-
CMAJ : Canadian Medical Association... Aug 2021
Topics: Adolescent; Bone Density; Canada; Contraception; Contraceptive Agents, Female; Desogestrel; Female; Humans; Intrauterine Devices, Copper; Levonorgestrel; Long-Acting Reversible Contraception; Medroxyprogesterone Acetate; Pregnancy; Pregnancy, Unplanned; Sexually Transmitted Diseases
PubMed: 34373270
DOI: 10.1503/cmaj.202413 -
Autophagy May 2021Autophagy is a highly conserved catabolic process and a major cellular pathway for the degradation of long-lived proteins and cytoplasmic organelles. An increasing body... (Review)
Review
Autophagy is a highly conserved catabolic process and a major cellular pathway for the degradation of long-lived proteins and cytoplasmic organelles. An increasing body of evidence has unveiled autophagy as an indispensable biological function that helps to maintain normal tissue homeostasis and metabolic fitness that can also lead to severe consequences for the normal cellular functioning when altered. Recent accumulating data point to autophagy as a key player in a wide variety of physiological and pathophysiological conditions in the human endometrium, one of the most proficient self-regenerating tissues in the human body and an instrumental player in placental species reproductive function. The current review highlights the most recent findings regarding the process of autophagy in the normal and cancerous endometrial tissue. Current research efforts aiming to therapeutically exploit autophagy and the methodological approaches used are discussed. 3-MA: 3-methyladenine; ACACA (acetyl-CoA carboxylase alpha); AICAR: 5-aminoimidazole-4-carboximide riboside; AKT: AKT serine/threonine kinase; AMPK: AMP-activated protein kinase; ATG: autophagy related; ATG12: autophagy related 12; ATG16L1: autophagy related 16 like 1; ATG3: autophagy related 3; ATG4C: autophagy related 4C cysteine peptidase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG9: autophagy related 9; Baf A1: bafilomycin A; BAX: BCL2 associated X, apoptosis regulator; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; CACNA1D: calcium voltage-gated channel subunit alpha1 D; CASP3: caspase 3; CASP7: caspase 7; CASP8: caspase 8; CASP9: caspase 9; CD44: CD44 molecule (Indian blood group); CDH1: cadherin 1; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; CMA: chaperone-mediated autophagy; CQ: chloroquine; CTNNB1: catenin beta 1; DDIT3: DNA damage inducible transcript 3; EC: endometrial cancer; EGFR: epidermal growth factor receptor; EH: endometrial hyperplasia; EIF4E: eukaryotic translation initiation factor 4E; EPHB2/ERK: EPH receptor B2; ER: endoplasmic reticulum; ERBB2: er-b2 receptor tyrosine kinase 2; ERVW-1: endogenous retrovirus group W member 1, envelope; ESR1: estrogen receptor 1; FSH: follicle-stimulating hormone; GCG/GLP1: glucagon; GFP: green fluorescent protein; GIP: gastric inhibitory polypeptide; GLP1R: glucagon-like peptide-1 receptor; GLS: glutaminase; H2AX: H2A.X variant histone; HIF1A: hypoxia inducible factor 1 alpha; HMGB1: high mobility group box 1; HOTAIR: HOX transcript antisense RNA; HSPA5: heat shock protein family A (HSP70) member 5; HSPA8: heat shock protein family A (HSP70) member 8; IGF1: insulin like growth factor 1; IL27: interleukin 27; INS: insulin; ISL: isoliquiritigenin; KRAS: KRAS proto-oncogene, GTPase; LAMP2: lysosomal-associated membrane protein 2; lncRNA: long-non-coding RNA; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK8: mitogen-activated protein kinase 8; MAPK9: mitogen-activated protein kinase 9; MPA: medroxyprogesterone acetate; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; MYCBP: MYC-binding protein; NFE2L2: nuclear factor, erythroid 2 like 2; NFKB: nuclear factor kappa B; NFKBIA: NFKB inhibitor alpha; NK: natural killer; NR5A1: nuclear receptor subfamily 5 group A member 1; PARP1: poly(ADP-ribose) polymerase 1; PAX2: paired box 2; PDK1: pyruvate dehydrogenase kinase 1; PDX: patient-derived xenograft; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PIK3R1: phosphoinositide-3-kinase regulatory subunit 1; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; PPD: protopanaxadiol; PRKCD: protein kinase C delta; PROM1/CD133: prominin 1; PtdIns3K: class III phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PTEN: phosphatase and tensin homolog; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RFP: red fluorescent protein; RPS6KB1/S6K1: ribosomal protein S6 kinase B1; RSV: resveratrol; SGK1: serum/glucocorticoid regulated kinase 1; SGK3: serum/glucocorticoid regulated kinase family member 3; SIRT: sirtuin; SLS: stone-like structures; SMAD2: SMAD family member 2; SMAD3: SMAD family member 3; SQSTM1: sequestosome 1; TALEN: transcription activator-like effector nuclease; TGFBR2: transforming growth factor beta receptor 2; TP53: tumor protein p53; TRIB3: tribbles pseudokinase 3; ULK1: unc-51 like autophagy activating kinase 1; ULK4: unc-51 like kinase 4; VEGFA: vascular endothelial growth factor A; WIPI2: WD repeat domain, phosphoinositide interacting 2; XBP1: X-box binding protein 1; ZFYVE1: zinc finger FYVE domain containing 1.
Topics: Apoptosis Regulatory Proteins; Autophagy; Endometrium; Female; Humans; Hyperplasia; Neoplasms; Placenta; Pregnancy
PubMed: 32401642
DOI: 10.1080/15548627.2020.1752548 -
Obstetrics and Gynecology Sep 2022To evaluate associations between use of seven progestogens and incident acute venous thromboembolism (VTE) among women of reproductive age.
OBJECTIVE
To evaluate associations between use of seven progestogens and incident acute venous thromboembolism (VTE) among women of reproductive age.
METHODS
This nested matched case-control study identified women aged 15-49 years from January 1, 2010, through October 8, 2018, in the IBM MarketScan databases, a nationwide sample of private insurance claims in the United States. After exclusions, 21,405 women with incident acute VTE (case group), identified by diagnosis codes, were matched 1:5 by year of birth and index date through risk set sampling to 107,025 women without prior VTE (control group). From lowest to highest systemic dose based on a modified hierarchy, progestogens studied were levonorgestrel-releasing intrauterine device (LNG-IUD), oral norethindrone, etonogestrel implant, oral progesterone, oral medroxyprogesterone acetate, oral norethindrone acetate, and depot medroxyprogesterone acetate (DMPA). Conditional logistic regression models adjusted for 16 VTE risk factors were used to estimate odds ratios and 99% CIs for incident acute VTE associated with current progestogen use compared with nonuse. The primary analysis treated each progestogen as a binary exposure. Dose, which varied for oral formulations, and chronicity were explored separately. Significance was set at P <.01 to allow for multiple comparisons.
RESULTS
Current use of higher-dose progestogens was significantly associated with increased odds of VTE compared with nonuse (oral norethindrone acetate: adjusted odds ratio [aOR] 3.00, 99% CI 1.96-4.59; DMPA: aOR 2.37, 99% CI 1.95-2.88; and oral medroxyprogesterone acetate: aOR 1.98, 99% CI 1.41-2.80). Current use of other progestogens was not significantly different from nonuse (LNG-IUD, etonogestrel implant, and oral progesterone) or had reduced odds of VTE (oral norethindrone). Sensitivity analyses that assessed misclassification bias supported the primary findings.
CONCLUSION
Among reproductive-aged women using one of seven progestogens, only use of norethindrone acetate and medroxyprogesterone acetate-considered higher-dose progestogens-was significantly associated with increased odds of incident acute VTE. The roles of progestogen type, dose, and indication for use warrant further study.
Topics: Adult; Female; Humans; Case-Control Studies; Intrauterine Devices, Medicated; Levonorgestrel; Medroxyprogesterone Acetate; Norethindrone; Norethindrone Acetate; Progesterone; Progestins; Venous Thromboembolism
PubMed: 35926206
DOI: 10.1097/AOG.0000000000004896 -
JAMA Jul 2020The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials. (Randomized Controlled Trial)
Randomized Controlled Trial
Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials.
