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Molecular Pain 2022Orofacial pain disorders are predominately experienced by women. Progesterone, a major ovarian hormone, is neuroprotective and antinociceptive. We recently reported that...
Sigma-1 receptors and progesterone metabolizing enzymes in nociceptive sensory neurons of the female rat trigeminal ganglia: A neural substrate for the antinociceptive actions of progesterone.
Orofacial pain disorders are predominately experienced by women. Progesterone, a major ovarian hormone, is neuroprotective and antinociceptive. We recently reported that progesterone attenuates estrogen-exacerbated orofacial pain behaviors, yet it remains unclear what anatomical substrate underlies progesterone's activity in the trigeminal system. Progesterone has been reported to exert protective effects through actions at intracellular progesterone receptors (iPR), membrane-progesterone receptors (mPR), or sigma 1 receptors (Sig-1R). Of these, the iPR and Sig-1R have been reported to have a role in pain. Progesterone can also have antinociceptive effects through its metabolite, allopregnanolone. Two enzymes, 5α-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD), are required for the metabolism of progesterone to allopregnanolone. Both progesterone and allopregnanolone rapidly attenuate pain sensitivity, implicating action of either progesterone at Sig-1R and/or conversion to allopregnanolone which targets GABA receptors. In the present study, we investigated whether Sig-1 Rs are expressed in nociceptors within the trigeminal ganglia of cycling female rats and whether the two enzymes required for progesterone metabolism to allopregnanolone, 5α-reductase and 3α-hydroxysteroid dehydrogenase, are also present. Adult female rats from each stage of the estrous cycle were rapidly decapitated and the trigeminal ganglia collected. Trigeminal ganglia were processed by either fluorescent immunochemistry or western blotting to for visualization and quantification of Sig-1R, 5α-reductase, and 3α-hydroxysteroid dehydrogenase. Here we report that Sig-1Rs and both enzymes involved in progesterone metabolism are highly expressed in a variety of nociceptive sensory neuron populations in the female rat trigeminal ganglia at similar levels across the four stages of the estrous cycle. These data indicate that trigeminal sensory neurons are an anatomical substrate for the reported antinociceptive activity of progesterone via Sig-1R and/or conversion to allopregnanolone.
Topics: Analgesics; Animals; Female; Humans; Nociception; Nociceptors; Progesterone; Rats; Receptors, sigma; Sensory Receptor Cells; Trigeminal Ganglion; Sigma-1 Receptor
PubMed: 35040378
DOI: 10.1177/17448069211069255 -
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 -
Oncotarget Jul 2023A practice-changing, randomized, controlled clinical study established that preoperative hydroxyprogesterone administration improves disease-free and overall survival in... (Randomized Controlled Trial)
Randomized Controlled Trial
A practice-changing, randomized, controlled clinical study established that preoperative hydroxyprogesterone administration improves disease-free and overall survival in patients with node-positive breast cancer. This research perspective summarizes evidences from our studies that preoperative hydroxyprogesterone administration may improve disease-free and overall survival in patients with node-positive breast cancer by modulating cellular stress response and negative regulation of inflammation. Non-coding RNAs, particularly , play a regulatory role in this process, along with the upregulation of the kinase gene and activation of the axis. Progesterone-induced modification of the progesterone receptor and estrogen receptor genomic binding pattern is also involved in orchestrating estrogen signaling in breast cancer, preventing cell migration and invasion, and improving patient outcomes. We also highlight the role of progesterone in endocrine therapy resistance, which could lead to novel treatment options for patients with hormone receptor-positive breast cancer and for those who develop resistance to traditional endocrine therapies.
Topics: Humans; Female; Breast Neoplasms; Progesterone; Receptors, Progesterone; Signal Transduction; Hydroxyprogesterones
PubMed: 37395734
DOI: 10.18632/oncotarget.28455 -
Biomedicine & Pharmacotherapy =... Mar 2024Progesterone (P4) is a crucial reproductive hormone that acts as a precursor for all other endogenous steroids. P4 modulates transcriptional activity during reproduction...
