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Steroid receptors and hormones in relation to cell proliferation and apoptosis in poorly differentiated epithelial ovarian tumors.

Lindgren P, Backstrom T, Mahlck CG, Ridderheim M, Cajander S.

Department of Obstetrics and Gynecology, Umea University, Umea, Sweden.

The purpose of this study was to further investigate the role of estrogen but especially progesterone on epithelial ovarian tumor development since previous studies have suggested a relationship between serum progesterone, progesterone receptor expression and prognosis. Serum progesterone concentration, the immunohistochemical expression of estrogen receptor alpha (ER), progesterone receptor A/B (PR), Ki-67, Bcl-2, p53, apoptosis and morphology were determined in 33 patients, all with poorly differentiated surface epithelial ovarian tumors of different types. ER was expressed in 79% and PR in 33% of the tumors. This group of aggressive tumors was highly proliferative as indicated by Ki-67 index (mean 38.9%), and in some cases proliferation appeared to be mainly located to areas with a high ER density. The majority of cases (76%), both receptor-positive and -negative, overexpressed p53. High ER expression was related to a lower apoptotic activity as compared with tumors with a low expression of the ER (p = 0.008). Serum progesterone in itself did not show any clear relationship to steroid receptor status, expression of Ki-67, p53, Bcl-2 or signs of apoptosis. Survival in this small but homogeneous group of advanced epithelial ovarian cancers, showed an improved survival rate in patients with high serum progesterone, especially in combination with expression of progesterone receptors (p = 0.04). In conclusion, estrogen and progesterone receptors in parallel with deranged p53 and Ki-67 were expressed to a great extent. The finding of a lower apoptotic activity in tumors with a high expression of ER and an indication of increased proliferation in areas with high ER density gives a rationale for antiestrogen therapy even in poorly differentiated epithelial ovarian cancers. Improved survival is related to serum progesterone, especially in combination with PR expression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11408919&dopt=Abstract progesterone, progesterone cream



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Luteinizing hormone secretion from wild-type and progesterone receptor knockout mouse anterior pituitary cells.

Turgeon JL, Waring DW.

Department of Human Physiology, School of Medicine, University of California, Davis, Davis, California 95616, USA. jlturgeon ucdavis.edu

The progesterone receptor (PR) has a central role in the hypothalamo-pituitary events culminating in the preovulatory LH surge, and mice with genetically ablated PR provide a model for dissecting cellular pathways subserving this role. The aims of this study were to determine 1) whether the GnRH self-priming response and acute progesterone augmentation of secretagogue-stimulated LH secretion are present in cultured wild-type (WT) mouse pituitary cells, and 2) whether the PR is essential for self-priming by comparing the responses in PR knockout (PRKO) cells. Pituitary cells from ovariectomized WT or PRKO mice cultured +/- 17beta-estradiol (E(2)) for 3 days were challenged with hourly pulses of 1 nM GnRH or 54 mM K(+). A background of E(2) had no effect on the initial LH secretory response for either WT or PRKO cells. However, for subsequent GnRH pulses, E(2) was permissive for the GnRH self-priming response in WT cells. PRKO cells exhibited a blunted GnRH self-priming response. Exposure to progesterone for 90 min before secretagogue stimulation resulted in a modest (1.5-fold) augmentation of the LH response to GnRH but not K(+) pulses in WT cells; progesterone had no effect in PRKO cells. Unlike in the rat, the PR antagonists RU486 or ZK98299 failed to prevent potentiation of LH secretory responses to multiple GnRH pulses in WT cells. Although RU486 blocked progesterone augmentation of the initial GnRH pulse, it was ineffective in blocking progesterone's action after multiple GnRH pulses. In WT cells, 8- bromo-cAMP (8-Br-cAMP) was able to substitute for the GnRH priming pulse; 8-Br-cAMP also augmented GnRH-stimulated secretion in PRKO cells but less effectively. 8-Br-cAMP augmented K(+)-stimulated LH secretion in WT and PRKO cells equally. These results suggest that, although mouse gonadotropes show GnRH self-priming, they have adapted strategies different than rat cells for amplifying the GnRH signal as shown by the residual self-priming in PRKO cells, the modest or absent augmentation by acute progesterone of GnRH- or K(+)-stimulated secretion in WT cells, and the reduced ability of PR antagonists to interfere with GnRH self-priming and progesterone augmentation. We speculate that the adaptations could involve, at least in part, differences in the ratio of PR isoforms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11416033&dopt=Abstract progesterone, progesterone cream



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Immunolocalization of progesterone receptors in the canine ovary and their relation to sex steroid hormone concentrations.

