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Abstract
Recent studies suggest that hormonal control of uterine cell proliferation may be moderated by polypeptide growth factors. It remains to be determined, however, whether growth factors cause or are the consequence of hormone action. Basic fibroblast growth factor (bFGF) has been shown to influence cell proliferation and differentiation of a variety of mesoderm-derived cells. To elucidate the regulatory mechanisms controlling stromal cell proliferation and differentiation required for embryo implantation further, immunohistochemical localization of the progesterone receptor and bFGF have been studied. The cell-specific distribution of these proteins was determined in the rat uterus during early pregnancy and after injection of the progesterone receptor antagonist mifepristone (RU 486) at days 1 and 2 post coitum (p.c.) to block implantation. Cell division was restricted to luminal and glandular epithelial cells in pregnant and RU 486-treated rats at day 3 p.c. At day 4 of pregnancy, cell proliferation switched from the epithelia to the stroma in pregnant rats, but after RU 486 treatment division of stromal cells was inhibited significantly (P < 0·05). Progesterone receptor distribution was altered and bFGF was absent in RU 486-blocked stromal cells. Expression of bFGF in luminal and glandular epithelial cells, however, was insensitive to the effects of progesterone receptor antagonism. bFGF content was stimulated in the luminal epithelium and in decidual cells by the implanting embryo. These results indicate that repression of progesterone receptor function in early pregnancy results in a cell-specific loss of bFGF from stromal cells and inhibition of their proliferation. The results further suggest that the regulation of endometrial cell bFGF content is modulated at the site of implantation by the embryo.
Journal of Endocrinology (1994) 140, 239–249
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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
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ABSTRACT
Pregnant mice were injected 32 h post coitum (p.c.) with a monoclonal antibody against progesterone (5·7 or 9·5 nmol immunoglobulin G (IgG)) or 0·9% (w/v) NaCl (controls). Progesterone was injected starting on day 2, 3, 4 or 5 p.c. Progesterone reversed the antifertility effect of the lower dose of antibody when replacement began on day 2, 3 or 4, though the number of implantation sites was reduced when treatment started on day 3 or 4. By day 5 only one of six treated animals remained pregnant, showing that antibody action was reversible only up to day 4. At the higher dose of antibody, exogenous nidatory oestrogen was also required.
Pseudopregnant mice were injected 32 h p.c. with this antibody (5·7 nmol IgG) or 0·9% NaCl (controls). At 16.00 h on day 4 p.c., oil was injected into the lumen of one uterine horn and the magnitude of the decidual cell reaction was assessed 72 h later. Injected horns of antibody-treated females did not respond to intraluminal oil, whereas those of control mice increased fivefold in weight. Steroid treatment after the induction stimulus did not promote decidual growth, indicating that passive immunization reduced endometrial sensitivity. The results show that in the event that antibody fails to arrest the development of all embryos, the absence of endometrial sensitization will preclude the initiation of implantation, unless progesterone is given within 48 h of antibody treatment.
J. Endocr. (1985) 104, 153–158
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ABSTRACT
Anti-progesterone monoclonal antibody injected intraperitoneally as a single dose 32 h post coitum completely blocked pregnancy in BALB/c and CBA nulliparous mice. The dose required was greater in CBA than in BALB/c females, but in both strains no implantation sites were detectable at autopsy on day 10 after mating. The action of the antibody in BALB/c females was associated with a failure to initiate an implantation response as indicated by the Pontamine Blue reaction. The most pronounced effect, however, was an arrest of embryonic development at a stage prior to cavitation. Plasma progesterone concentration in blood taken by cardiac puncture was greatly increased after treatment, by virtue of high-affinity binding by antibody in circulation. The results show that passive immunization against progesterone shortly after mating interferes with early hormone-dependent steps which are essential for normal embryonic development.
