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American Journal of Reproductive... Mar 2020Injectable contraceptive use may impact immune cell responsiveness and susceptibility to infection. We measured responsiveness of T-cells from women before and after...
PROBLEM
Injectable contraceptive use may impact immune cell responsiveness and susceptibility to infection. We measured responsiveness of T-cells from women before and after initiating depot medroxyprogesterone acetate (DMPA) or norethisterone enanthate (Net-En).
METHOD OF STUDY
Peripheral blood mononuclear cells collected from women aged 18-34 years prior to, at steady state, and nadir concentrations after initiating DMPA (n = 30) or Net-En (n = 36) and from women initiating copper intrauterine device (CU-IUD; n = 32) were stimulated with phorbol myristate acetate and analyzed using flow cytometry. We evaluated percentage change in T-cells expressing programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte associated protein-4 (CTLA-4).
RESULTS
Compared to baseline, there were decreased numbers of CD4+CTLA4+ (P < .001) and CD8+CTLA4+ (P < .01) T-cells following ex vivo stimulation challenge at steady state DMPA concentrations and no differences at nadir concentrations (P = .781 and P = .463, respectively). In Net-En users, no differences in CD4+CTLA4+ T-cells at steady state (P = .087) and nadir concentrations (P = .217) were observed. DMPA users had fewer CD4+PD-1+ (P < .001) and CD8+PD-1+ (P < .001) T-cells at nadir concentrations. Number of CD4+PD-1+ and CD8+PD-1+ T-cells decreased at steady state concentration (P = .002 and P = .001, respectively) and at nadir concentrations after Net-En initiation (P < .001 and P < .001). In CU-IUD users, there were no changes in number of CD4+CTLA4+ (P = .426) and CD8+CTLA4+ (P = .169) and no changes in CD4+PD-1+ (P = .083) and CD8+PD-1+ (P = .936) compared to baseline.
CONCLUSION
Activation of T-cells in response to ex vivo stimulation is suppressed at steady state DMPA concentration and resolves at nadir concentration, suggesting DMPA immunosuppressive effects may be transient.
Topics: Adolescent; Adult; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; CTLA-4 Antigen; Cells, Cultured; Contraceptive Agents, Female; Female; Humans; Immunophenotyping; Lymphocyte Activation; Medroxyprogesterone Acetate; Norethindrone; Programmed Cell Death 1 Receptor; Young Adult
PubMed: 31729087
DOI: 10.1111/aji.13210 -
Pharmacological Research Feb 2020Endometriosis is a common gynecological disorder, which is treated surgically and/ or pharmacologically with an unmet clinical need for new therapeutics. A completed... (Review)
Review
Endometriosis is a common gynecological disorder, which is treated surgically and/ or pharmacologically with an unmet clinical need for new therapeutics. A completed phase I trial and a recent phase II trial that investigated the steroidal aldo-keto reductase 1C3 (AKR1C3) inhibitor BAY1128688 in endometriosis patients prompted this critical assessment on the role of AKR1C3 in endometriosis. This review includes an introduction to endometriosis with emphasis on the roles of prostaglandins and progesterone in its pathophysiology. This is followed by an overview of the major enzymatic activities and physiological functions of AKR1C3 and of the data published to date on the expression of AKR1C3 in endometriosis at the mRNA and protein levels. The review concludes with the rationale for using AKR1C3 inhibitors, a discussion of the effects of AKR1C3 inhibition on the pathophysiology of endometriosis and a brief overview of other drugs under clinical investigation for this indication.
Topics: Aldo-Keto Reductase Family 1 Member C3; Animals; Endometriosis; Endometrium; Female; Humans
PubMed: 31546014
DOI: 10.1016/j.phrs.2019.104446 -
Przeglad Menopauzalny = Menopause Review Sep 2022Two important studies evaluating the safety profile of oral estrogen-progestogen hormonal therapies conducted in standard clinical practice with respect to the venous... (Review)
Review
Two important studies evaluating the safety profile of oral estrogen-progestogen hormonal therapies conducted in standard clinical practice with respect to the venous system were recently published. A large prospective controlled cohort study (PRO-E2) based on the non-inferiority design has shown that the relative risk of developing venous thrombosis (VTE) in women using combined oral hormonal contraceptives (COHC) containing 17β-estradiol (1.5 mg) and nomegestrol acetate (2.5 mg) (E2/NOMAC) was not statistically different from that in users of COHC containing ethinylestradiol and levonorgestrel (EE/LNG). The aim of the recently presented study was to compare the risk of VTE in patients treated with a product for oral continuous combined menopausal hormone therapy containing 1 mg of 17ß-estradiol and 100 mg of micronized progesterone (1 mgE2/100 mgP4) with patients taking conjugated equine estrogens and medroxyprogesterone acetate (CEE/MPA). The study was based on an analysis of records retrieved from a US health insurance database, and was therefore concerned the real-life clinical practice. The hazard ratio of VTE when comparing 1 mgE2/100 mgP4 with CEE/MPA was 0.70 (95% CI: 0.53-0.92). The difference was found to be statistically significant ( < 0.05). The rewieved studies provide further evidence that the use of hormones bioidentical with endogenous steroids in oral contraception and menopausal hormone therapy creates an opportunity to combine high efficacy with a favorable safety profile.
