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SUMMARY
The effects of some oestrogens and progestogens on the glycerylphosphorylcholine (GPC) diesterase activity and the protein concentration of rinsings of the rat uterus have been studied in relation to changes in the weight of this organ. Both enzyme activity and protein concentration were increased by subcutaneous administration of oestradiol-3:17β, oestriol, oestrone and diethylstilboestrol to ovariectomized rats and these responses were inhibited by progesterone and 17α-ethyl-19-nortestosterone. The GPC diesterase activity and protein content of uterine rinsings were affected independently of each other and of changes in the uterine weight.
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ABSTRACT
Progesterone receptor concentrations increased in fetal guinea-pig uterus in organ culture to as high as 13·15±1·22 pmol/mg DNA without any added steroid, although cytosol and nuclear oestrogen receptor levels were very low (0·41−1·92 pmol/mg DNA). Even after a 3-day exposure to 5×10−8 m-progesterone, which inhibits its own receptor (1·14±0·31 pmol/mg DNA), progesterone receptor levels rose to 8·58±1·39 pmol/mg DNA when progesterone was removed. This replenishment was inhibited by progesterone and 5α-dihydroprogesterone but was not affected by oestradiol, tamoxifen or dexamethasone. The incorporation of [3H]thymidine into nucleic acids was not decreased by progesterone so that its inhibition of its own receptor in the explants was not due to an inhibition of cell replication. Fetal uterine explants from oestrogen-primed fetuses, after an initial decrease in progesterone receptor, also showed a rise to 7 pmol/mg DNA on day 2 which could be decreased by exposure to progesterone and replenished by removal of this hormone (6–8 pmol/mg DNA), the entire process occurring without apparent oestrogen stimulation. Progesterone rather than oestradiol appears to be a key regulator of progesterone receptor synthesis in the fetal guinea-pig uterus, although oestradiol, along with other factors, may also be involved.
J. Endocr. (1985) 105,415–421
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The effects of primary and catechol oestrogens on the uterus of the immature rat were compared. Because differences between the in-vivo and in-vitro oestrogenic actions of catechol oestrogens on the secretion of LH had been observed, their effects on a peripheral target organ, the uterus, were examined under similar conditions. In-vivo effects were assessed by measurement of uterine weight, induction of uterine cytoplasmic progestogen receptors, and by histological examination. In-vitro actions were determined by measurement of oestrogen-specific induced protein. It was found that the uterotrophic effects in vivo of 4-hydroxyoestradiol were indistinguishable from those of oestradiol whereas 2-hydroxyoestradiol was only weakly oestrogenic and 2-hydroxyoestrone had no effect. However, in vitro, 2-hydroxyoestradiol was as effective as 4-hydroxyoestradiol or oestradiol in stimulating synthesis of uterine induced protein, and 2-hydroxyoestrone, although less potent than oestradiol, had a significant effect. These results were consistent with the observed effects on the secretion of LH. The differences between in-vivo and in-vitro uterotrophic properties of catechol oestrogens can be explained on the basis of known pharmacokinetic factors.
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SUMMARY
High-affinity binding of [2,4,6,7-3H]oestradiol-17β has been studied in cytosols prepared from hypothalami, pituitaries and uteri of female rats killed at different stages of the oestrous cycle, and in cytosols prepared from the hypothalami and pituitaries of male rats. In all cases the equilibrium dissociation constant of reaction was of the order of 10−10 mol/l. The number of available high affinity sites per tissue (n) varied with physiological state. In females, n fluctuated with the oestrous cycle. In hypothalamus and pituitary, n fell by about 60 and 40% respectively in pro-oestrus, replenishment occurred during oestrus but could be delayed by phenobarbitone administration during the afternoon of pro-oestrus. In the uterus, n varied biphasically, there being peaks during dioestrus and oestrus, and troughs at pro-oestrus and metoestrus. The numbers of available sites at metoestrus were 12·5 × 109, 10·6 × 1010 and 24·4 × 1010 for hypothalamus, pituitary and uterus respectively. In male rats, values for n were similar to those obtained for females at pro-oestrus (n/hypothalamus = 6·8 × 109, n/pituitary = 4·2 × 1010). Binding was oestrogen specific in all the tissues studied.
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SUMMARY
The output of prostaglandin-like material and the spontaneous contractions of the pregnant rat uterus in vitro have been studied during the last 6 days of pregnancy and for 3 days post partum. Both prostaglandin release and uterine activity were minimal on days 17–18 of pregnancy but both parameters gradually increased, reaching a peak on day 22, the expected day of delivery. Post partum both uterine prostaglandin release and spontaneous activity declined. Progesterone (25 mg, i.m.) given to rats from days 16–21 of pregnancy did not alter uterine activity or prostaglandin output when compared with uteri taken on day 22 from animals which had received ethyl oleate over the same period. On day 22 the spontaneous activity of uteri in vitro taken from animals ovariectomized on day 17 was very low compared with that seen in preparations from sham-operated controls, although prostaglandin release in these groups was not significantly different. Oestrogen (1 μg, i.m.) was given to one group of ovariectomized animals on days 19 and 20; uterine activity was determined on day 21 of pregnancy and found to be of greater intensity and amplitude than that seen in an ovariectomized control group. Prostaglandin output was similar in these groups. Thus although exogenous progesterone and oestrogen do not influence uterine prostaglandin release at term, oestrogen appears essential for the occurrence of spontaneous contractions. It is concluded that, in the pregnant rat uterus in vitro, prostaglandin release may contribute to uterine activity but oestrogen is essential for this to become apparent.
