-
Endocrinology Nov 2023Decidualization is a progesterone-dependent cellular differentiation process that is essential for establishing pregnancy. Robust activation of glycolysis and lactate...
Decidualization is a progesterone-dependent cellular differentiation process that is essential for establishing pregnancy. Robust activation of glycolysis and lactate synthesis during decidualization is remarkable, but their developmental functions remain largely unknown. Herein, we identify that endometrial lactate production plays a critical role in establishing local histone lactylation, a newly identified histone modification, and is important for ensuring normal decidualization. Enhanced endometrial glycolysis is the hallmark metabolic change and is tightly coupled with H4K12la during decidualization. Inhibition of histone lactylation impaired decidualization, in either physiological conception or in vivo and in vitro induced decidualization models. Mechanistic study based on CUT&Tag and ATAC-seq revealed that a transcriptional factor hypoxia-inducible factor 1 α (Hif1α) is the critical regulatory target of H4K12la, and in turn forms an H4K12la-Hif1α-glycolysis feedback loop to drive decidualization. Moreover, we demonstrate that the loop is directly activated by progesterone during decidualization. Our study not only advances the current knowledge of the role of lactate in regulating uterine function, but also establishes a novel functional link among the major endocrine factors, endometrial metabolic change, and epigenetic modification during endometrial remodeling. These findings present valuable clues to develop clinical intervention strategies to improve pregnancy outcomes following both natural conception and assisted reproduction.
Topics: Pregnancy; Female; Humans; Progesterone; Histones; Decidua; Feedback; Endometrium; Lactates; Glycolysis; Stromal Cells
PubMed: 37950883
DOI: 10.1210/endocr/bqad169 -
Clinical and Experimental Reproductive... Dec 2023Endometriosis is characterized by the implantation of endometrial cells outside the uterus. This hormone-dependent disease is highly prevalent among women of...
Endometriosis is characterized by the implantation of endometrial cells outside the uterus. This hormone-dependent disease is highly prevalent among women of reproductive age. Clinical symptoms of endometriosis include dysmenorrhea, pelvic pain, and infertility, which can negatively impact the overall quality of life of those affected. The medical treatment of endometriosis serves as an important therapeutic option, aimed at alleviating pain associated with the condition and suppressing the growth of endometriotic lesions. As such, it is employed as an adjuvant therapy following surgery or an empirical treatment after the clinical diagnosis of endometriosis. Dienogest, a fourth-generation progestin, has received approval for the treatment of endometriosis in many countries. A growing body of evidence has demonstrated its efficacy in managing endometriosis-associated pain, preventing symptoms, and reducing lesion recurrence. In this review, we examine the clinical efficacy, safety, and tolerability of dienogest in treating endometriosis. We also provide updated findings, drawing from clinical studies that focus on the long-term use of this medication in patients with endometriosis.
PubMed: 37995750
DOI: 10.5653/cerm.2023.06128 -
Vascular Pharmacology Oct 2023Vascular endothelial and smooth muscle cell dysfunction proceed the development of numerous vascular diseases, such as atherosclerosis. Both estrogen and progesterone... (Review)
Review
Vascular endothelial and smooth muscle cell dysfunction proceed the development of numerous vascular diseases, such as atherosclerosis. Both estrogen and progesterone receptors are present on vascular endothelial and smooth muscle cells, and therefore it has been postulated that these compounds may affect vascular function. It has been well-established that estrogen is a vasoprotective compound, however, the effects of progesterone on vascular function are not well understood. This narrative review summarizes the current research investigating the impact of both endogenous progesterone, and exogenous synthetic progestin on vascular endothelial and smooth muscle cell function and identifies discrepancies on their effects in vitro and in vivo. We speculate that an inverted-U dose response curve may exist between nitric oxide bioavailability and progesterone concentration, and that the androgenic properties of a progestin may influence vascular function. Future research is needed to discern the effects of both endogenous progesterone and exogenous progestin on vascular endothelial and smooth muscle cell function with consideration for the impacts of progesterone/progestin dose, and progestin type.
