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R M Brenner

Publications and source records attributed to R M Brenner.

At least 19 recordsLinked to original sources
PubMed2001

The endocrinology of menstruation--a role for the immune system.

The human endometrium displays characteristic features, both structural and functional, across the menstrual cycle. It is the sex steroid hormones, oestrogen and progesterone, that drive the endometrium through the different phases of the cycle. Oestrogen and progesterone act sequentially to regulate cellular concentrations of their respective receptors, this interaction initiates gene transcription. Thereafter a cascade of local events prepares the endometrium for implantation, but in the absence of pregnancy, progesterone withdrawal leads to menstruation and cyclic repair. Withdrawal of progesterone from an oestrogen-progesterone primed endometrium is the initiating event for the cascade of molecular and cellular interactions that result in menstruation. Progesterone withdrawal first affects cells with progesterone receptors. Early events in the menstrual process are vasoconstriction and cytokine up-regulation. The activation of lytic mechanisms is a later event and involves cells that may lack progesterone receptors, for example, uterine leucocytes and epithelial cells. Hence progesterone withdrawal results in a local increase of inflammatory mediators and the enzymes responsible for tissue breakdown. The total complex of local factors implicated in normal menstrual and aberrant menstrual bleeding are yet to be fully defined.

Adult↗
PubMed2001

Reversible suppression of menstruation with progesterone antagonists in rhesus macaques.

BACKGROUND: A reliable means of menstrual suppression would greatly improve the quality of life for women. Information is lacking on the direct endometrial effects and appropriate dosages of new antiprogestins that may be useful for this purpose. METHODS: The current work evaluated three different systems in macaque monkeys. First, the range of doses of two relatively new antiprogestins, ZK 137 316 and ZK 230 211, that would block progesterone action directly on the endometrium in artificially cycled, spayed rhesus macaques; second, the direct endometrial effects of ZK 230 211, a type III antiprogestin; and third, investigation of whether endometrial-suppressive doses administered chronically to intact, cycling monkeys could be used for reversible, menstrual suppression. RESULTS: The results in naturally cycling animals showed that ZK 137 316 blocked menstruation in all animals, but doses of 0.05 mg/kg blocked ovulation in 55.5% of animals and doses of 0.1 mg/kg blocked ovulation in 66.6% of the animals. However, all doses of ZK 230 211 that blocked menstruation also blocked ovulation. All progesterone antagonist (PA)-treated animals, regardless of dose, maintained normal follicular phase concentrations of oestradiol and returned to normal menstrual cyclicity within 15--41 days post-treatment. Therefore ZK 137 316, depending on dose, can allow ovulation but block menstruation, while ZK 230 211, a much more potent PA, blocks both ovulation and menstruation at all effective doses. Both PAs block unopposed oestrogenic action on the endometrium through their antiproliferative effects. CONCLUSIONS: Reversible amenorrhoea can be achieved with these two PAs, and they can protect the endometrium from the effects of unopposed oestrogen whether or not ovulation is blocked. Chronic, low dose PA treatment may provide a new option for women who wish to suppress their menstrual periods.

Animals↗
PubMed2001

Estrogen receptor beta, but not estrogen receptor alpha, is present in the vascular endothelium of the human and nonhuman primate endometrium.

