastructural response of the uterine luminal epithelium of the spayed virgin rat was studied as a parameter in screening the effects of antifertility agents which may interfere with implantation. The agents studied were bis-(p-acetoxyphenyl-2-methyl-cyclohexlidene-methane (F-6103), bis-(p-acetoxyphenyl)-2-methyl-4-methylidene-cyclohexylidene-methane (F- 6255), bis-(p-acetoxyphenyl)-1,2,3,4-tetrahydro-1-naphtylidene-methane ( F-6278), trans-(p-2-dimethylaminoethoxyphenyl) -1,2-diphenyl-1-ene (ICI- 46474), 1-(p-(2-diethylaminoethoxy) phenyl) -2-(p-methoxyphenyl-1-phenylethane (MER-25), 3-ethyl-2-methyl-4-pheny; -4-cyclohexenecarboxylic acid, sodium salt (ORF-4563), 1-(2-(p-(3,4,-dihydro-6-methoxy-2-phenyl-1-naphtyl)-phenoxy) ethyl)pyrro lidine, HCI(U-11100A), 2(p-(6-methoxy-2-phenylinden-3-yl) phenoxy)trieth ylamine, HCI (U-11555A) and 2-phenyl-1-p-(beta-pyrrolidinoethoxy) phenyl naphto(2,1-b)-furan (66/179). The substances were tested in spayed rats in spayed rats given progesterone and in spayed rats given progesterone plus estradiol-17 beta. All agents gave an estrogen-like response when given separatly. The response was most marked with the F-compounds and ORF-4563. The F-compounds and ORF-4563 changed the ultrastructure profoundly in progesterone-treated rats while the other compounds had little effect. Progesterone plus estradiol rendered the epithelium suitable for implantation. Each compound except U-1155A inhibited the attachment reaction when given before estradiol.
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PMID:Attachment reaction of rat uterine luminal epithelium. V. Suppression of the attachment reaction by some antifertility agents. 465 Jun 61

Primary cultures of oligodendrocytes and astrocytes and purified cultures of Schwann cells were prepared respectively from forebrain and sciatic nerves of newborn rats. The effects of steroid hormones and growth factors on glial cell growth and on the production of myelin-specific proteins and lipids were investigated. Progesterone (P, 100 nM) decreased the proliferation of glial cells of the central nervous system. This inhibitory effect of P was abolished by the simultaneous administration of the antagonist RU486, thus suggesting a receptor-mediated action of the hormone. The expression of myelin-specific proteins, including the myelin basic protein (MBP) and the 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase), and of a myelin-specific lipid, galactocerebroside (Gal C), was also measured during cell differentiation under different hormonal conditions. The expression of MBP in oligodendrocytes was increased by P, and this effect was not blocked by RU486. The combined application of P and insulin promoted a synergistic stimulation of MBP expression. Insulin, by itself, also increased the number of MBP-positive oligodendrocytes in culture. The effects of P and insulin appeared to be selective as dexamethasone, dehydroepiandrosterone, pregnanolone and epidermal growth factor (EGF) had no effect. Only estradiol (E2, 500 nM) increased the number of MBP-immunoreactive cells, but in contrast to P, only a small synergism between E2 and insulin on MBP expression was observed. The expression of CNPase, another myelin-specific protein, was also increased by P and, here again, a synergy between P and insulin could be observed. In contrast, the expression of Gal C, a myelin-specific lipid, was not modified by P or other steroid hormones. Moreover, the increase in Gal C-positive cells observed in response to insulin alone was not further potentiated by P. Glial cells of the peripheral nervous system, namely Schwann cells, are also sensitive to steroid hormones. Schwann cells contain estrogen receptors, and E2 stimulates their proliferation in the presence of forskolin or dibutyryl cyclic AMP (dbcAMP). The mitogenic effect of E2 was abolished by the pure antiestrogen ICI-164,384. Insulin, at micromolar concentration, also stimulated Schwann cell growth when forskolin or dbcAMP were present in the culture medium. The mitogenic effect of insulin was mediated by insulin-like growth factor I (IGF-I) receptors. Indeed, at a physiological nanomolar concentration, IGF-I but not insulin or IGF-II, increased the proliferation of Schwann cells in synergy with forskolin. In addition, Schwann cells express receptors for IGF-I.
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PMID:Actions of steroid hormones- and growth factors on glial cells of the central and peripheral nervous system. 813


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