Thesis (Ph. D.)--University of Wisconsin--Madison, 1957. / Typescript. Abstracted in Dissertation abstracts, v. 17 (1957) no. 8, p. 1669-1670. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1968. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis--Wisconsin. / Vita. Includes bibliographical references (leaves 110-116).

Thesis (M.S.)--Miami University, Dept. of Zoology, 2006. / Title from first page of PDF document. Includes bibliographical references (p. 25-30).

Thesis (M. Sc.)--University of Canterbury, 2006. / Typescript (photocopy). Includes bibliographical references (leaves 104-109). Also available via the World Wide Web.

Thesis (Ph. D.)--Ohio State University, 2007. / Full text release at OhioLINK's ETD Center delayed at author's request

Thesis (M. Med. Sc.)--University of Hong Kong, 2006.

Anti-estrogen drugs such as Tamoxifen and Raloxifene are widely prescribed for breast cancer patients. While they are effective, they also have serious side effects. Alternative drugs are therefore being developed. In the drug discovery process, the in vitro binding of estrogen receptors and lead compounds were studied. The binding strength was conventionally quantified in terms of equilibrium dissociation constants (K0 ). However, the binding kinetic rates and especially off-rates (k0 ff) were recently shown to be better indicators of drug potency. In this thesis, we identified a few dietary estrogens as candidate lead compounds. We studied the binding of full-length human recombinant ERa with these dietary estrogens. In particular, we measured for the first time their binding kinetics rate constants. We also measured the change in the receptor-ligand binding kinetics upon its recruitment of co-activators, as a means to gauge agonist/antagonist propensity ofthe ligand. Our results showed that the following dietary estrogens, a-Zearalenol, Zearalenone, and Coumestrol bind favorably to the estrogen receptor alpha.

Abstract 17β-Hydroxysteroid dehydrogenases (17HSDs)/17-ketosteroid reductases (17KSRs) modulate the biological activity of certain estrogens and androgens by catalyzing dehydrogenase and reductase reactions between 17β-hydroxy and 17-ketosteroids. In the present study, cDNAs encoding mouse and rat 17HSD/KSR1 were cloned in order to study the role of rodent type 1 enzyme in ovarian estradiol (E2) biosynthesis and its enzymatic characteristics. Both rat and mouse 17HSD/KSR1 were expressed in granulosa cells of developing follicles, where diethylstilbestrol and follicle-stimulating hormone stimulated follicular maturation and up-regulated the expression of 17HSD/KSR1, whereas human chorionic gonadotropin caused luteinization of follicles and down-regulation of the enzyme. In line with this, the rodent type 1 enzymes are not expressed in the corpus luteum (CL). Mouse 17HSD/KSR1 showed substrate specificity different from that of the human counterpart. The mouse type 1 enzyme catalyzed the reaction from androstenedione to testosterone at least as efficiently as estrone (E1) to E2, while human 17HSD/KSR1 clearly preferred the E1 to E2 reaction. A mouse mammary epithelial cell line was found to possess strong estrogenic 17KSR activity. A novel type of 17HSD/KSR responsible for this activity was expression-cloned on the basis of its ability to convert E1 to E2 and it was chronologically named 17HSD/KSR7. Interestingly, it showed 89 % identity with a rat protein called prolactin receptor-associated protein (PRAP), which is expressed in the CL. Enzymatic characterization showed that both mouse 17HSD/KSR7 and PRAP efficiently catalyzed the reaction from E1 to E2. The mouse type 7 enzyme was most abundantly expressed in the ovary and placenta. Similar primary structure, enzymatic characteristics, and tissue distribution of mouse 17HSD/KSR7 and PRAP suggest that PRAP is rat 17HSD/KSR7. Further studies showed that in rat ovaries 17HSD/KSR7 is primarily expressed in the middle and second half of pregnancy, in parallel with E2 secretion from the CL. Using in situ hybridization, cell-specific expression of 17HSD/KSR7 was studied in the mouse ovary, uterus and placenta. In the mouse ovary, the enzyme was expressed exclusively in the CL. In the uterus on day 5 post coitum (p.c.), the type 7 enzyme was expressed in the decidua, mostly in the inner zone of antimesometrial decidua. Between day 8 and 9 p.c. the enzyme was abundant in decidua capsularis of the developing placenta, after which expression moved to the basal zone. On days 12 and 14 p.c., mouse type 7 enzyme was abundantly expressed in the spongiotrophoblasts, where expression decreased towards parturition. Altogether, rodent 17HSD/KSR7 is a new 17HSD/KSR which is involved in the biosynthesis of E2 in the ovaries. In addition, E2 produced locally in the decidua and placenta by the type 7 enzyme may have a role in decidualization and/or implantation and placentation.

The physiological effects of partially purified estrogenic extracts from forage plants of widespread economic importance have been studied, using the laboratory mouse and rat as experimental animals. The main purpose of these studies was to compare physiological activities of estrogenic substances from plants with those of a well known synthetic estrogen, diethylstilbestrol (D.E.S.). The latter, like many of the "natural" animal estrogens, is well known to influence the fundamental processes of animal production namely, reproduction, lactation, and growth. The estrogenic treatments were administered orally, either mixed with the diet, or by means of a rubber catheter. Dosage levels were in most cases designed with the grazing animal in mind, so as to allow some opportunity for tentative extrapolations of the results to farm animals which are the chief consumers of estrogen-like substances in forage plants. Red clover estrogenic extracts were used mainly, although some effects of subterranean clover, and birdsfoot trefoil are discussed. Non estrogenic timothy grass extracts were used to help control the experimental conditions. No effect of red clover "estrogens" on Maternal Performance of lactating mice as determined by the total weights of their litters at 12 days was detected. Performances calculated on the basis of 17th day total litter weights appeared to be adversely affected although not to the same extent as a similar level of D.E.S. The high estrogenic content of the diet is believed responsible for this result. Red clover "estrogens" induced increased testes weights, decreased seminal vesicle weights and lowered fertility in intact male mice. Remarkable recovery to normal, of these organs took place within eight days after cessation of estrogenic treatment. Some differences both in genital organ weights, and fertility data between males weaned from normally fed dams and those weaned from dams receiving estrogenic materials throughout the lactation period were observed. Per cent fertility data from females were essentially similar. The effects of red clover "estrogens" on uterine weight and histology, in intact, ovariectomized, hypophysectomized, and hypophysectomized-ovariectomized rats were studied. The absence of the hypophysis, and, or, the ovary does not interfere with the rate or degree of uterine response. The histology of uteri from "estrogen" treated animals is discussed in relation to fertilization, and implantation i.e. fertility. Method of administration of red clover "estrogens" influences the physiological effectiveness of a given dose. When mixed with feed their effect is more marked in terms of uterine response than when the same quantity is administered orally by means of a catheter, in two equal portions, twice daily. Once daily catheterization is even less effective. These results are discussed in relation to quantitative comparisons between injected or implanted doses of "natural" animal estrogens and D.E.S., and the quantities of estrogenic materials likely to be consumed by a grazing animal. Finally, red clover estrogenic extract from 8.4. gm. of dry ground forage increased thyroid uptake of radioactive sodium iodide (I¹³¹ ) in ovariectomized rats with a mean weight of 110 gm. Scintillation count data were confirmed by histological examination of carefully prepared thyroid sections. The likely endocrinological interpretation of this observation is discussed. / Land and Food Systems, Faculty of / Graduate