Estrogen action is dependent upon the presence of specific ligand-activated receptors in target tissues. The aim of the present experiments was to compare the spatial and temporal pattern of expression of estrogen receptor beta (ERbeta) with that of ERalpha in full thickness endometrial samples (from the superficial to the basal zone) obtained from both women and rhesus macaques. Immunohistochemical localization with specific antibodies revealed that ERalpha and ERbeta were both expressed in nuclei of the glands and stroma. Consistent with previous studies, expression of ERalpha declined in the glands and stroma of the functionalis during the secretory phase. The luminal epithelium also displayed positive immunoreactivity for ERbeta. Expression of ERbeta declined in glandular cell nuclei, but not stroma, within the functionalis during the late secretory phase. Levels of expression of ERalpha and ERbeta in all cellular compartments remained unchanged in the basalis. Both receptor subtypes were detected on Western blots using proteins extracted from uterine samples obtained throughout the menstrual cycle. There was a striking contrast between the pattern of expression of ERalpha and ERbeta in the vascular endothelium and the perivascular cells surrounding endometrial blood vessels; only ERbeta was present in the endothelial cell population, although both forms of ER were expressed in perivascular cells. We conclude that estrogen action(s) within the vascular endothelium in the endometrium may be mediated via direct binding to the ERbeta isoform and that these cells could therefore be a target for agonists or antagonists that selectively target the beta form of the ER.

Adult↗
PubMed2001

Progesterone antagonists increase androgen receptor expression in the rhesus macaque and human endometrium.

Antiprogestins (APs) inhibit estradiol (E(2))-stimulated endometrial growth in women and nonhuman primates, but the mechanism of this "antiestrogenic" action is unknown. Here, we report that APs up-regulate endometrial androgen receptor (AR) in both women and macaques, an effect that might play a role in the antiproliferative effects of APs on the primate endometrium. In addition, because there are discrepancies in the literature on the regulation and localization of AR in the primate endometrium, we used both in situ hybridization and immunocytochemistry to evaluate hormonal influences on endometrial AR in women and macaques. In ovariectomized macaques, the following treatments were given for 4 weeks each: E(2) alone, E(2) + progesterone (P), E(2) + mifepristone (RU 486), and E(2) + P + RU 486. In women, samples were obtained during the normal menstrual cycle and after treatment with either RU 486 for 30 days at 2 mg/day, or after a single oral administration of 200 mg RU 486 on cycle day LH + 2. In macaques, E(2) significantly increased AR expression above vehicle controls; E(2) + RU 486 increased binding further; E(2) + P decreased AR binding; and E(2) + P + RU 486 treatment caused an intermediate elevation in AR binding. In macaques treated with E(2) alone, stromal AR staining was predominant, and P treatment suppressed that staining. E(2) + RU 486 or E(2) + P + RU 486 treatment produced a striking up-regulation of glandular epithelial AR staining and enhanced the stromal AR signal. In situ hybridization analyses confirmed the immunocytochemistry data. Similar induction of glandular AR staining and enhanced stromal AR staining were obtained in macaques treated with ZK 137 316 and ZK 230 211. During the natural cycle in women, stromal AR staining predominated and was greater in the proliferative than the late secretory phase. RU 486 treatment of women up-regulated glandular epithelial AR staining after either daily treatment for 30 days with 2 mg/day or after a single oral dose of 200 mg. In summary, endometrial AR was highest in the stroma during the human proliferative phase (or during E(2) treatment in macaques) and lowest during the late secretory phase in women (or after E(2) + P treatment in macaques). In both species, RU 486 induced AR expression in the glands and enhanced AR expression in stromal cells. Because androgens can antagonize E(2) action, enhanced endometrial AR expression induced by APs could play a role in the antiproliferative, "antiestrogenic" effects of APs in primates.

Animals↗
PubMed2000

Effects of keratinocyte growth factor in the endometrium of rhesus macaques during the luteal-follicular transition.

