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Neuroscience Letters Jan 2021Progesterone acts on neurons directly by activating its receptor and through metabolic conversion to neurosteroids. There is emerging evidence that progesterone exerts... (Review)
Review
Progesterone acts on neurons directly by activating its receptor and through metabolic conversion to neurosteroids. There is emerging evidence that progesterone exerts excitatory effects by activating its cognate receptors (progesterone receptors, PRs) through enhanced expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). Progesterone metabolite 5α,3α-tetrahydro-progesterone (allopregnanolone, THP) mediates its anxiolytic and sedative actions through the potentiation of synaptic and extrasynaptic γ-aminobutyric acid type-A receptors (GABARs). Here, we review progesterone's neuromodulatory actions exerted through PRs and THP and their opposing role in regulating seizures, catamenial epilepsy, and seizure exacerbation associated with progesterone withdrawal.
Topics: Animals; Anticonvulsants; Epilepsy; GABA-A Receptor Antagonists; Humans; Neurons; Progesterone; Receptors, GABA-A; Receptors, Progesterone
PubMed: 33421486
DOI: 10.1016/j.neulet.2020.135619 -
BMJ Clinical Evidence Apr 2011Preterm birth occurs in about 5% to 10% of all births in resource-rich countries, but in recent years the incidence seems to have increased in some countries,... (Review)
Review
INTRODUCTION
Preterm birth occurs in about 5% to 10% of all births in resource-rich countries, but in recent years the incidence seems to have increased in some countries, particularly in the USA. We found little reliable evidence for incidence in resource-poor countries. The rate in northwestern Ethiopia has been reported to vary from 11% to 22%, depending on the age group of mothers studied, and is highest in teenage mothers.
METHODS AND OUTCOMES
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of preventive interventions in women at high risk of preterm delivery? What are the effects of interventions to improve neonatal outcome after preterm rupture of membranes? What are the effects of treatments to stop contractions in preterm labour? What are the effects of elective compared with selective caesarean delivery for women in preterm labour? What are the effects of interventions to improve neonatal outcome in preterm delivery? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
RESULTS
We found 58 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
CONCLUSIONS
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: amnioinfusion for preterm rupture of membranes, antenatal corticosteroids, antibiotic treatment, bed rest, beta-mimetics, calcium channel blockers, elective caesarean, enhanced antenatal care programmes, magnesium sulphate, oxytocin receptor antagonists (atosiban), progesterone, prophylactic cervical cerclage, prostaglandin inhibitors (e.g., indometacin), selective caesarean, and thyrotropin-releasing hormone (TRH) (plus corticosteroids).
Topics: Adrenal Cortex Hormones; Adrenergic beta-Agonists; Cerclage, Cervical; Humans; Infant, Newborn; Obstetric Labor, Premature; Premature Birth; Progesterone; Thyrotropin-Releasing Hormone
PubMed: 21463540
DOI: No ID Found -
Endocrine Reviews Feb 2013Progesterone receptor (PR) mediates the actions of the ovarian steroid progesterone, which together with estradiol regulates gonadotropin secretion, prepares the... (Review)
Review
Progesterone receptor (PR) mediates the actions of the ovarian steroid progesterone, which together with estradiol regulates gonadotropin secretion, prepares the endometrium for implantation, maintains pregnancy, and differentiates breast tissue. Separation of estrogen and progesterone actions in hormone-responsive tissues remains a challenge. Pathologies of the uterus and breast, including endometrial cancer, endometriosis, uterine fibroids, and breast cancer, are highly associated with estrogen, considered to be the mitogenic factor. Emerging evidence supports distinct roles of progesterone and its influence on the pathogenesis of these diseases. Progesterone antagonizes estrogen-driven growth in the endometrium, and insufficient progesterone action strikingly increases the risk of endometrial cancer. In endometriosis, eutopic and ectopic tissues do not respond sufficiently to progesterone and are considered to be progesterone-resistant, which contributes to proliferation and survival. In uterine fibroids, progesterone promotes growth by increasing proliferation, cellular hypertrophy, and deposition of extracellular matrix. In normal mammary tissue and breast cancer, progesterone is pro-proliferative and carcinogenic. A key difference between these tissues that could explain the diverse effects of progesterone is the paracrine interactions of PR-expressing stroma and epithelium. Normal endometrium is a mucosa containing large quantities of distinct stromal cells with abundant PR, which influences epithelial cell proliferation and differentiation and protects against carcinogenic transformation. In contrast, the primary target cells of progesterone in the breast and fibroids are the mammary epithelial cells and the leiomyoma cells, which lack specifically organized stromal components with significant PR expression. This review provides a unifying perspective for the diverse effects of progesterone across human tissues and diseases.
