-
Frontiers in Endocrinology 2023Natural menopause is an inevitable biological process with significant implications for women's health. However, the molecular mechanisms underlying menopause are not...
INTRODUCTION
Natural menopause is an inevitable biological process with significant implications for women's health. However, the molecular mechanisms underlying menopause are not well understood. This study aimed to investigate the molecular and cellular changes occurring in the ovary before and after perimenopause.
METHODS
Single-cell sequencing data from the GTEx V8 cohort (30-39: 14 individuals; 40-49: 37 individuals; 50-59: 61 individuals) and transcriptome sequencing data from ovarian tissue were analyzed. Seurat was used for single-cell sequencing data analysis, while harmony was employed for data integration. Cell differentiation trajectories were inferred using CytoTrace. CIBERSORTX assessed cell infiltration scores in ovarian tissue. WGCNA evaluated co-expression network characteristics in pre- and post-perimenopausal ovarian tissue. Functional enrichment analysis of co-expression modules was conducted using ClusterprofileR and Metascape. DESeq2 performed differential expression analysis. Master regulator analysis and signaling pathway activity analysis were carried out using MsViper and Progeny, respectively. Machine learning models were constructed using Orange3.
RESULTS
We identified the differentiation trajectory of follicular cells in the ovary as ARID5B+ Granulosa -> JUN+ Granulosa -> KRT18+ Granulosa -> MT-CO2+ Granulosa -> GSTA1+ Granulosa -> HMGB1+ Granulosa. Genes driving Granulosa differentiation, including RBP1, TMSB10, SERPINE2, and TMSB4X, were enriched in ATP-dependent activity regulation pathways. Genes involved in maintaining the Granulosa state, such as DCN, ARID5B, EIF1, and HSP90AB1, were enriched in the response to unfolded protein and chaperone-mediated protein complex assembly pathways. Increased contents of terminally differentiated HMGB1+ Granulosa and GSTA1+ Granulosa were observed in the ovaries of individuals aged 50-69. Signaling pathway activity analysis indicated a gradual decrease in TGFb and MAPK pathway activity with menopause progression, while p53 pathway activity increased. Master regulator analysis revealed significant activation of transcription factors FOXR1, OTX2, MYBL2, HNF1A, and FOXN4 in the 30-39 age group, and GLI1, SMAD1, SMAD7, APP, and EGR1 in the 40-49 age group. Additionally, a diagnostic model based on 16 transcription factors (Logistic Regression L2) achieved reliable performance in determining ovarian status before and after perimenopause.
CONCLUSION
This study provides insights into the molecular and cellular mechanisms underlying natural menopause in the ovary. The findings contribute to our understanding of perimenopausal changes and offer a foundation for health management strategies for women during this transition.
Topics: Female; Humans; Adult; Middle Aged; Ovary; Transcriptome; HMGB1 Protein; Serpin E2; Menopause; Transcription Factors
PubMed: 37564980
DOI: 10.3389/fendo.2023.1004245 -
International Journal of Molecular... Aug 2023The pathogenesis of obesity-related-renal disease is unknown. Menopause can promote renal disease in obese women, but this interaction is unclear. In a previous study,...
The pathogenesis of obesity-related-renal disease is unknown. Menopause can promote renal disease in obese women, but this interaction is unclear. In a previous study, we observed that obese male and female mice developed albuminuria, hyperfiltration, and glomerulomegaly, and these changes were more severe in those obese ovariectomized females. In this study, we also evaluated renal inflammation and lipotoxicity in that animal model. For six months, 43 males and 36 females C57BL6/J mice were randomized to standard diet (SD) or high fat diet (HFD). A group of female animals on SD or HFD was ovariectomized to simulate menopause. We evaluated cytokines: NF-κβ p65, IL-1β, MCP-1, TNF-α, total lipid content, lipid classes, and fatty acid profile in total lipid and individual lipid classes in renal tissue and urine. We found that obese males and females showed higher NF-kβ p-65, TNF-α and MCP-1 in renal tissue, and obese females ovariectomized had higher IL-1β and TNF-α compared with not-ovariectomized. Also, obese animals showed lower proinflammatory and higher anti-inflammatory fatty acids in kidney total lipids, while obese females ovariectomized had a more exacerbated pattern. In brief, obesity induces inflammation and an unbalanced lipidic profile in renal tissue. This pattern seems to be enhanced in obesity after menopause.
