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Elevated interleukin-10 and sex steroid levels in peritoneal fluid of patients with ovarian hyperstimulation syndrome.

Manolopoulos K, Lang U, Gips H, Braems GA.

Department of Obstetrics and Gynecology, Justus-Liebig University Giessen, Klinikstr 32, 35385, Giessen, Germany.

BACKGROUND: The ovarian hyperstimulation syndrome (OHSS) following ovulation induction is characterized by a cystic enlargement of the ovaries with an acute third space fluid sequestration. Inflammatory cytokines mediate the inflammatory response (IL-1, IL-2, IL-6, IL-8, TNFalpha) and play a crucial role in the pathogenesis of OHSS. OBJECTIVE: To determine the role of the anti-inflammatory cytokine interleukin-10 (IL-10) in OHSS and to examine its correlation with 17beta-estradiol and progesterone. STUDY DESIGN: Peritoneal fluid and serum samples were collected from 9 patients with severe OHSS after ovulation induction by administration of GnRH-analogues followed by hMG (n=5) or recombinant FSH (n=4). Patients (n=19) without pathological findings at laparoscopy served as non-pregnant controls and pregnant women (n=14) between 7 and 16 weeks of gestation served as positive controls. Samples were assayed for IL-10 by commercially available ELISA and for for 17beta-estradiol and progesterone by RIA. Statistical analysis was performed by non-parametric Mann-Whitney U-test and results are presented as the median and range. RESULTS: OHSS patients had significantly higher peritoneal fluid IL-10, 17beta-estradiol and progesterone levels than patients during early pregnancy and than the control group. No correlation was found between peritoneal fluid or serum IL-10 and 17beta-estradiol or progesterone in the different groups. Serum 17beta-estradiol and progesterone, but not serum IL-10 levels were elevated in OHSS and during early pregnancy. CONCLUSIONS: High concentrations of IL-10 in peritoneal fluid suggest a role of this anti-inflammatory cytokine during OHSS. 17beta-estradiol and progesterone were elevated in peritoneal fluid and serum during OHSS but no correlation with IL-10 concentrations was found. Therefore, we assume that IL-10 has a role in OHSS as a local mediator of inflammation, however, it presents different aspects of the OHSS than the sex steroids 17beta-estradiol and progesterone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11788177&dopt=Abstract progesterone, progesterone cream



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Effect of basal lamina on progesterone production by chicken granulosa cells in vitro--influence of follicular development.

Asem EK, Stingley-Salazar SR, Robinson JP, Turek JJ.

Department of Basic Medical Sciences, School of Veterinary Medicine, Purdue University, 1246 Lynn Hall, West Lafayette, IN 47907-1246, USA. eka vet.purdue.edu

Experiments were conducted in vitro to study the regulation of progesterone production in chicken granulosa cells by homologous basal lamina isolated from preovulatory follicles of chicken ovary. The majority of components of the basal lamina (90-95% by weight) were solubilized with guanidine-HCl (and designated fraction 1); the remaining components were solubilized with beta-mercaptoethanol containing guanidine-HCl (and designated fraction 2). The ability of fraction 1 to regulate progesterone production in granulosa cells obtained from the largest (F(1), mature), third largest (F(3), growing), fifth to seventh largest (F(5-7), growing) follicles and a pool of small yellow follicles (SYF, immature) of chicken ovary was assessed. Granulosa cells isolated from SYF follicles were in the least differentiated (undifferentiated) and those obtained from F(1) follicles were in the most differentiated state. The ability of fraction 1 to regulate progesterone production by chicken granulosa cells was influenced both by the state of cell differentiation and the form of the matrix material (whether solid or liquid). When fraction 1 was added as liquid to the incubation mixture, it promoted progesterone production by granulosa cells at all stages of differentiation; however, it caused a greater relative increase in the amount of progesterone produced by undifferentiated (SYF) and differentiating (F(3)) granulosa cells than by differentiated (F(1)) ones. In the presence of the liquid-form of fraction 1, luteinizing hormone (LH) stimulated progesterone production in differentiated (F(1)) and differentiating (F(5-7)) granulosa cells. Similarly, follicle-stimulating hormone (FSH) stimulated progesterone production by differentiating (F(3)) and undifferentiated (SYF) granulosa cells in the presence of the liquid-form of fraction 1 protein. In culture wells that had been pre-coated with fraction 1 (solid-form), progesterone production by less differentiated (SYF, F(5-7)) granulosa cells was enhanced, whereas progesterone production by differentiated (F(1)) cells was reduced. The solid-form of fraction 1 augmented LH-stimulated progesterone production by less differentiated (F(5-7)) granulosa cells however, it attenuated LH-induced progesterone production in differentiated (F(1)) cells. FSH-promoted progesterone production in granulosa cells from immature follicles (SYF) was augmented by solid-form of fraction 1 whereas the effect of FSH on cells obtained from older follicle (F(3)) was suppressed by solid-form of fraction 1. In experiments in which gonadotropin action was attenuated by solid-form of fraction 1, the amount of progesterone produced in the presence of maximally inhibiting concentrations of fraction 1 protein was greater than control values (no fraction 1, no gonadotropin). These results show that basal lamina of the ovarian follicle can regulate progesterone production by granulosa cells. The data demonstrate that the interactions between the components of basal lamina and LH or FSH on granulosa cell function were dependent on the stage of follicular development and were influenced by the form of the matrix material. It is concluded that the basal lamina of the chicken ovarian follicle is biologically active and regulates granulosa cell function.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11790345&dopt=Abstract progesterone, progesterone cream



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Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids.

