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Archives of Histology and Cytology Dec 2004This article reviews the effects of estradiol (E(2)), progesterone (P) and P receptor antagonists (PA) on the rhesus macaque endometrium. Ovariectomized macaques can be... (Review)
Review
This article reviews the effects of estradiol (E(2)), progesterone (P) and P receptor antagonists (PA) on the rhesus macaque endometrium. Ovariectomized macaques can be treated with implants of estradiol (E(2)) and P to induce precisely controlled, artificial menstrual cycles. During these cycles, treatment with E(2) alone induces an artificial proliferative phase marked by extensive endometrial epithelial cell proliferation and increased expression of stromal and epithelial estrogen receptor (ER) and P receptor (PR). Androgen receptor (AR) is also upregulated by E(2) but is expressed only by the endometrial stroma. Progesterone acts on the E(2) primed endometrium to induce secretory differentiation and causes suppression of epithelial and stromal ER, epithelial PR, and stromal AR in the functionalis zone. However, epithelial ER and PR are retained in the basalis zone during the secretory phase. When potent P antagonists (PA) are administered acutely at the end of an E(2) + P induced cycle, menses typically ensues similar to P withdrawal at the end of the menstrual cycle. When PAs are administered chronically there is significant blockage of all P- dependent effects including upregulation of ER, PR and AR and suppression of glandular secretory function. However, chronic PA administration also inhibits estrogen-dependent endometrial cell proliferation and growth. This endometrial antiproliferative effect is the basis of the clinical use of PA to control various diseases such as endometriosis.
Topics: Animals; Cell Proliferation; Drug Implants; Drug Synergism; Endometrium; Epithelial Cells; Estradiol; Female; Humans; Macaca mulatta; Menstrual Cycle; Menstruation-Inducing Agents; Mifepristone; Ovariectomy; Progesterone; Receptors, Androgen; Receptors, Estrogen; Receptors, Progesterone; Stromal Cells; Up-Regulation
PubMed: 15781981
DOI: 10.1679/aohc.67.393 -
IUBMB Life Oct 2011Embryonic stem (ES) cells have the capacity to differentiate into endodermal, mesodermal, and ectodermal lineages. Motor neuron (MN) differentiation of mouse ES cells...
Embryonic stem (ES) cells have the capacity to differentiate into endodermal, mesodermal, and ectodermal lineages. Motor neuron (MN) differentiation of mouse ES cells involves embryoid bodies formation with addition of Sonic hedgehog and retinoic acid. In this work, using immunocytochemistry, flow cytometry, and quantitative RT-PCR, we investigated whether progesterone or 17β-estradiol have inductive effects on ES cell-derived MN, as it has been demonstrated that these hormones modify proliferation and neural differentiation of pluripotent cells. When 100 nM progesterone was added during differentiation, we found higher proportions of MN, compared to the control condition; coincubation of progesterone with the progesterone receptor (PR) antagonist RU-486 caused a decrease in the number of MN to a percentage even lower than controls. The addition of nanomolar concentrations of 17β-estradiol also significantly induced MN differentiation. This effect of estradiol was completely antagonized by addition of the general estrogen receptor (ER) antagonist ICI 182,780. To identify the ER subtype mediating the increase on MN differentiation, we incubated estradiol with the ER-α antagonist MPP or with the ER-β blocker PHTPP. When we coincubated 17β-estradiol with MPP, we found a significant decrease in the percentage of MN. In contrast, the coincubation of 17β-estradiol with PHTPP had no effect on the induction of MN differentiation. All these effects on cell number were confirmed by significant changes in the expression of the MN markers Islet-1 and Choline acetyl transferase, assessed by real-time RT-PCR. Cell proliferation in embryoid bodies was significantly enhanced by progesterone treatment. No changes in apoptotic cell death were found in differentiating cells after progesterone or 17β-estradiol addition. Our findings indicate that progesterone and 17β-estradiol induce a higher proportion of MN derived from mouse ES cells through intracellular PR and ER, respectively. Furthermore, the effect of estradiol was mediated by specific activation of ER-α.
