A survey has been made of the mitotic activity of the reproductive system, the urinary system, the alimentary canal, various exocrine and endocrine glands, and other miscellaneous organs of the adult female mouse, both in relation to the normal oestrous cycle and to injections of oestrone. A similar survey has also been made of the mitotic activity associated with wound healing and with cancerous growth. Evidence is recorded which indicates that, in all these cases, mitosis is stimulated by oestrogenic hormones. In the ovary, the cells are highly resistant to the mitosis-stimulating effect of the oestrogen. Mitotic activity in this organ is induced mainly by the pools of follicular fluid which are particularly rich in oestrogenic hormone, and which stimulate the highest rate of division in any cells in direct contact with them. Thus, the follicular fluid causes the great mitotic activity associated with follicle growth, and after the follicle bursts, also induces the mitotic activity of the neighbouring germinal epithelium which it bathes. In the same way, some mitotic activity is stimulated in the developing corpus luteum before luteinization occurs. In the other body organs there exists the widest range of sensitivity to oestrogenic hormones. In the brain no mitotic activity was seen; in the kidney there was some activity at full oestrus or after many injections of oestrone; in the epidermis there was a considerable reaction; and some of the most sensitive tissues of the body proved to be the lining epithelia of the Müllerian duct system and the intestinal mucosa. The less active tissues responded slowly to oestrogen stimulation, while the more active tissues responded promptly and fully. The most active tissues examined proved to be the proliferating centres of the intestinal lymph nodules, which maintained a maximum rate of cell division even when, as on the first day of dioestrus, the oestrogen blood content was at a minimum. The results obtained indicate the existence of mitosis inhibitors. First, there is the force, termed the cell inertia, which must be overcome before any tissue can react by cell division to the presence of an oestrogen. In the case of less active tissues the cell inertia is great, and is overcome only after the oestrogen has exerted its influence for several days, but in the more active tissues the cell inertia, is slight, and is rapidly overcome by relatively small increases in the oestrogen blood content. The existence of a second mitosis inhibitor, termed the mitosis depressor, is shown by the fact that any sharp rise in mitotic activity is quickly brought under control, so that mitosis is again reduced to a minimum. With the continued presence of the stimulating oestrogen, there is, after a short interval, a second rise in mitotic activity which, like the first, is rapidly brought under control and in turn eliminated. Thus, even in the continued presence of oestrogen stimulation, mitotic activity proceeds in waves. However, an exception to the rule is furnished by the proliferating centres of the intestinal lymph nodules where it appears that both the mitosis-controlling forces are lacking, so that a maximum rate of cell division is always maintained. It was discovered that, during wound healing, the mitosis rate rises sharply to an abnormally high maximum, and that it does this quite irrespective of the oestrous cycle and of injections of oestrone. It is evident, therefore, that the mitotic activity associated with wound healing is under the control of some special mechanism, and evidence is summarized which indicates that one of the functions of wound hormones is the elimination of the two mitosis-regulating forces in tissues closely adjacent to the wound. Because of this, the local cells react immediately and in an abnormal degree to the stimulation of the oestrogenic hormones, even if these are present only in small concentrations. In cancerous growth it was found that great mitotic activity also proceeds without influence from the oestrous cycle or from injections of oestrone, and it is evident that in this case the two mitosis-regulating forces are permanently in abeyance, so that the maximum response to oestrogen stimulation is always possible. It is concluded that in the adult female mouse, and probably in other animals, there exist three types of substances influencing mitotic activity. First, there are the oestrogenic hormones which act as general mitosis stimulators; second, there are the mitosis-inhibiting forces of cell inertia and mitosis depression, which prevent the rate of cell division from becoming excessive and unregulated; and third, there are the wound hormones which, by weakening the mitosis-inhibiting forces, allow an abnormally high reaction to oestrogen stimulation and a consequent rapid production of new tissue to meet the emergency. This conclusion is discussed in relation to several biological problems, including ovarian function, pregnancy, embryonic growth, and cancer.
Mitotic activity in the adult female mouse,
Mus musculus
L. A study of its relation to the oestrous cycle in normal and abnormal conditions