Miyaura H, Iwata M.

Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida-shi, Tokyo 194-8511, Japan.

Progesterone may contribute to the maternal suppression of immunity to the fetus by modulating the Th1/Th2 balance. To clarify whether progesterone directly or indirectly affects T cell differentiation, we used two experimental systems with isolated T cells in vitro. In one system, isolated CD4+CD8+thymocytes differentiated into Th1 and Th2 by two pulse stimulations with defined combinations of ionomycin and PMA followed by the treatment with IL-12, IL-4, and IL-2. In the second system, functional differentiation was induced in purified naive CD4 T cells with cytokines and Abs to CD3 and CD28. In both systems, progesterone added with cytokines suppressed Th1 development at concentrations associated with pregnancy, but enhanced the development of IL-10-producing Th2 cells. Because IL-10 is known to inhibit APC production of IL-12, Th1 development may be also suppressed indirectly by progesterone. However, progesterone failed to enhance IL-10 production in the absence of IL-12. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 inhibited Th1 development and enhanced Th2 development, as did progesterone, indicating that p38 MAPK and extracellular signal-regulated kinase pathways are involved in Th1 development. However, the progesterone effects may not be simply due to a modulation of MAPK activities, because the inhibitor did not significantly affect the development of IL-10-producing cells in the presence or absence of progesterone. Glucocorticoids exerted effects similar to those of progesterone on Th1/Th2 development even at lower concentrations. These results suggest that progesterone as well as glucocorticoids directly inhibit Th1 development and enhance Th2 development.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11801642&dopt=Abstract progesterone, progesterone cream



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Steroidogenesis in cumulus cells of bovine cumulus-oocyte-complexes matured in vitro with BSA and different concentrations of steroids.

Mingoti GZ, Garcia JM, Rosa-e-Silva AA.

Department of Animal Health, UNESP, P.O. Box 341, CEP 16050-680, Aracatuba, SP, Brazil. gmingoti fmva.uesp.br

The present in vitro experiments were designed to evaluate the ability of bovine cumulus-oocyte-complexes (COCs) to produce steroids and also to evaluate the modulatory effects of added estradiol, progesterone and testosterone on the steroidogenic activity of COCs. Considerable estradiol accumulation was observed in the control maturation medium for in vitro maturation of bovine COCs during the 24h of maturation (P<0.05). When testosterone was added to the medium at various concentrations, a slight estradiol accumulation occurred, which, however, was lower (P<0.05) than that observed in the control medium. Slight estradiol accumulation was observed in maturation medium containing progesterone at concentrations of 2.5, 5.0 and 10.0 microg/ml, but these increases were less (P<0.05) than those observed in the control medium. However, in the presence of 1.0 microg/ml progesterone, estradiol accumulation was equal to that of the control medium (P>0.05). Progesterone accumulation (P<0.05) was observed in the control medium for in vitro maturation of bovine COCs. When estradiol was added to the maturation medium, progesterone accumulation was observed, but was significant (P<0.05) only when the medium was supplemented with the lesser concentrations of estradiol utilized in the experiment (1.0 microg/ml). The results demonstrated that (1) cumulus cells of bovine COCs are able to secrete estradiol and progesterone in culture systems for in vitro maturation, and this steroidogenesis is modulated by the steroids progesterone, testosterone and estradiol, and (2) the addition of estradiol to the in vitro maturation medium of bovine oocytes should be reviewed, since cumulus cells of COCs have been demonstrated to secrete estradiol in the maturation medium.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11812628&dopt=Abstract progesterone, progesterone cream



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Effect of progesterone combined with chemotherapy on epithelial ovarian cancer.

Chen X, Feng Y.

Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.

