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Search for other papers by J. F. WOESSNER JR in
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Search for other papers by JANET N. RYAN in
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Treatment of parturient rats with 100 μg oestradiol/day caused a significant retardation of uterine involution and collagen breakdown. The post-partum uterus had a peroxidase activity of 180 μmol H2O2 reduced/min per uterus. Treatment with oestradiol caused an eight- to tenfold increase in this activity within 3–4 days. Treatment of rats with 4 mg cortisol/day commencing 3 days prepartum had no effect on uterine peroxidase activity but it blocked the oestradiol-induced increase in peroxidase. Cortisol had no effect on collagen breakdown and did not reverse the inhibition of collagen breakdown produced by oestradiol. It is postulated that the effects of oestradiol on peroxidase activity are mediated by uterine epithelial cells but that oestradiol effects on collagen breakdown may be mediated by another cell type.
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The detection of corticotropin-releasing hormone (CRH) in the pregnant and non-pregnant uterus has driven research to determine the role of this 41 amino acid neuropeptide in the female reproductive system. As concentrations of CRH mRNA and its peptide product are greater in the implantation sites of the early pregnant uterus compared with the regions between implantation sites, CRH has been hypothesised to participate in blastocyst implantation. Using the mouse system as an experimental model, we studied the distribution of CRH in the uterus during the oestrus cycle and early gestational period, and now provide evidence for its involvement in embryo implantation using cell culture techniques. The percentage of CRH-positive uterine cells and the amount of CRH released during anoestrus, pro-oestrus and oestrus were determined by immunofluorescence and ELISA experiments respectively. The highest number of intracellularly CRH-positive cells was obtained during pro-oestrus, whereas the highest CRH concentration in uterine cell culture supernatants was detected during anoestrus. At early stages of gestation, CRH was detected in the endometrium on days 2, 3 and 4 of pregnancy and in the myometrium on days 3 and 4, whereas it was undetectable on day 5. The functional role of CRH during early gestation was evaluated by administering anti-CRH antibody to mice from day 3 to day 8 of pregnancy. This treatment resulted in implantation failure in 60% of the cases, in which implantation sites, although clearly present in the uterus, had failed to host an embryo. These results provide direct evidence about the involvement of CRH in murine embryo implantation and are in agreement with hypotheses postulated in humans.
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Androgen receptors (AR) are highly expressed in female reproductive organs. In order to define the possible involvement of estrogens in the regulation of AR expression in the uterus and vagina, we have studied the effect of short-term administration of 17beta-estradiol (E2) to ovariectomized adult mice on AR mRNA levels. Seven days after ovariectomy, the mice received a single injection of E2 (0.05 microg/mouse) 3, 12 or 24 h before they were killed. The levels of AR mRNA were measured in the different uterine and vaginal compartments using quantitative in situ hybridization. In the uterus, AR mRNA was expressed in the luminal and glandular epithelial cells, stromal cells and smooth muscle cells. In the vagina, AR mRNA was localized in both epithelial and stromal cells. In the uterus after ovariectomy, AR mRNA levels were decreased by 18% in the epithelial cells, 23% in the stromal cells and 50% in the myometrial cells. AR mRNA levels were completely restored as early as 3 h after E2 administration in the epithelium and stroma, and at the 12-h time-interval in the myometrium. In the vaginal epithelium, ovariectomy induced a 70% decrease in AR mRNA expression. No effect could be detected 3 h after E2 administration, while at the longest time-intervals (12 and 24 h) there was an increase in mRNA levels corresponding to 70% of the levels observed in intact animals. In the vaginal stroma, ovariectomy was responsible for a 55% decrease in mRNA levels. While no significant changes were observed at the 3-h time-interval, a complete restoration of AR mRNA levels in stromal cells could be recorded at the longest time-intervals after E2 administration. The data obtained indicated that, in adult mice, estrogens exert a positive regulation of AR mRNA expression in the different compartments of both the uterus and the vagina.