Topics: Animals; Female; Male; Mice; Fatty Acids; Inflammation; Kidney Diseases; Menopause; Nephritis; Sex Factors; Tumor Necrosis Factor-alpha; Random Allocation; Disease Models, Animal; Obesity
PubMed: 37629165
DOI: 10.3390/ijms241612984 -
BMC Gastroenterology Oct 2023Sex and reproductive status differences exist in both non-alcoholic fatty liver disease (NAFLD) and body composition. Our purpose was to investigate the relationship...
BACKGROUND
Sex and reproductive status differences exist in both non-alcoholic fatty liver disease (NAFLD) and body composition. Our purpose was to investigate the relationship between body composition and the severity of liver steatosis and fibrosis in NAFLD in different sex and reproductive status populations.
METHODS
This cross-sectional study included 880 patients (355 men, 417 pre-menopausal women, 108 post-menopausal women). Liver steatosis and fibrosis and body composition data were measured using FibroScan and a bioelectrical impedance body composition analyzer (BIA), respectively, and the following parameters were obtained: liver stiffness measurement (LSM), controlled attenuation parameter (CAP), waist circumference (WC), body mass index (BMI), percent body fat (PBF), visceral fat area (VFA), appendicular skeletal muscle mass (ASM), appendicular skeletal muscle mass index (ASMI), fat mass (FM), fat free mass (FFM), and FFM to FM ratio (FFM/FM). Multiple ordinal logistic regression (MOLR) was used to analyze the independent correlation between body composition indicators and liver steatosis grade and fibrosis stage in different sex and menopausal status populations.
RESULTS
Men had higher WC, ASM, ASMI, FFM, and FFM/FM than pre- or post-menopausal women, while pre-menopausal women had higher PBF, VFA, and FM than the other two groups (p < 0.001). Besides, men had greater CAP and LSM values (p < 0.001). For MOLR, after adjusting for confounding factors, WC (OR, 1.07; 95% CI, 1.02-1.12; P = 0.011) and FFM/FM (OR, 0.52; 95% CI, 0.31-0.89; P = 0.017) in men and visceral obesity (OR, 4.16; 95% CI, 1.09-15.90; P = 0.037) in post-menopausal women were independently associated with liver steatosis grade. WC and visceral obesity were independently associated with liver fibrosis stage in men (OR, 1.05; 95% CI, 1.01-1.09, P = 0.013; OR, 3.92; 95% CI, 1.97-7.81; P < 0.001, respectively).
CONCLUSIONS
Increased WC and low FFM/FM in men and visceral obesity in post-menopausal women were independent correlates of more severe liver steatosis. In addition, increased WC and visceral obesity were independent correlates of worse liver fibrosis in men. These data support the sex- and reproductive status-specific management of NAFLD.
Topics: Female; Humans; Male; Body Composition; Body Mass Index; Cross-Sectional Studies; Liver Cirrhosis; Non-alcoholic Fatty Liver Disease; Obesity, Abdominal; Menopause; Sex Factors
PubMed: 37875811
DOI: 10.1186/s12876-023-02997-9 -
International Journal of Molecular... Oct 2023It has been observed that plasmatic concentrations of estrogens, progesterone, or both correlate with symptoms in asthmatic women. Fluctuations in female sex steroid... (Review)
Review
It has been observed that plasmatic concentrations of estrogens, progesterone, or both correlate with symptoms in asthmatic women. Fluctuations in female sex steroid concentrations during menstrual periods are closely related to asthma symptoms, while menopause induces severe physiological changes that might require hormonal replacement therapy (HRT), that could influence asthma symptoms in these women. Late-onset asthma (LOA) has been categorized as a specific asthmatic phenotype that includes menopausal women and novel research regarding therapeutic alternatives that might provide relief to asthmatic women suffering LOA warrants more thorough and comprehensive analysis. Therefore, the present review proposes phytoestrogens as a promising HRT that might provide these females with relief for both their menopause and asthma symptoms. Besides their well-recognized anti-inflammatory and antioxidant capacities, phytoestrogens activate estrogen receptors and promote mild hormone-like responses that benefit postmenopausal women, particularly asthmatics, constituting therefore a very attractive potential therapy largely due to their low toxicity and scarce side effects.
Topics: Female; Humans; Phytoestrogens; Estrogen Replacement Therapy; Hormone Replacement Therapy; Menopause; Estrogens; Asthma
PubMed: 37895016
DOI: 10.3390/ijms242015335 -
Obesity (Silver Spring, Md.) Dec 2023Steatotic liver disease (SLD) is frequent in individuals with obesity. In this study, type 2 diabetes (T2D), sex, and menopausal status were combined to refine the...