Topics: Animals; Breast Neoplasms; Cell Differentiation; Cell Proliferation; Endometrial Neoplasms; Endometriosis; Estrogens; Female; Humans; Leiomyoma; Pregnancy; Progesterone; Receptors, Progesterone; Stromal Cells
PubMed: 23303565
DOI: 10.1210/er.2012-1043 -
Breast Cancer Research : BCR Aug 2021The ovarian hormones estrogen and progesterone (EP) are implicated in breast cancer causation. A specific consequence of progesterone exposure is the expansion of the...
BACKGROUND
The ovarian hormones estrogen and progesterone (EP) are implicated in breast cancer causation. A specific consequence of progesterone exposure is the expansion of the mammary stem cell (MSC) and luminal progenitor (LP) compartments. We hypothesized that this effect, and its molecular facilitators, could be abrogated by progesterone receptor (PR) antagonists administered in a mouse model.
METHODS
Ovariectomized FVB mice were randomized to 14 days of treatment: sham, EP, EP + telapristone (EP + TPA), EP + mifepristone (EP + MFP). Mice were then sacrificed, mammary glands harvested, and mammary epithelial cell lineages separated by flow cytometry using cell surface markers. RNA from each lineage was sequenced and differential gene expression was analyzed using DESeq. Quantitative PCR was performed to confirm the candidate genes discovered in RNA seq. ANOVA with Tukey post hoc analysis was performed to compare relative expression. Alternative splicing events were examined using the rMATs multivariate analysis tool.
RESULTS
Significant increases in the MSC and luminal mature (LM) cell fractions were observed following EP treatment compared to control (p < 0.01 and p < 0.05, respectively), whereas the LP fraction was significantly reduced (p < 0.05). These hormone-induced effects were reversed upon exposure to TPA and MFP (p < 0.01 for both). Gene Ontology analysis of RNA-sequencing data showed EP-induced enrichment of several pathways, with the largest effect on Wnt signaling in MSC, significantly repressed by PR inhibitors. In LP cells, significant induction of Wnt4 and Rankl, and Wnt pathway intermediates Lrp2 and Axin2 (confirmed by qRTPCR) were reversed by TPA and MFP (p < 0.0001). Downstream signaling intermediates of these pathways (Lrp5, Mmp7) showed similar effects. Expression of markers of epithelial-mesenchymal transition (Cdh1, Cdh3) and the induction of EMT regulators (Zeb1, Zeb2, Gli3, Snai1, and Ptch2) were significantly responsive to progesterone. EP treatment was associated with large-scale alternative splicing events, with an enrichment of motifs associated with Srsf, Esrp, and Rbfox families. Exon skipping was observed in Cdh1, Enah, and Brd4.
CONCLUSIONS
PR inhibition reverses known tumorigenic pathways in the mammary gland and suppresses a previously unknown effect of progesterone on RNA splicing events. In total, our results strengthen the case for reconsideration of PR inhibitors for breast cancer prevention.