J. Endocr. (1984) 101, 95–100
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Differentiation of uterine stromal cells is critical for the establishment of pregnancy. This study had two purposes: (i) to validate the use of the UIII rat uterine stromal cell model for investigating mechanisms underlying decidual cell differentiation, and (ii) to use this cell model to identify a molecular switch for cellular entry into the decidual cell differentiation pathway. Quiescent rat uterine stromal cells were transfected with a 500 bp segment of the decidual prolactin-related protein (dPRP) promoter ligated to a luciferase reporter gene. Cells were incubated in low-serum medium, or in low-serum medium containing progesterone (1 μM), estradiol 17-β (10 nM), cholera toxin (10 ng/ml) and interleukin-11 (10 ng/ml). Protein extracts were collected 48 h later and luciferase was measured in the cellular lysates. Cholera toxin and interleukin-11 stimulated luciferase expression (P< 0.05) and addition of sex steroids further increased (P< 0.05) dPRP promoter activity. Stromal cells did not proliferate (P< 0.05) under differentiation conditions. Deletion analysis of the dPRP promoter revealed maximal luciferase expression between −250 and −500 bp relative to the transcription start site. Comparison of cyclin E/Cdk2 activity between proliferating and differentiating cells showed a 3-fold increase (P< 0.05) at 12 h in differentiating cells. The results suggest that cyclin E/Cdk2 serves as a molecular switch for uterine stromal cell entry into the decidual cell differentiation pathway.
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ABSTRACT
The anti-fertility effect of a monoclonal progesterone antibody injected i.p. 32 h after mating is influenced by genotype since a single dose of 5·7 nmol immunoglobulin G successfully blocked the establishment of pregnancy in BALB/c but not in F1 hybrid mice (CBA male × BALB/c female). Progesterone concentrations in circulation were significantly higher at days 3 and 4 after mating in F1 females compared with those of the BALB/c stock. Moreover, the pattern of mitotic activity in the endometrium after passive immunization differed between the two genotypes. In treated BALB/c mice there was no increase in mitotic activity in stromal cells at days 3, 4 and 5 after mating (in contrast to BALB/c control females in which the number of stromal mitoses increased sharply). In F1 females there was a transient effect of antibody at day 3 (no increase in stromal mitoses but enhanced mitotic activity in the glandular epithelium compared with F1 control females), and subsequently a normal increase in mitotic divisions in stromal cells. The hypothesis is proposed that passive immunization against progesterone at 32 h after mating will only block the establishment of pregnancy in genotypes in which there is a gradual, rather than a steep rise in circulating progesterone concentrations during the preimplantation period. In F1 mice, high concentrations of circulating progesterone at days 3 and 4 of pregnancy apparently over-ride the effect of antibody and facilitate the normal development of stromal mitotic activity associated with the onset of implantation.
J. Endocr. (1986) 108, 117–121
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ABSTRACT
Anti-progesterone monoclonal antibody prevents the establishment of pregnancy in BALB/c mice by the prevention of implantation when injected i.p. 32 h after mating. To determine the specificity of this effect, mice were injected with immune and non-immune purified mouse immunoglobulins. The results show that anti-implantation efficacy was due to high-affinity antibody which bound progesterone since two further mouse immunoglobulin (Ig) G1 preparations, mouse IgA and mouse IgM which failed to bind the steroid, had no effect on pregnancy rates. From a panel of anti-progesterone monoclonal antibodies, six with a high affinity (affinity constant, 0·24–0·80 litres/nmol) and specificity for progesterone were selected for additional studies. Anti-implantation efficacy for five antibodies was similar, with a 50% effective dose within the range of 0·8–2·0 nmol. Antibody reached high concentrations in plasma within 12 h after i.p. injection, and declined with a half-life of about 80 h. Purified F(ab′)2 fragments of antibody also bound progesterone, but were less effective than the native molecule in blocking pregnancy. The results show that implantation in the mouse can be blocked by a high-affinity antibody that binds progesterone and which is removed from the blood at a slow rate.
J. Endocr. (1988) 118, 69–80