Combining diabetes, sex, and menopause as meaningful clinical features associated with NASH and liver fibrosis in individuals with class II and III obesity: A retrospective cohort study.
OBJECTIVE
Steatotic liver disease (SLD) is frequent in individuals with obesity. In this study, type 2 diabetes (T2D), sex, and menopausal status were combined to refine the stratification of obesity regarding the risk of advanced SLD and gain further insight into disease physiopathology.
METHODS
This study enrolled 1446 participants with obesity from the ABOS cohort (NCT01129297), who underwent extensive phenotyping, including liver histology and transcriptome profiling. Hierarchical clustering was applied to classify participants. The prevalence of metabolic disorders associated with steatohepatitis (NASH) and liver fibrosis (F ≥ 2) was determined within each identified subgroup and aligned to clinical and biological characteristics.
RESULTS
The prevalence of NASH and F ≥ 2 was, respectively, 9.5% (N = 138/1446) and 11.7% (N = 159/1365) in the overall population, 20.3% (N = 107/726) and 21.1% (N = 106/502) in T2D patients, and 3.4% (N = 31/920) and 6.1% (N = 53/863) in non-T2D patients. NASH and F ≥ 2 prevalence was 15.4% (33/215) and 15.5% (32/206) among premenopausal women with T2D vs. 29.5% (33/112) and 30.3% (N = 36/119) in postmenopausal women with T2D (p < 0.01); and 21.0% (21/100) / 27.0% (24/89) in men with T2D ≥ age 50 years and 17.9% (17/95) / 18.5% (17/92) in men with T2D < age 50 years (NS). The distinct contribution of menopause was confirmed by the interaction between sex and age with respect to NASH among T2D patients (p = 0.048). Finally, several NASH-associated biological traits (lower platelet count; higher serum uric acid; gamma-glutamyl transferase; aspartate aminotransferase) and liver expressed genes AKR1B10 and CCL20 were significantly associated with menopause in women with T2D but not with age in men with T2D.
CONCLUSIONS
This study unveiled a remarkably high prevalence of advanced SLD after menopause in women with T2D, associated with a dysfunctional biological liver profile.
Topics: Male; Humans; Female; Middle Aged; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus, Type 2; Retrospective Studies; Uric Acid; Liver Cirrhosis; Liver; Obesity; Menopause
PubMed: 37987186
DOI: 10.1002/oby.23904 -
BMC Women's Health Jan 2024Menopause hormone therapy (MHT), as an effective method to alleviate the menopause-related symptoms of women, its benefits, risks, and potential influencing factors for... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Menopause hormone therapy (MHT), as an effective method to alleviate the menopause-related symptoms of women, its benefits, risks, and potential influencing factors for the cardiovascular system of postmenopausal women are not very clear.
OBJECTIVES
To evaluate cardiovascular benefits and risks of MHT in postmenopausal women, and analyze the underlying factors that affect both.
SEARCH STRATEGY
The EMBASE, MEDLINE, and CENTRAL databases were searched from 1975 to July 2022.
SELECTION CRITERIA
Randomized Clinical Trials (RCTs) that met pre-specified inclusion criteria were included.
DATA COLLECTION AND ANALYSIS
Two reviewers extracted data independently. A meta-analysis of random effects was used to analyze data.
MAIN RESULTS
This systematic review identified 33 RCTs using MHT involving 44,639 postmenopausal women with a mean age of 60.3 (range 48 to 72 years). There was no significant difference between MHT and placebo (or no treatment) in all-cause death (RR = 0.96, 95%CI 0.85 to 1.09, I = 14%) and cardiovascular events (RR = 0.97, 95%CI 0.82 to 1.14, I = 38%) in the overall population of postmenopausal women. However, MHT would increase the risk of stroke (RR = 1.23, 95%CI 1.08 to 1.41,I = 0%) and venous thromboembolism (RR = 1.86, 95%CI 1.39 to 2.50, I = 24%). Compared with placebo, MHT could improve flow-mediated arterial dilation (FMD) (SMD = 1.46, 95%CI 0.86 to 2.07, I = 90%), but it did not improve nitroglycerin-mediated arterial dilation (NMD) (SMD = 0.27, 95%CI - 0.08 to 0.62, I = 76%). Compared with women started MHT more than 10 years after menopause, women started MHT within 10 years after menopause had lower frequency of all-cause death (P = 0.02) and cardiovascular events (P = 0.002), and more significant improvement in FMD (P = 0.0003). Compared to mono-estrogen therapy, the combination therapy of estrogen and progesterone would not alter the outcomes of endpoint event. (all-cause death P = 0.52, cardiovascular events P = 0.90, stroke P = 0.85, venous thromboembolism P = 0.33, FMD P = 0.46, NMD P = 0.27).
