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Regulation and expression of progesterone receptor mRNA isoforms A and B in the male and female rat hypothalamus and pituitary following oestrogen treatment.

Scott RE, Wu-Peng XS, Pfaff DW.

Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY, USA. rscott helicontherapeutics.com

Progesterone receptors play a central role in neuroendocrine and behavioural regulation. To gain insight into the sex- and tissue-specific regulation of progesterone receptors, protein binding on a progesterone receptor-oestrogen response element and mRNA levels for progesterone receptor (PR)-A and PR-B were compared between female and male rats following oestradiol benzoate replacement treatment in hypothalamic and pituitary tissue. Both male and female pituitary protein extracts demonstrated an increase in nuclear protein binding activity to a progesterone receptor-oestrogen response element following oestradiol benzoate treatment. However, there was a greater difference in total binding activity seen in the female pituitary extracts compared to male pituitary protein extracts. In both cases, reflecting the binding data, oestradiol benzoate pretreatment led to an increase in pituitary PR-B messenger RNA, although this increase was significantly larger in females than in males. Oestradiol benzoate treatment also led to a significant increase in specific binding of hypothalamic nuclear proteins to the progesterone receptor oestrogen response element from both females and male hypothalamic extracts. In addition, PR-B messenger RNA was induced by oestradiol benzoate treatment in the female rat hypothalamus, under circumstances where no PR-A could be detected. The male also demonstrated an increase in PR-B messenger RNA following oestradiol benzoate treatment, with undetectable levels of PR-A, although to a lesser degree than that seen in the female. The predominance of PR-B over PR-A messenger RNA in rat hypothalamus and pituitary, and the quantitative differences between female and male rats, could both contribute to the greater responsiveness of female rats to progesterone with respect to control over luteinizing hormone release from the pituitary, and lordosis behaviour regulated by hypothalamic neurones.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11999716&dopt=Abstract progesterone, progesterone cream



progesterone cream
Regulation of cyclooxygenase activity and progesterone production in the rat corpus luteum by inducible nitric oxide synthase.

Hurwitz A, Finci-Yeheskel Z, Milwidsky A, Mayer M.

Department of Obstetrics and Gynecology, Hadassah University Hospital, Mt Scopus, Jerusalem, IL-91240, Israel. hurwitz cc.huji.ac.il

This study explores interactions between the nitric oxide synthase (NOS) and the cyclooxygenase (COX) pathways in the regulation of progesterone production in early corpus luteum cells of rats. Nitric oxide (NO), prostaglandin E (PGE) and progesterone production was analysed in luteal cells of the rat corpus luteum exposed to inhibitors of non-specific NOS, inhibitors of inducible NOS (iNOS) and inhibitors of COX. Equine chorionic gonadotrophin (eCG)/hCG-primed rat corpus luteum cells produced NO, PGE and progesterone in a linear manner during 66 h of culture. Exposure of the cells to the non-specific NOS inhibitor, N(omega)-nitro-L-arginine (0.15 mmol l(-1)) for 48 h reduced NO, PGE and progesterone production to 21, 32 and 60% of that of the controls, respectively (P < 0.05 to P < 0.01). Another non-specific NOS inhibitor, N(omega)-methyl-L-arginine, produced similar inhibitions. Exposure of the cultured cells to S-ethylisothiourea (1 mmol l(-1)), a selective inhibitor of iNOS, suppressed the production of NO by 63%, PGE by 69% and progesterone by 48%. These findings indicate that production of PGE is regulated partly by iNOS, and that progesterone is probably regulated indirectly by the secondary changes in PGE. The addition of arachidonic acid to N(omega)-methyl-L-arginine-treated cells resulted in a significant increase in PGE and progesterone production (273 and 186%, respectively) without stimulating NO production. In contrast to the regulation exerted by the NO system on COX activity, the COX system does not modulate NO production in this model. This notion stems from the observation that the COX inhibitors acetylsalicylic acid (5 mmol l(-1)) and indomethacin (5 micromol l(-1)) suppressed PGE by 86 and 89%, respectively, and progesterone by 34 and 57%, respectively, but failed to inhibit NO production. The results from the present study indicate that iNOS-mediated NO production is involved in stimulating PGE synthesis in rat luteal cells, which may upregulate progesterone production.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12006094&dopt=Abstract progesterone, progesterone cream



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

Haluska GJ, Wells TR, Hirst JJ, Brenner RM, Sadowsky DW, Novy MJ.

Division of Reproductive Sciences, Oregon Regional Primate Research Center/Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006-3499, USA.

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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12009386&dopt=Abstract progesterone, progesterone cream



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Progesterone fails to modulate Toxoplasma gondii replication in the RAW 264.7 murine macrophage cell line.

Gay-Andrieu F, Cozon GJ, Ferrandiz J, Peyron F.

Laboratoire de Parasitologie et Pathologie Exotique, Hopital de la Croix-Rousse, Lyon, France.

Cell mediated immunity is very important for host defence against intracellular pathogens and many studies have shown the role of the production of nitric oxide (NO) by interferon (IFN)-gamma/lipopolysaccharide (LPS)-activated macrophages. As the progesterone level increases during pregnancy in mammals, and as previous studies have shown that progesterone inhibits inducible nitric oxide synthase (iNOS) expression and NO production, we aimed to investigate whether progesterone might modulate intracellular replication of Toxoplasma gondii in macrophages. Our results showed that progesterone does not influence T. gondii replication in non-activated RAW 264.7 cells, and although progesterone inhibits NO production induced by IFN-gamma/LPS, we observed that it fails to restore the growth of T. gondii blocked by IFN-gamma/LPS. After discussing the reasons for this apparent discrepancy, we concluded that progesterone has no direct effect on the macrophage response. The real effect of the sex steroids in T. gondii infection and their implication in clinical toxoplasmosis therefore need to be investigated further to involve wider mechanisms of the immune system.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12010482&dopt=Abstract progesterone, progesterone cream



progesterone cream
The rate of loss of eyelid reflex following thiopental administration in hypo- and hypergonadism in rabbits.

