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Role of ovarian progesterone and potential role of prostaglandin F2alpha and prostaglandin E2 in modulating the uterine response to infectious bacteria in postpartum ewes.

Lewis GS.

ARS, USDA, US Sheep Experiment Station, Dubois, ID 83423-9602, USA. glewis pw.ars.usda.gov

In sheep and cattle, the postpartum uterus is resistant to bacterial challenge until after corpora lutea develop. A 2 x 2 factorial arrangement of treatments was used to determine whether prostaglandins may mediate the effects of progesterone in transforming the postpartum uterus from resistant to susceptible. On d 14 postpartum, ewes (n = 6/group) were ovariectomized or sham ovariectomized, and the vena cava was catheterized for daily collection of uteroovarian-enriched blood. From d 15 to 20, ewes received twice daily intramuscular injections of progesterone in sesame oil or plain sesame oil. On d 20, each uterus received 75 x 10(7) cfu of Arcanobacterium pyogenes and 35 x 10(7) cfu of Escherichia coli. Uteri were collected on d 25 and examined for signs of infection. For each blood sample, unstimulated and mitogen-stimulated lymphocyte proliferation was measured as [3H]thymidine incorporation, smears were prepared for differential white blood cell (WBC) counts, and progesterone, prostaglandin F2alpha, (PGF2alpha), and prostaglandin E2 (PGE2) were quantified. All 12 progesterone-treated, but only two of the 12 oil-treated, ewes developed uterine infections (P < 0.001). Progesterone treatment increased (P < 0.001; 3.1 vs 1.5 ng/mL) and ovariectomy decreased (P < 0.001; 3.7 vs 0.9 ng/mL) vena caval progesterone. Progesterone treatment reduced (P < 0.01) PGF2alpha, (303.9 vs 801.3 pg/mL), and PGF2alpha was greater (P < 0.05) before than after inoculation (626.4 vs 478.8 pg/mL). The PGE2 concentration was greater in progesterone-treated, ovary-intact ewes than in ewes in the other groups (ovariectomy x progesterone treatment; P < 0.01). Ovariectomy increased (P < 0.005; 4.4 vs 2.9 pmol) and progesterone treatment decreased (P < 0.05; 3.2 vs 4.1 pmol) concanavalin A-stimulated lymphocyte proliferation. Ovariectomy increased lipopolysaccharides-stimulated proliferation (P < 0.05; 2.4 vs 1.9 pmol). For neutrophils per 100 WBC, the ovariectomy x progesterone and progesterone x period interactions were significant (P < 0.01). The ovariectomy x progesterone interaction was significant (P < 0.01) for lymphocytes per 100 WBC. Ovariectomy decreased monocytes (P < 0.001; 10 vs 13) and increased eosinophils (P < 0.001; 10 vs 5) per 100 WBC. Progesterone makes the postpartum uterus in ewes susceptible to infection, but ovariectomy allows ewes to remain resistant; uterine prostaglandins may mediate this change. This model creates opportunities to determine the mechanisms responsible for the shift from resistance to susceptible.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12597400&dopt=Abstract progesterone, progesterone cream



progesterone cream
Molecular tools to reestablish progestin control of endometrial cancer cell proliferation.

Dai D, Kumar NS, Wolf DM, Leslie KK.

Division of Basic Reproductive Science, Department of Obstetrics and Gynecology, The University of Colorado Health Sciences Center, Denver, USA.