We previously reported that keratinocyte growth factor (KGF) is up-regulated by the action of progesterone (P) in the primate endometrium, and we suggested that this protein is a likely mediator of P-dependent stromal-epithelial paracrine interactions in this tissue. At the end of the menstrual cycle, P levels fall, and the abundance of endometrial KGF transcripts decreases approximately 9-fold. In macaques, withdrawal of P induces the luteal-follicular transition (LFT), marked by menstrual sloughing of the functionalis zone and apoptotic regression of the basalis zone. Because KGF levels fall so dramatically during the LFT, we hypothesized that replacement with exogenous KGF during the LFT would prevent some of the endometrial changes seen after P withdrawal. Here we describe two studies of the effects of exogenously administered KGF during the LFT in rhesus macaques. In one experiment we administered KGF systemically to ovariectomized, juvenile rhesus macaques during an LFT induced by hormonal manipulations. KGF had dramatic proliferative effects on the bladder and salivary glands, known targets of KGF, but did not affect cell proliferation in the endometrium or block menstrual sloughing and bleeding. However, KGF strongly inhibited apoptosis in the basalis zone, increased glandular sacculation and folding in this zone, and had a marked trophic effect on the spiral arteries. In the second experiment we installed oviductal catheters in ovariectomized adult rhesus macaques and infused KGF directly into the uterine lumen during a hormonally induced LFT. Again, arteriotrophic, antiapoptotic, and basalis gland sacculation effects were observed in the absence of any effect on cell proliferation. We concluded that although KGF is mitogenic for many epithelial cell types, it does not play this role in the primate endometrium. Its most important roles may be to stimulate spiral artery growth and inhibit glandular apoptosis during the nonfertile menstrual cycle. Because its expression rises coincident with the time of implantation and because spiral arteries are essential to successful establishment of pregnancy, the role of KGF in the fertile menstrual cycle deserves further study.

Animals↗
PubMed2000

Progesterone withdrawal up-regulates vascular endothelial growth factor receptor type 2 in the superficial zone stroma of the human and macaque endometrium: potential relevance to menstruation.

Several reports indicate that vascular endothelial growth factor (VEGF) expression is increased in endometrial glands and stroma during the menstrual phase in the human endometrium. Here we report that VEGF receptor type 2 (KDR), normally expressed only in the vascular endothelium, was dramatically up-regulated in the stromal cells of the superficial endometrial zones during the premenstrual phase in both human and macaque endometrium. This increase was detectable by Northern analysis, in situ hybridization, and immunocytochemistry and was cell specific, zone specific, cycle phase specific, and VEGF receptor type specific. That is, it only occurred during the premenstrual/menstrual phase, did not occur in glandular epithelium, endothelium, or stromal cells of the deepest endometrial zones, and was not observed for VEGF receptor type 1. The upregulation of stromal KDR was induced by progesterone (P) withdrawal in both women and macaques, and adding back P 24 h after P withdrawal in macaques blocked stromal, but not vascular, endothelial KDR expression. Promatrix metalloproteinase-1 (MMP-1) was coordinately up-regulated in the same stromal cell population by P withdrawal. Because of reports that VEGF can enhance MMP expression, we hypothesize that VEGF-KDR interactions may influence MMP expression in the superficial zones of the primate endometrium during the premenstrual phase, and that these interactions play a role in the induction of menstruation.

Adult↗
PubMed1998

Chronic treatment of female rhesus monkeys with low doses of the antiprogestin ZK 137 316: establishment of a regimen that permits normal menstrual cyclicity.

Large doses of antiprogestin typically disrupt menstrual cyclicity. A chronic low-dose regimen of the potent new antiprogestin ZK 137 316, which permits continued menstrual cyclicity but alters gonadal-reproductive tract activity, was established. Rhesus monkeys received vehicle (n = 6) or 0.01 (n = 8), 0.03 (n = 8) or 0.1 (n = 5) mg ZK 137 316/kg body weight daily for five menstrual cycles (C-1 to C-5). Oestradiol, progesterone and gonadotrophin profiles were normal during cycles involving vehicle and 0.01 and 0.03 mg ZK 137 316/kg body weight. In the 0.1 mg/kg group, mid-cycle oestradiol and gonadotrophin surges, and subsequent progesterone production, were absent in C-3 and C-5. Ovarian cyclicity was accompanied by timely menstruation in the vehicle and 0.01 mg/kg groups. By C-3, half the animals in the 0.03 mg/kg group and all animals in the 0.1 mg/kg group were amenorrhoeic. A corpus luteum was noted during the mid-luteal phase of C-5 in the vehicle, 0.01 mg/kg and 0.03 mg/kg groups. Large antral and cystic follicles were evident in the 0.1 mg/kg group. Thus, a daily treatment with 0.01 mg/kg ZK 136317 permitted normal menstrual cyclicity in macaques. While the daily administration of 0.03 mg/kg ZK 136 317 allowed ovarian cyclicity, menstruation was disrupted in some animals. Increasing the dose to 0.1 mg/kg antagonized pituitary function and resulted in anovulation and amenorrhoea. A chronic low-dose regimen of the antiprogestin ZK 137 316, which permits normal ovarian/menstrual cyclicity, has potential as a contraceptive in women.