Topics: Humans; Progestins; Progesterone; Progesterone Congeners; Estrogens; Endothelial Cells; Atherosclerosis; Myocytes, Smooth Muscle
PubMed: 37591444
DOI: 10.1016/j.vph.2023.107209 -
Reproduction in Domestic Animals =... Sep 2023Methods to diagnose and monitor equine pregnancy continue to advance with improved instrumentation enabling the development of novel, non-invasive approaches to assess... (Review)
Review
Methods to diagnose and monitor equine pregnancy continue to advance with improved instrumentation enabling the development of novel, non-invasive approaches to assess fetal well-being and viability using ultrasound and endocrine testing. From early embryonic loss to placentitis, that is typically encountered later in gestation, fetal viability and development as well as placental function can be evaluated using two fundamentally different, structural and functional, approaches. Ultrasound provides structural information on embryonic and fetal growth using such parameters as combined thickness of the uterus and placenta (CTUP), visual assessment of fetal fluids, activity, heart rate and multiple biometrics involving the fetal head and eyes, limbs and joints among many others, depending on the stage of gestation. Endocrine profiles that include progesterone and 5α-dihydroprogesterone, other metabolites, androgens and estrogens can be evaluated simultaneously using liquid chromatography-tandem mass spectrometry (LC-MS/MS) providing more functional information on fetal and placental competence and development. Endocrine information can be used in making clinical decisions including the need for progestin supplementation or when it can cease, and even estimating gestational stage in mares that cannot be easily palpated or scanned, as with mini-breeds or rancorous animals most notably. When used together, monitoring gestation by ultrasound and hormonal analysis provides unusual insight into feto-placental well-being and the progress of pregnancy, helping to identify problems needing therapeutic intervention.
Topics: Pregnancy; Horses; Animals; Female; Placenta; Chromatography, Liquid; Tandem Mass Spectrometry; Progesterone; Fetal Development
PubMed: 37191550
DOI: 10.1111/rda.14392 -
Channels (Austin, Tex.) Dec 2023Sex hormones and the reproductive cycle (estrus in rodents and menstrual in humans) have a known impact on arterial function. In spite of this, sex hormones and the... (Review)
Review
Sex hormones and the reproductive cycle (estrus in rodents and menstrual in humans) have a known impact on arterial function. In spite of this, sex hormones and the estrus/menstrual cycle are often neglected experimental factors in vascular basic preclinical scientific research. Recent research by our own laboratory indicates that cyclical changes in serum concentrations of sex -hormones across the rat estrus cycle, primary estradiol, have significant consequences for the subcellular trafficking and function of K. Vascular potassium channels, including K, are essential components of vascular reactivity. Our study represents a small part of a growing field of literature aimed at determining the role of sex hormones in regulating arterial ion channel function. This review covers key findings describing the current understanding of sex hormone regulation of vascular potassium channels, with a focus on K channels. Further, we highlight areas of research where the estrus cycle should be considered in future studies to determine the consequences of physiological oscillations in concentrations of sex hormones on vascular potassium channel function.
Topics: Female; Humans; Rats; Animals; Progesterone; Potassium Channels; Gonadal Steroid Hormones; Estradiol; Menstrual Cycle
PubMed: 37243715
DOI: 10.1080/19336950.2023.2217637 -
IScience Aug 2023Progestin-primed ovarian stimulation (PPOS) is a new ovulation stimulation protocol, and its role in ovulation and regulatory mechanism is unclear. The clinical PPOS...
Progestin-primed ovarian stimulation (PPOS) is a new ovulation stimulation protocol, and its role in ovulation and regulatory mechanism is unclear. The clinical PPOS protocol was simulated in mice. The ovulated oocytes, estradiol, progesterone, and luteinizing hormone (LH) levels were analyzed at different hours after trigger. mRNA extraction and real-time PCR, hematoxylin and eosin staining, and immunofluorescence of ovaries were used to explore the involved signaling pathways. The PPOS group had a delayed ovulation at 12.5 h after trigger. Its suppressed LH level reduced the expression of luteinizing hormone/choriogonadotropin receptor (LHCGR) on the preovulatory follicles before trigger and significantly decreased the following progesterone synthesis, blood progesterone level, and progesterone receptor (PGR) expression within 4-6 h after trigger. Furthermore, the important ovulatory genes regulated by PGR including ADAMTS-1, VEGF-A, and EDN2 were downregulated, ultimately delaying the ovulation. PPOS suppresses the LH level before trigger and decreases the synthesis of progesterone after trigger, thus delaying the ovulation by downregulating the LHCGR-PGR pathway.
PubMed: 37520702
DOI: 10.1016/j.isci.2023.107357 -
Frontiers in Global Women's Health 2024Hormone replacement therapy (HRT), also known as menopausal hormone therapy (MHT), was looked upon as a fountain of youth that kept women young and reduced...
