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Journal of Natural Products Jan 2022Baicalein is a flavonoid extracted from the root of (Chinese skullcap) and is consumed as part of this botanical dietary supplement to reduce oxidative stress, pain,...
Baicalein is a flavonoid extracted from the root of (Chinese skullcap) and is consumed as part of this botanical dietary supplement to reduce oxidative stress, pain, and inflammation. We previously reported that baicalein can also modify receptor signaling through the progesterone receptor (PR) and glucocorticoid receptor (GR) , which is interesting due to the well-established roles of both PR and GR in reducing inflammation. To understand the effects of baicalein on PR and GR signaling in the uterus, ovariectomized CD-1 mice were treated with DMSO, progesterone (P4), baicalein, P4 with baicalein, and P4 with RU486, a PR antagonist, for a week. The uteri were collected for histology and RNA sequencing. Our results showed that baicalein attenuated the antiproliferative effect of P4 on luminal epithelium as well as on the PR target genes HAND2 and ZBTB16. Baicalein did not change levels of PR or GR RNA or protein in the uterus. RNA sequencing data indicated that many transcripts significantly altered by baicalein were regulated in the opposite direction by P4. Similarly, a large portion of GO/KEGG terms and GSEA gene sets were altered in the opposite direction by baicalein as compared to P4 treatment. Treatment of baicalein did not change body weight, organ weight, or blood glucose level. In summary, baicalein functioned as a PR antagonist and therefore may oppose P4 action under certain conditions such as uterine hyperplasia, fibroids, and uterine cancers.
Topics: Animals; Female; Flavanones; Gene Expression Regulation; Mice; Ovariectomy; Progesterone; Receptors, Glucocorticoid; Receptors, Progesterone; Sequence Analysis, RNA; Uterus
PubMed: 34935393
DOI: 10.1021/acs.jnatprod.1c01008 -
Fertility and Sterility Aug 2014To assess the impact of elevated early follicular progesterone (P) levels in gonadotropin-releasing hormone (GnRH) antagonist cycles on clinical outcome using... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To assess the impact of elevated early follicular progesterone (P) levels in gonadotropin-releasing hormone (GnRH) antagonist cycles on clinical outcome using prospective data in combination with a systematic review and meta-analysis.
DESIGN
Nested study within a multicenter randomized controlled trial and a systematic review and meta-analysis.
SETTING
Reproductive medicine center in an university hospital.
PATIENT(S)
158 in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) patients.
INTERVENTION(S)
Recombinant follicle-stimulating hormone (FSH) (150-225 IU) administered daily from cycle day 2 onward; GnRH antagonist treatment randomly started on cycle day 2 or 6; assignment into two groups according to P level on cycle day 2: normal or elevated (>4.77 nmol/L or >1.5 ng/mL, respectively).
MAIN OUTCOME MEASURE(S)
Ongoing pregnancy rate (OPR) per started cycle.
RESULT(S)
The incidence of elevated P was 13.3%. A non-statistically-significant difference in OPR was present between the normal and elevated P groups (27.0% vs. 19.0%). No differential impact of early or late GnRH antagonist initiation on the effect of elevated or normal P on OPR was observed. A systematic search of Medline and EMBASE from 1972-2013 was performed to identify studies analyzing elevated early P levels in GnRH antagonists. The meta-analysis (n=1,052) demonstrated that elevated P levels statistically significantly decreased the OPR with 15% (95% CI -23, -7 %). Heterogeneity across the studies, presumably based on varying protocols, may have modulated the effect of elevated P.
CONCLUSION(S)
From the present meta-analysis it appears that early elevated P levels are associated with a lower OPR in GnRH antagonists. The incidence of such a condition, however, is low.
CLINICAL TRIAL REGISTRATION NUMBER
NCT00866034.
Topics: Adult; Biomarkers; Female; Fertility Agents, Female; Fertilization in Vitro; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Infertility; Netherlands; Ovarian Follicle; Ovulation Induction; Pregnancy; Pregnancy Rate; Progesterone; Randomized Controlled Trials as Topic; Recombinant Proteins; Sperm Injections, Intracytoplasmic; Time Factors; Treatment Outcome; Up-Regulation
PubMed: 24929258
DOI: 10.1016/j.fertnstert.2014.05.002 -
Cells Apr 2023The enteric nervous system (ENS) is an intrinsic network of neuronal ganglia in the intestinal tube with about 100 million neurons located in the myenteric plexus and...
