This relationship is in marked contrast to that demonstrated during the first few hours following application of a hormone to a previously deprived target tissue. It represents, instead, the response of hormone-maintained tissues to continued stimulation and maintenance. As such, the results of such maintenance are the gradual changes in blood supply, oxygen availability, and substrate availability, subtle parameters which gradually modulate the rates of the more rapid, hormone-induced intracellular phenomena. These are the same kinds of changes which might be observed in any stable, non-endocrine tissue exposed to environmental modifications.

The relationship displayed in Figure 16 exists to a varying degree during each day from proestrus through Day 5 of progestation: changes in the availability of oxygen and other exogenous substrates affect the rate of utilization of glucose by the cell. The state of energy metabolism on any single day (a reflection of prior metabolic control) is translated on that day to an alteration in the rates of biosynthetic activity. Such activity is reflected during the next day as an alteration in the products of metabolism. Thus, the more rapid intracellular actions of estrogen and/or progesterone would be modulated by the state of the uterine cell, established by metabolic events which occurred 1-2 days earlier.

Figure 17 illustrates a possible relationship between the major changes in "energy metabolism" described above, and biosynthetic activity in the progestational endometrium. The increased energy metabolism on Day 2 apparently supports a spontaneous wave of stromal mitoses—both phenomena are dependent upon estrogen: progestogen interaction. The second peak of "energy metabolism", on Day 4, also provides potential support for increased mitotic activity should a decidualizing stimulus be applied. These phenomena See PDF for Figure See PDF for Figure also are estrogen: progestogen dependent. The basic action of estrogen in both instances is to regulate the rate and magnitude of the anabolic activity. By contrast, progesterone regulates the quality of anabolic activity.

Though the validation of such a model will require much further study, the phase relationships summarized in Figures 15, 16 and 17 may help to understand why: (a) estrogen priming is required to allow progestrone to act (Yochim and De Feo, 1963; Marcus and Shelesnyak, 1967); (b) progesterone therapy in the rat is required for 48 hours before estrogen sensitization for implantation is effective (Psychoyos, 1967, 1973); (c) stromal mitoses are initiated 48-72 hrs after the onset of progestation (Marcus, 1974); (d) the appearance of "estrogen-like" changes in the uterus is observed after Day 2 of progestation, but not sooner (Shelesnyak and Tic, 1963); (e) intervention at the endocrine level on Day 3 will interfere with nidation whereas intervention on Day 4 will not (Zeilmaker, 1963; Psychoyos, 1973); (f) both the duration and magnitude of decidual sensitivity are so strictly dependent upon the daily level of estrogen stimulation (Yochim and De Feo, 1963).