Search for other papers by SUSAN L. RUSSELL in
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Search for other papers by G. H. THOMAS in
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SUMMARY
The metabolism and uptake of [2,4,6,7-3H]oestrone and [2,4,6,7-3H]oestradiol-17β were examined in explants of rabbit uterus, vagina and skeletal muscle in organ culture for 1 and 3 days. Irrespective of whether the uterus was cultured in the presence of [3H]oestrone or [3H]oestradiol-17β, the tissue contained predominantly [3H]oestradiol-17β. This was also true for vagina, but muscle showed only a limited ability to interconvert the two oestrogens.
The oestradiol-17β binding capacity of cultured uterus was also determined, and was shown to decline rapidly over the first 24 h of culture.
Search for other papers by H. Al-Khouri in
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Search for other papers by B. D. Greenstein in
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ABSTRACT
Cytosols were incubated from the hypothalamus and mid-brain and from the uterus, and incubated with [3H]progesterone alone or in the presence of excess radioinert steroid to reveal saturable binding sites. Bound and free hormone were separated by gel filtration. Scatchard analysis of the binding sites yielded evidence for only one class of binding sites of high affinity and limited capacity. The binding components in the hypothalamus and uterus appeared to fluctuate during the oestrous cycle, attaining a nadir at metoestrus, while those in the mid-brain were apparently unchanged. During pregnancy hypothalamic [3H]progesterone-binding sites appeared to lose affinity for the steroid while in the uterus the affinity for the steroid was unchanged but the absolute numbers of binding sites were greatly increased at day 10. It is concluded, both from studies of the properties intrinsic to the binding reaction and from endocrine correlates, that the macromolecular progesterone-binding components in the brain may be receptors for the hormone and that there may be differences between the properties of progesterone receptors in different tissues. Furthermore, during pregnancy there may be qualitative changes in the neural progesterone receptors which are not mediated by oestradiol.
J. Endocr. (1985) 107, 159–162
Search for other papers by F. A. DUGAN in
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Search for other papers by G. S. BERENSON in
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SUMMARY
Glycoproteins from immature and immature, oestrogen-stimulated and adult rat uteri were isolated and analysed by chemical and gel electrophoretic methods. Esterase, acid phosphatase, alkaline phosphatase and peroxidase activities were found. Changes in electrophoretic mobilities of certain enzyme bands in polyacrylamide gel were also observed after hydrolysis of the preparations with neuraminidase. These latter observations and chemical analyses provide additional evidence of the carbohydrate nature of the enzymes. The influence of 17β-oestradiol on immature rat uteri caused a significant increase in total protein and sialic acid per uterus compared with controls. Oestrogen treatment also resulted in an increase in the total activity of esterase and acid and alkaline phosphatases per uterus, but there was no increase in specific activities. Observations of electrophoretic patterns of glycoprotein preparations from untreated and oestrogen-stimulated, immature uteri did not show the evolution to a more adult pattern by oestrogen stimulation. These studies show that stimulation with oestrogen increases the synthesis of glycoprotein in the immature rat uterus. Factors which are involved in the more intricate control of glycoprotein biosynthesis need to be elucidated.
Search for other papers by R. J. B. KING in
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Search for other papers by J. GORDON in
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SUMMARY
The uptake of [6,7-3H]oestradiol-17β (oestradiol) by the rat uterus in vivo has been studied. By pressing uteri between two glass plates much, but not all, of the epithelium is removed with minimal effect on the underlying stroma and myometrium. This procedure removes 11 % of the DNA, 10·6 % of the radioactivity and about 3 % of the wet weight of the intact uterus, indicating that, as judged from the DNA content, there is no accumulation of [6,7-3H]oestradiol in the epithelium relative to the rest of the uterus. In the epithelium, the major portion of the [6,7-3H]oestradiol was in the soluble fraction although a considerable amount of the radioactivity was associated with the nuclei. Similar results were obtained with nuclei isolated by differential or gradient centrifugation. It has been shown that an interchange of [6,7-3H]oestradiol can occur between the nucleus and cytoplasm and that, under the experimental conditions used, the equilibrium favours the cytoplasm.
Some of the [6,7-3H]oestradiol in the soluble fraction from uterine epithelium was associated with a component of high molecular weight that may be a protein.
