-
Seminars in Reproductive Medicine Feb 2005The steroid hormone progesterone (P) is a critical regulator of embryo implantation and maintenance of pregnancy. P acting through the nuclear progesterone receptors... (Review)
Review
The steroid hormone progesterone (P) is a critical regulator of embryo implantation and maintenance of pregnancy. P acting through the nuclear progesterone receptors (PRs) regulates the expression of specific gene networks that in turn control the extensive cell proliferation, differentiation, and remodeling that occur in various uterine cell types during the progressive phases of implantation. To identify the P-regulated pathways that underlie the implantation process in the mouse, we employed RU 486, a well-characterized PR antagonist that binds to the receptor and blocks its gene regulatory function. We performed messenger RNA (mRNA) profiling in the peri-implantation uterus using oligonucleotide microarrays to analyze changes in mRNA levels in response to RU 486. This analysis provided, for the first time, a comprehensive profile of PR-regulated gene networks with potential roles during implantation. Our study identified a variety of novel PR-regulated molecules, such as growth factors, protease inhibitors, metabolic enzymes, peptide hormones, transcription factors, immune response molecules, cytoskeletal proteins, and cell adhesion molecules, that are potential mediators of P action in the peri-implantation mouse uterus. This article provides a brief description of the expression and function of these newly identified molecular pathways.
Topics: Animals; Decidua; Embryo Implantation; Female; Gene Expression Regulation; Hormone Antagonists; Mifepristone; Oligonucleotide Array Sequence Analysis; Progesterone; Receptors, Progesterone; Up-Regulation; Uterus
PubMed: 15714388
DOI: 10.1055/s-2005-864032 -
Seminars in Reproductive Medicine Feb 2005Progesterone exhibits diverse biological activities, inducing proliferation of the mammary gland epithelium, but it opposes the mitogenic activity of estrogen in the... (Review)
Review
Progesterone exhibits diverse biological activities, inducing proliferation of the mammary gland epithelium, but it opposes the mitogenic activity of estrogen in the uterus. These tissue-selective activities of progesterone are mediated by the progesterone receptor (PR), a member of the nuclear receptor superfamily of ligand-dependent transcription factors. Several clinically useful PR antagonists that block progesterone activity have been described, yet some of these compounds exhibit tissue-selective partial agonist activity, leading them to be termed selective progesterone receptor modulators (SPRMs). This partial agonist activity is mediated primarily through the N-domain of the B isoform of PR, although the mechanism has not yet been defined. In this review, we discuss mechanisms by which PR activates transcription and ways in which antagonists oppose progesterone activity. We discuss mechanisms by which the N-domain mediates tissue specific partial agonist activity of SPRMs, as well as receptor interacting coregulatory proteins that influence this activity of the N-domain. We also describe newly developed SPRMs that mediate subsets of agonist and/or antagonist activities, and discuss the clinical potential of these compounds.
Topics: Hormone Antagonists; Humans; Mifepristone; Progesterone; Protein Structure, Tertiary; Receptors, Progesterone; Transcription, Genetic; Transcriptional Activation
PubMed: 15714386
DOI: 10.1055/s-2005-864030 -
British Medical Bulletin Jan 1993Antigestogens are compounds which inhibit the synthesis of progesterone or antagonise its biological action. The progesterone antagonist mifepristone (RU 486) binds with... (Review)
Review
Antigestogens are compounds which inhibit the synthesis of progesterone or antagonise its biological action. The progesterone antagonist mifepristone (RU 486) binds with high affinity to progesterone receptors throughout the body, blocking the action of endogenous progesterone. In the last 10 years it has been demonstrated that mifepristone, in combination with a suitable prostaglandin, is a safe, effective alternative to vacuum aspiration for termination of pregnancy in the first two months. Preliminary trials suggest that antigestogens may be useful true contraceptives by inhibiting ovulation or by preventing implantation as once a month pills and postcoital agents. In late pregnancy, by sensitising the uterus to prostaglandins and by promoting cervical dilatation, they may induce labour and facilitate lactation. In non-pregnant women mifepristone may have application in the treatment of hormone-dependent conditions such as endometriosis, fibromyomata, meningioma and breast cancer. The availability of hormone antagonists to oestrogens, androgens and progesterone offers the possibility of new methods of regulating reproductive function in health and disease.