Topics: Analysis of Variance; Animals; Cell Differentiation; Choline O-Acetyltransferase; DNA Primers; Embryonic Stem Cells; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Flow Cytometry; Fulvestrant; Immunohistochemistry; LIM-Homeodomain Proteins; Mice; Mifepristone; Motor Neurons; Progesterone; Pyrazoles; Pyrimidines; Real-Time Polymerase Chain Reaction; Transcription Factors
PubMed: 21901819
DOI: 10.1002/iub.560 -
American Journal of Physiology.... Feb 2004Islet cells undergo major changes in structure and function to meet the demand for increased insulin secretion during pregnancy, but the nature of the hormonal...
Islet cells undergo major changes in structure and function to meet the demand for increased insulin secretion during pregnancy, but the nature of the hormonal interactions and signaling events is incompletely understood. Here, we used the glucose-responsive MIN6 beta-cell line treated with prolactin (PRL), progesterone (PRG), and dexamethasone (DEX, a synthetic glucocorticoid), all elevated during late pregnancy, to study their effects on mechanisms of insulin secretion. DEX alone or combined with PRL and PRG inhibited insulin secretion in response to 16 mM glucose-stimulating concentrations. However, in the basal state (3 mM glucose), the insulin levels in response to DEX treatment were unchanged, and the three hormones together maintained higher insulin release. There were no changes of protein levels of GLUT2 or glucokinase (GK), but PRL or PRG treatment increased GK activity, whereas DEX had an inhibitory effect on GK activity. alpha-Ketoisocaproate (alpha-KIC)-stimulated insulin secretion was also reduced by DEX alone or combined with PRL and PRG, suggesting that DEX may inhibit distal steps in the insulin-exocytotic process. PRL treatment increased the concentration of intracellular cAMP in response to 16 mM glucose, suggesting a role for cAMP in potentiation of insulin secretion, whereas DEX alone or combined with PRL and PRG reduced cAMP levels by increasing phosphodiesterase (PDE) activity. These data provide evidence that PRL and to a lesser extent PRG, which increase in early pregnancy, enhance basal and glucose-stimulated insulin secretion in part by increasing GK activity and amplifying cAMP levels. Glucocorticoid, which increases throughout gestation, counteracts only glucose-stimulated insulin secretion under high glucose concentrations by dominantly inhibiting GK activity and increasing PDE activity to reduce cAMP levels. These adaptations in the beta-cell may play an important role in maintaining the basal hyperinsulinemia of pregnancy while limiting the capacity of PRL and PRG to promote glucose-stimulated insulin secretion during late gestation.
Topics: Animals; Cell Line; Cyclic AMP; Dexamethasone; Drug Synergism; Glucocorticoids; Glucokinase; Glucose; Insulin; Insulin Antagonists; Insulin Secretion; Islets of Langerhans; Keto Acids; Phosphoric Diester Hydrolases; Progesterone; Prolactin; Rats; Signal Transduction
PubMed: 14559722
DOI: 10.1152/ajpendo.00210.2003 -
Journal of Applied Physiology... Aug 2002We investigated the effects of 17beta-estradiol and progesterone on transepithelial electrical resistance (R(TE)) in sheep visceral and parietal pleurae. Specimens of...
We investigated the effects of 17beta-estradiol and progesterone on transepithelial electrical resistance (R(TE)) in sheep visceral and parietal pleurae. Specimens of intact pleurae from adult female sheep were used. The samples were transferred to the laboratory within 30 min after death of the animal in a Krebs-Ringer solution at 4 degrees C. The pleura was then mounted as a planar sheet in Ussing-type chambers, and electrical measurements were made. There was an increase in R(TE) in all of the samples examined after addition of 17beta-estradiol and progesterone in visceral and parietal pleurae. This increase was rapid within 1 min, lasted for ~15 min, returned to the basal level within 30-45 min, and was dose dependent. Tamoxifen, an estrogen receptor antagonist, did not significantly eliminate the effect of 17beta-estradiol. Furthermore, no steroid receptors were identified in cytosolic preparations of visceral and parietal pleura with ligand binding assays. The estrogen- and progesterone-induced increase in R(TE) in both visceral and parietal pleurae was affected by addition of an inhibitor of nitric oxide synthase. Indeed, previous administration of N(omega)-nitro-L-arginine methyl ester prevented the increase in R(TE) by 17beta-estradiol and progesterone. These results suggest that 17beta-estradiol and progesterone induce an increase in R(TE) in both visceral and parietal pleura and thus alter the transepithelial permeability. The effect of steroids may be accounted for by rapid release of nitric oxide in pleura.