PubMed: 36254131
DOI: 10.5114/pm.2022.119861 -
Monaldi Archives For Chest Disease =... Sep 2022Thoracic endometriosis is very rare. Usually, the thorax is the most frequent affected site outside the pelvis. Common symptoms include chest pain, dyspnea, and...
Thoracic endometriosis is very rare. Usually, the thorax is the most frequent affected site outside the pelvis. Common symptoms include chest pain, dyspnea, and hemoptysis. Common manifestations include pneumothorax, hemothorax, and pulmonary or pleural nodules. In addition, symptoms and manifestations can be "catamenial" happening a few days after menstruation onset. This disease can be debilitating, causing a significant impact on the quality of life of young women. We present a case of a young female who was referred to our hospital with recurrent right-sided pleural effusions and pneumothoraces. Pleural fluid drainage was consistent with hemothorax. Transvaginal ultrasound showed mild intraperitoneal fluid in the Cul-de-Sac. Due to concerns for thoracic endometriosis, video-assisted thoracoscopic surgery was performed confirming the diagnosis by pathology. Therapeutic pleurectomy with diaphragmatic repair and pleurodesis was performed. The patient was started on medroxyprogesterone acetate injections two weeks after with great clinical response.
Topics: Female; Humans; Endometriosis; Hemothorax; Hemopneumothorax; Quality of Life; Pneumothorax; Thoracic Surgery, Video-Assisted
PubMed: 36172717
DOI: 10.4081/monaldi.2022.2401 -
Medicina 2021The choice of a contraceptive method considered highly effective in epileptic women of childbearing age is important, since it requires taking into account the...
The choice of a contraceptive method considered highly effective in epileptic women of childbearing age is important, since it requires taking into account the eligibility criteria and the possible pharmacological interactions between certain types of anti-seizure drugs (mainly enzyme inducers drugs of the hepatic system P450 such as: carbamazepine, phenytoin, phenobarbital, oxacarbamazepine, eslicarbazepine, rufinamide, lacosamide and topiramate in high doses) and certain contraceptive methods (oral contraceptives combined or only with progesterone and subdermal progesterone implants), which may accelerate the metabolism of the latter with the consequent risk of failure or vice versa, reduction of plasma concentration (such as lamotrigine) predisposing to seizures, risk of unwanted pregnancies, abortions, teratogenicity due to valproato, maternal- fetal complications and difficulty in the management of epileptic activity during pregnancy. In case of prescribing both medications, the combined use with a barrier method should be considered or the use of a depot injection of medroxyprogesterone acetate or intrauterine device as contraception should be considered. Family planning counseling at the first visit has been shown to influence the choice of the contraceptive method and the early initiation of folic acid in the search for fertility. In conclusion, the different therapeutic options should be analyzed together with the epileptic patients in order to achieve and optimize the best goal for each one.
Topics: Anticonvulsants; Contraception; Epilepsy; Female; Humans; Pregnancy; Seizures
PubMed: 33611246
DOI: No ID Found -
Cells Mar 2022Cachexia may be caused by congestive heart failure, and it is then called cardiac cachexia, which leads to increased morbidity and mortality. Cardiac cachexia also... (Review)
Review
Cachexia may be caused by congestive heart failure, and it is then called cardiac cachexia, which leads to increased morbidity and mortality. Cardiac cachexia also worsens skeletal muscle degradation. Cardiac cachexia is the loss of edema-free muscle mass with or without affecting fat tissue. It is mainly caused by a loss of balance between protein synthesis and degradation, or it may result from intestinal malabsorption. The loss of balance in protein synthesis and degradation may be the consequence of altered endocrine mediators such as insulin, insulin-like growth factor 1, leptin, ghrelin, melanocortin, growth hormone and neuropeptide Y. In contrast to many other health problems, fat accumulation in the heart is protective in this condition. Fat in the heart can be divided into epicardial, myocardial and cardiac steatosis. In this review, we describe and discuss these topics, pointing out the interconnection between heart failure and cardiac cachexia and the protective role of cardiac obesity. We also set the basis for possible screening methods that may allow for a timely diagnosis of cardiac cachexia, since there is still no cure for this condition. Several therapeutic procedures are discussed including exercise, nutritional proposals, myostatin antibodies, ghrelin, anabolic steroids, anti-inflammatory substances, beta-adrenergic agonists, medroxyprogesterone acetate, megestrol acetate, cannabinoids, statins, thalidomide, proteasome inhibitors and pentoxifylline. However, to this date, there is no cure for cachexia.
