Thesis--Wisconsin. / Vita. Includes bibliographical references (leaves 124-131).

Thesis--Wisconsin. / Vita. Includes bibliographical references (leaves 81-92).

No description available.

No description available.

Thesis (M.S.)--Virginia Polytechnic Institute and State University, 1993. / Vita. Abstract. Includes bibliographical references. Also available via the Internet.

Thesis (Ph. D.)--Virginia Polytechnic Institute and State University, 1992. / Vita. Abstract. Includes bibliographical references (leaves 108-122). Also available via the Internet.

Thesis (PhD)--Stellenbosch University, 2004. / ENGLISH ABSTRACT: Although the progestins medroxyprogesterone acetate (MPA) and norethisterone acetate (NET-A) are widely used in reproductive therapy, the steroid receptors and their target genes involved in the actions of MPA and NET-A are not well understood. Surprisingly, it had not yet been investigated whether doses of MPA and NET-A used for contraception and HRT cause significant side effects through various target genes via the glucocorticoid receptor (GR). In this thesis results of in vitro studies showed that, MPA, like dexamethasone (dex) and prog, significantly repressed tumour necrosis factor (TN F)-stimulated IL-6 protein production, and IL-6 and IL-8 promoter reporter constructs at the transcriptional level in L929sA cells, via interference with nuclear factor KB (NFKB) and activator protein-1 (AP-1) transcription factors. Like dex and prog, MPA did not affect NFKB DNA-binding activity. Furthermore, unlike dex and prog, MPA did not inhibit mitogen-activated protein kinase (MAPK) activity. The antagonistic effects of the GR and progesterone receptor (PR) antagonist, RU486, as well as the MPAinduced nuclear translocation of the GR, strongly suggest that the actions of MPA in these cells are mediated at least in part via the GR. Although the mechanism was not investigated as extensively as for MPA, NET-A was shown to repress IL-8 promoter reporter activity very weakly relative to dex, MPA and prog in Hek293 cells stably transfected with the rat GR. Furthermore, NET-A, like MPA, dex and prog did not interfere with the DNA-binding activity of NFKB. Significant transactivation of a GRE-driven promoter reporter construct by MPA and dex in L929sA via endogenous GR and COS-1 cells via expressed rat GR, and by MPA, dex and prog in Hek293 cells via expressed rat GR was also observed. In contrast, NET-A, unlike MPA, dex and prog showed no transactivation in Hek293 cells. MPA, NET-A and prog were shown to compete with dex for binding to the endogenous human GR in human lung carcinoma A549 cells. Similarly, MPA and NET-A were shown to compete with dex for binding to expressed rat GR in COS-1 cells. MPA displayed a higher relative binding affinity than NET-A for the GR in both systems, and a higher relative binding affinity than prog in A549 cells. Equilibrium dissociation constants (Ki values) for MPA (Ki = 10.8 ± 1.1 nM), NET-A (Ki = 270 ± 1.3 nM) and prog (Ki = 215 ± 1.1 nM) towards the human GR in A549 cells were also established. Furthermore, dose-response curves showed that MPA displays significantly greater GC agonist potency and efficacy than NET-A and prog for both transactivation of a synthetic GRE-reporter construct and transrepression of a synthetic IL-8 reporter construct via expressed rat GR in Hek293 cells, as NET-A showed no transactivation and very weak partial agonist activity for transrepression. Based on these observations, MPA behaves as a GR agonist whereas NET-A is proposed to be a weak antagonist. These results show that MPA and NET-A are not alike and not the same as prog in their mechanism of action via the GR, which may have serious health implications in vivo. Such insights may provide women and their clinicians with more information to facilitate the selection of contraception or reproductive therapy regimes with fewer side effects. / AFRIKAANSE OPSOMMING: Alhoewel MPA en NET-A algemeen gebruik word in hormoontherapie, is dit nie duidelik watter steroïedreseptore en teikengene betrokke is by die werking van MPA en NET-A nie. Verrassend is dat geen studie nog gedoen is om te bepaal of die dosisse van MPA en NET-A wat gebruik word in voorbehoeding en hormoonvervangingsterapie (HVT), newe-effekte veroorsaak deur die glukokortikoïedreseptor (GR) en verskeie teikengene nie. In hierdie tesis is in L929sA selle aangetoon dat MPA, net soos deksametasoon (dex) en prog, TNF-gestimuleerde IL-6 produksie onderdruk, en dat IL-6 en IL-8 promoter-rapporteerderkonstrukte op transkripsionele vlak onderdruk word deur middel van inmenging met NF-KB en AP-1 transkripsie-faktore. Net soos dex en prog het MPA nie die DNA-bindingsaktiwiteit van NF-KB beïnvloed nie. Anders as dex en prog het MPA egter nie MAPK aktiwiteit onderdruk nie. Die antagonistiese effekte van RU486, asook die MPA-geïnduseerde translokasie van die GR na die selkern, dui sterk daarop dat die effekte van MPA in hierdie selle ten minste gedeeltelik deur die GR geskied. Alhoewel die meganisme vir NET -A nie so breedvoerig bestudeer is as dié van MPA nie, is tog aangetoon dat, in Hek293 selle wat stabiel getransfekteer is met die rot GR, die onderdrukking van die IL-8 promoter deur NET-A baie swakker is as met dex, prog en MPA. Verder is daar ook gevind dat NET-A, net soos MPA, dex en prog, nie kon inmeng met die DNA-bindingsaktiwiteit van NF-KB nie. Beduidende transaktivering van 'n GRE-bevattende promoterrapporteerderkonstruk deur MPA en dex in L929sA en COS-1 selle, en deur MPA, dex en prog in Hek293 selle, is ook gevind. Daarteenoor het NET-A, anders as MPA, dex en prog, geen transaktivering in Hek293 selle getoon nie. Verder moes die relatiewe bindingsaffiniteit (ewewigs-dissosiasiekonstantes) van MPA, NET-A en prog vir die GR, asook die relatiewe sterkte en effektiwiteit vir transaktivering en transonderdrukking van verskeie teikengene deur die GR, ook bepaal word. Daar is gevind dat MPA, NET-A en prog meeding met dex vir binding aan die endogene GR in mens longkarsinoom A549 selle. Soortgelyk hieraan is ook gevind dat MPA en NET-A meeding met dex vir binding aan rot GR wat in COS-1 selle uitgedruk is. MPA het in beide sisteme 'n hoër relatiewe bindingsaffiniteit vir die GR getoon as NET-A, asook 'n hoër relatiewe bindingsaffiniteit as prog in A549 selle. Ewewigs-dissosiasiekonstantes (Ki waardes) vir MPA (Ki = 10.8 ± 1.1 nM), NET- A (Ki = 270 ± 1.3 nM) en prog (Ki = 215 ± 1.1 nM) vir die mens GR in A549 selle is ook bereken. Dosisrespons-grafieke het ook aangedui dat MPA 'n beduidend beter GC sterkte en effektiwiteit as NET-A en prog het, vir beide transaktivering van 'n sintetiese GRE-rapporteerderkonstruk en transonderdrukking van 'n sintetiese IL-8 rapporteerderkonstruk via rot GR wat uitgedruk is in Hek293 selle. Dit kon afgelei word aangesien NET-A geen transaktivering en slegs baie swak gedeeltelike agonisaktiwiteit vir transonderdrukking getoon het. Op grond van hierdie waarnemings tree MPA op as 'n GR agonis, terwyl dit lyk asof NET-A 'n swak antagonis is. Hierdie resultate dui aan dat MPA en NET-A nie dieselfde is nie, en ook nie dieselfde meganisme van werking deur die GR het as prog nie. Dit kan ernstige gesondheidsimplikasies inhou in vivo. Hierdie insigte kan dus meer inligting aan vroue en kliniese personeel verskaf om sodoende die keuse van voorbehoeding of voortplantingsterapie met minder newe-effekte te vergemaklik.