Topics: Animals; Dose-Response Relationship, Drug; Electric Impedance; Enzyme Inhibitors; Estradiol; Estrogen Antagonists; Female; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pleura; Progesterone; Sheep; Tamoxifen
PubMed: 12133888
DOI: 10.1152/japplphysiol.00425.2001 -
PloS One 2013A decline in serum progesterone or antagonism of progesterone receptor function results in preterm labor and birth. Whether characteristics of premature remodeling of...
A decline in serum progesterone or antagonism of progesterone receptor function results in preterm labor and birth. Whether characteristics of premature remodeling of the cervix after antiprogestins or ovariectomy are similar to that at term was the focus of the present study. Groups of pregnant rats were treated with vehicle, a progesterone receptor antagonist (onapristone or mifepristone), or ovariectomized on day 17 postbreeding. As expected, controls given vehicle delivered at term while rats delivered preterm after progesterone receptor antagonist treatment or ovariectomy. Similar to the cervix before term, the preterm cervix of progesterone receptor antagonist-treated rats was characterized by reduced cell nuclei density, decreased collagen content and structure, as well as a greater presence of macrophages per unit area. Thus, loss of nuclear progesterone receptor-mediated actions promoted structural remodeling of the cervix, increased census of resident macrophages, and preterm birth much like that found in the cervix at term. In contrast to the progesterone receptor antagonist-induced advance in characteristics associated with remodeling, ovariectomy-induced loss of systemic progesterone did not affect hypertrophy, extracellular collagen, or macrophage numbers in the cervix. Thus, the structure and macrophage census in the cervix appear sufficient for premature ripening and birth to occur well before term. With progesterone receptors predominantly localized on cells other than macrophages, the findings suggest that interactions between cells may facilitate the loss of progesterone receptor-mediated actions as part of a final common mechanism that remodels the cervix in certain etiologies of preterm and with parturition at term.
Topics: Animals; Cervix Uteri; Female; Macrophages; Peripartum Period; Pregnancy; Premature Birth; Progesterone; Rats; Rats, Sprague-Dawley; Receptors, Progesterone
PubMed: 24339918
DOI: 10.1371/journal.pone.0081340 -
The Journal of Biological Chemistry Jan 1990Progesterone and 17 alpha-hydroxyprogesterone (but not other steroids such as testosterone, corticosterone, beta-estradiol, estrone, dehydroepiandrosterone, 20...
Progesterone and 17 alpha-hydroxyprogesterone (but not other steroids such as testosterone, corticosterone, beta-estradiol, estrone, dehydroepiandrosterone, 20 alpha-hydroxypregnen-3-one, androstenedione, and pregnenolone) were shown to cause an immediate increase, in free cytosolic calcium ([Ca2+]i) in both capacitated and noncapacitated human sperm, using the fluorescent indicator fura 2. Significant increases in [Ca2+]i were observed with 10 ng/ml progesterone, while maximum effects were seen with 1 microgram/ml progesterone. Two other steroids 11 beta-hydroxyprogesterone and 5 alpha-pregnane-3,20-dione exhibited significant activity to increase [Ca2+]i. This increase in [Ca2+]i elicited by progesterone was entirely due to Ca2+ influx from the extracellular medium since the increase in [Ca2+]i was blocked by the Ca2+ chelator EGTA (2.5 mM) and the Ca2+ channel antagonist La3+ (0.25 mM) when added to the medium containing 2.5 mM Ca2+. Progesterone also stimulated the uptake of Mn2+ into sperm as measured by the quenching of fura 2 fluorescence. Progesterone has been found in human follicular fluid at levels capable of stimulating increases in [Ca2+]i. The similarities in responses induced by human follicular fluid and progesterone an increase in [Ca2+]i, and hence the acrosome reaction, is progesterone and/or 17 alpha-hydroxyprogesterone. Progesterone (1 microgram/ml) did not increase [Ca2+]i in somatic cells such as adipocytes, hepatocytes, Balb/c 3T3 cells, normal rat kidney, or DDT1 MF-2 cells. The effects of these progestins to increase [Ca2+]i, by activating a receptor-operated calcium channel, is the first report of such an activity in sperm. This phenomena possibly opens up a new field of steroid action in the area of sterility, fertility, and contraception at the level of the sperm.
