Biomedical subjects

R M Brenner

Publications and source records attributed to R M Brenner.

93 records · Page 6Linked to original sources

PubMedDate not supplied

Antiproliferative effects of progesterone antagonists and progesterone receptor modulators on the endometrium.

Progesterone antagonists (PAs, antiprogestins) can modulate estrogenic effects in various estrogen-dependent tissues. These modulatory effects are complex and depend on species, tissue, type of compound, dose, and duration of treatment. In non-human primates, PAs, including mifepristone, ZK 137 316 and ZK 230 211, inhibit endometrial proliferation and induce amenorrhea. When administered chronically at relatively low doses, these compounds block the mitotic activity of endometrial epithelium and induce stromal compaction in a dose-dependent manner in both spayed and intact monkeys at high estradiol concentrations. These effects were accompanied by an atrophy of spiral arteries. The antiproliferative effects were endometrium-specific, since the estrogenic effects in the oviduct and vagina were not inhibited by PAs. Similar endometrial antiproliferative effects were also found after treatment with the progesterone receptor modulator (PRM), mesoprogestin J1042. The endometrial antiproliferative effects of PAs, particularly within the endometrial glands, were also observed in spayed rabbits. In spayed rats, however, the PAs did not inhibit, but rather enhanced, various estrogen responses, including endometrial proliferation, pointing to species-specific differences. In conclusion, our studies indicate that both pure PAs and PRMs selectively inhibit estrogen-dependent endometrial proliferation in the primate endometrium without affecting estrogenic response in other estrogen-dependent tissues or inducing unscheduled bleeding. Our studies indicate that the spiral arteries, which are unique to the primate endometrium, are the primary targets that are damaged or inhibited by PAs and PRMs. The damage to these unique vessels may underlay the paradoxical, endometrium-specific, antiproliferative effects of these compounds. Hence, the properties of PAs and PRMs (mesoprogestins) open up new applications in gynecological therapy and hormone replacement therapy.

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PubMedDate not supplied

Keratinocyte growth factor and its receptor in the rhesus macaque placenta during the course of gestation.

Keratinocyte growth factor (KGF) is synthesized and secreted exclusively by mesenchymal cells, and acts through its receptor (KGFR) to stimulate epithelial proliferation. In vivo, KGF and KGFR comprise a mesenchymal-epithelial cell paracrine system that can mediate epithelial cell mitosis. In preliminary work, we noted that KGF was expressed in the rhesus monkey placenta, and we now report on the expression of placental KGF and KGFR mRNAs during the course of gestation in this species. In-situ hybridization revealed that during early gestation, KGF mRNA was strongly expressed in placental mesenchymal cells. These cells, which were also immunoreactive for vimentin, were mainly located on the periphery of the mesenchymal cores of both anchoring and floating villi. KGFR mRNA was expressed in the adjacent trophoblastic epithelium, which was immunoreactive for cytokeratin. In-situ hybridization revealed that KGF mRNA expression was very high in the youngest placentae (34-days gestation) and decreased gradually to minimal levels by late gestation (157 days). Northern blot analysis indicated also that the KGF MRNA signal was strongest in early gestation samples and weakest by late gestation. Analysis for KGFR mRNA by a reverse transcriptase-polymerase chain reaction technique showed that KGFR mRNA expression could be detected at all stages. However, in-situ hybridization indicated that KGFR mRNA expression was highest in early gestation placentae and least in the oldest placentae. Autoradiographs of frozen sections of placenta that had been incubated with [125I]KGF to detect receptor binding showed that grain density over the trophoblast was highest in the youngest and least in the oldest placentae. PCNA and Ki-67 expression followed this same temporal trend. We conclude that the KGF/KGFR system may be important in proliferation of the placental trophoblast during early- to mid-pregnancy in rhesus monkeys.

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PubMedDate not supplied

Progesterone receptor localization and isoforms in myometrium, decidua, and fetal membranes from rhesus macaques: evidence for functional progesterone withdrawal at parturition.

OBJECTIVE: It is not known whether withdrawal of progesterone (P) action is a prerequisite for parturition in women or in nonhuman primates because concentrations of circulating progesterone or progesterone receptors (PR) in myometrium and decidua do not decrease before delivery. To examine this potentially important regulatory mechanism, we determined PR isoforms, PR localization, and mRNA in myometrium, decidua, and fetal membranes from rhesus monkeys during pregnancy and in spontaneous labor at term. METHODS: Gestational tissues were obtained midpregnancy (day 80-100), late pregnancy (day 130-145), and during spontaneous labor at term (day 161-167). Samples of rhesus monkey myometrium, decidua, chorion-decidua, and amnion were collected and analyzed for total nuclear and cytosolic PR by competitive binding assay. Progesterone receptor isoforms were identified and quantified by Western blot analysis, and PR mRNA was determined by a specific ribonuclease protection assay. Nuclear PR was localized by immunohistochemistry with monoclonal anti-PR (JZB39) after microwave stabilization. RESULTS: Myometrium and decidua showed no change in total PR during pregnancy and labor. Nuclear PR was not detected in fetal membranes by binding assay but was localized in amnion epithelial and mesenchymal cells and in chorion laeve cytotrophoblasts by immunohistochemistry. Staining for PR was substantially less by serial antibody dilution in fetal membranes than in decidua. Message for PR was confirmed in all tissues analyzed. A significant (P <.05) shift in the ratio of PR isoforms (from PR-B dominance at midpregnancy to PR-A dominance in labor) was observed in myometrium but not in decidua. Both PR-A and PR-B isoforms and PR nuclear staining were nearly undetectable in amnion obtained during labor. CONCLUSION: A shift to PR-A dominance in myometrium at term together with a loss of PR in fetal membranes provides evidence for a functional progesterone withdrawal mechanism, which may facilitate the initiation of parturition in primates.

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