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

Call number: LD2668 .T4 1986 K58 / Master of Science / Animal Sciences and Industry

Two commercially available progestogen products for cattle, melengestrol acetate (MGA) and norgestomet (SMB) , were evaluated for their ability to induce synchronized estrus in anovulatory ewes. Seasonally anestrous ewes (n=232; determined by blood serum progesterone concentration) of mixed breeding were randomly assigned within broad age groups to one of seven treatments: 1) control (C); 2) MGA only (OMGA); 3) MGA + zeranol (RMGA); 4) MGA + PG-600 (PMGA; 400 IU pregnant mare's serum gonadotropin + 200 IU human chorionic gonadotropin in a 5 mL dose); 5) 5MB only (OSMB); 6) 5MB + zeranol (RSMB); and 7) 5MB + PG-600 (PSMB). Beginning 10 d before breeding, OMGA, RMGA, and PMGA ewes were fed .3 mg MGA/d provided through a mixture of shelled com and a commercially prepared pelleted supplement containing MGA. Concomitantly, OSMB, RSMB, and PSMB ewes were given a 3 mg norgestomet implant inserted subcutaneously on the back of the ear. Immediately preceding initiation of the MGA and 5MB treatments, RMGA and RSMB ewes were given a single i.m. injection of 2.5 mg zeranol. At the end of the 10-d treatment period, MGA feeding was discontinued and the norgestomet implants were removed. Concomitantly, PMGA and PSMB ewes were given a single i.m. injection of PG-600 (5 mL). All treatment groups were combined into one breeding group on May 4, 1992, with a ram to ewe ratio of 1: 17 for a 30-d breeding period. Mating to synchronized estrus was greater (P < .0001) for progestogentreated ewes. Within progestogen treatments, more (P < .000 1) 5MB ewes were marked within the first 5 d of breeding than MGA ewes. Overall, there were no treatment differences in estrus response for the 30-d breeding period. Blood serum samples collected during the first 14 d of breeding were analyzed for progesterone as an indicator of corpora lutea formation. Even though a large proportion of C ewes displayed luteal activity, only 12 % exhibited behavioral estrus within the first 17 d of breeding. Progestogen treated ewes exhibited a shorter mean interval (P < .0001) from ram introduction to lambing. Fertility and prolificacy were not different for C, MGA, or 5MB ewes. Of the two progestogen treatments used alone, lambing rate was 85 and 59 % (P < .03) for OMGA and OSMB ewes, respectively. Ewes plimed with zeranol before MGA or 5MB treatment exhibited similar levels of fertility and intervals from ram introduction to lambing compared with ewes receiving an injection of PG-600 after progestogen treatment. These data indicate that progestogen products commercially available for cattle may be useful in enhancing out-of-season breeding performance in sheep. / Master of Science

Call number: LD2668 .T4 1985 M52 / Master of Science

Thesis (Ph. D.)--University of Oregon, 2007. / Typescript. Includes vita and abstract. Includes results of four studies conducted at the University of Oregon. Includes bibliographical references (leaves 221-244). Also available for download via the World Wide Web; free to University of Oregon users.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.