The enteric nervous system (ENS) is an intrinsic network of neuronal ganglia in the intestinal tube with about 100 million neurons located in the myenteric plexus and submucosal plexus. These neurons being affected in neurodegenerative diseases, such as Parkinson's disease, before pathological changes in the central nervous system (CNS) become detectable is currently a subject of discussion. Understanding how to protect these neurons is, therefore, particularly important. Since it has already been shown that the neurosteroid progesterone mediates neuroprotective effects in the CNS and PNS, it is now equally important to see whether progesterone has similar effects in the ENS. For this purpose, the RT-qPCR analyses of laser microdissected ENS neurons were performed, showing for the first time the expression of the different progesterone receptors (PR-A/B; mPRa, mPRb, PGRMC1) in rats at different developmental stages. This was also confirmed in ENS ganglia using immunofluorescence techniques and confocal laser scanning microscopy. To analyze the potential neuroprotective effects of progesterone in the ENS, we stressed dissociated ENS cells with rotenone to induce damage typical of Parkinson's disease. The potential neuroprotective effects of progesterone were then analyzed in this system. Treatment of cultured ENS neurons with progesterone reduced cell death by 45%, underscoring the tremendous neuroprotective potential of progesterone in the ENS. The additional administration of the PGRMC1 antagonist AG205 abolished the observed effect, indicating the crucial role of PGRMC1 with regard to the neuroprotective effect of progesterone.
Topics: Rats; Animals; Progesterone; Parkinson Disease; Neuroprotective Agents; Enteric Nervous System; Intestines
PubMed: 37190115
DOI: 10.3390/cells12081206 -
Reproductive Biology and Endocrinology... Feb 2009Implantation in humans involves cross talk between an active blastocyst and receptive endometrium. The role of the endometrial receptors in this complex embryo-maternal... (Comparative Study)
Comparative Study
BACKGROUND
Implantation in humans involves cross talk between an active blastocyst and receptive endometrium. The role of the endometrial receptors in this complex embryo-maternal interaction is still unclear. We tested gene and protein expression of endometrial receptors (Progesterone receptor (PR) and c-Met) and the effect of theses receptors in endometrial receptivity.
METHODS
Two endometrial cell lines were used: HEC-1A and RL95-2 considered as being of low and high receptivity, respectively. Western blot and RT-PCR analysis were utilized to study the receptor expression profile.The role of endometrial receptors in endometrial receptivity was studied by attachment and invasion assays of JAR spheroids (made of a trophoblast cell line) on endometrial cells. Different manipulations of inhibition and stimulation of the endometrial receptors were used including: inhibition by specific antibodies against the receptors, or antagonist of the receptors, as well as transfection with antisense for the endometrial receptors, stimulation by specific ligands for the receptors and transfection with the gene for endometrial receptors.
RESULTS
Different protein expression patterns of endometrial receptors were observed between the tested endometrial cell lines. The expression levels of PRA ratio to PRB, and the 50 kDa c-MET isoform were significantly lower in HEC-1A as compared with RL95-2. Attachment rates and growth of JAR spheroids into HEC-1A were significantly lower as compared with RL95-2. Stimulation of PR with progesterone altered attachment rates to HEC-1A. Inhibition of PR with RU-486 mildly increased attachment rate to HEC-1A whereas it slightly decreased attachment rate to RL95-2. c-Met inhibition decreased attachment rates only to HEC-1A cells that expressing high levels of Plexin-B1 (PB1). Immunoprecipitation studies revealed that c-Met and PB1 associate in complexes in the endometrial cell lines.
CONCLUSION
Differential endometrial receptor profiles are expressed during the receptivity period. The attachment and invasion processes are separately regulated. We suggest a biologically functional role for PRA in endometrial receptivity and in the attachment process. c-Met contribution is minor and related with creation of a complex with PB1.
Topics: Antisense Elements (Genetics); Cell Adhesion; Cell Line; Endometrium; Female; Humans; Mifepristone; Nerve Tissue Proteins; Progesterone; Proto-Oncogene Proteins c-met; Receptors, Cell Surface; Receptors, Progesterone; Spheroids, Cellular; Trophoblasts
PubMed: 19220894
DOI: 10.1186/1477-7827-7-14 -
Gynecological Endocrinology : the... 2016The aim of the presented study is to investigate the impact of progesterone change in the late follicular phase on the pregnancy rates of both agonist and antagonist...
