progesterone cream
Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis.

Chwalisz K, Perez MC, Demanno D, Winkel C, Schubert G, Elger W.

TAP Pharmaceutical Products, Inc., 675 North Field Drive, Lake Forest, Illinois 60045, USA. Kristof.Chwalisz TAP.com

Selective progesterone receptor modulators (SPRMs) represent a new class of progesterone receptor ligands. SPRMs exert clinically relevant tissue-selective progesterone agonist, antagonist, or mixed agonist/antagonist effects on various progesterone target tissues in vivo. Asoprisnil (J867) is the first SPRM to reach an advanced stage of clinical development for the treatment of symptomatic uterine fibroids and endometriosis. Asoprisnil belongs to the class of 11beta-benzaldoxime-substituted estratrienes that exhibit partial progesterone agonist/antagonist effects with high progesterone receptor specificity in animals and humans. Asoprisnil has no antiglucocorticoid activity in humans at therapeutic doses. It exhibits endometrial antiproliferative effects on the endometrium and breast in primates. Unlike progesterone antagonists, asoprisnil does not induce labor in relevant models of pregnancy and parturition. It induces amenorrhea primarily by targeting the endometrium. In human subjects with uterine fibroids, asoprisnil suppressed both the duration and intensity of uterine bleeding in a dose-dependent manner and reduced tumor volume in the absence of estrogen deprivation. In subjects with endometriosis, asoprisnil was effective in reducing nonmenstrual pain and dysmenorrhea. Asoprisnil may, therefore, provide a novel, tissue-selective approach to control endometriosis-related pain. SPRMs have the potential to become a novel treatment of uterine fibroids and endometriosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15857972&dopt=Abstract progesterone, progesterone cream



progesterone cream
DIF-1, an anti-tumor substance found in Dictyostelium discoideum, inhibits progesterone-induced oocyte maturation in Xenopus laevis.

Kubohara Y, Hanaoka Y, Akaishi E, Kobayashi H, Maeda M, Hosaka K.

Biosignal Research Center, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Showa-machi 3-39-15, Maebashi 371-8512 , Japan. kubohara showa.gunma-u.ac.jp

Differentiation-inducing factor-1 (DIF-1; 1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one) is a putative morphogen that induces stalk-cell formation in the cellular slime mold Dictyostelium discoideum. DIF-1 has previously been shown to suppress cell growth in mammalian cells. In this study, we examined the effects of DIF-1 on the progesterone-induced germinal vesicle breakdown in Xenopus laevis, which is thought to be mediated by a decrease in intracellular cAMP and the subsequent activation of mitogen-activated protein kinase (MAPK) and maturation-promoting factor, a complex of cdc2 and cyclin B, which regulates germinal vesicle breakdown. DIF-1 at 10-40 microM inhibited progesterone-induced germinal vesicle breakdown in de-folliculated oocytes in a dose-dependent manner. Progesterone-induced cdc2 activation, MAPK activation, and c-Mos accumulation were inhibited by DIF-1. Furthermore, DIF-1 was found to inhibit the progesterone-induced cAMP decrease in the oocytes. These results indicate that DIF-1 inhibits progesterone-induced germinal vesicle breakdown possibly by blocking the progesterone-induced decrease in [cAMP](i) and the subsequent events in Xenopus oocytes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12559368&dopt=Abstract progesterone, progesterone cream



progesterone cream
Miscarriage in the first trimester according to the presence or absence of the progesterone-induced blocking factor at three to five weeks from conception in progesterone supplemented women.

Check JH, Levin E, Bollendorf A, Locuniak J.

The University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School at Camden, Cooper Hospital/University Medical Center, Department of Obstetrics and Gynecology, USA.

PURPOSE: To determine if the failure to detect the immonomodulatory protein progesterone induced blocking factor (PIBF) at three to five weeks of seemingly normal pregnancies in women supplemented by extra progesterone is associated with a higher miscarriage rate. METHODS: Progesterone-induced blocking factor expression by lymphocytes was measured by an immunocytochemistry technique. The serum beta human chorionic gonadotropin (hCG) and/or ultrasound were also deemed appropriate so that by these criteria there was no evidence of a poor pregnancy. The minimum progesterone dosage was 200 mg twice daily vaginal suppositories. RESULTS: Progesterone-induced blocking factor was detected in 17/39 (43.5%) of pregnant patients at this early time. There were three miscarriages by 12 weeks in this group (17.6%). The miscarriage rate was 6/21 (28.5%) in those where it was not detected. CONCLUSIONS: There was insufficient power to show significance. However there seems to be a trend for higher rates of miscarriage when PIBF is absent so these preliminary data encourage continuation of the study.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15864927&dopt=Abstract progesterone, progesterone cream



progesterone cream
Progesterone-Induced Inhibition of Growth and Differential Regulation of Gene Expression in PRA- and/or PRB-Expressing Endometrial Cancer Cell Lines.