Progesterone (P4) is a crucial reproductive hormone that acts as a precursor for all other endogenous steroids. P4 modulates transcriptional activity during reproduction by binding to progesterone receptors (PR). However, the physiological role of P4 in the liver is understudied. P4-mediated lipid metabolism in the liver was investigated in this study, as P4 facilitates insulin resistance and influences energy metabolism. While exogenous lipids are mainly obtained from food, the liver synthesizes endogenous triglycerides and cholesterol from a carbohydrate diet. Hepatic de novo lipogenesis (DNL) is primarily determined by acetyl-CoA and its biosynthetic pathways, which involve fatty acid and cholesterol synthesis. While P4 increased the hepatic levels of sterol regulatory element-binding protein 1 C (SREBP-1 C), peroxisome proliferator-activated receptor-gamma (PPARγ), acetyl-CoA carboxylase (ACC), and CD36, co-treatment with the P4 receptor antagonist RU486 blocked these proteins and P4-mediated lipogenesis. RNA sequencing was used to assess the role of P4 in lipogenic events, such as fatty liver and fatty acid metabolism, lipoprotein signaling, and cholesterol metabolism. P4 induced hepatic DNL and lipid anabolism were confirmed in the liver of ovarian resection mice fed a high-fat diet or in pregnant mice. P4 increased lipogenesis directly in mice exposed to P4 and indirectly in fetuses exposed to maternal P4. The lipid balance between lipogenesis and lipolysis determines fat build-up and is linked to lipid metabolism dysfunction, which involves the breakdown and storage of fats for energy and the synthesis of structural and functional lipids. Therefore, P4 may impact the lipid metabolism and reproductive development during gestation.
Topics: Female; Pregnancy; Animals; Mice; Lipogenesis; Progesterone; Liver; Cholesterol; Fatty Acids; Lipids
PubMed: 38364736
DOI: 10.1016/j.biopha.2024.116281 -
Reproductive Biomedicine Online Nov 2013Embryo attachment and implantation is critical to successful reproduction of all eutherian mammals, including humans; a better understanding of these processes could... (Review)
Review
Embryo attachment and implantation is critical to successful reproduction of all eutherian mammals, including humans; a better understanding of these processes could lead to improved infertility treatments and novel contraceptive methods. Experience with assisted reproduction, especially oocyte donation cycles, has established that despite the diverse set of hormones produced by the ovary in a cycle-dependent fashion, the sequential actions of only two of them, oestrogen and progesterone, are sufficient to prepare a highly receptive endometrium in humans. Further investigation on the endometrial actions of these two hormones is currently providing significant insight into the implantation process in women, strongly suggesting that an abnormal response to progesterone underlies infertility in some patients.
Topics: Embryo Implantation; Endometriosis; Endometrium; Estrogens; Female; Humans; Infertility, Female; Models, Biological; Progesterone
PubMed: 23933037
DOI: 10.1016/j.rbmo.2013.06.010 -
Frontiers in Endocrinology 2024Historically, progesterone has been studied significantly within the context of reproductive biology. However, there is now an abundance of evidence for its role in... (Review)
Review
Historically, progesterone has been studied significantly within the context of reproductive biology. However, there is now an abundance of evidence for its role in regions of the central nervous system (CNS) associated with such non-reproductive functions that include cognition and affect. Here, we describe mechanisms of progesterone action that support its brain-protective effects, and focus particularly on the role of neurotrophins (such as brain-derived neurotrophic factor, BDNF), the receptors that are critical for their regulation, and the role of certain microRNA in influencing the brain-protective effects of progesterone. In addition, we describe evidence to support the particular importance of glia in mediating the neuroprotective effects of progesterone. Through this review of these mechanisms and our own prior published work, we offer insight into why the effects of a progestin on brain protection may be dependent on the type of progestin (e.g., progesterone versus the synthetic, medroxyprogesterone acetate) used, and age, and as such, we offer insight into the future clinical implication of progesterone treatment for such disorders that include Alzheimer's disease, stroke, and traumatic brain injury.