Topics: 17-alpha-Hydroxyprogesterone; Calcium; Dose-Response Relationship, Drug; Egtazic Acid; Humans; Hydroxyprogesterones; In Vitro Techniques; Lanthanum; Male; Manganese; Progesterone; Spermatozoa; Steroids; Time Factors
PubMed: 2104840
DOI: No ID Found -
Fertility and Sterility May 2009To define the long-term effects of GnRH antagonist, GnRH agonist, and estrogen plus progesterone treatments on apoptosis and apoptosis-related gene expressions,...
OBJECTIVE
To define the long-term effects of GnRH antagonist, GnRH agonist, and estrogen plus progesterone treatments on apoptosis and apoptosis-related gene expressions, including bcl2, bax, and cyt c in rat ovary.
DESIGN
Prospective placebo-controlled experimental study.
SETTING
Obstetrics and Gynecology and Medical Biology and Genetics university departments.
ANIMAL(S)
Forty female wistar rats that were 3 to 4 months of age.
INTERVENTION(S)
Forty rats were randomly divided into 4 groups of 10 each. In group 1 (control) each rat received normal saline as placebo by gastric lavage. In group 2 (GnRH agonist) 1 mg/kg leuprolide acetate in depot form was given for 30 days. In group 3 (GnRH antagonist) each animal received 0.1 mg/kg cetrorelix every 2 days. In group 4 (estrogen plus progesterone) 0.5 mg/kg estradiol valerate and norethisterone enantate in depot form was given every 30 days. After 60 days, the animals were killed.
MAIN OUTCOME MEASURE(S)
Assessment of morphology, histology of ovaries, determination of the number of apoptotic cells, and analysis of apoptosis-related gene expression of bcl2, bax, and cyt c in the rat ovaries.
RESULT(S)
Long-term GnRH antagonist treatment significantly increased bax gene expression, but the ratio of bcl2:bax gene expression was constant compared with control group. The GnRH agonist treatment significantly increased cyt c gene expression, and estrogen plus progesterone treatment significantly decreased bcl 2 and significantly increased cyt c expressions. In the estrogen plus progesterone group, ovaries were cystic and larger than in the other groups. There was no significant morphologic change between the other groups.
CONCLUSION(S)
Long-term administration of GnRH agonist, GnRH antagonist, and estrogen plus progesterone can modulate the apoptosis-related genes in rat ovary. Although GnRH antagonist treatment does not influence apoptosis, GnRH antagonist and estrogen plus progesterone treatments seem to influence apoptosis in rat the ovary. Further clinical studies focusing on the effect of these agents on apoptosis-related genes could be performed.
Topics: Animals; Apoptosis; Estradiol; Estrogens; Female; Gonadotropin-Releasing Hormone; Leuprolide; Norethindrone; Ovary; Progesterone; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; bcl-2-Associated X Protein
PubMed: 18829022
DOI: 10.1016/j.fertnstert.2008.07.1728 -
Fertility and Sterility Nov 2008To investigate whether the balance between progesterone and FSH levels has a role in ulcer formation/inhibition.
OBJECTIVE
To investigate whether the balance between progesterone and FSH levels has a role in ulcer formation/inhibition.
DESIGN
Animal study.
SETTING
Ataturk University, Faculty of Medicine, Laboratory of Pharmacology Department.
PATIENT(S)
One hundred thirty-two female Albino Wistar rats.
INTERVENTION(S)
Ovariectomy. Chronic administration of progesterone and estrogen to ovariectomized rats. Acute administration of progesterone to ovariectomized rats. Acute administration of progesterone and FSH to intact rats. Combined administration of mifepristone with progesterone or FSH to intact rats. Indomethacin administration to all rats.
MAIN OUTCOME MEASURE(S)
Gastric ulcer areas as mm(2).
RESULT(S)
Indomethacin-induced ulcers were significantly higher in ovariectomized rats than in intact rats. Chronic progesterone (1 mg/kg) inhibited gastrointestinal system ulcers by 51.2%, whereas 2 and 5 mg/kg chronic progesterone and 1, 2, and 5 mg/kg chronic estrogen were not effective. Acute progesterone (5 mg/kg) increased indomethacin ulcers significantly in ovariectomized rats. FSH increased indomethacin ulcers significantly. In addition, progesterone increased indomethacin ulcers significantly in intact rats. Mifepristone antagonized the ulcerogenic effects of FSH and progesterone.