Smid-Koopman E, Kuhne LC, Hanekamp EE, Gielen SC, De Ruiter PE, Grootegoed JA, Helmerhorst TJ, Burger CW, Brinkmann AO, Huikeshoven FJ, Blok LJ.

Department of Obstetrics and Gynecology, Erasmus Medical Center, Rotterdam.

OBJECTIVE: Progesterone plays an important role in controlling proliferation and differentiation of the human endometrium. Because there are two progesterone receptor isoforms (PRA and PRB), it was important to generate tools to be able to study the role of these two progesterone receptors separately. METHODS: Using stable transfection techniques, both human progesterone receptor isoforms (hPRA and hPRB) were reintroduced into a hPR-negative subclone of the well-differentiated endometrial cancer cell line Ishikawa. Several Ishikawa subcell lines were constructed, each expressing different levels of hPRA, hPRB, or hPRA and hPRB, respectively. RESULTS: These Ishikawa subcell lines showed a marked progesterone-induced growth inhibition with induction of apoptosis after long-term culture in the presence of hormone. Upon measuring gene regulation, a clear difference in regulation of expression of the selected genes by progesterone treatment was observed between the PRA-, PRB-, or PRA/B-expressing cell lines. Integrin beta4 (ITGB4) was only regulated in PRA-expressing cells; amphiregulin was highly regulated in PRB-expressing cells; inuslin-like gwoth factor binding protein 3 (IGFBP3) was only regulated in PRB- and PRA/B-expressing cells; and metallothionein 1L (MT1L) was highly regulated in PRA/B-expressing cells. Interestingly, based on literature data, these genes can be implicated in induction of apoptosis, but are modulated here in such a way that suggests induction of resistance against apoptosis. CONCLUSION: Reintroduction of PRs into Ishikawa cells rescued progesterone responsiveness in these cells. Furthermore, using these human endometrial cancer subcell lines, clear and distinct functional differences between the PR isoforms were observed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15866122&dopt=Abstract progesterone, progesterone cream



progesterone cream
Progesterone suppresses the inflammatory response and nitric oxide synthase-2 expression following cerebral ischemia.

Gibson CL, Constantin D, Prior MJ, Bath PM, Murphy SP.

Institute of Cell Signalling, Queen's Medical Centre, Clifton Boulevard, Nottingham, NG7 2UH, UK; Institute of Neuroscience, University of Nottingham, Nottingham, UK.

Gender differences in outcome following cerebral ischemia have frequently been observed and attributed to the actions of steroid hormones. Progesterone has been shown to possess neuroprotective properties following transient ischemia, with respect to decreasing lesion volume and improving functional recovery. The present study was designed to determine the mechanisms of progesterone neuroprotection, and whether these relate to the inflammatory response. Male mice underwent either 60 min or permanent middle cerebral artery occlusion (MCAO) and received progesterone (8 mg/kg ip) or vehicle 1 h, 6 h and 24 h post-MCAO. Forty-eight hours following transient MCAO, structural magnetic resonance imaging revealed a significant decrease in the amount of edematous tissue present in progesterone-treated mice as compared with vehicle. Using real-time PCR we found that progesterone treatment significantly suppressed the injury-induced upregulation of interleukin (IL)-1beta, transforming growth factor (TGF)beta(2), and nitric oxide synthase (NOS)-2 mRNAs in the ipsilateral hemisphere while having no effect on tumor necrosis factor (TNF)-alpha mRNA expression. Progesterone treatment following permanent MCAO also resulted in a significant decrease in lesion volume. This was not apparent in mice lacking a functional NOS-2 gene. Thus, progesterone is neuroprotective in both permanent and transient ischemia, and this effect is related to the suppression of specific aspects of the inflammatory response.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15869954&dopt=Abstract progesterone, progesterone cream



progesterone cream
Enzyme immunoassay of progesterone in the feces from beef cattle to monitor the ovarian cycle.

Isobe N, Nakao T, Yamashiro H, Shimada M.

Graduate School for International Development and Cooperation, Hiroshima University, Higashi-Hiroshima 739-8529, Japan.