Hormone replacement therapy (HRT), also known as menopausal hormone therapy (MHT), was looked upon as a fountain of youth that kept women young and reduced cardiovascular disease. This led to a large-scale study called the Women's Health Initiative (WHI) that was conducted to show the cardiovascular benefits of HRT. This study was suspended early because of adverse side effects. The USFDA responded by slapping a "black box" warning on all HRT products. USFDA-approved bioidentical HRT formulations are safe and effective. We propose that these formulations have the "black box" warning removed so that doctors feel more confident in prescribing these products for symptoms of menopause and chronic conditions such as cardiovascular health. We propose eliminating the sale of products containing medroxyprogesterone acetate (MPA) because of the increased risk of heart attacks and breast cancers associated with this medication.
PubMed: 38832110
DOI: 10.3389/fgwh.2024.1397123 -
Clinical Obstetrics and Gynecology Dec 2023Twins represent 3.2% of all live births. However, they account for 20% of all preterm deliveries, 60% delivering <37 weeks, 10.7% <32 weeks, and 5 times higher risk of...
Twins represent 3.2% of all live births. However, they account for 20% of all preterm deliveries, 60% delivering <37 weeks, 10.7% <32 weeks, and 5 times higher risk of infant death. Risk factors for preterm birth (PTB) include the history of preterm delivery, monochorionic twins, short cervical length, and cervical surgery. Transvaginal cervical length <24 weeks is the best tool to predict PTB. Only vaginal progesterone in women with transvaginal cervical length <25 mm and physical exam indicated cerclage in women with cervical dilation >1 cm have shown a significant decrease in PTB and improvement in neonatal outcomes.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Cerclage, Cervical; Cervix Uteri; Pregnancy, Twin; Premature Birth; Progesterone; Risk Factors
PubMed: 37910049
DOI: 10.1097/GRF.0000000000000822 -
Medical Oncology (Northwood, London,... May 2024Despite decades of basic and clinical research and trials of promising new therapies, cancer remains a major cause of morbidity and mortality due to the emergence of... (Review)
Review
Despite decades of basic and clinical research and trials of promising new therapies, cancer remains a major cause of morbidity and mortality due to the emergence of drug resistance to anticancer drugs. These resistance events have a very well-understood underlying mechanism, and their therapeutic relevance has long been recognized. Thus, drug resistance continues to be a major obstacle to providing cancer patients with the intended "cure". PAQR4 (Progestin and AdipoQ Receptor Family Member 4) gene is a recently identified novel protein-coding gene associated with various human cancers and acts through different signaling pathways. PAQR4 has a significant influence on multiple proteins that may regulate various gene expressions and may develop chemoresistance. This review discusses the roles of PAQR4 in tumor immunity, carcinogenesis, and chemoresistance. This paper is the first review, discussing PAQR4 in the pathogenesis of cancer. The review further explores the PAQR4 as a potential target in various malignancies.
Topics: Humans; Neoplasms; Drug Resistance, Neoplasm; Oncogenes; Molecular Targeted Therapy; Antineoplastic Agents; Membrane Proteins; Animals; Signal Transduction
PubMed: 38767705
DOI: 10.1007/s12032-024-02382-w -
British Journal of Cancer Mar 2024The enriched proteins within in vitro fertilisation (IVF)-generated human embryonic microenvironment could reverse progestin resistance in endometrial cancer (EC).
BACKGROUND
The enriched proteins within in vitro fertilisation (IVF)-generated human embryonic microenvironment could reverse progestin resistance in endometrial cancer (EC).
METHODS
The expression of thymic stromal lymphopoietin (TSLP) in EC was evaluated by immunoblot and IHC analysis. Transcriptome sequencing screened out the downstream pathway regulated by TSLP. The role of TSLP, androgen receptor (AR) and KANK1 in regulating the sensitivity of EC to progestin was verified through a series of in vitro and in vivo experiments.
RESULTS
TSLP facilitates the formation of a BMP4/BMP7 heterodimer, resulting in activation of Smad5, augmenting AR signalling. AR in turn sensitises EC cells to progestin via KANK1. Downregulation of TSLP, loss of AR and KANK1 in EC patients are associated with tumour malignant progress. Moreover, exogenous TSLP could rescue the anti-tumour effect of progestin on mouse in vivo xenograft tumour.
CONCLUSIONS
Our findings suggest that TSLP enhances the sensitivity of EC to progestin through the BMP4/Smad5/AR/KANK1 axis, and provide a link between embryo development and cancer progress, paving the way for the establishment of novel strategy overcoming progestin resistance using embryo original factors.
Topics: Animals; Female; Humans; Mice; Adaptor Proteins, Signal Transducing; Cytokines; Cytoskeletal Proteins; Endometrial Neoplasms; Progestins; Receptors, Androgen; Signal Transduction; Thymic Stromal Lymphopoietin; Tumor Microenvironment
PubMed: 38172534
DOI: 10.1038/s41416-023-02545-y