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    Mammogenesis in the ovariectomized mouse : a study of the effects of estradiol and progesterone : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Physiology at Massey University
    (Massey University, 1972) Mackenzie, Helen Mary
    Immature ovariectomized female mice of the NOS albino strain were administered a series of estradiol treatments, and estradiol plus three different levels of progesterone, for 21 days in two separate experiments. Uterine weights, mammary gland areas, duct junctions/unit area, total duct junctions, mammary DNA and RNA were measured for all animals. Statistical analysis was carried out on all data. At estradiol doses between 0.00125-0.320 ug/day there was a steady increase in uterine weight, while mammary areas, unit junctions and total junctions increased to a peak at 0.020 and 0.040 ug/day estradiol respectively followed by an inhibition at higher levels. Changes in DNA and RNA did not follow this pattern but were more constant. At all progesterone doses an inhibition in uterine growth was seen when combined with 0.0050 ug/day estradiol, and a maximum was reached when the progesterone was combined with 0.010 ug/day estradiol, above which paint the curve remained flat showing an inhibition from growth observed with estradiol alone. The inhibition when 0.0050 ug/day estradiol was combined with progesterone was observed with all other parameters and also the inhibition at high levels of estradiol. However the final levels were higher than with estradiol alone. A third smaller experiment was carried out to show the time course of development of the mammary glands with 0.010 ug/estradiol and 0.010 ug/day estradiol plus 1 progesterone tablet. Mice were slaughtered at 3 day intervals during the 21 day treatment period. The results are discussed in relation to previous studies on mammary growth in ovariectomized mice and further areas of work suggested.
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    Mammogenesis in the mouse : a study of the responses of the immature mammary gland to minimal oestrogenic stimulation : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University
    (Massey University, 1979) Aye, Khin Maung
    The response of the mammary glands of immature ovariectomized mice of the NOS strain to minimal levels of oestradiol monobenzoate was investigated in two experiments using both objective and subjective measurements as indices of response. Uterus weight, thickness of the uterine wall and vaginal opening were used as additional measures of the effectiveness of the oestrogenic stimulation. In the first experiment single injections of OMB at four levels (0.01, 0.03, 0.09 and 0.27µg) were used and mice were killed at four intervals after the injection (1,2,4 and 8 days). A significant dose response relationship was observed for mammary gland area to OMB which was essentially linear. Different stages of the response were observed both with respect to the morphology (in whole mounts) and the micro-anatomy (in serial histological sections) of the duct system. The sampling errors of a histometric estimate of volume of glandular tissue were investigated and the results used to design a stratified sampling system for the second experiment. In the second experiment dual injections at one of three levels (0.04, 0.1 and 0.2µg total), given at one of three spacings (2, 4 and 8 days) were used and mice were killed at one of three intervals after the second injection (2, 6 and 14 days). The response of the mammary gland to log-dose of OMB was essentially linear for the estimate of volume of glandular tissue, but no response to increasing level of OMB was seen with mammary gland area. The detailed observations of the morphological and histological changes have been discussed in relation to the results reported in other studies. The following stages have been proposed as the sequence of events, which can extend over a period greater than a week, following discrete doses of oestrogen at minimally effective levels: (1) Increase in width of principal ducts, thickening of the epithelial wall and the appearance of a non-specific secretion: (2) Formation of peripheral 'clubs' accompanied by mitotic activity along the length of the principal ducts; (3) Extension of the principal ducts from the peripheral clubs and formation of small end buds at discrete points along the principal ducts. (4) Extension of the small end buds to form higher order duct branches.