OBJECTIVE
The aim of the presented study is to investigate the impact of progesterone change in the late follicular phase on the pregnancy rates of both agonist and antagonist protocols in normoresponders.
STUDY DESIGN
A total of 201 normoresponder patients, who underwent embryo transfer were consecutively selected. 118 patients were stimulated using a long luteal GnRH agonist protocol and 83 using a flexible antagonist protocol. The level of change in late follicular phase progesterone was calculated according to the progesterone levels on the hCG day and pre-hCG day (1 or 2 days prior to hCG day) measurement.
RESULTS
Clinical pregnancy rates were comparable between long luteal and antagonist group (35.6 and 41%, respectively). The incidence of progesterone elevation on the hCG day was 11% in long luteal and 18% in antagonist group (p = 0.16). In pregnant cycles, p levels both on the hCG day and pre-hCG day measurement were significantly higher in antagonist than agonist cycles (p = 0.029, p = 0.038, respectively). The change of p level was statistically significant in non-pregnant cycles both for the agonist (-0.17 ± 0.07; 95% CI: -0.29 to -0.37) and antagonist groups (-0.18 ± 0.07; 95%CI: -0.31 to -0.04).
CONCLUSIONS
Late follicular phase progesterone levels were stable during the cycles of pregnant patients irrespective of the protocols and were shown to be higher in pregnant patients in antagonist cycles when compared to agonist cycles.
Topics: Adult; Case-Control Studies; Embryo Transfer; Estradiol; Female; Follicle Stimulating Hormone; Follicular Phase; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Luteinizing Hormone; Ovulation Induction; Pregnancy; Pregnancy Rate; Progesterone; Sperm Injections, Intracytoplasmic
PubMed: 26654315
DOI: 10.3109/09513590.2015.1121226 -
BioMed Research International 2015Basal phenotype breast cancer is one of the most aggressive breast cancers that frequently metastasize to brain. The role of sex hormones and their receptors in...
Basal phenotype breast cancer is one of the most aggressive breast cancers that frequently metastasize to brain. The role of sex hormones and their receptors in development of this disease is largely unclear. We demonstrated that mPRα was expressed at a moderate level in a brain metastatic BPBC cell line MB231Br, which was derived from the parent mPRα undetectable MB231 cells. It functioned as an essential mediator for progesterone induced inhibitory effects on cell migration of MB231Br and, when coincubated with PP1, synergistically enhanced the progesterone's inhibitory effect on cell migration and invasion in vitro. Progesterone and PP1 cotreatment induced a cascade of molecular signaling events, such as dephosphorylation of FAK, downregulation of MMP9, VEGF, and KCNMA1 expressions. Our in vitro study demonstrated that mPRα was expressed and functioned as an essential mediator for progesterone induced inhibitory effects on cell migration and invasion in BPBC cells. This inhibitory effect was enhanced by PP1 via FAK dephosphorylation, MMP9, VEGF, and KCNMA1 downregulation mechanisms. Our study provides a new clue toward the development of novel promising agents and pathways for inhibiting nuclear hormonal receptor-negative and endocrine-resistant breast cancers.
Topics: Breast Neoplasms; Cell Line, Tumor; Cell Movement; Female; Humans; Neoplasm Invasiveness; Neoplasm Proteins; Progesterone; Pyrazoles; Pyrimidines; Signal Transduction; src-Family Kinases
PubMed: 26075237
DOI: 10.1155/2015/426429 -
Nature Reviews. Cancer Jun 2013Understanding the biology of the breast and how ovarian hormones impinge on it is key to rational new approaches in breast cancer prevention and therapy. Because of the... (Review)
Review
Understanding the biology of the breast and how ovarian hormones impinge on it is key to rational new approaches in breast cancer prevention and therapy. Because of the success of selective oestrogen receptor modulators (SERMs), such as tamoxifen, and aromatase inhibitors in breast cancer treatment, oestrogens have long received the most attention. Early progesterone receptor (PR) antagonists, however, were dismissed because of severe side effects, but awareness is now increasing that progesterone is an important hormone in breast cancer. Oestrogen receptor-α (ERα) signalling and PR signalling have distinct roles in normal mammary gland biology in mice; both ERα and PR delegate many of their biological functions to distinct paracrine mediators. If the findings in the mouse model translate to humans, new preventive and therapeutic perspectives might open up.