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The steroid hormone, estrogen, plays an important role in various physiological events which are mediated via its nuclear estrogen receptors, ERalpha and ERbeta. However, the molecular mechanisms that are regulated by estrogen in the uterus remain largely unknown. To identify genes that are regulated by estrogen, the ovariectomized mouse uterus was exposed to 17beta-estradiol (E2) for 6 h and 12 h, and the data were analyzed by cDNA microarray. The present study confirms previous findings and identifies several genes with expressions not previously known to be influenced by estrogen. These genes include small proline-rich protein 2A, receptor-activity-modifying protein 3, inhibitor of DNA binding-1, eukaryotic translation initiation factor 2, cystatin B, decorin, secreted frizzled-related protein 2, integral membrane protein 2B and chemokine ligand 12. The expression patterns of several selected genes identified by the microarray analysis were confirmed by RT-PCR. In addition, laser capture microdissection (LCM) was conducted to determine the expression of selected genes in specific uterine cell types. Analysis of early and late responsive genes using LCM and cDNA microarray not only suggests direct and indirect effects of E2 on uterine physiological events, but also demonstrates differential regulation of E2 in specific uterine cell types. These results provide a basic background on global gene alterations or genetic pathways in the uterus during the estrous cycle and the implantation period.
Search for other papers by B. F. CLARK in
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SUMMARY
In the mouse uterus the development of sensitivity to a decidualizing stimulus requires large amounts of progesterone and small amounts of oestradiol-17β. During this process progesterone induces changes in the sensitivity of the tissues of the uterus to oestrogen. From observations of human endometrium it has been suggested that progesterone modulates the biological activity of oestradiol-17β by stimulating the metabolic conversion of oestradiol-17β to oestrone. Accordingly [6,7-3H]oestradiol-17β was injected subcutaneously into ovariectomized mice at various stages of the development of sensitivity to a decidualizing injection of oil into the uterine lumen. Radioactivity was extracted 4 h later, fractionated and identified. There was no alteration in the amounts of oestradiol, oestrone or water-soluble metabolites in the uteri whether the mice were treated with progesterone or with progesterone plus oestrogen or whether the uterine horns were decidualized for 24 or 48 h. The results suggest that in vivo the metabolism of oestradiol-17β by the uterus is not stimulated by progesterone.
Search for other papers by V Rider in
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Search for other papers by D L Carlone in
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Search for other papers by R T Foster in
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Abstract
Cell proliferation and differentiation in the rodent uterus are probably controlled by the interaction of female sex steroids with polypeptide growth factors. Uterine basic fibroblast growth factor (bFGF) mRNA was measured by RNase protection during the time (days 2–4) of endometrial cell proliferation in the pregnant rat. bFGF transcripts were detected at each of the 3 days of pregnancy examined. To investigate the influence of oestrogen and progesterone on bFGF mRNA accumulation, ovariectomized rats were treated with oestradiol for 48 h followed by a single injection of oestradiol, progesterone, the two steroids co-injected or oil vehicle alone. Uterine RNA was collected 6 h after the last hormone injection. Steroid treatments increased steady-state uterine bFGF mRNA compared with vehicle control animals as measured by RNase protection. Northern blot analysis of c-fos and c-jun mRNAs from these same treatment groups revealed increased protooncogene expression in the uterus of hormone treated rats compared with the control animals. Temporal analysis of bFGF mRNA in ovariectomized rats at 1, 3 and 6 h after acute oestrogen and oestrogen-progesterone co-administration showed a dual pattern of transcript accumulation. Both hormone treatments increased bFGF mRNA within 1 h compared with vehicle injected rats. Co-administration of the two hormones, however, repressed bFGF mRNA accumulation relative to oestrogen at 3 and 6 h. Together, these studies provide evidence that bFGF control of uterine cell proliferation in pregnant rats can occur from newly synthesized bFGF. Moreover, the results suggest that progesterone is a potent stimulator of bFGF expression in the uterus.
Journal of Endocrinology (1997) 154, 75–84