Animals↗
PubMed1998

Chronic treatment of cycling rhesus monkeys with low doses of the antiprogestin ZK 137 316: morphometric assessment of the uterus and oviduct.

The long-term effects of the antiprogestin ZK 137 316 on reproductive tract morphology in rhesus macaques were investigated. The monkeys were injected daily (i.m.) for five menstrual cycles with vehicle or 0.01, 0.03 or 0.1 mg ZK 137 316/kg body weight. Reproductive tracts (n = 3/ group) were collected during the mid-luteal phase (day 8) of the fifth cycle in the control, 0.01 and 0.03 mg/kg groups, or 6-7 days after the oestradiol peak in the 0.1 mg/kg group. ZK 137 316 treatment resulted in a dose-dependent atrophy of the endometrium, marked by reduced mitotic activity in the glands, compaction of the stroma, degradation of spiral arteries and dilation of veins. There was no effect of ZK 137 316 on myometrial or oviductal weight. Treatment with 0.1 and 0.03 mg/kg, but not 0.01 mg/kg resulted in fully ciliated and secretory oviducts, indicating a dose-dependent blockade of progesterone antagonism of oestrogen-dependent oviductal differentiation. In the endometrium, the suppressive action of progesterone on oestrogen and progestin receptors was also blocked by ZK 137 316 in a dose-dependent manner. However, endometrial atrophy appeared due to inhibition of progesterone action together with a blockade of oestrogen-dependent proliferation. The profoundly suppressed endometrium produced by chronic low-dose ZK 137 316 treatment is unlikely to support implantation. Such treatment may therefore provide a novel contraceptive modality.

Animals↗
PubMed1998

A chronic, low-dose regimen of the antiprogestin ZK 137 316 prevents pregnancy in rhesus monkeys.

Continual administration of low doses of the antiprogestin ZK 137 316 was previously reported to permit ovarian/menstrual cyclicity, but disrupt endometrial growth in macaques. The contraceptive efficacy of this regimen was tested in female rhesus monkeys (10 per group) treated daily with vehicle (controls), 0.01 or 0.03 mg ZK 137 316 per kg body weight for 30 days before and during continual co-habitation with males of proven fertility. Treatment continued until confirmation of pregnancy or for 5 months after pair-housing with males. Mating and vaginal sperm were evident in all females. A cumulative pregnancy rate of 90% (9/10) was observed in the controls. Of the 10 animals receiving 0.01 mg/kg, four conceived during the first 2 months of pairing (P = 0.06) with no further conceptions. No pregnancies were observed in the 0.03 mg/kg group (P < 0.01). Timely, overt menses occurred at a higher frequency in the 0.01 mg/kg group than the 0.03 mg/kg group. However, corpora lutea were present in ovaries from both groups during the last treatment cycle, indicating that ovarian cycles occurred. Thus, chronic administration of low-dose ZK 137 316 that permits continued ovarian cyclicity and a high incidence of timely menses, prevents pregnancy in non-human primates. This regimen may provide a novel method of contraception for women.

Animals↗
PubMed1998

Matrix metalloproteinase expression in Macaca mulatta endometrium: evidence for zone-specific regulatory tissue gradients.