Topics: Alternative Splicing; Animals; Cell Proliferation; Epithelial Cells; Epithelial-Mesenchymal Transition; Estrogens; Female; Hormone Antagonists; Mammary Glands, Animal; Mice; Progesterone; RNA Splicing Factors; RNA-Binding Proteins; Receptors, Progesterone; Signal Transduction; Stem Cells
PubMed: 34344445
DOI: 10.1186/s13058-021-01455-2 -
BMC Medicine Feb 2014The ovarian steroid hormone, progesterone, and its nuclear receptor, the progesterone receptor, are implicated in the progression of breast cancer. Clinical trial data... (Review)
Review
The ovarian steroid hormone, progesterone, and its nuclear receptor, the progesterone receptor, are implicated in the progression of breast cancer. Clinical trial data on the effects of hormone replacement therapy underscore the importance of understanding how progestins influence breast cancer growth. The progesterone receptor regulation of distinct target genes is mediated by complex interactions between the progesterone receptor and other regulatory factors that determine the context-dependent transcriptional action of the progesterone receptor. These interactions often lead to post-translational modifications to the progesterone receptor that can dramatically alter receptor function, both in the normal mammary gland and in breast cancer. This review highlights the molecular components that regulate progesterone receptor transcriptional action and describes how a better understanding of the complex interactions between the progesterone receptor and other regulatory factors may be critical to enhancing the clinical efficacy of anti-progestins for use in the treatment of breast cancer.
Topics: Animals; Breast Neoplasms; Female; Gene Expression Regulation, Neoplastic; Hormone Antagonists; Humans; Progesterone; Receptors, Progesterone
PubMed: 24552158
DOI: 10.1186/1741-7015-12-32 -
Molecular Pharmacology Jan 2022The cation channel of sperm (CatSper) is the principal entry point for calcium in human spermatozoa and its proper function is essential for successful fertilization. As...
The cation channel of sperm (CatSper) is the principal entry point for calcium in human spermatozoa and its proper function is essential for successful fertilization. As CatSper is potently activated by progesterone, we evaluated a range of steroids to define the structure-activity relationships for channel activation and found that CatSper is activated by a broad range of steroids with diverse structural modifications. By testing steroids that failed to elicit calcium influx as inhibitors of channel activation, we discovered that medroxyprogesterone acetate, levonorgestrel, and aldosterone inhibited calcium influx produced by progesterone, prostaglandin E, and the fungal natural product -sirenin, but these steroidal inhibitors failed to prevent calcium influx in response to elevated K and pH. In contrast to these steroid antagonists, we demonstrated for the first time that the T-type calcium channel blocker ML218 acts similarly to mibefradil, blocking CatSper channels activated by both ligands and alkalinization/depolarization. These T-type calcium channel blockers produced an insurmountable blockade of CatSper, whereas the three steroids produced antagonism that was surmountable by increasing concentrations of each activator, indicating that the steroids selectively antagonize ligand-induced activation of CatSper rather than blocking channel function. Both the channel blockers and the steroid antagonists markedly reduced hyperactivated motility of human sperm assessed by computer-aided sperm analysis, consistent with inhibition of CatSper activation. Unlike the channel blockers mibefradil and ML218, which reduced total and progressive motility, medroxyprogesterone acetate, levonorgestrel, and aldosterone had little effect on these motility parameters, indicating that these steroids are selective inhibitors of hyperactivated sperm motility. SIGNIFICANCE STATEMENT: The steroids medroxyprogesterone acetate, levonorgestrel, and aldosterone selectively antagonize progesterone- and prostaglandin E-induced calcium influx through the CatSper cation channel in human sperm. In contrast to T-type calcium channel blockers that prevent all modes of CatSper activation, these steroid CatSper antagonists preferentially reduce hyperactivated sperm motility, which is required for fertilization. The discovery of competitive antagonists of ligand-induced CatSper activation provides starting points for future discovery of male contraceptive agents acting by this unique mechanism.
Topics: Aldosterone; Alprostadil; Azabicyclo Compounds; Benzamides; Calcium Channels; Dose-Response Relationship, Drug; Humans; Levonorgestrel; Male; Progesterone; Semen; Sperm Motility; Steroids; Structure-Activity Relationship
PubMed: 34718225
DOI: 10.1124/molpharm.121.000349 -
Annals of Clinical and Translational... Jul 2019Progesterone is a potent neuromodulator that exerts effects on the brain through neurosteroids, progesterone receptors (PRs), and other molecules. Whether PR activation...