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    The role of the mammary fat pad during mammogenesis : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Animal Science at Massey University, New Zealand
    (Massey University, 1996) Hovey, Russell Charles; Hovey, Russell Charles
    Development of the female mammary gland involves the proliferation and morphogenesis of epithelial cells within a matrix of adipose and connective tissue which constitutes the mammary fat pad. The objective of this research was to investigate the mechanisms by which this stromal environment locally regulates postnatal mammogenesis. Initial experiments showed that the mouse mammary fat pad liberates a diffusible activity in vitro which stimulates the growth of mouse mammary epithelial cells and enhances their proliferative response to insulin-like growth factor-I, epidermal growth factor and insulin. This effect was specific to these mitogens, and of a variety of cell lines tested was most pronounced for mouse mammary epithelial cells. Subsequent investigations indicated that these responses were likely induced by unsaturated fatty acids, particularly linoleic acid, from mammary adipocytes. Such responses may be effected by increased intracellular signalling via the actions of protein kinase C. The mitogenic capacity of the mouse mammary fat pad was also evaluated across several physiological states. Mammary fat pad-stimulated proliferation during the estrus cycle was increased at estrus concomitant with a phase of ductal elongation in vivo. In certain medium treatments there was evidence for epithelial upregulation of the mitogenic effect of the mammary fat pad, where intact mammary tissue was more stimulatory than mammary fat pad cleared of endogenous epithelium. Further experiments demonstrated that while the mitogenic effect of the mammary fat pad was unaltered by ovariectomy, ovarian function was required for this effect to be increased by exogenous progesterone. The effect of estrogen was independent of ovarian function but was altered by the local epithelial-stromal interaction, where it increased the mitogenic effect of epithelium-free mammary fat pad and decreased that of intact mammary tissue. Mitogenic stimulation by mammary tissues also declined during virginal development to be least in mature virgin and mid-pregnant states. Stimulation by intact mammary tissue increased during lactation, while that from epithelium-free mammary fat pad remained constant in the presence of steroid hormones and increased in the presence of growth factors. Further experiments investigated the stromal regulation of epithelial growth within the ruminant mammary gland. Differences between the ruminant and rodent mammary fat pad were emphasised in vitro where ovine mammary fat pad stimulated the growth of mouse mammary epithelial cells but did not markedly potentiate their growth factor-responsiveness. A subsequent study examined the expression of stroma-derived growth factors within the ruminant mammary gland during postnatal development, and their regulation by several physiological influences. The level of insulin-like growth factor (IGF)-I mRNA in the ovine mammary fat pad was elevated prior to puberty and during late gestation, while IGF-II mRNA was upregulated in mammary parenchyma of virgin ewes in a transcript-specific manner. Abundance of IGF-I mRNA in mammary tissues of prepubertal ewe lambs tended to be increased by exogenous estrogen whereas IGF-II mRNA levels were reduced. Messenger RNA for keratinocyte growth factor (KGF) was detected within the ovine mammary fat pad throughout development as 2.4 and 1.5 kb mRNA transcripts which were expressed by stromal adipocytes and fibroblasts, respectively. The level of KGF mRNA in mammary tissues of prepubertal lambs was increased by ovariectomy and decreased by estrogen, while KGF mRNA expression in cultures of mammary fibroblasts was suppressed by dexamethasone. Messenger RNA for hepatocyte growth factor, a paracrine mitogen and morphogen for mammary epithelial cells, was expressed in the ovine mammary fat pad and by cultured mammary fibroblasts. The abundance of basic fibroblast growth factor (bFGF) mRNA was highest within the ovine mammary fat pad, while in vitro results suggest bFGF may be a paracrine/autocrine mitogen for multiple cell types within the mammary gland. Basic FGF gene expression in mammary tissues of prepubertal ewes was reduced by estrogen treatment. For each of these growth factors there was evidence suggesting that their expression within the mammary fat pad was upregulated by the adjacent mammary epithelium. In conclusion, these findings indicate that the mammary fat pad may stimulate the proliferation of mammary epithelial cells during postnatal mammogenesis by a variety of influences. Such mechanisms may involve the direct stimulation of epithelial growth or the modulation of epithelial responsiveness to other mitogens. These effects may function to mediate the actions of certain mammogenic hormones. Furthermore, strong evidence indicates that mammary growth may be locally regulated by the interaction between epithelial and stromal cells.