Vermeirsch H, Simoens P, Coryn M, Van den Broeck W.

Department of Morphology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium. Hilde.Vermeirsch rug.ac.be

The aim of the present study was to describe the normal cellular distribution of progesterone receptors in the canine ovary at different stages of the oestrous cycle. Samples of both ovaries were obtained from 75 healthy adult bitches of various breeds and ages, including five pregnant bitches and three bitches that had just delivered. The presence of progesterone receptors was visualized by immunohistochemistry on paraffin wax sections using a monoclonal antibody. Nuclear staining for progesterone receptors was observed in the surface epithelium, cortical tubules, rete ovarii, follicle cells, thecal cells, luteal cells, granulosa cell cords and ovarian stroma. The staining intensity for progesterone receptors in the follicle cells increased with the stage of follicle development, indicating an intrafollicular role of progesterone in the mechanism of ovulation and luteinization. The stronger staining intensities for progesterone receptors in thecal cells compared with follicle cells may be explained by the fact that thecal cells mediate some effects of steroid hormones on the follicle cells in secondary and tertiary follicles. Little correlation was found between the expression of progesterone receptors in follicle cells and oestradiol, progesterone or testosterone concentrations. This finding indicates a different regulating mechanism for progesterone receptors in canine ovarian follicles compared with other tissues of the genital tract. During pregnancy all groups of ovarian cells had lower staining intensity scores than during the oestrous cycle, although the sex steroid hormone concentrations in pregnant bitches were similar to those in non-pregnant bitches during the luteal phase of the oestrous cycle. The lower expression of progesterone receptors during pregnancy may be due to higher tissue concentrations of progesterone that are not reflected in the serum because of haemodilution and increased metabolism and clearance during pregnancy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11425331&dopt=Abstract progesterone, progesterone cream



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Progesterone induced modulations of serum hormonal profiles in adult male and female rats.

Jeyaraj DA, Mani Maran RR, Aruldhas MM, Govindarajulu P.

Department of Cell Biology and Anatomy, University of North Carolina at Chapel Hill, 27599, USA. antojeya hotmail.com

The impact of progesterone on serum hormonal profiles in the presence and absence of gonads was studied in adult male and female albino rats. Progesterone was administered intramuscularly for 30 days at a dose of 1 mg/100g body weight/day. Serum testosterone, estradiol and prolactin titres decreased in male and female rats with intact gonads given progesterone. While the levels of both luteinizing hormone (LH) and follicle stimulating hormone (FSH) decreased in male rats with intact gonads, only FSH decreased in female rats. The inhibitory effect of progesterone on serum estradiol, LH, FSH and prolactin persisted even after gonadectomy in male rats. This persistent inhibitory effect of progesterone was also seen on serum testosterone, FSH and prolactin levels of female rats. Ovariectomy modified progesterone action on LH, as is evident from the decreased levels of LH observed only in ovariectomized rats given progesterone. While progesterone had no effect on serum T3 and T4 in male rats, gonadectomy altered the levels of T3 and T4 in male and female rats. Progesterone increased the levels of T3 and decreased the levels of T4 in ovariectomized rats. Growth hormone (GH) and thyroid stimulating hormone (TSH) levels seem to be resistant to changes in progesterone titre, irrespective of the sex and gonadal status. The present data suggest the existence of a sex specific effect of progesterone on gonadotrophins. The data on T3, T4 and TSH reveals that progesterone has no effect on the pituitary thyroid axis in the presence of gonads.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11428714&dopt=Abstract progesterone, progesterone cream



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Effect of progesterone on the contractile response of isolated pulmonary artery in rabbits.

Li HF, Zheng TZ, Li W, Qu SY, Zhang CL.

Life Science College, Lanzhou University, Gansu Province, People's Republic of China.

The purpose of this study was to assess the direct effect of progesterone on rabbit pulmonary arteries and to examine the mechanism of its action. Rings of pulmonary artery from male rabbits were suspended in organ baths containing Krebs solution, and isometric tension was measured. The response to progesterone was investigated in arterial rings contracted with noradrenaline (NA), KCl, and CaCl2. The effects of endothelium, nitric oxide (NO), prostaglandins, cyclic GMP (cGMP), and the adrenergic beta-receptor on progesterone-induced relaxation were also assessed. Progesterone inhibited the vasocontractivity to NA, KCl, and CaCl2, and relaxed rabbit pulmonary artery. The relaxing response of progesterone in pulmonary artery was significantly reduced by removal of endothelium, inhibitors of nitric oxide synthase and guanylate cyclase, but not by prostaglandin synthase inhibitor and blockage of the adrenergic beta-receptor. In Ca2+-free (0.1 mM EGTA) Krebs solution, progesterone inhibited NA-induced contraction that was intracellular Ca2+-dependent, but didn't affect the contraction of extracellular Ca2+-dependent component. Our results suggest that progesterone induces relaxation of isolated rabbit pulmonary arteries partially via NO and cGMP. Progesterone may also inhibit Ca2+ influx through potential-dependent calcium channels (PDCs) and Ca2+ release from intracellular stores.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11430592&dopt=Abstract progesterone, progesterone cream