OBJECTIVE: Endometrial cancers often arise in a setting of estrogen stimulation unopposed by the differentiating effects of progesterone. Our laboratory and others have previously shown that progesterone receptor down-regulation or perturbation of progesterone receptor isoform A or B expression is associated with the development of poorly differentiated endometrial cancers that are not growth inhibited by progestins. The purpose of these studies was to reestablish high progesterone receptor isoform A and B gene expressions in such endometrial cancer cells and to examine the effects of progestin treatment on cell growth and metastatic potential after this transformation. STUDY DESIGN: To induce high levels of expression of the progesterone receptor isoforms in KLE and Hec50 endometrial cancer cells, adenoviral vectors encoding the genes for progesterone receptor isoforms A and B were created. The characteristic ability of cancer cells to grow independently of anchorage to the surrounding solid matrix was measured by counting colony formation on soft agar for 8 to 14 days. Cell proliferation in response to a time course of progestin treatment was tested with flow cytometry. RESULTS: After treatment with a control vector without a progesterone receptor--encoding insert, no effect of progestin treatment on cell proliferation was found; after treatment with vectors encoding progesterone receptor isoform A or B, however, progestin treatment resulted in significant inhibition of cell growth. The anchorage-independent cell growth on soft agar assay showed that by 8 to 14 days the number of cell colonies was reduced by 50% relative to control preparations in the presence of progesterone receptor isoform A plus progestin (P <.0001, both Hec50 and KLE cell lines) and by 90% in the presence of progesterone receptor isoform B plus progestin (P <.0001, both Hec50 and KLE cell lines). Progestin treatment also resulted in a time-dependent reduction in cell proliferation as measured by flow cytometry. Although transfection with both progesterone receptor isoforms A and B reduced cell proliferation according to our assays, progesterone receptor isoform B caused a much more dramatic decrease in cell growth (P =.001, Hec50 cells; P <.0001, KLE cells). CONCLUSION: In poorly differentiated endometrial cancer cells that are resistant to progestin therapy, adenovirus-induced expressions of progesterone receptors A and B reestablish progestin control of endometrial cancer cell proliferation.

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Regulation of plasminogen activator inhibitor 1 expression by interaction of epidermal growth factor with progestin during decidualization of human endometrial stromal cells.

Lockwood CJ.

Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY 10016, USA.

OBJECTIVE: During human pregnancy implantation, trophoblasts invade maternal blood vessels in a process that risks hemorrhage. Previous studies have demonstrated enhanced expression of type 1 plasminogen activator inhibitor, the primary inhibitor of fibrinolysis, during progestin-induced decidualization of estradiol-primed human endometrial stromal cells in vivo and in vitro. Decidual cell-expressed plasminogen activator inhibitor 1 is appropriately positioned to avert implantational hemorrhage. Because of the absence of estrogen or progesterone response elements from the plasminogen activator inhibitor 1 gene promoter, I posited that epidermal growth factor mediates these steroid effects and that expression of epidermal growth factor receptor in human endometrial stromal cells is under ovarian steroid control. STUDY DESIGN: Confluent human endometrial stromal cells were exposed to vehicle control or to either estradiol (10(-8) mol/L) or medroxyprogesterone acetate (10(-7) mol/L), or both, with or without growth factors. After 40 hours the cultures were analyzed for plasminogen activator inhibitor 1 protein and messenger ribonucleic acid expressions. Immunostaining for epidermal growth factor receptor was carried out in sections of cycling and gestational endometrial tissues. RESULTS: In the absence of steroids, epidermal growth factor did not alter plasminogen activator inhibitor 1 expression. In the absence of epidermal growth factor, estradiol and medroxyprogesterone acetate enhanced human endometrial stromal cell-secreted plasminogen activator inhibitor 1 protein levels 8-fold (n = 12; P <.001), whereas estradiol alone had no effect. Marked synergistic increases in plasminogen activator inhibitor 1 levels were elicited when epidermal growth factor was added with estradiol and medroxyprogesterone acetate (n = 12; 65-fold; P <.0001). Both transforming growth factor alpha and epidermal growth factor, which act through epidermal growth factor receptor, increased steady-state plasminogen activator inhibitor 1 messenger ribonucleic acid levels several-fold when added with estradiol and medroxyprogesterone acetate. In contrast, transforming growth factor beta, which does not activate epidermal growth factor receptor, did not elevate plasminogen activator inhibitor 1 messenger ribonucleic acid or protein levels whether added alone or with estradiol and medroxyprogesterone acetate. In correspondence with these in vitro observations, immunostaining for epidermal growth factor receptor was increased in human endometrial stromal cells undergoing decidualization in sections of secretory phase and first-trimester endometrial tissue. CONCLUSIONS: Taken together, these in vitro and in vivo results indicate that both epidermal growth factor and progesterone receptors are required for maximal plasminogen activator inhibitor 1 expression by human endometrial stromal cells.

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Effects of indomethacin, luteinizing hormone (LH), prostaglandin E2 (PGE2), trilostane, mifepristone, ethamoxytriphetol (MER-25) on secretion of prostaglandin E (PGE), prostaglandin F2alpha (PGF2alpha) and progesterone by ovine corpora lutea of pregnancy or the estrous cycle.

Kim L, Weems YS, Bridges PJ, LeaMaster BR, Ching L, Vincent DL, Weems CW.

Dept. of Animal Science, University of Hawaii, Honolulu 96822, USA.