OBJECTIVE
Progesterone is a potent neuromodulator that exerts effects on the brain through neurosteroids, progesterone receptors (PRs), and other molecules. Whether PR activation regulates seizures is not known. We determined whether PR activation increased seizure susceptibility.
METHODS
Adult female rats that developed epilepsy following lithium-pilocarpine-induced status epilepticus (SE) were used. Seizures were recorded by continuous-video EEG and read by an individual blinded to the treatment of the animals. The animals were treated for a week with progesterone (50 mg/kg per day), and the effect of progesterone withdrawal on seizure frequency was assessed during the subsequent week. During the week of progesterone treatment, the animals were treated with PR antagonist RU-486 (10 mg/kg per day) or a vehicle control, which was administered 30 min before progesterone. In another set of animals, we determined the effect of the PR agonist Nestorone (3 mg/kg per day) on seizure frequency. The animals were treated with Nestorone or vehicle for a week, and seizure frequencies at baseline and during the treatment week were compared.
RESULTS
Progesterone withdrawal induced twofold increase in seizures in 57% of animals (n = 14). RU-486 treatment in combination with progesterone, prevented this increase, and a smaller fraction of animals (17%) experienced withdrawal seizures (n = 13). The specific activation of PRs by Nestorone also increased the seizure frequency. Forty-six percent (n = 14) of Nestorone-treated animals experienced at least a 50% increase in seizures compared to only 9% of the vehicle-treated animals (n = 11).
INTERPRETATION
PR activation increased seizure frequency in epileptic animals. Thus, PRs may be novel targets for treating catamenial epilepsy.
Topics: Animals; Female; Mifepristone; Norprogesterones; Pilocarpine; Progesterone; Rats; Rats, Sprague-Dawley; Receptors, Progesterone; Seizures; Status Epilepticus; Substance Withdrawal Syndrome
PubMed: 31353848
DOI: 10.1002/acn3.50830 -
Archives of Gynecology and Obstetrics Apr 2014Tocolysis is an important treatment in the improvement of outcome in preterm labor and preterm birth, provided that its use follows clear evidence-based recommendations.... (Review)
Review
Tocolysis is an important treatment in the improvement of outcome in preterm labor and preterm birth, provided that its use follows clear evidence-based recommendations. In this expert opinion, the most recent evidence about efficacy and side effects of different tocolytics is being reviewed and evidence-based recommendation about diagnosis and treatment of preterm labor is given. Further aspects such as progesterone administration or antibiotic treatment for the prevention of preterm birth are included. Our review demonstrates that an individualized choice of different tocolytics and additional treatments is necessary to improve short- and long-term neonatal outcome in preterm labor and preterm birth.
Topics: Anti-Bacterial Agents; Bed Rest; Calcium Channel Blockers; Cervical Length Measurement; Contraindications; Cyclooxygenase Inhibitors; Drug Approval; Female; Fenoterol; Fetal Membranes, Premature Rupture; Hexoprenaline; Humans; Infant, Newborn; Kalanchoe; Labor Stage, First; Magnesium Sulfate; Nitric Oxide Donors; Obstetric Labor, Premature; Phytotherapy; Pregnancy; Premature Birth; Progesterone; Progestins; Receptors, Oxytocin; Tocolysis; Tocolytic Agents; Ultrasonography, Prenatal
PubMed: 24385286
DOI: 10.1007/s00404-013-3137-9 -
The Cochrane Database of Systematic... Jul 2009The steroid hormone, progesterone, inhibits contractions of the pregnant uterus at all gestations. Antiprogestins (including mifepristone) have been developed to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The steroid hormone, progesterone, inhibits contractions of the pregnant uterus at all gestations. Antiprogestins (including mifepristone) have been developed to antagonise the action of progesterone, and have a recognised role in medical termination of early or mid-trimester pregnancy. Animal studies have suggested that mifepristone may also have a role in inducing labour in late pregnancy.
OBJECTIVES
To determine the effects of mifepristone for third trimester cervical ripening or induction of labour.