Matrix metalloproteinases (MMPs) are highly expressed in the human endometrium during menstruation, and these enzymes participate in the cyclic destruction and regeneration characteristic of the primate endometrium. To examine hormonal regulation of MMPs in vivo, we evaluated MMP expression and localization in the endometrium of ovariectomized rhesus macaques under various hormonal conditions. Although all MMPs were up-regulated by progesterone (P4) withdrawal, their expression declined spontaneously after menstruation in the absence of P4. Of 7 MMPs examined, only matrilysin and stromelysin-3 were suppressed any further when P4 levels were experimentally re-elevated. MMP expression was confined to the upper functionalis zone during menstruation, but after menstrual breakdown was complete, matrilysin and the tissue inhibitor of MMPs, TIMP-1, shifted expression from the functionalis to the basalis zone in the absence of both estradiol and P4. The spiral arteries in the functionalis, but not the basalis, were intense foci of MMP and TIMP-1 expression. Menstruation and MMP expression after P4 withdrawal were similar in both the presence and absence of estradiol. In sum, endometrial MMPs in vivo are strongly up-regulated by P4 withdrawal, but zone-specific tissue gradients greatly influence the pattern and degree of MMP expression.

Animals↗
PubMed1997

Immunologic and molecular characterization of an estrogen-dependent glycoprotein in the rhesus (Macaca mulatta) oviduct.

The objective of this study was to detect and characterize a secreted oviduct-specific glycoprotein (OGP) in the rhesus macaque (Macaca mulatta) and to compare the characteristics of this OGP to those previously characterized in baboons and women. Oviducts were obtained from untreated ovariectomized rhesus and from ovariectomized rhesus either treated with estradiol (E2) for 14 days or treated sequentially with E2 for 14 days and then with E2 plus progesterone (P4) for an additional 14 days. Segments of oviducts were either fixed for morphological analysis, cultured for OGP synthesis and release, or frozen for RNA analysis. The proteins present in the culture media were separated by one-dimensional SDS-PAGE, and OGP was detected on Western blots using polyclonal antibodies generated against the reduced form of baboon OGP or a 17-amino acid segment of the baboon core protein. Cross-reacting antigens were present in the 120-kDa region, identical to what was observed for baboon and human OGP. Indirect immunogold localization of OGP on thin sections demonstrated specific clustering of gold particles over the apical secretory granules of the secretory cells of the oviductal epithelium. A cDNA was generated using RT-PCR and 5' and 3' rapid amplification of cDNA ends (RACE), and sequenced. The total transcript was 2237 nucleotides in length plus a poly(A) tail. The largest open reading frame was 624 amino acids, which would produce a protein of 69.3 kDa. The nucleotide sequence was more than 95% identical to the nucleotide sequences of baboon and human OGP. Northern blots revealed a single message at 2.4 kilobases (kb) in oviduct samples obtained from E2-treated rhesus. This message was absent in oviducts obtained from untreated ovariectomized and from sequential E2 plus P4-treated rhesus macaques. In summary, the rhesus oviduct synthesizes and secretes an OGP in the presence of E2 that is immunologically and structurally similar to the baboon and human OGP. The presence of a highly homologous glycoprotein in several primates suggests a similar function for OGP in the reproductive process.

Amino Acid Sequence↗
PubMed1997

The rise and fall of atrial natriuretic peptide for acute renal failure.

Atrial natriuretic peptide can increase glomerular filtration rate and filtration fraction and can promote natriuresis, effects that would logically seem to improve renal function after acute tubular necrosis from ischemic or toxic injury. Early human trials suggested a beneficial effect of atrial natriuretic peptide on creatinine clearance, and a reduction in the need for dialysis in treated patients. However, randomized, placebo-controlled trials have failed to show a clinically relevant benefit on survival, dialysis-free survival, or renal function in patients treated with this agent.

Acute Kidney Injury↗
PubMed1996

Non-human primate models; artificial menstrual cycles, endometrial matrix metalloproteinases and s.c. endometrial grafts.

