Stimulatory and Inhibitory Effects of Estrogen on Uterine DNA Synthesis¹²

Abstract

The induction of long-term responses in the uterus following estrogen treatment is discussed, with special reference to DNA synthesis. Immature female rats injected daily with estradiol-17beta or estriol (0.01 to 1 mug) or a combination of the two steroids for one, two or three consecutive days were sacrificed at intervals from 12 to 24 h after the last injection of vehicle or steroid. In vitro incorporation of [3H]thymidine into DNA [14C]leucine into protein, and oxidation of [14C)glucose to 14CO2 were determined. Nuclear-bound estradiol was determined by use of exchange assay or following incubation of intact uteri with 1 X 10(-8)M ([3H]estradiol for 1 h at 37 C. Injection of estriol only partially stimulated DNA synthesis by 18 to 24 h post-treatment. However, injection of estriol followed by injection of estradiol 6 h later resulted in increased DNA synthesis, suggesting that estrogen must be present for up to 6 h to induce subsequent DNA synthesis. Maximal DNA and protein synthesis and oxidation of glucose occurred at 24 h after injection of estradiol (0.1 or 1 mug) but was depressed to control levels by 24 h after the last of three daily injections. Daily injections of 0.01 mug of estradiol resulted in a similar pattern of DNA synthesis, although of lesser magnitude than that observed after injection of 0.1 or 1 mug of estradiol. However, if rats receiving daily injections of 0.01 mug estradiol were challenged with a higher dose of estradiol (1 mug), uterine DNA synthesis was markedly increased. The data suggest that prolonged exposure to estrogen causes uterine cells to become metabolically "refractory" to further estrogen stimulation. Sequential injections of estriol (1 mug) or intermittent injections of estradiol (1 mug) were ineffective in causing this uterine "refractoriness". Receptor binding of estrogen, translocation to the nucleus, and retention of receptor in the nucleus were not affected by sequential estrogen treatment. The accumulation of an inhibitory product is suggested as a possible explanation for this phenomenon.

Cell Proliferation in the Principal Target Organs of the Dog (Beagle) Ovary during Various Periods of the Estrous Cycle

“…This could be explained by the assumption that a certain time is neces sary for the synthesis of inhibitors. Inhibitors are said to be responsible for the inhibition of cell proliferative activity and, consequently, cause an estrogen refractory period [Stormshak et al, 1976;Gorski et al, 1977], The lowest LI was seen in the dog ovary between days 6 and 8 or proestrus as has been described in the foregoing paper [Spanel-Borowksi et al. 1984].…”

Cell Proliferation in the Dog (Beagle) Ovary during Proestrus and Early Estrus

“…Second, the end of a refractory period to a joint stimulation by these horrfiones has to be considered. Such a refractory period developing under continuous estrogen administration has been sug gested for immature female rats [Stormshak et al, 1976], Parallel to a decrease in labelling of antral follicles during the first 6 days of proestrus, there is an increase in their number of necrotic granulosal cells. By contrast, a paucity of granulosal cell necrosis is evident for antral follicles independent of their stage of atresia at the preand postovulatory period.…”

Non-Monotonic Dose Responses in Studies of Endocrine Disrupting Chemicals: Bisphenol a as a Case Study

“…For some receptors, the response at higher doses is also affected by desensitization, a process whereby receptors are biochemically inactivated when hormone concentrations increase (Freedman and Lefkowitz, 1996;Lohse, 1993). Other mechanisms that produce NMDRCs include cell and tissue specific receptors and co-factors (Jeyakumar et al, 2008;Maffini et al, 2008), receptor selectivity (McLachlan et al, 2001;Sohoni and Sumpter, 1998;Tilghman et al, 2010), receptor competition (Kohn and Melnick, 2002), and endocrine negative feedback loops (Bruchovsky et al, 1975;Lesser and Bruchovsky, 1974;Stormshak et al, 1976).…”