Previous work in this laboratory revealed that hormone analysis using fecal samples may predict the number of fetuses carried by pregnant ewes at mid- to late gestation. Reliable lambing number prediction is useful to the producer. Using gas chromatography/mass spectrometry the 5��- and 5��-series of pregnanes and selected 4- and 5-pregnenes were monitored in the feces of 36 black and white-face cross ewes during early gestation. Feces were collected at d 5, 19, and 30 post-mating. Endoscopy was used at d 6 to determine the number of corpora lutea, and litter size data were collected at term. The number of copora lutea was not related (P>.05) to hormone concentrations at any of the sampling times (ANOVA-GLM). No differences in hormone levels were detected at d 5 in response to lambing number. At d 19, 5��-pregnane-3,20-dione and 5��-pregnane-3��,20��-diol were higher in ewes carrying triplets than ewes carrying twins (P���.008). At d 30, 3��-hydroxy-5��-pregnan-20-one was higher in ewes carrying triplets than twins (P<.05). Five progestins, including progesterone and 20��-hydroxy-4-pregnen-3- one, were lower at d 5 in ewes that conceived (n=26) than in ewes that did not conceive (n=6) at the first mating (P<.05). Concentrations of ten progestins were different (P<.05) (some higher and some lower) between groups of ewes that conceived at the first mating versus those that conceived at the second mating. In ewes that conceived at the second mating, pregnenolone and 5��-pregnane-3,20- dione were higher (P<.05) at d 5 than at d 5 of their previous non-conceptive cycle. Of the six ewes that were mated a second time, two still did not conceive but had elevated concentrations of three 5��-pregnanes (P<.05). Although there are differences in progestin profiles in ewes carrying different numbers of fetuses, concentrations alone are not adequate predictors of prolificacy at early gestation. It is inconclusive whether detection of pregnancy is possible as early as d 5 of gestation. / Graduation date: 2001

Title from PDF of title page (University of Missouri--Columbia, viewed on March 10, 2010). The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Thesis advisor: Dr. David J. Patterson. Includes bibliographical references.

Thesis (M.S.)--West Virginia University, 2005. / Title from document title page. Document formatted into pages; contains vii, 101 p. : ill. Includes abstract. Includes bibliographical references.