IMPORTANCE
The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials.
OBJECTIVE
To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women's Health Initiative clinical trials.
DESIGN, SETTING, AND PARTICIPANTS
Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017.
INTERVENTIONS
In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years' median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years' median intervention duration.
MAIN OUTCOMES AND MEASURES
The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer.
RESULTS
Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93; P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P < .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95; P= .11).
CONCLUSIONS AND RELEVANCE
In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.
Topics: Aged; Breast Neoplasms; Estrogens, Conjugated (USP); Female; Follow-Up Studies; Hormone Replacement Therapy; Humans; Hysterectomy; Incidence; Medroxyprogesterone Acetate; Middle Aged; Postmenopause; Risk
PubMed: 32721007
DOI: 10.1001/jama.2020.9482 -
Proceedings of the National Academy of... Nov 2019The human endometrium is essential in providing the site for implantation and maintaining the growth and survival of the conceptus. An unreceptive endometrium and...
The human endometrium is essential in providing the site for implantation and maintaining the growth and survival of the conceptus. An unreceptive endometrium and disrupted maternal-conceptus interactions can cause infertility due to pregnancy loss or later pregnancy complications. Despite this, the role of uterine glands in first trimester human pregnancy is little understood. An established organoid protocol was used to generate and comprehensively analyze 3-dimensional endometrial epithelial organoid (EEO) cultures from human endometrial biopsies. The derived EEO expand long-term, are genetically stable, and can be cryopreserved. Using endometrium from 2 different donors, EEO were derived and then treated with estrogen (E2) for 2 d or E2 and medroxyprogesterone acetate (MPA) for 6 d. EEO cells were positive for the gland marker, FOXA2, and exhibited appropriate hormonal regulation of steroid hormone receptor expression. Real-time qPCR and bulk RNA-sequencing analysis revealed effects of hormone treatment on gene expression that recapitulated changes in proliferative and secretory phase endometrium. Single-cell RNA sequencing analysis revealed that several different epithelial cell types are present in the EEO whose proportion and gene expression changed with hormone treatment. The EEO model serves as an important platform for studying the physiology and pathology of the human endometrium.
Topics: Endometrium; Epithelium; Estrogens; Female; Gene Expression Profiling; Humans; Organoids; Progesterone; Sequence Analysis, RNA; Single-Cell Analysis
PubMed: 31666317
DOI: 10.1073/pnas.1915389116 -
International Journal of Molecular... Mar 2023Osteoporosis resulting from an imbalance of bone turnover between resorption and formation is a critical health issue worldwide. Estrogen deficiency following a nature... (Review)
Review
Osteoporosis resulting from an imbalance of bone turnover between resorption and formation is a critical health issue worldwide. Estrogen deficiency following a nature aging process is the leading cause of hormone-related osteoporosis for postmenopausal women, while glucocorticoid-induced osteoporosis remains the most common in drug-induced osteoporosis. Other medications and medical conditions related to secondary osteoporosis include proton pump inhibitors, hypogonadism, selective serotonin receptor inhibitors, chemotherapies, and medroxyprogesterone acetate. This review is a summary of the cellular and molecular mechanisms of bone turnover, the pathophysiology of osteoporosis, and their treatment. Nuclear factor-κβ ligand (RANKL) appears to be the critical uncoupling factor that enhances osteoclastogenesis. In contrast, osteoprotegerin (OPG) is a RANKL antagonist secreted by osteoblast lineage cells. Estrogen promotes apoptosis of osteoclasts and inhibits osteoclastogenesis by stimulating the production of OPG and reducing osteoclast differentiation after suppression of IL-1 and TNF, and subsequent M-CSF, RANKL, and IL-6 release. It can also activate the Wnt signaling pathway to increase osteogenesis, and upregulate BMP signaling to promote mesenchymal stem cell differentiation from pre-osteoblasts to osteoblasts rather than adipocytes. Estrogen deficiency leads to the uncoupling of bone resorption and formation; therefore, resulting in greater bone loss. Excessive glucocorticoids increase PPAR-2 production, upregulate the expression of Dickkopf-1 (DKK1) in osteoblasts, and inhibit the Wnt signaling pathway, thus decreasing osteoblast differentiation. They promote osteoclast survival by enhancing RANKL expression and inhibiting OPG expression. Appropriate estrogen supplement and avoiding excessive glucocorticoid use are deemed the primary treatment for hormone-related and glucocorticoid-induced osteoporosis. Additionally, current pharmacological treatment includes bisphosphonates, teriparatide (PTH), and RANKL inhibitors (such as denosumab). However, many detailed cellular and molecular mechanisms underlying osteoporosis seem complicated and unexplored and warrant further investigation.