Topics: Cachexia; Ghrelin; Heart; Heart Failure; Humans; Obesity
PubMed: 35326490
DOI: 10.3390/cells11061039 -
Journal For Immunotherapy of Cancer Jun 2023Progress in breast cancer (BC) research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best studied...
BACKGROUND
Progress in breast cancer (BC) research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best studied mouse strain, C57BL/6, is also the only one for which multiple genetic variants are available to facilitate the exploration of the cancer-immunity dialog. Driven by the fact that no hormone receptor-positive (HR) C57BL/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines.
METHODS
BC was induced in female C57BL/6 mice using a synthetic progesterone analog (medroxyprogesterone acetate, MPA) combined with a DNA damaging agent (7,12-dimethylbenz[a]anthracene, DMBA). Cell lines were established from these tumors and selected for dual (estrogen+progesterone) receptor positivity, as well as transplantability into C57BL/6 immunocompetent females.
RESULTS
One cell line, which we called B6BC, fulfilled these criteria and allowed for the establishment of invasive estrogen receptor-positive (ER) tumors with features of epithelial to mesenchymal transition that were abundantly infiltrated by myeloid immune populations but scarcely by T lymphocytes, as determined by single-nucleus RNA sequencing and high-dimensional leukocyte profiling. Such tumors failed to respond to programmed cell death-1 (PD-1) blockade, but reduced their growth on treatment with ER antagonists, as well as with anthracycline-based chemotherapy, which was not influenced by T-cell depletion. Moreover, B6BC-derived tumors reduced their growth on CD11b blockade, indicating tumor sustainment by myeloid cells. The immune environment and treatment responses recapitulated by B6BC-derived tumors diverged from those of ER TS/A cell-derived tumors in BALB/C mice, and of ER E0771 cell-derived and MPA/DMBA-induced tumors in C57BL/6 mice.
CONCLUSIONS
B6BC is the first transplantable HR BC cell line derived from C57BL/6 mice and B6BC-derived tumors recapitulate the complex tumor microenvironment of locally advanced HR BC naturally resistant to PD-1 immunotherapy.
Topics: Mice; Female; Animals; Progesterone; Epithelial-Mesenchymal Transition; Mice, Inbred BALB C; Mice, Inbred C57BL; Cell Line, Tumor; Carcinoma; Tumor Microenvironment
PubMed: 37344100
DOI: 10.1136/jitc-2023-007117 -
Research and Practice in Thrombosis and... Jul 2021Abnormal or excessive menstrual bleeding affects one-third of reproductive-aged women. This number increases to 70% among women on direct oral anticoagulants (DOACs).... (Review)
Review
Abnormal or excessive menstrual bleeding affects one-third of reproductive-aged women. This number increases to 70% among women on direct oral anticoagulants (DOACs). While there is some variation in frequency of heavy menstrual bleeding (HMB) with different DOAC options, all menstruating individuals should receive counseling about the risk of HMB at the time of DOAC initiation. Management options include progestin-only therapies such as the levonorgestrel intrauterine system and etonogestrel subdermal implant or the progestin-only pill. Combined hormonal contraceptives and depot medroxyprogesterone acetate are associated with increased rates of thrombosis in nonanticoagulated women but may be continued, or even initiated, so long as therapeutic anticoagulation is ongoing. Procedural therapies, such as endometrial ablation, uterine artery embolization, or hysterectomy, are considerations for women who have completed childbearing and for whom more conservative measures are objectionable or ineffective. Given the high rates of HMB in women on DOACs, management strategies should be discussed even before heavy bleeding is diagnosed, particularly in women who experienced HMB prior to DOAC initiation. As iron deficiency with or without anemia is a common complication of HMB, complete blood count and ferritin levels should be monitored periodically, and iron deficiency should be treated with oral or intravenous iron supplementation.