Rhesus monkeys are useful models in which to examine the hormonal regulation of endometrial matrix metalloproteinases (MMP) and to evaluate the role of MMP in uterine bleeding. Artificial 28 day menstrual cycles can be induced in ovariectomized monkeys by inserting an oestradiol implant for 2 weeks, then inserting a progesterone implant for 2 weeks, and then, with the oestradiol implant remaining in place, removing and reinserting the progesterone implant at 2 week intervals. To examine MMP during menses, we established such cycles and removed uteri by hysterectomy at closely spaced intervals before, during and after menses, as well as at later time points. Some samples were also obtained during menses induced by the withdrawal of both progesterone and oestradiol. We examined mRNA of the following MMP by Northern blotting: matrilysin, stromelysin-1, stromelysin-2, stromelysin-3 and the tissue inhibitor of MMP TIMP-1. The expression of these MMP mRNA increased substantially by 2-3 days after progesterone withdrawal, whether or not oestradiol was maintained. The expression of some of the MMP (stromelysins-1 and -2) returned very rapidly to baseline levels by 5 days after progesterone withdrawal, while the expression of others (matrilysin, stromelysin-3 and TIMP-1) declined more slowly, reaching a baseline level by 10 days after progesterone withdrawal, with little or no further decline after progesterone concentrations rose during the induced luteal phase. Immunocytochemical studies showed that matrilysin was expressed primarily in the glands of the upper functionalis. In other work with the rhesus monkey model, we used a s.c. endometrial autograft technique in which pieces of endometrium were autotransplanted to the abdominal skin. During menses in the grafts, matrilysin was expressed in the glands of the grafts similar to the glands in the eutopic endometrium. Endometrial autografts can serve as a useful model for the study of MMP in uterine bleeding.

Animals↗
PubMed1995

Microwave stabilization enhances immunocytochemical detection of estrogen receptor in frozen sections of macaque oviduct.

We have found that microwave (MW) stabilization greatly improves detection of the estrogen receptor (ER) in frozen sections of rhesus monkey oviduct by immunocytochemistry (ICC). Fresh samples of fimbriae were MW-irradiated, frozen, and then cryosectioned. The frozen sections were also MW-treated and then fixed in a paraformaldehyde-based fixative before ICC processing. A parallel set of samples from each monkey were frozen, sectioned and processed for ICC without any MW treatment. MW stabilization clearly increased immunostaining intensity with either of two ER-specific monoclonal antibodies, namely, H222 and 1D5. The greatest increase was noted in tissues collected from spayed or progesterone-treated animals. An antibody dilution series indicated that MW stabilization increased the sensitivity approximately 20- to 40-fold. In addition, we incubated spayed macaque fimbriae at 4 C in the presence of 10 nM [3H]Moxestrol and then either froze the tissues immediately (non-MW) or treated them with MW. Slide-mounted cryosections of non-MW and MW-treated tissue were then incubated with either a Tris-EDTA buffer (low salt) or the same buffer containing 4 M KCl (high salt). The quantity of [3H]Moxestrol-occupied ER extracted from the frozen sections by each buffer was determined by a sucrose gradient shift assay. The low salt buffer extracted significantly more radiolabeled ER from non-MW sections than from MW-treated sections (P < 0.01), whereas the high salt buffer extracted equal amounts of ER from both the MW-treated and non-MW sections. MW-irradiation enhanced ICC detectability of ER in frozen sections by greatly reducing the amount of ER extracted during the various washes used during normal ICC processing.

Animals↗
PubMed1994

Progesterone-dependent expression of keratinocyte growth factor mRNA in stromal cells of the primate endometrium: keratinocyte growth factor as a progestomedin.