Topics: Animals; Breast Neoplasms; Cell Proliferation; Estrogens; Female; Humans; Mammary Glands, Human; Menstrual Cycle; Progesterone; Receptors, Progesterone; Signal Transduction
PubMed: 23702927
DOI: 10.1038/nrc3518 -
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 -
BioMed Research International 2017Leiomyomas, also known as uterine fibroids, are a common benign tumor in women of reproductive age. These lesions disrupt the function of the uterus causing menorrhagia... (Review)
Review
Leiomyomas, also known as uterine fibroids, are a common benign tumor in women of reproductive age. These lesions disrupt the function of the uterus causing menorrhagia and pelvic pressure as well as reproductive disorders. These women pose a true challenge for clinicians in the attempt of choosing the suitable treatment for each patient. Patient's age, interest in fertility preservation, and leiomyoma location and size are all factors to be taken into account when deciding upon the preferable therapeutic option. For the past few decades, surgical treatment was the only reliable long-term treatment available. A variety of surgical approaches have been developed over the years but these developments have come at the expense of other treatment options. The classical medical treatment includes gonadotropin-releasing hormone (GnRH) agonists and antagonists. These agents are well known for their limited clinical effect as well as their broad spectrum of side effects, inspiring a need for new pharmacological treatments. In recent years, promising results have been reported with the use of selective progesterone receptor modulators (SPRM). Long-term clinical trials have shown a reduction in bleeding and shrinkage of leiomyoma mass. These results instill hope for women suffering from symptomatic leiomyomas seeking an effective, long-term medical option for their condition.
Topics: Antineoplastic Agents; Female; Gonadotropin-Releasing Hormone; Humans; Leiomyoma; Progesterone; Receptors, Progesterone; Uterine Neoplasms
PubMed: 29312996
DOI: 10.1155/2017/4705164 -
Cell Proliferation Oct 2017Progesterone (P4) has the potential therapeutic effects for traumatic brain injury (TBI) whose recovery depended on the enhanced angiogenesis. Endothelial progenitor...
Progesterone-mediated angiogenic activity of endothelial progenitor cell and angiogenesis in traumatic brain injury rats were antagonized by progesterone receptor antagonist.
OBJECTIVES
Progesterone (P4) has the potential therapeutic effects for traumatic brain injury (TBI) whose recovery depended on the enhanced angiogenesis. Endothelial progenitor cell (EPC) plays an essential role in vascular biology. We previously demonstrated that P4 administration improved circulating EPC level and neurological recovery of rat with TBI. Here, we hypothesized that P4 augmented angiogenic potential of EPC and the angiogenesis-related neurorestoration after TBI through classical progesterone receptor (PR).
MATERIALS AND METHODS
EPC derived from rats were stimulated with graded concentrations (0, 10 , 10 , 5 × 10 , 10 , 10 mol/L) of P4 or 10 mol/L ulipristal acetate (UPA, a PR antagonist). Male rats were subjected to cortical impact injury and treated with (i) DMSO (dimethyl sulfoxide), (ii) P4 and (iii) P4 and UPA.
RESULTS
It showed that P4 improved the angiogenic potential of EPC, including tube formation, adhesion, migration and vascular endothelial growth factor secretion, in a dose-dependent fashion with the maximal effect achieved at 10 mol/L P4. High concentration (10 mol/L) of P4 impaired the angiogenic potential of EPC. Notably, 10 mol/L UPA antagonized the stimulatory effects of 10 mol/L P4. After administrating P4, a significant improvement of neurological function and the restoration of the leaked blood-brain barrier were observed as well as a reduction of the brain water content. Both vessel density and expression of occludin of vessels were increased. When UPA was administered with P4, the neural restoration and angiogenesis were all reversed. Western blot showed that 10 mol/L P4 increased the content of PRA and PRB of EPC, while 10 mol/L P4 reduced the content of both PR isoforms, but there was no change found in the TBI rats.
CONCLUSIONS
It may suggest that P4-mediated angiogenic activity of EPC and angiogenesis in TBI rats were antagonized by PR antagonist.
Topics: Angiogenesis Inducing Agents; Animals; Brain; Brain Injuries, Traumatic; Endothelial Progenitor Cells; Male; Neovascularization, Physiologic; Progesterone; Rats, Wistar; Receptors, Progesterone; Vascular Endothelial Growth Factor A
PubMed: 28752929
DOI: 10.1111/cpr.12362