Topics: Progesterone; Progestins; Neuroprotection; Receptors, Progesterone; Brain
PubMed: 38469139
DOI: 10.3389/fendo.2024.1286066 -
Reproduction, Nutrition, Development 2006The relationship between nutrition and reproduction in sheep has been the subject of research in several international groups. This review will particularly focus on the... (Review)
Review
The relationship between nutrition and reproduction in sheep has been the subject of research in several international groups. This review will particularly focus on the effects of undernutrition on the potential causes of reproductive failure including abnormalities of the ovum or the embryo, luteal inadequacy and failure of the supply of progesterone to the uterus, or the mechanisms involved in maternal recognition of pregnancy. The level of nutrition and peripheral progesterone concentrations are inversely related, and increased rates of embryo loss, associated with higher progesterone concentrations in ewes with low levels of nutrition have been reported. Undernutrition may act through changes in the distribution of progesterone in the endometrium. Thus, lower endometrial levels on day 5 of the cycle in ewes fed half of their maintenance requirements have been observed, providing a link between the known role of progesterone in embryo survival by the modulation of uterine function and the higher embryo losses found in undernourished ewes. The evidence of an effect of maternal nutrition on IFNtau secretion from the conceptus and of PGF2alpha production from the uterus is presented. Moreover, undernutrition provokes a reduction in the sensitivity of the endometrium to progesterone that may affect embryo survival. Finally, a state of undernutrition induces changes in the endometrial sensitivity to steroid hormones at early stages of pregnancy that could adversely alter uterine environment to the detriment of embryo survival.
Topics: Animal Nutritional Physiological Phenomena; Animals; Female; Malnutrition; Pregnancy; Pregnancy Rate; Progesterone; Sheep; Sheep Diseases
PubMed: 16824446
DOI: 10.1051/rnd:2006018 -
Acta Medica Indonesiana Jul 2013Osteoarthritis (OA) is a condition found worldwide, is strongly associated with aging and is the most common type of arthritis. Because of its effect on ambulation and... (Review)
Review
Osteoarthritis (OA) is a condition found worldwide, is strongly associated with aging and is the most common type of arthritis. Because of its effect on ambulation and mobility, it has significant functional impact and is associated with considerable medical costs. Because of the aging of the society and the obesity epidemic, the burden of OA can be expected to increase over the next 20 years. Although OA has been regarded primarily as a non-inflammatory arthropathy, symptoms of local inflammation and synovitis are present in many patients and have been observed and even in the absence of classical inflammation, which is characterized by infiltration of neutrophils and macrophages into joint tissue, elevated levels of inflammatory cytokines have been measured in OA synovial fluid. Although the cartilage lesion is present at sites remote from synovium, the fibroblast- and macrophage-like synovial cells, as well as the chondrocytes itself, are potential sources of cytokines that could induce chondrocytes to synthesize and secrete cartilage-degrading proteases, cytokines, and other inflammatory mediators. The bio-identical progesterone shows its anti-inflammatory effects in OA by suppressing gene expressions in the production of inflammatory cytokines through the negative interaction between nuclear transcription factor and the progesterone receptor and/or the progesterone-induced increase of nuclear transcription factor inhibition in the nucleus. The bio-identical progesterone may indirectly regulate bone remodeling and may also play a role in the development and maintenance of cartilage. This review will discuss about transdermal bio-identical progesterone cream as suggested hormonal treatment of OA, based on its pathogenic process.