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Combined effects of estrogen and progesterone on the anterior cruciate ligament.

Yu WD, Panossian V, Hatch JD, Liu SH, Finerman GA.

Department of Orthopaedic Surgery, UCLA School of Medicine, Los Angeles, CA, USA.

Previous studies from the authors' laboratory have established the presence of estrogen and progesterone receptors in the human anterior cruciate ligament. The purpose of the current study was to investigate the combined effects of 1beta-estradiol and progesterone on cell proliferation and procollagen synthesis of the human anterior cruciate ligament fibroblasts. Fibroblast proliferation and procollagen synthesis in response to logarithmic concentrations of 17beta-estradiol (0.0025 ng/mL, 0.025 ng/mL, 0.25 ng/mL) and progesterone (1 ng/mL, 10 ng/mL, 100 ng/mL) were assessed with the measurement of 3H-thymidine incorporation and Types I and III procollagen specific equilibrium radioimmunoassays. On Days 1, 3, and 5 there was a dose dependent decrease in the fibroblast proliferation and procollagen Type I synthesis with increasing estradiol concentrations. The effect was attenuated with increasing progesterone concentrations. Controlling for estrogen levels, a dose dependent increase in fibroblast proliferation and procollagen Type I synthesis was observed with increasing progesterone concentrations. The effect was more pronounced at lower concentrations of estrogen, suggesting estrogen levels were the dominant factor. The effects of estrogen and progesterone became less apparent by Day 7. No significant differences in Type III procollagen synthesis were seen with varying estradiol concentrations at any of the designated times. These early physiologic changes in fibroblast proliferation and Type I procollagen synthesis may provide a biologic explanation for the increased anterior cruciate ligament injury rate observed in female athletes, suggesting the acute cyclical hormonal variations in the female athlete during menstruation predispose her to ligamentous injury.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11210964&dopt=Abstract progesterone, progesterone cream



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Progesterone together with estrogen attenuates homologous upregulation of gonadotropin-releasing hormone receptor mRNA in primary cultured rat pituitary cells.

Cheon M, Park D, Park Y, Kam K, Park SD, Ryu K.

Endocrine Laboratory, College of Medicine, Yonsei University, Seoul, South Korea.

In a previous study, we clearly demonstrated that an application of gonadotropin-releasing hormone (GnRH) to cultured rat pituitary cells increased the expression of GnRH receptor (GnRH-R) mRNA through transcriptional activation of GnRH-R gene rather than suppression of the turnover rate of GnRH-R mRNA. Along with GnRH, gonadal steroids seem to be an important regulator for GnRH-R expression in the pituitary gland. Recent in vivo studies reported that an application of gonadal steroids to gonadectomized animals modulated GnRH-R mRNA expression in the pituitary gland. However, it has not been clearly understood whether steroids may act directly at the pituitary or indirectly via modulation of hypothalamic GnRH release. Therefore, we assessed the effects of estrogen and progesterone on GnRH-R mRNA expression in primary cultured female rat pituitary cells. Neither estradiol nor progesterone modulates the basal expression of GnRH-R mRNA in primary cultured pituitary cells. When cultured pituitary cells were exposed to different doses of estradiol in combination with GnRH (0.2 nM), the GnRH-stimulated increment of GnRH-R mRNA expression was not significantly changed by estradiol at any given doses. However, when different doses of progesterone were added to primary cultured pituitary cells in combination with GnRH (0.2 nM), GnRH-induced increases in GnRH-R mRNA levels were reduced in a dose-related manner, showing a significant reduction at 100 nM progesterone. Furthermore, the addition of estradiol reinforced the suppressive effect of progesterone on the homologous upregulation of GnRH-R mRNA expression. Collectively, our results clearly demonstrated that progesterone directly attenuates the homologous upregulation of GnRH-R mRNA expression at the pituitary level, and that estradiol potentiates the effect of progesterone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11216651&dopt=Abstract progesterone, progesterone cream