SEARCH STRATEGY
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register and reference lists of relevant papers (May 2009).
SELECTION CRITERIA
Clinical trials comparing mifepristone used for third trimester cervical ripening or labour induction with placebo/no treatment or other labour induction methods.
DATA COLLECTION AND ANALYSIS
A strategy was developed to deal with the large volume and complexity of trial data relating to labour induction. This involved a two-stage method of data extraction. For this update, two review authors independently assessed trial quality and extracted data.
MAIN RESULTS
Ten trials (1108 women) are included. Compared to placebo, mifepristone treated women were more likely to be in labour or to have a favourable cervix at 48 hours (risk ratio (RR) 2.41, 95% confidence intervals (CI) 1.70 to 3.42) and this effect persisted at 96 hours (RR 3.40, 95% CI 1.96 to 5.92). They were less likely to need augmentation with oxytocin (RR 0.80, 95% CI 0.66 to 0.97). Mifepristone treated women were less likely to undergo caesarean section (RR 0.74, 95% CI 0.60 to 0.92) but more likely to have an instrumental delivery (RR 1.43, 95% CI 1.04 to 1.96). Women receiving mifepristone were less likely to undergo a caesarean section as a result of failure to induce labour (RR 0.40, 95% CI 0.20 to 0.80). There is insufficient evidence to support a particular dose but a single dose of 200 mg mifepristone appears to be the lowest effective dose for cervical ripening (increased likelihood of cervical ripening at 72 hours (RR 2.13, 95% CI 1.15 to 3.97). Abnormal fetal heart rate patterns were more common after mifepristone treatment (RR 1.85, 95% CI 1.17 to 2.93), but there was no evidence of differences in other neonatal outcomes. There is insufficient information on the occurrence of uterine rupture/dehiscence in the reviewed studies.
AUTHORS' CONCLUSIONS
There is insufficient information available from clinical trials to support the use of mifepristone to induce labour. However, the studies suggest that mifepristone is better than placebo in reducing the likelihood of caesarean sections being performed for failed induction of labour; therefore, this may justify future trials comparing mifepristone with the routine cervical ripening agents currently in use. There is little information on effects on the baby.
Topics: Female; Humans; Labor Stage, First; Labor, Induced; Mifepristone; Oxytocics; Pregnancy; Progesterone; Randomized Controlled Trials as Topic
PubMed: 19588336
DOI: 10.1002/14651858.CD002865.pub2 -
Fertility and Sterility Apr 2008To update clinicians on different regimens of luteal phase supplementation in IVF-stimulated cycles and to identify areas that need further research in this subject. (Review)
Review
OBJECTIVE
To update clinicians on different regimens of luteal phase supplementation in IVF-stimulated cycles and to identify areas that need further research in this subject.
DESIGN
Literature review and critical analysis of published studies on luteal phase supplementation during the last 20 years.
CONCLUSION(S)
Luteal phase supplementation in IVF-stimulated cycles, both in gonadotropin releasing hormone agonist and antagonist protocols, is considered an essential requirement for optimal success rates. The date of initiation and discontinuation of supplemented hormones is not adequately studied in the literature. In most major controlled and randomized studies, there are no significant differences in success rates with progesterone supplementation alone, progesterone and estradiol, progesterone and human chorionic gonadotropin, and human chorionic gonadotropin alone. Success rates seem similar with intramuscular and vaginal progesterone administration with patient preference for the vaginal route. The optimal dose of progesterone has not been studied in a scientific way in the literature. The use of gonadotropin releasing hormone agonists for luteal phase supplementation in antagonist cycles appears to be promising, and is worthy of further investigation.
Topics: Chorionic Gonadotropin; Dosage Forms; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Drug Therapy, Combination; Estradiol; Female; Fertility Agents, Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Infertility, Female; Luteal Phase; Patient Compliance; Patient Satisfaction; Pregnancy; Pregnancy Rate; Progesterone; Treatment Outcome
PubMed: 18406833
DOI: 10.1016/j.fertnstert.2008.02.095