Topics: Abortion, Induced; Adult; Contraceptives, Postcoital; Female; Humans; Labor, Induced; Mifepristone; Ovulation; Progesterone; Uterine Contraction
PubMed: 8324617
DOI: 10.1093/oxfordjournals.bmb.a072607 -
Cancer Treatment and Research 1996
Review
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Female; Gonanes; Hormone Antagonists; Humans; Mice; Mifepristone; Progesterone
PubMed: 8826648
DOI: 10.1007/978-1-4613-1259-8_10 -
Psychoneuroendocrinology Jul 2011Progesterone withdrawal has been proposed as an underlying factor in premenstrual syndrome and postpartum depression. Progesterone withdrawal induces forced swim test... (Comparative Study)
Comparative Study
Progesterone withdrawal has been proposed as an underlying factor in premenstrual syndrome and postpartum depression. Progesterone withdrawal induces forced swim test (FST) immobility in mice, a depression-like behavior, but the contribution of specific receptors to this effect is unclear. The role of progesterone's GABA(A) receptor-modulating metabolite allopregnanolone in depression- and anxiety-related behaviors has been extensively documented, but little attention has been paid to the role of progesterone receptors. We administered the classic progesterone receptor antagonist mifepristone (RU-38486) and the specific progesterone receptor antagonist CDB-4124 to mice that had been primed with progesterone for five days, and found that both compounds induced FST immobility reliably, robustly, and in a dose-dependent fashion. Although CDB-4124 increased FST immobility, it did not suppress initial activity in a locomotor test. These findings suggest that decreased progesterone receptor activity contributes to depression-like behavior in mice, consistent with the hypothesis that progesterone withdrawal may contribute to the symptoms of premenstrual syndrome or postpartum depression.
Topics: Animals; Depression; Depression, Postpartum; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Finasteride; Locomotion; Mice; Mice, Inbred DBA; Mifepristone; Norpregnadienes; Premenstrual Syndrome; Progesterone; Receptors, Progesterone; Single-Blind Method; Swimming
PubMed: 21163582
DOI: 10.1016/j.psyneuen.2010.11.004 -
Reproductive Sciences (Thousand Oaks,... Aug 2019Pregnant women at risk of preterm labor routinely receive glucocorticoids (GCs) and frequently also progesterone. Administration of GCs accelerates intrauterine...
Pregnant women at risk of preterm labor routinely receive glucocorticoids (GCs) and frequently also progesterone. Administration of GCs accelerates intrauterine surfactant synthesis and lung maturation, thereby reducing the incidence of neonatal respiratory distress syndrome; progesterone has the potential to prevent preterm birth. Little is known about possible interactions of GCs and progesterone. Our aim was to clarify whether progesterone can affect dexamethasone (DXM)-regulated expression of surfactant protein A (SP-A), SP-B, and SP-D in lung epithelial cells. H441 cells were exposed to DXM and progesterone and expression of SPs was analyzed by quantitative real-time polymerase chain reaction and immunoblotting. Although progesterone had no direct effect on the expression of SP-B, DXM-mediated induction was inhibited dose dependently on the transcriptional (64 µM [ < .0001], 32 µM [ = .0005], 16 µM [ = .0019]) and the translational level. Furthermore, progesterone inhibited stimulatory effects of other GCs as well. While exogenous tissue growth factor β1 (TGF-β1) inhibited DXM-induced SP-B expression (messenger RNA [mRNA]: = .0014), progesterone itself did not influence TGF-β1 mRNA expression and/or TGF-β1/Smad signaling, demonstrating that TGF-β1 and/or Smad activation is not involved. The inhibitory effect of progesterone could be imitated by the GC and progesterone receptor (PR) antagonist RU-486, but not by the specific PR antagonist PF-02413873, indicating that progesterone acts as a competitive antagonist of DXM. The effect of progesterone on DXM-regulated genes was not specific for SP-B, as expression of SP-A and SP-D mRNAs was also antagonized. The present study highlights a new action of progesterone as a potential physiological inhibitor of GC-dependent SP expression in lung epithelial cells. The clinical relevance of this in vitro finding is currently unknown.