Two experiments were conducted to determine the luteotropin of pregnancy in sheep and to examine autocrine and paracrine roles of progesterone and estradiol-17 beta on progesterone secretion by the ovine corpus luteum (CL). Secretion of progesterone per unit mass by day-8 or day-11 CL of the estrous cycle was similar to day-90 CL of pregnancy (P > or = 0.05). In experiment 1, secretion of progesterone in vitro by slices of CL from ewes on day-8 of the estrous cycle was increased (P < or = 0.05) by LH or PGE2. Secretion of progesterone in vitro by CL slices from day-90 pregnant ewes was not affected by LH (P > or = 0.05) while PGE2 increased (P < or = 0.05) secretion of progesterone. Day 8 ovine CL of the estrous cycle did not secrete (P > or = 0.05) detectable quantities of PGF2alpha or PGE while day-90 ovine CL of pregnancy secreted PGE (P < or = 0.05) but not PGF2alpha. Secretion of progesterone and PGE in vitro by day-90 CL of pregnancy was decreased (P < or = 0.05) by indomethacin. The addition of PGE2, but not LH, in combination with indomethacin overcame the decreases in progesterone by indomethacin (P < or = 0.05). In experiment 2, secretion of progesterone in vitro by day-11 CL of the estrous cycle was increased at 4-h (P < or = 0.05) in the absence of treatments. Both day-11 CL of the estrous cycle and day-90 CL of pregnancy secreted detectable quantities of PGE and PGF2alpha (P < or = 0.05). In experiment 1, PGF2alpha secretion by day-8 CL of the estrous cycle and day-90 ovine CL of pregnancy was undetectable, but was detectable in experiment 2 by day-90 CL. Day 90 ovine CL of pregnancy also secreted more PGE than day-11 CL of the estrous cycle (P < or = 0.05), whereas day-8 CL of the estrous cycle did not secrete detectable quantities of PGE (P > or = 0.05). Trilostane, mifepristone, or MER-25 did not affect secretion of progesterone, PGE, or PGF2alpha by day- 11 CL of the estrous cycle or day-90 CL of pregnancy (P > or = 0.05). It is concluded that PGE2, not LH, is the luteotropin at day-90 of pregnancy in sheep and that progesterone does not modify the response to luteotropins. Thus, we found no evidence for an autocrine or paracrine role for progesterone or estradiol-17 36 on luteal secretion of progesterone, PGE or PGF2alpha.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11305696&dopt=Abstract progesterone, progesterone cream



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Luteal phase hormonal profile in prediction of pregnancy outcome after assisted reproduction.

Vicdan K, Zeki Isik A.

Assisted Reproductive Technologies Center, Bayindir Hospital, Menevis Sokak 30/6, 06540 A. Ayranci, Ankara, Turkey. kvicdan surf.net.tr

The clinical efficacy of luteal phase hormones including estradiol and progesterone in the prediction of pregnancy and its outcome in ICSI-ET cycles was evaluated. In 121 ICSI-ET cycles, serial estradiol and progesterone levels were measured in the luteal phase. The day of ovum pick-up was designated as day 0. All the patients had luteal support with vaginal progesterone suppositories after embryo transfer (ET). Serial estradiol measurements were performed on days 8, 11 and 13 and progesterone level on day 11. A single dose of hCG was given for corpus luteum rescue 5000 IU, if day 8 estradiol level <200pg/ml; 2000IU, if estradiol between 200 and 800pg/ml; no hCG if estradiol level >800pg/ml). On day 15, beta-hCG level was measured to detect pregnancy and if positive, injected on day 17. Fifty-seven pregnancies were achieved in 121 cases after ET (47%). Clinical pregnancy rate and ongoing pregnancy rate per ET were 37.1 and 30%, respectively. While there was no difference between progesterone levels measured on day 11, estradiol levels on days 11 and 13 were significantly higher in women who became pregnant. In 40 patients taking only progesterone and in 81 cases taking hCG plus progesterone, estradiol levels on days 11 and 13 were significantly higher in women who became pregnant. Progesterone levels on day 11, in progesterone treated groups, did not differ between pregnant and non-pregnant patients. Estradiol and progesterone levels on day 11 and estradiol levels on day 13 showed a big overlap between pregnant and non-pregnant patients. The efficacy of serial testing was evaluated. An increase in estradiol level from day 11 to 13 was associated with 71% pregnancy rate (72% ongoing). In the case of a decrease in estradiol level, the pregnancy rate was 18% of which 80% had to implant. Rising estradiol in the late luteal phase is associated with higher pregnancy rate and more successful pregnancy outcome.