Topics: Humans; Female; Glycoproteins; Glucocorticoids; Osteoclasts; Osteoprotegerin; Osteoblasts; Osteoporosis; Cell Differentiation; Estrogens; RANK Ligand
PubMed: 36982891
DOI: 10.3390/ijms24065814 -
Steroids Nov 2022Quantification of serum progestin levels in clinical contraceptive studies is now routinely performed to understand progestin pharmacokinetics and to correct for... (Review)
Review
Quantification of serum progestin levels in clinical contraceptive studies is now routinely performed to understand progestin pharmacokinetics and to correct for unreliable self-reporting of contraceptive use by study participants. Many such studies are focussed on the three-monthly progestin-only intramuscular (IM) injectable contraceptive depot medroxyprogesterone acetate (DMPA-IM). Methods commonly used to measure serum MPA levels include liquid chromatography coupled to mass spectrometry (LC/MS) and radioimmunoassay (RIA); however, RIA methods have not been used in recent years. We review the available literature and find that these methods vary widely in terms of use of organic solvent extraction, use of derivitization and choice of organic solvent and chromatography columns. There is a lack of standardization of LC/MS methodology, including a lack of detailed extraction protocols. Limited evidence suggests that RIA, without organic solvent extraction, likely over-estimates progestin levels. Maximum MPA concentrations in the first two weeks post-injection show wide inter-individual and inter-study variation, regardless of quantification method used. Standardization of quantification methods and sampling time post-injection is required to improve interpretation of clinical data, in particular the side effects arising at different times depending on the pharmacokinetic profile unique to injectable contraceptives.
Topics: Contraceptive Agents; Contraceptive Agents, Female; Female; Humans; Medroxyprogesterone Acetate; Progestins; Radioimmunoassay; Solvents
PubMed: 35964796
DOI: 10.1016/j.steroids.2022.109100 -
American Journal of Epidemiology Feb 2021The health benefits and risks of menopausal hormone therapy among women aged 50-59 years are examined in the Women's Health Initiative randomized, placebo-controlled... (Randomized Controlled Trial)
Randomized Controlled Trial
The health benefits and risks of menopausal hormone therapy among women aged 50-59 years are examined in the Women's Health Initiative randomized, placebo-controlled trials using long-term follow-up data and a parsimonious statistical model that leverages data from older participants to increase precision. These trials enrolled 27,347 healthy postmenopausal women aged 50-79 years at 40 US clinical centers during 1993-1998, including 10,739 post-hysterectomy participants in a trial of conjugated equine estrogens and 16,608 participants with a uterus in the trial of these estrogens plus medroxyprogesterone acetate. Over a (median) 18-year follow-up period (1993-2016), risk for a global index (defined as the earliest of coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and all-cause mortality) was reduced with conjugated equine estrogens with a hazard ratio of 0.82 (95% confidence interval: 0.71, 0.95), and with nominally significant reductions for coronary heart disease, breast cancer, hip fracture, and all-cause mortality. Corresponding global index hazard ratio estimates of 1.06 (95% confidence interval: 0.95, 1.19) were nonsignificant for combined estrogens plus progestin, but increased breast cancer risk and reduced endometrial cancer risk were observed. These results, among women 50-59 years of age, substantially agree with the worldwide observational literature, with the exception of breast cancer for estrogens alone.
Topics: Coronary Disease; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Hip Fractures; Humans; Medroxyprogesterone Acetate; Middle Aged; Neoplasms; Postmenopause; Proportional Hazards Models; Pulmonary Embolism; Stroke
PubMed: 33025002
DOI: 10.1093/aje/kwaa210