Mechanistic insights into how enduring menstrual cycle hormonal signaling promotes tumorigenesis are emerging. We performed a genome-wide screen in primary epithelial cells to identify hormonally-regulated candidates that initiate pro-tumorigenic phenotypes in normal cells. One candidate, DACH2, has been described as part of a network that regulates organogenesis during development. In vitro, we find that DACH2 expression is regulated by estrogen and progesterone in a dosage dependent manner. Lentiviral-mediated shRNA silencing of DACH2 in hormonally responsive tissues promotes expansion of cells with progenitor characteristics. Within gene expression profiles of fallopian tubes, DACH2 is a member of a minimal gene classifier that distinguishes follicular versus luteal phases. Decreased DACH2 is characteristic of luteal-phase tubal cells and the majority of ovarian serous carcinomas. These studies suggest that DACH2 may orchestrate a physiological program that, when deregulated, locks cells in a progenitor-state, induces uncontrolled proliferation, and predisposes cells for breast and ovarian carcinogenesis.

Mechanistic insights into how enduring menstrual cycle hormonal signaling promotes tumorigenesis are emerging. We performed a genome-wide screen in primary epithelial cells to identify hormonally-regulated candidates that initiate pro-tumorigenic phenotypes in normal cells. One candidate, DACH2, has been described as part of a network that regulates organogenesis during development. In vitro, we find that DACH2 expression is regulated by estrogen and progesterone in a dosage dependent manner. Lentiviral-mediated shRNA silencing of DACH2 in hormonally responsive tissues promotes expansion of cells with progenitor characteristics. Within gene expression profiles of fallopian tubes, DACH2 is a member of a minimal gene classifier that distinguishes follicular versus luteal phases. Decreased DACH2 is characteristic of luteal-phase tubal cells and the majority of ovarian serous carcinomas. These studies suggest that DACH2 may orchestrate a physiological program that, when deregulated, locks cells in a progenitor-state, induces uncontrolled proliferation, and predisposes cells for breast and ovarian carcinogenesis.

Typescript. / Thesis (Ph. D.)--University of Hawaii, 1971. / Bibliography: leaves 216-232. / xx, 232 l illus., tables

This thesis investigates the age - related decline in the various available measures and estimates of serum testosterone levels in men. Testosterone circulates predominantly bound with high affinity to sex - hormone binging globulin ( SHBG ) in plasma ( ~ 60 % ) and with lower affinity to albumin ( < 40 % ) ; approximately 1 - 2 % circulates unbound in plasma. It is the albumin - bound and free fractions ( termed " bioavailable testosterone " ) that are most likely to have biological effects on target tissues. This thesis reports the establishment, validation and derivation of normal ranges for an ammonium sulphate precipitation method for the measurement of bioavailable testosterone in serum. This method is in use by a number of laboratories at present including the laboratory of Professor John Morley at St Louis University with whom we collaborated. Testosterone has been shown, both cross - sectionally and longitudinally, to decline progressively beginning around the age of thirty. Total testosterone declines at approximately 0.4 % per year while bioavailable and free testosterone decline at approximately 1.2 % per year. The mechanisms that may be responsible for this include age - related changes to the hypothalamic - pituitary - testicular axis, increased SHBG levels, environmental factors, medication and chronic illness. This decline may contribute to a multitude of physiological, psychosexual and cognitive changes associated with ageing in men. This thesis crosssectionally examines the possible determinants of the various fractions of serum testosterone and the associations with various physical, psychosexual and lifestyle variables and with chronic disease and medication use. These cross - sectional data were generated from the Florey Adelaide Male Ageing study, which randomly recruited 568 men from the north and west suburbs of Adelaide, between August 2001 and August 2002. Moreover, this thesis includes a randomised controlled trial of testosterone replacement therapy in men aged 60 years and over with low - normal testosterone levels at baseline, recruited by newspaper advertisement. The goals of testosterone replacement therapy might be to prevent osteoporosis, age related frailty and falls, and to maintain optimal physical, sexual, emotional and cognitive health during the ageing process. This intervention study focused on the effect of treatment on body composition and muscle strength, symptoms of testosterone deficiency, visuospatial cognition, mood, wellbeing and quality of life. Finally, preliminary work was initiated to develop an in vitro bioassay for the measurement of serum testosterone bio - action. This was done using a transient transfection protocol in cultured cells, where androgen receptor and androgen response elements were introduced into the cells, subsequently treated with testosterone containing media and the amplitude of response quantified using a dual - luciferasereporter assay. In summary, this thesis discusses the issues with the measurement of testosterone in plasma and the factors that determine the concentration of the various fractions of testosterone in plasma. A cross - sectional study, using random recruitment procedures was used to investigate associations between testosterone levels and health - related - factors and finally a randomised - controlled - trial of testosterone replacement in ageing men with low - normal testosterone levels is reported. Throughout the thesis, the following themes are common ; body composition, physical function and strength, sexual function, lower urinary tract symptoms and the prostate, visuospatial cognition, mood, quality - of - life and wellbeing. / Thesis (Ph.D.)--Medical School, 2005.

Thesis (M.Sc.) -- University of Adelaide,Department of Animal Physiology, 1977.

Thèses (M.Sc.)--Université de Sherbrooke (Canada), 2002. / Titre de l'écran-titre (visionné le 20 juin 2006). Publié aussi en version papier.

Thesis--University of Copenhagen. / Summary in Danish. Bibliography: p. 86-95.

Thesis--University of Wisconsin--Madison. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 94-109).

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

Thesis (M.Med.Sc.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 69-72). Also available in print.