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Progesterone and testosterone in combination act in the hypothalamus of castrated rams to regulate the secretion of LH.

Turner AI, Tilbrook AJ, Clarke IJ, Scott CJ.

Department of Physiology, Monash University, Victoria 3800, Australia. ann.turner med.monash.edu.au

We tested the hypotheses that progesterone enhances the negative feedback actions of testosterone in rams and that this occurs through actions at the hypothalamus. In the first part of this study, blood samples were collected every 10 min for 12 h before and after 7 days of treatment (i.m.) of castrated Romney Marsh rams (n=5 per group) with vehicle, progesterone (4 mg/12 h), testosterone (4 mg/12 h) or a combination of progesterone (4 mg/12 h) and testosterone (4 mg/12 h). In the second part of this study the brains of four gonad-intact Romney Marsh rams were collected, the hypothalamus was sectioned and in situ hybridisation of mRNA for progesterone receptors conducted. After 7 days of treatment with vehicle or progesterone or testosterone alone, there were no changes in the secretion of LH. In contrast, treatment with a combination of progesterone and testosterone resulted in a significant (P<0.01, repeated measures ANOVA) decrease in mean plasma concentrations of LH, the number of LH pulses per hour and the pre-LH pulse nadir and a significant (P<0.01) increase in the inter-LH pulse interval. We found cells containing mRNA for progesterone receptors throughout the hypothalamus, including the preoptic area (where most GnRH neurons are located in sheep), the periventricular, ventromedial and arcuate nuclei and the bed nucleus of the stria terminalis. This study shows that progesterone is capable of acting centrally with testosterone to suppress the secretion of LH in castrated rams and that cells containing mRNA for progesterone receptors are located in the hypothalamus of rams in the vicinity of GnRH neurons.

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Short-term treatment with a controlled internal drug releasing (CIDR) device and FSH to induce fertile estrus and increase prolificacy in anestrous ewes.

Knights M, Maze TD, Bridges PJ, Lewis PE, Inskeep EK.

Division of Animal and Veterinary Sciences, West Virginia University, Morgantown 26506, USA.

The objectives were to evaluate, in anestrous ewes, the effectiveness of a CIDR-G device (0.3 g progesterone) administered for 5 d to induce estrus; and FSH (Folltropin; 55 mg NIH-FSH-P1 equivalent) in saline:propylene glycol (1:4) 24 h before insert removal (Day 0), to increase ovulation rate and prolificacy. Ewes of mixed breeding were assigned at random to 3 treatments: control (C; n = 125), 5 d progesterone (P5; n = 257) and 5 d progesterone plus FSH (P5F; n = 271). Intact rams were joined at insert removal and ewes were observed every 24 h for 3 d. On Day 14, the ovulation rates of all ewes detected in estrus in the treated groups were determined using transrectal ultrasonography. Rams were removed on Day 26 to 31. Ewes were examined for pregnancy then, and again 20 to 25 d later to detect ewes that conceived to the second service period. Percentage of ewes marked by rams was higher in progesterone-treated (77%) than in C (20%; P < 0.01), but did not differ between P5 and P5F. The ovulation rate (1.95+/-0.04) did not differ due to FSH. Conception (68%) and pregnancy (52%) rates were higher in progesterone-treated (P < 0.01) than in C (0%) ewes. Estrous response varied quadratically with time after ram introduction, and the conception rate varied quadratically with the time of observation of onset of estrus. Over two service periods more progesterone-treated than C ewes lambed (65 vs 45%; P < 0.01). Lambs born per ewe exposed (0.7+/-0.1, 1.0+/-0.1, and 1.1+/-0.1 for C, P5 and P5F, respectively) was increased by progesterone (P < 0.05). Litter size to the first service period (1.59+/-0.04) and overall (1.54+/-0.03) did not differ among treatment groups. FSH-treated ewes tended to have more lambs (1.67+/-0.1) than did ewes receiving progesterone alone (1.5+/-0.1; P = 0.06) and than did ewes lambing to the second service period (1.5+/-0.1; P = 0.06). In summary, a 5-d progesterone pre-treatment of anestrous ewes induced estrous cycles and increased the pregnancy rates. A single injection of FSH only tended to increase litter size.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11322244&dopt=Abstract progesterone, progesterone cream