In vitro studies have shown that keratinocyte growth factor (KGF, also known as FGF-7) is secreted by fibroblasts and is mitogenic specifically for epithelial cells. Therefore, KGF may be an important paracrine mediator of epithelial cell proliferation in vivo. Because stromal cells are thought to influence glandular proliferation in the primate endometrium, we investigated the hormonal regulation and cellular localization of KGF mRNA expression in the rhesus monkey uterus. Tissues were obtained both from naturally cycling monkeys in the follicular and luteal phases of the cycle, and from spayed monkeys that were either untreated or treated with estradiol (E2) alone, E2 followed by progesterone (P), E2 plus P, or E2 plus P plus an antiprogestin (RU 486). Northern blot analysis of total RNA with 32P-labeled probes revealed that the level of KGF mRNA in the endometrium was 70-100-fold greater in the luteal phase or after P treatment than in untreated, E2-treated, or follicular phase animals. Northern analysis also showed that KGF mRNA was present in the myometrium but was unaffected by hormonal state. RU 486 treatment prevented the P-induced elevation of endometrial KGF mRNA. P-dependent elevation of endometrial KGF expression was confirmed by measurement of KGF protein in tissue extracts using a two-site enzyme-linked immunosorbent assay. In situ hybridization with nonradioactive digoxigenin-labeled cDNA probes revealed that the KGF mRNA signal, which was present only in stromal and smooth muscle cells, was substantially increased by P primarily in the stromal cells located in the basalis region. Smooth muscle cells in the myometrium and the walls of the spiral arteries also expressed KGF mRNA, but the degree of this expression did not differ with hormonal state. P treatment led to increased proliferation in the glandular epithelium of the basalis region and to extensive growth of the spiral arteries. We conclude that the P-dependent increase in endometrial KGF resulted from a dual action of P: (a) a P-dependent induction of KGF expression in stromal cells, especially those in the basalis (zones III and IV), and (b) a P-dependent increase in the number of KGF-positive vascular smooth muscle cells caused by the proliferation of the spiral arteries. KGF is one of the first examples in primates of a P-induced, stromally derived growth factor that might function as a progestomedin.

Animals↗
PubMed1994

Oestrogen action in the endometrium and oviduct of rhesus monkeys during RU486 treatment.

Two experiments were conducted to determine how RU486 affected oestradiol action in the non-human primate female reproductive tract. In the first experiment, spayed rhesus monkeys were first treated with a sequential regimen of oestradiol and progesterone to cause regression and deciliation in the oviduct and progestational development in the endometrium. The ability of oestradiol to stimulate oviductal differentiation and endometrial regeneration in the presence of RU486, progesterone, and progesterone plus RU486 was then tested. RU486 was found to block the ability of oestradiol to increase endometrial growth but did not prevent oestradiol-dependent oviductal differentiation. Also, in the endometrium but not the oviduct, RU486 action differed from simple progesterone withdrawal by causing stromal compaction and glandular apoptosis. In the second experiment, spayed monkeys were first treated with oestradiol for 2 weeks to produce a fully differentiated, ciliated-secretory oviduct and an hypertrophied, proliferative endometrium. The ability of oestradiol to maintain these conditions in oviduct and endometrium during treatment with RU486, progesterone, and progesterone plus RU486 was then tested. It was found that RU486 suppressed the ability of oestradiol to maintain the endometrium in a hypertrophied state but not its ability to maintain the oviduct in a fully ciliated-secretory state. As before, RU486 induced extensive glandular apoptosis and stromal compaction in the endometrium, but not the oviduct. These endometrial effects appeared to be due to a combination of a decrease in proliferation, an increase in epithelial cell death by apoptosis, an increase in stromal compaction and a concomitant decrease in interstitial fluid content, all of which led to a decrease in endometrial wet weight and thickness. These effects of RU486 on oestradiol action were similar in the presence and absence of progesterone and were therefore separate and distinct from the classical antiprogestin effects of RU486. Because RU486 did not inhibit the ability of oestradiol to either stimulate or maintain oviductal differentiation or wet weight, these results suggest that the endometrium is much more sensitive to the anti-proliferative effects of RU486 than the oviducts.

Animals↗