OBJECTIVE: To identify an effective auxiliary therapy for epithelial ovarian cancer. METHODS: Progesterone acetate given at 250 mg intramuscularly twice a week for 1 month followed by increased administration to 500 mg intramuscularly every two weeks for 3 years was used in combination with platinum based chemotherapy to treat patients with epithelial ovarian cancer as a first-line therapy. Prognoses of the patients receiving progesterone combined with chemotherapy (progesterone group) and those receiving chemotherapy only (control group) were compared. RESULTS: Three-year recurrence and survival conditions of the progesterone and control groups were as follows. Stage Ia: no patient relapsed or died in either group. Stage Ib-Ic: three-year recurrence rates were 14.2% and 37.5%, respectively (P = 0.2845); three-year survival rates were 92.3% and 87.5% (P = 0.7221). Stage II: 1 patient relapsed and died among the 3 patients in the progesterone group; among the 4 patients in the control group, 1 patient relapsed, none died. Stage III: three-year recurrence rates were 30.8% and 64.3%, respectively (P = 0.1170); three-year survival rates were 85.7% and 42.9%, respectively (P = 0.005). Stage IV: 4 patients relapsed and 1 patient died among the 7 patients in the progesterone group; both the patients in the control group relapsed and died. CONCLUSIONS: The results indicated that progesterone combined with platinum based chemotherapy as a first-line therapy may improve the prognosis of advanced epithelial ovarian cancer, but would not change the prognosis of early stage epithelial ovarian cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12781043&dopt=Abstract progesterone, progesterone cream



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Progesterone inhibits human endometrial cancer cell growth and invasiveness: down-regulation of cellular adhesion molecules through progesterone B receptors.

Dai D, Wolf DM, Litman ES, White MJ, Leslie KK.

The Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of New Mexico Health Sciences Center, 2211 Lomas Boulevard NE, Albuquerque, New Mexico 87131-5286, USA.

Progesterone is a critical steroid hormone that controls cell proliferation and differentiation in the female reproductive tract. Progesterone acts through two nuclear receptor isoforms, progesterone receptors A and B (PRA and PRB, respectively), each with unique cellular effects. Loss of PRB has recently been linked to the development of poorly differentiated endometrial tumors, a lethal form of cancer. To study the molecular effects of progesterone, progesterone receptors were introduced into Hec50co endometrial cancer cells by adenoviral vectors encoding either PRA or PRB. Progesterone induced the cyclin-dependent kinase inhibitors p21 and p27, thereby significantly reducing the percentage of proliferating cells. Cancer cell invasion was also markedly inhibited as measured by Matrigel invasion studies. Similarly, a differentiated, secretory phenotype was induced by progesterone in cells expressing PRB. However, replicative senescence was induced by progesterone only in cells expressing PRA. Expression array analysis followed by confirmatory semiquantitative reverse transcription-PCR experiments demonstrated a significant progesterone-dependent inhibition of expression of a cadre of cellular adhesion molecules, including fibronectin, integrin alpha3, integrin beta1, integrin beta3, and cadherin 6. The level of down-regulation of adhesion molecule expression was significantly greater in the presence of the B isoform, demonstrating that progesterone acts principally through B receptors to inhibit cancer cell invasiveness modulated by adhesion molecules.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11830547&dopt=Abstract progesterone, progesterone cream



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Alterations in ovarian follicular progesterone secretion by elevated exposures to the drinking water disinfection by-product dibromoacetic acid: examination of the potential site(s) of impact along the steroidogenic pathway.

Goldman JM, Murr AS.

Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA. goldman.jerome epa.gov

Previous data from our laboratory indicated that the drinking water disinfection by-product, dibromoacetic acid (DBA), when applied in vitro to rat preovulatory follicles at a concentration consistent with blood levels found to disrupt estrous cyclicity, was able to block the stimulated secretion of progesterone. The present experiments focused on establishing a dose-response for such an effect and identifying the point(s)of impact of this compound along the steroidogenic pathway that underlie this suppression. Immature Sprague-Dawley rats were primed with PMSG on day 26 and killed 48 h later. Preovulatory follicles were removed and paired in culture with or without DBA (2-50 microg/ml) to reassess progesterone secretion under hCG-stimulated or baseline conditions. In addition, media supplemented with pregnenolone or 22(R)-hydroxycholesterol (22R-HC) were used to determine the effects of 50 microg/ml DBA on the initial steps leading to progesterone synthesis. Samples taken over the course of 24 h reaffirmed a significant DBA-associated suppression in baseline and stimulated progesterone release, while estradiol secretion was unaffected. This effect was mirrored by a reduction in follicular progesterone content in these DBA groups. The addition of pregnenolone eliminated this decrease, with the DBA-exposed follicles exhibiting a linear increase in progesterone release over the sampling period. The follicular progesterone content at 24 h showed that DBA treatment under pregnenolone supplementation caused marked elevations under both the hCG stimulated and non-stimulated conditions, something not reflected in the release data. Substitution of 22R-HC for pregnenolone eliminated the effect on baseline progesterone release, although the attenuation in stimulated secretion was still present. This suggests both an effect of DBA exposure on mitochondrial cholesterol transport by steroidogenic acute regulatory protein (StAR) and a possible impact on the receptor or postreceptor events triggered by hCG.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11836015&dopt=Abstract progesterone, progesterone cream