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The binding characteristics, content and intracellular distribution of cytosolic and nuclear progesterone receptors have been investigated, using [3H]progesterone as ligand, in the rat uterus bearing a unilateral intra-uterine device (IUD) during the oestrous cycle and from days 3 to 6 of pregnancy. The dissociation constants of nuclear and cytosolic progesterone–receptor complexes for IUD-containing and control uterine horns were similar. Cytosolic receptor concentrations in the IUD-containing uterus were always lower but changed in a manner similar to the control during the periods studied. Nuclear receptor concentrations in the control horn reflected changes in hormone levels during the oestrous cycle although concentrations measured were greater than previously reported. However, in IUD-containing uteri the pattern was completely reversed with minimal levels at pro-oestrus. Nuclear receptor concentrations were little different in both horns during early pregnancy. Total progesterone receptor synthesis determined between metoestrus and pro-oestrus in IUD-containing horns was significantly less than that of control horns. This correlated with the attenuated rise of nuclear oestrogen receptor levels previously observed between these times in IUD-containing uterine horns.
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Glucocorticoids have been known to be involved in the regulation of some aspects of estrogen action on the uterus. However, the effect of glucocorticoids on changes in uterine morphogens produced by chronic estrogen exposure is not known. Therefore, the aim of this work was to examine the role of glucocorticoids on proliferative and morphogenetic uterine reactions induced by continuous estrogen treatment. Ovariectomized mice received subcutaneous injections of estradiol dipropionate in olive oil (2 microg per 100 g body weight once a week) or vehicle and drank water with or without dexamethasone (2 mg/l) for 30, 60 and 90 days. Treatment with dexamethasone caused a marked reduction in estradiol-induced changes in uterine weight, in proliferation (estimated from the proportion of mitotic and BrdU-labeled cells in all uterine tissues), and in changes in estradiol-dependent morphogenesis, which was redirected from the formation of atypical hyperplasia in animals receiving only estradiol to the appearance of simple or cystic endometrial hyperplasia in animals receiving both estradiol and dexamethasone. Estradiol alone increased dramatically the number of perpendicular oriented mitoses in luminal and glandular epithelia, and administration of dexamethasone inhibited this effect. In the absence of estradiol, chronic treatment with dexamethasone has no effect on all uterine parameters tested. Thus, chronic glucocorticoid treatment produces a complex antiestrogenic effect in the uterus of mice. Estradiol-induced changes in mitosis orientation are probably responsible for changes in the shape of glands and development of endometrial hyperplasia.
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SUMMARY
1. The effect of oxytocin on both the rat uterus and frog bladder is abolished by solutions of 1 mm N-ethylmaleimide (NEM).
2. NEM, however, has a variety of effects on these tissues. It inhibits sodium transport across the bladder, it prevents relaxation of the uterus and the return of water transfer to normal after it has been affected by oxytocin, and it inhibits contraction of the uterus by acetylcholine.
3. Reduced and oxidized glutathione (GSH and GSSG) inhibit the action of oxytocin on the uterus reversably and this inhibition is competitive.
4. GSH and GSSG also inhibited the increase in water transfer by oxytocin across the frog bladder, GSSG was more potent. Sodium transport across the bladder was transiently reduced by GSH and decreases by about 50% in the presence of GSSG.
5. The results are discussed in relation to the possible mechanism of interaction of neurohypophysial hormones with their receptors. It is concluded that both S-S and SH groups are present at the receptor sites in both the rat uterus and frog bladder.
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The Research Institute, Smith Kline & French Laboratories Ltd, Welwyn Garden City, Herts., AL7 1EY
(Received 11 February 1978)
Treatment with oestradiol induces vasodilatation and increased vascular permeability in the uterus of the intact immature or gonadectomized adult rat. These vascular changes result in an increase in the wet weight of the uterus 4–6 h after treatment. Oestradiol itself is not vasoactive and histamine, 5-hydroxytryptamine (5-HT) and prostaglandins have been proposed as mediators of the vascular effects of oestrogens (see Spaziani, 1975). Oestradiol is known to release histamine and 5-HT from uterine mast cells (McKercher, Van Orden, Bhatnagar & Burke, 1973) and to raise the uterine prostaglandin content (Aizawa, Kogo, Yamada & Sakai, 1974) within 6 h of administration to the ovariectomized rat. Some of the vascular actions of oestrogen in the rat uterus have been reported to be inhibited by intrauterine administration of lysergic acid diethylamide, an antagonist of
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Incorporation of [U-14C]glucose in vitro was determined in ampullary, ampullary–isthmic junction and isthmic segments of the Fallopian tube and uterus of intact (oestrous) rabbits and also at various times after mating. In the oestrous animals, incorporation was slightly higher in the ampullary segment compared with the isthmic and the ampullary–isthmic junction and finally the uterus. The pattern changed significantly in the pregnant animals. At 14 and 24 h post coitum, the pattern of incorporation was similar to that found at oestrus except for an increase in uterine incorporation. However, at 48 and 72 h post coitum, incorporation by the isthmic segment and the uterus was significantly increased compared with corresponding values at oestrus, and 14 and 24 h post coitum.
The implication of these changes during egg transport through the Fallopian tube is discussed.