CONCLUSION(S)
Our data suggest that progesterone is not an antiulcer hormone, and produces ulcers via its own receptor. In addition, FSH may produce ulcerogenic effects via progesterone receptors. The low doses of progesterone (inhibits endogenous FSH) cannot stimulate its own receptors sufficiently for ulcer formation and prevent the ulcerogenic effects of FSH by decreasing FSH concentration.
Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Estrogens; Female; Follicle Stimulating Hormone; Hormone Antagonists; Indomethacin; Mifepristone; Ovariectomy; Progesterone; Rats; Rats, Wistar; Stomach Ulcer
PubMed: 18054921
DOI: 10.1016/j.fertnstert.2007.08.027 -
Thoracic Cancer Aug 2020The aim of this study was to determine whether progesterone could inhibit the growth of lung adenocarcinoma cells via membrane progesterone receptor alpha (mPRα) and...
BACKGROUND
The aim of this study was to determine whether progesterone could inhibit the growth of lung adenocarcinoma cells via membrane progesterone receptor alpha (mPRα) and elucidate its potential mechanism. The relationship between mPRα expression and the survival prognosis of lung adenocarcinoma patients was studied.
METHODS
A mPRα knockdown lung adenocarcinoma cell line was constructed and treated with P4 and Org (a derivative of P4 and specific agonist of mPRα). Cell proliferation was assessed using CCK-8 and plate colony formation assays. Protein expression was detected by western blotting. A nude mouse model of lung adenocarcinoma was established to assess the antitumor effect of P4/Org in vivo.
RESULTS
We initially determined that mPRα could promote the development of lung adenocarcinoma through the following lines of evidence. High expression of mPRα both at the mRNA and protein level was significantly associated with the poor prognosis of lung adenocarcinoma patients. The downregulation of mPRα inhibited the proliferation of lung adenocarcinoma cells. We further showed that mPRα mediates the ability of P4 to inhibit the growth of lung adenocarcinoma cells through the following lines of evidence: P4/Org inhibited the proliferation of lung adenocarcinoma cells; mPRα mediated the ability of P4/Org to inhibit lung adenocarcinoma cell proliferation; mPRα mediated the ability of P4/Org to inhibit the PKA (cAMP-dependent protein kinase)/CREB (cAMP responsive element binding protein) and PKA/β-catenin signaling pathways; and P4/Org inhibited the growth of a lung adenocarcinoma tumor model in vivo.
CONCLUSIONS
In summary, the results of our study show that progesterone can inhibit lung adenocarcinoma cell growth via mPRα.
Topics: Adenocarcinoma of Lung; Animals; Female; Humans; Male; Mice; Progesterone; Receptors, Progesterone; Transfection; Xenograft Model Antitumor Assays
PubMed: 32529777
DOI: 10.1111/1759-7714.13528 -
Hormones and Behavior Aug 2010Stimulant abuse continues to be a problem, particularly for women. There is increasing preclinical and clinical evidence showing that the hormone progesterone attenuates...
Stimulant abuse continues to be a problem, particularly for women. There is increasing preclinical and clinical evidence showing that the hormone progesterone attenuates the behavioral effects of cocaine, and this effect is primarily observed in females. The purpose of the present study was to determine if progesterone would also alter the behavioral effects of another stimulant, oral d-amphetamine (AMPH) in women. Eighteen normal non-drug abusing women completed eight outpatient sessions over two menstrual cycles. During the follicular phase of each cycle, women were administered AMPH (0, 10, 20 mg); in one cycle they were pretreated with oral micronized progesterone (200 mg) and in another cycle they were pretreated with placebo progesterone. Each session, participants completed a range of tasks including subjective measures of abuse liability, cognitive performance tasks, and behavioral measures of impulsivity and risk-taking. AMPH produced dose-related increases in positive subjective effects and these effects were enhanced by progesterone pretreatment. AMPH alone, or in combination with progesterone, had little effect on performance or behavioral measures of impulsivity. These results are in contrast with previous studies showing that progesterone attenuates the subjective response to cocaine and nicotine. Additional studies are needed to explore the modulatory role of progesterone on the effects of AMPH to determine whether progesterone has any clinical utility for AMPH abuse.
Topics: Administration, Oral; Adult; Central Nervous System Stimulants; Cognition; Dextroamphetamine; Dose-Response Relationship, Drug; Female; Humans; Impulsive Behavior; Menstrual Cycle; Placebos; Progesterone; Risk-Taking
PubMed: 20399212
DOI: 10.1016/j.yhbeh.2010.04.003