PubMed: 34368613
DOI: 10.1002/rth2.12570 -
Best Practice & Research. Clinical... Dec 2021Dementia is a pandemic chronic non-communicable disease. 10 in 100 women above age 65 will be diagnosed with dementia, primarily Alzheimer's disease (AD). Apart from age... (Review)
Review
Dementia is a pandemic chronic non-communicable disease. 10 in 100 women above age 65 will be diagnosed with dementia, primarily Alzheimer's disease (AD). Apart from age and hereditary risk factors, there are multiple acquired risk and protective factors. So far, Menopausal Hormone Therapy (MHT) is not recommended as preventive measure. A systematic literature search on MHT and dementia risk and MHT and cognitive performance in demented women, respectively, was performed. Two recent meta-analyses identified 18 and 16 studies analyzing the impact of MHT on dementia/AD risk. Our systematic literature search identified eight additional original articles. The majority of studies found a risk reducing impact of MHT by 11-33%. However, results may vary depending on MHT type, age at initiation and study design. For example, the Women's Health Initiative Memory Study (WHIMS) reported an approximately 2-fold increased risk of dementia/Alzheimer's disease if MHT comprising conjugated equine estrogens and medroxyprogesterone acetate was initiated in predominantly comorbid postmenopausal women above age 65. In general, MHT displays a beneficial effect on several dementia risk factors and also augments some protective factors. Accordingly, clinicians can be reassured that MHT can be safely prescribed in the context of cognition in women free of dementia. However, MHT is not indicated for cognitive improvement in demented women. International scientific guidelines on MHT and dementia should consider incorporating most recent data.
Topics: Aged; Cognition; Estrogen Replacement Therapy; Female; Hormone Replacement Therapy; Humans; Menopause; Women's Health
PubMed: 34538724
DOI: 10.1016/j.beem.2021.101565 -
Reproductive Biology and Endocrinology... Oct 2023Endometriosis-related infertility is a common worldwide reproductive health concern. Despite ongoing research, the causes of infertility remain unclear. Evidence...
METTL3-regulated m6A modification impairs the decidualization of endometrial stromal cells by regulating YTHDF2-mediated degradation of FOXO1 mRNA in endometriosis-related infertility.
BACKGROUND
Endometriosis-related infertility is a common worldwide reproductive health concern. Despite ongoing research, the causes of infertility remain unclear. Evidence suggests that epigenetic regulation is crucial in reproduction. However, the role of N6-methyladenosine (m6A) modification of RNA in endometriosis-related infertility requires further investigation.
METHODS
We examined the expression of m6A and methyltransferase-like 3 (METTL3) in endometrial samples taken from normal fertile women in the proliferative phase (the NP group) or the mid-secretory phase (the NS group) or from women with endometriosis-related infertility at the mid-secretory phase (the ES group). We treated primary endometrial stromal cells (ESCs) with medroxyprogesterone acetate and 8-Bromo-cyclic adenosine monophosphate for in vitro decidualization and detected the expression of m6A, METTL3, and decidual markers. We analyzed the expression of m6A, METTL3, and forkhead box O1 (FOXO1) in ESCs from normal fertile women (the ND group) or women with endometriosis-related infertility (the ED group). We also assessed the expression of m6A, METTL3, and decidual markers, as well as the embryo adhesion rate, upon METTL3 overexpression or knockdown. Additionally, we investigated the role of METTL3 in embryo implantation in vivo by applying mice with endometriosis. Furthermore, we performed RNA stability assays, RNA immunoprecipitation (RIP), and methylated RIP assays to explore the mechanisms underlying the regulation of FOXO1 by METTL3-mediated m6A.
RESULTS
The expression of m6A and METTL3 was reduced only in the NS group; the NP and ES groups demonstrated increased m6A and METTL3 levels. m6A and METTL3 levels decreased in ESCs with prolonged decidual treatment. Compared to the ND group, m6A and METTL3 levels in the ED group increased after decidual treatment, whereas the expression of FOXO1 decreased. METTL3 overexpression suppressed the expression of decidual markers and embryo implantation in vitro; METTL3 knockdown exhibited the opposite effect. Inhibition of METTL3 promoted embryo implantation in vivo. Furthermore, we observed that METTL3-mediated m6A regulated the degradation of FOXO1 mRNA through YTHDF2, a m6A binding protein.
CONCLUSIONS
METTL3-regulated m6A promotes YTHDF2-mediated decay of FOXO1 mRNA, thereby affecting cellular decidualization and embryo implantation. These findings provide novel insights into the development of therapies for women with endometriosis-related infertility.
Topics: Animals; Female; Humans; Mice; Endometriosis; Epigenesis, Genetic; Forkhead Box Protein O1; Methyltransferases; RNA, Messenger; RNA-Binding Proteins; Stromal Cells; Transcription Factors; Infertility, Female
PubMed: 37891533
DOI: 10.1186/s12958-023-01151-0