Topics: Cell Line; Cell Survival; Dexamethasone; Dose-Response Relationship, Drug; Epithelial Cells; Hormone Antagonists; Humans; Lung; Mifepristone; Progesterone; Pulmonary Surfactant-Associated Proteins; Transforming Growth Factor beta1
PubMed: 30317939
DOI: 10.1177/1933719118804668 -
Gynecological Endocrinology : the... Jun 1999Neurological diseases are frequently observed in perimenopausal women and can be characterized by their gender-specific occurrence. These observations raise the question... (Review)
Review
Neurological diseases are frequently observed in perimenopausal women and can be characterized by their gender-specific occurrence. These observations raise the question whether sex steroids are also involved in neurological diseases. Epidemiological data have shown that in Austria in 1993, the prescription rate of psychotropics, hypnotics, and analeptics for women aged 50-55 years increased over 300% compared to other age groups. In males of the same age, an increase of the prescription rate was not observed. Molecular pharmacology research over the last ten years has shown that sex steroids may interact with the central nervous system via GABA receptors as well as with the peripheral nervous system. These observations confirm the epidemiological finding that neurological and psychological functions may also be directly influenced by sex steroids and their metabolites.
Topics: Adult; Female; Humans; Meningioma; Menopause; Middle Aged; Migraine Disorders; Multiple Sclerosis; Nervous System Diseases; Postmenopause; Progesterone; Receptors, GABA
PubMed: 12227900
DOI: 10.1080/gye.13.s4.41.45 -
Contraception 1987
Review
Topics: Abortifacient Agents, Steroidal; Abortion, Induced; Estrenes; Female; Humans; Hydrocortisone; Menstruation-Inducing Agents; Mifepristone; Pregnancy; Progesterone; Receptors, Glucocorticoid
PubMed: 2824124
DOI: 10.1016/0010-7824(87)90116-8 -
American Journal of Obstetrics and... Apr 2007Whereas the essential role of progesterone in the maintenance of pregnancy is accepted generally, the mechanisms that suppress progesterone's function near term to allow... (Review)
Review
Whereas the essential role of progesterone in the maintenance of pregnancy is accepted generally, the mechanisms that suppress progesterone's function near term to allow labor and delivery of the conceptus are still shrouded in uncertainty. In most subprimate placental mammals, the withdrawal of progesterone before the initiation of labor is manifest by a significant drop in circulating progesterone levels, which is due to either luteolysis or changes in placental steroidogenesis, which shunts precursors towards estrogen production. No such events can be demonstrated in human pregnancy. In this review, we shall present a brief historic background of the research that led to the concepts of "progesterone block" and its withdrawal, based on experiments with rabbits and laboratory rodents, and discuss some of the more recent ideas about "functional progesterone withdrawal," in an attempt to bridge the apparent differences between the regulation of parturition in human and subprimate mammals.
Topics: Animals; Biomarkers; Female; Mifepristone; Myometrium; Parturition; Pregnancy; Pregnancy, Animal; Progesterone; Rabbits; Rats; Receptors, Progesterone; Sensitivity and Specificity; Sheep
PubMed: 17403397
DOI: 10.1016/j.ajog.2006.09.005 -
The Anatomical Record Apr 1989The possibility that ovarian steroids may participate in the inhibition of meiosis has not been rigorously examined. Since progesterone levels are extremely high in...
The possibility that ovarian steroids may participate in the inhibition of meiosis has not been rigorously examined. Since progesterone levels are extremely high in follicular fluid prior to ovulation, we tested the possibility that this steroid may be involved in oocyte maturation. To this end, we collected follicular oocytes and cultured them in the presence of dibutyrl cAMP (Bt2), progesterone, and/or the progesterone antagonist RU486 and assessed maturation evidenced by germinal vesicle breakdown (GVBD). Denuded oocytes or cumulus masses collected in the presence of 1 mM Bt2 and subsequently cultured in 25 microM progesterone did not undergo GVBD. However, denuded oocytes and cumulus masses collected in the presence of progesterone and not Bt2 did undergo GVBD (93%). Concentrations of Bt2 (150 microM) that would not inhibit GVBD were inhibitory when used in the presence of progesterone (1-25 microM). Competition experiments using increasing concentrations of the progesterone antagonist RU486 (1-100 microM) did not block the ability of progesterone to enhance the activity of Bt2. We conclude that progesterone alone does not block GVBD; however, in the presence of low concentrations of cAMP it is extremely effective in blocking GVBD. The synergistic activity of progesterone does not appear to be mediated by the progesterone receptor. The data suggest that progesterone and cAMP may operate cooperatively to inhibit meiosis in the ovarian follicle.
Topics: Animals; Bucladesine; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Synergism; Estrenes; Female; Meiosis; Mice; Mifepristone; Oocytes; Osmolar Concentration; Progesterone
PubMed: 2540678
DOI: 10.1002/ar.1092230407