The present study was undertaken to measure fecal progesterone concentration of beef cattle using antibody against authentic progesterone and to examine whether this method can monitor the ovarian cycle in beef cattle. Rectal fecal samples collected from 14 beef cattle were mixed with 6ml of 100% methanol and shaken for 15min. After centrifugation, supernatant was extracted with petroleum ether followed by an enzyme immunoassay (EIA) for progesterone. Specificity of the assay was examined by HPLC separation of fecal solution followed by the EIA in each fraction. The present assay identified only progesterone but not other metabolites in the feces sample that was extracted with petroleum ether. Sensitivity of the assay was estimated to be 0.0055ng/ml (0.11ng/g). Coefficient variations of intra- and inter-assay were 9.6-10.9% and 10.8-16.6%, respectively. Recovery rates ranged between 73 and 84%. Patterns in the fecal progesterone concentrations during the ovarian cycle were almost parallel to the plasma concentrations. A significant positive correlation was established between the fecal and plasma progesterone concentrations in individual animal (r=0.59-0.84, P<0.001, n=10) as well as pooled data (r=0.70, P<0.001, n=65). Fecal progesterone concentrations of day 0 (showing the nadir of concentration) of the ovarian cycle were less than 50ng/g, which increased significantly toward day 9 (P<0.01). From days 14 to 18, there was significant reduction of fecal progesterone concentration (P<0.01). Ovarian cycles had at least 48ng/g (mean=74ng/g) of difference between minimum and maximum fecal progesterone concentrations. All cattle at days 9, 11 and 14 had higher fecal progesterone concentrations by more than 20ng/g compared with day 0. These results suggest that the present EIA is suitable to measure the progesterone in cattle feces and can monitor ovarian cycle.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15885436&dopt=Abstract progesterone, progesterone cream



progesterone cream
Pregnancy effects on distribution of progesterone receptors, oestrogen receptor alpha, glucocorticoid receptors, Ki-67 antigen and apoptosis in the bovine interplacentomal uterine wall and foetal membranes.

Boos A, Kohtes J, Janssen V, Mulling C, Stelljes A, Zerbe H, Hassig M, Thole HH.

Institute of Veterinary Anatomy, Vetsuisse Faculty, University of Zurich, Winterthurerstrasse 260, CH-8057 Zurich, Switzerland.

Until recently, studies dealing with the uterus of the pregnant cow focus primarily on the placentome or on early and late pregnancy. Thus, there is a paucity of information about many aspects of the interplacentomal uterine wall including adherent foetal membranes. Corresponding tissue specimens were collected at the slaughterhouse and in animals undergoing premature caesarean section. Two specimens per month of pregnancy were assessed immunohistochemically for progesterone receptors, oestrogen receptor alpha and glucocorticoid receptors, Ki-67 protein and TUNEL procedure was performed. The latter two methods were employed in three animals each per months 1 and 2, 3 and 4, 7 and 8 and in six animals undergoing caesarean section at days 274 and 275 post insemination or during spontaneous labour. Results indicate that proliferation and apoptosis are of minor importance for tissue homeostasis since both can histochemically be detected only sporadically. Thus, at the sites investigated here, cellular hypertrophy plays an important role for tissue growth during pregnancy. Progesterone receptors, oestrogen receptor alpha and glucocorticoid receptors, however, exhibit cell type and pregnancy stage specific distribution patterns within the tissues assessed. Progesterone receptor immunoreactive scores remained fairly unchanged during pregnancy. Oestrogen receptor alpha scores, however, generally decreased and glucocorticoid receptors increased with ongoing gestation. Progesterone receptors and oestrogen receptor alpha were present in endometrial stroma and in myometrial smooth muscle cells during whole pregnancy. Oestrogen receptor alpha was detectable during whole pregnancy also in uterine glands. Progesterone receptors were, however, present at a very low level at the latter site only during months 1-3 and 6-9. Oestrogen receptor alpha and glucocorticoid receptors may also mediate uterine blood flow since they were present in the tunica media of uterine blood vessels. Results of the present study indicate, that progesterone and its receptor play an important role during whole gestation, mainly for uterine quiescence. Glucocorticoids and their receptors - possibly in cooperation with oestrogens and decreasing amounts of the oestrogen receptor alpha - should trigger processes initiating parturition, such as endometrial prostaglandin production. Further studies - including the periparturient period - should help to understand the exact role of the extraplacental compartment of the uterine wall for the initiation and progress of parturition.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15885934&dopt=Abstract progesterone, progesterone cream