Szymanski B, Pakulski C, Drobnik L, Starczewski A, Badowicz B.

Department of Anesthesiology and Intensive Care, Clinical Hospital No 1, Szczecin, Poland.

BACKGROUND: The aim of this research was to explain whether different hormonal conditions caused by disturbed concentrations of estrogens and progesterone might lead to alteration of CNS reaction following administration of the hypnotic agent thiopental. The investigated factor was the rate of loss of the eyelid reflex after intravenous thiopental administration, since this corresponds with loss of consciousness. MATERIAL/METHODS: The investigation was performed in 24 sexually mature female Chinchilla rabbits divided into 4 groups of 6 rabbits each. The animals were oophorectomized (hypoprogesterone/hypoestrogen), hyperestrogen (sham surgery plus estradiol injections), hyperprogesterone (sham surgery plus 17 alpha-hydroxyprogesterone injections), or normal (sham surgery). Twelve weeks later, thiopental (40 mg/ml) was infused through the intravenous cannula at a constant rate (90 ml/hour) until loss of the eyelid reflex, at which time blood was sampled for determination of thiopental, b-estradiol, progesterone and 17 alpha-hydroxyprogesterone concentrations. The ANOVA and Tukey tests were applied in statistical analysis (p=0.05). RESULTS: Hyperprogesterone rabbits lost consciousness faster (138 +/- 34.6 sec), at a lower plasma thiopental concentration (46.3 +/- 6.6 microg/ml), and required less thiopental (24.63 +/- 6.44 mg/kg) than controls; hypoprogesterone rabbits lost consciousness slower (207.5 +/- 30.9 sec), at a higher plasma thiopental concentration (129.2 +/- 24.9 microg/ml), and required more thiopental (38.51 +/- 2.33 mg/kg) than controls. The time of sleep induction in the control group was 190 +/- 25.7 sec.; the serum thiopental concentration was 77.8 +/- 13.9 microg/ml, and the total thiopental consumption was 35.8 +/- 3.51 mg/kg. Estrogen status has no effect. CONCLUSIONS: Various hormonal states are accompanied by different CNS reactions to thiopental. Among the studied groups of sex steroids, only progestins significantly modify the CNS response to barbiturate infusion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12011766&dopt=Abstract progesterone, progesterone cream



progesterone cream
Protective effects of progesterone on implantation failure induced by dibutyltin dichloride in rats.

Ema M, Harazono A, Hirose A, Kamata E.

Division of Risk Assessment, Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, 158-8501, Tokyo, Japan. ema nihs.go.jp

We previously showed that dibutyltin dichloride (DBTCl) at 7.6 mg/kg and higher on days 0-3 of pregnancy caused implantation failure and a decline in serum progesterone levels in rats and hypothesized that the decline is responsible for the implantation failure. This study was conducted to determine the protective effects of progesterone on the DBTCl-induced implantation failure in rats. Rats were given oral DBTCl at 0, 7.6, or 15.2 mg/kg on days 0-3 of pregnancy and/or subcutaneous progesterone at 2 mg/rat on days 0-8 of pregnancy. The reproductive outcome was determined on day 9 of pregnancy. No effects of administration of progesterone alone on the pregnancy rate and number of implantations were found. The pregnancy rate and number of implantations were significantly decreased after administration of DBTCl alone. The pregnancy rate and number of implantations were higher in the groups given DBTCl and progesterone than the groups given DBTCl alone. The present data indicate that progesterone protects, at least in part, against the DBTCl-induced implantation failure and support our hypothesis that the decline in progesterone levels is a primary mechanism for the implantation failure due to DBTCl.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12749827&dopt=Abstract progesterone, progesterone cream



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Menopausal bone loss in long-term users of depot medroxyprogesterone acetate contraception.

Cundy T, Cornish J, Roberts H, Reid IR.

Department of Medicine, Faculty of Medicine and Health Science, the University of Auckland, and the Family Planning Association of New Zealand. t.cundy auckland.ac.nz

OBJECTIVE: The purpose of this study was to determine the rate of early postmenopausal bone loss in women who had used depot medroxyprogesterone acetate contraception through to menopause. STUDY DESIGN: Bone mineral density at the lumbar spine and femoral neck was assessed prospectively over 3 years in 15 women who reached a natural menopause and who did not undergo hormone replacement therapy and in 16 long-term users of depot medroxyprogesterone acetate who discontinued depot medroxyprogesterone acetate only on reaching menopause. Of the latter, 5 women subsequently underwent hormone replacement therapy. RESULTS: Early menopausal bone loss was rapid in the control group (6% from both sites over 3 years), but the users of depot medroxyprogesterone acetate (who did not take hormone replacement therapy) showed little change in bone mineral density. Between-group differences were statistically significant at years 2 and 3 at both sites (P <.03-<.002). In the users of depot medroxyprogesterone acetate who underwent hormone replacement therapy, bone mineral density increased significantly (P <.03) at the lumbar spine and was stable at the femoral neck. CONCLUSION: Women who use depot medroxyprogesterone acetate through to menopause have attenuated rates of bone loss from the lumbar spine and femoral neck, presumably because they have already lost the estrogen-sensitive component of bone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12015524&dopt=Abstract progesterone, progesterone cream