Topics: Administration, Cutaneous; Hormones; Humans; Inflammation; Osteoarthritis; Progesterone
PubMed: 24045394
DOI: No ID Found -
The Cochrane Database of Systematic... Oct 2006In the past, progesterone has been advocated for prevention of pre-eclampsia and its complications. Although progestogens are not used for this purpose in current... (Review)
Review
BACKGROUND
In the past, progesterone has been advocated for prevention of pre-eclampsia and its complications. Although progestogens are not used for this purpose in current clinical practice, it remains relevant to assess the evidence on their possible benefits and harms.
OBJECTIVES
To assess the effects of progesterone during pregnancy on the risk of developing pre-eclampsia and its complications.
SEARCH STRATEGY
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, Issue 2), and EMBASE (1974 to August 2005).
SELECTION CRITERIA
Randomised trials evaluating progesterone or any other progestogen during pregnancy for prevention of pre-eclampsia and its complications were included.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for inclusion and extracted data.
MAIN RESULTS
Two trials of uncertain quality were included (296 women). These trials compared progesterone injections with no progesterone. There was insufficient evidence to demonstrate any clear differences between the two groups on the risk of pre-eclampsia (one trial, 128 women; relative risk (RR) 0.21, 95% confidence interval (CI) 0.03 to 1.77), death of the baby (two trials, 296 women; RR 0.72, 95% CI 0.21 to 2.51), preterm birth (one trial, 168 women; RR 1.10, 95% CI 0.33 to 3.66), small-for-gestational-age babies (one trial, 168 women; RR 0.83, 95% CI 0.19 to 3.57) or major congenital defects (one trial, 168 women; RR 1.65, 95% CI 0.28 to 9.62). There were no reported cases of masculinisation of female babies (one trial, 128 women). Long-term follow up for the children has been reported in one trial, but the data are excluded from the review as 54% were lost to follow up at one year and 80% at 16 years.
AUTHORS' CONCLUSIONS
There is insufficient evidence for reliable conclusions about the effects of progesterone for preventing pre-eclampsia and its complications. Therefore, progesterone should not be used for this purpose in clinical practice at present. Unless new and plausible hypotheses emerge for the role of progesterone in development of pre-eclampsia, further trials of progesterone are unlikely to be a priority.
Topics: Female; Humans; Obstetric Labor, Premature; Pre-Eclampsia; Pregnancy; Progesterone
PubMed: 17054277
DOI: 10.1002/14651858.CD006175 -
Medical Science Monitor : International... Nov 2022BACKGROUND Previous studies have confirmed that progesterone has a protective effect on traumatic brain injury (TBI). In this paper, network pharmacology and molecular...
BACKGROUND Previous studies have confirmed that progesterone has a protective effect on traumatic brain injury (TBI). In this paper, network pharmacology and molecular docking technology were used to further explore the potential mechanism of progesterone in the treatment of TBI. MATERIAL AND METHODS Based on network pharmacology, potential targets of progesterone for TBI were obtained. The network diagram of interactions between target proteins was established to screen the key targets of progesterone for TBI. The DAVID database was used to analyze its biological function and enrichment pathway, and to explore and determine the biological pathway of progesterone in treating TBI. Molecular docking technology was used to simulate the interaction between progesterone and key target proteins. RESULTS Progesterone can treat TBI by anti-inflammatory action, repairing damaged cell membranes, stabilizing the structure of the blood-brain barrier, alleviating brain edema, reducing neuronal apoptosis, and improving neurological function. The molecular mechanism involves the PI3K/Akt signaling pathway, MAPK signaling pathway, and Ras signaling pathway. CONCLUSIONS Progesterone is a potential clinical treatment for TBI. Exploring the potential targets and pathways of TBI therapy through network pharmacology can provide a direction for subsequent research.
Topics: Humans; Phosphatidylinositol 3-Kinases; Progesterone; Molecular Docking Simulation; Network Pharmacology; Brain Injuries, Traumatic; Drugs, Chinese Herbal; Technology
PubMed: 36336891
DOI: 10.12659/MSM.937564