CONCLUSIONS
MHT improves flow-mediated arterial dilation (FMD) but fails to lower the risk of all-cause death and cardiovascular events, and increases the risk of stroke and venous thrombosis in postmenopausal women. Early acceptance of MHT not only reduces the risk of all-cause death and cardiovascular events but also further improves FMD, although the risk of stroke and venous thrombosis is not reduced. There is no difference in the outcome of cardiovascular system endpoints between mono-estrogen therapy and combination therapy of estrogen and progesterone.
Topics: Female; Humans; Middle Aged; Aged; Venous Thromboembolism; Postmenopause; Progesterone; Arteries; Stroke; Estrogens; Hormone Replacement Therapy; Venous Thrombosis; Risk Assessment
PubMed: 38263123
DOI: 10.1186/s12905-023-02788-0 -
Complementary Therapies in Medicine Dec 2023This study examined the role of gut microbiome changes in mediating the effects of a dietary intervention on the frequency and severity of postmenopausal vasomotor... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This study examined the role of gut microbiome changes in mediating the effects of a dietary intervention on the frequency and severity of postmenopausal vasomotor symptoms METHODS: Postmenopausal women (n = 84) reporting ≥2 moderate-to-severe hot flashes daily were randomly assigned, in 2 successive cohorts, to an intervention including a low-fat, vegan diet and cooked soybeans (½ cup [86 g] daily) or to stay on their usual diet. Over a 12-week period, frequency and severity of hot flashes were recorded with a mobile application. In a subset of 11 women, gut microbiome was analyzed at baseline and after 12 weeks of the dietary intervention (low-fat vegan diet with soybeans), using deep shotgun metagenomic sequencing. Differences in the microbiome between baseline and 12 weeks were assessed by comparing alpha diversity with Wilcoxon signed rank tests, beta diversity with permanovaFL, and taxon abundance with Wilcoxon signed rank tests. Pearson correlations were used to assess the association between changes in hot flashes and gut bacteria.
RESULTS
In the subset for which microbiome testing was done, total hot flashes decreased by 95 % during the dietary intervention (p = 0.007); severe hot flashes disappeared (from 0.6 to 0.0/day; p = 0.06); and moderate-to-severe hot flashes decreased by 96 % (p = 0.01). Daytime and nighttime hot flashes were reduced by 96 % (p = 0.01) and 94 % (p = 0.004), respectively. Alpha and beta diversity did not significantly differ in the intervention group between baseline and 12 weeks. Two families (Enterobacteriaceae and Veillonellaceae), 5 genera (Erysipelatoclostridium, Fusicatenibacter, Holdemanella, Intestinimonas, and Porphyromonas), and 6 species (Clostridium asparagiforme, Clostridium innocuum, Bacteroides thetaiotaomicron, Fusicatenibacter saccharivorans, Intestinimonas butyriciproducens, Prevotella corporis, and Streptococcus sp.) were differentially abundant, but after correction for multiple comparisons, these differences were no longer significant. Changes in the relative abundance of Porphyromonas and Prevotella corporis were associated with the reduction in severe day hot flashes both unadjusted (r = 0.61; p = 0.047; and r = 0.69; p = 0.02), respectively), and after adjustment for changes in body mass index (r = 0.63; p = 0.049; and r = 0.73; p = 0.02), respectively). Changes in relative abundance of Clostridium asparagiforme were associated with the reduction in total severe hot flashes (r = 0.69; p = 0.019) and severe night hot flashes (r = 0.82; p = 0.002) and the latter association remained significant after adjustment for changes in body mass index (r = 0.75; p = 0.01).
CONCLUSIONS
This exploratory analysis revealed potential associations between changes in vasomotor symptoms in response to a diet change and changes in the gut microbiome. Larger randomized clinical trials are needed to investigate these findings.
Topics: Female; Humans; Hot Flashes; Postmenopause; Gastrointestinal Microbiome; Menopause
PubMed: 37949415
DOI: 10.1016/j.ctim.2023.103002 -
Methodist DeBakey Cardiovascular Journal 2024Cardiovascular disease (CVD) remains a leading cause of mortality in women, necessitating innovative primary prevention strategies. Contemporary guidelines on primary... (Review)
Review
Cardiovascular disease (CVD) remains a leading cause of mortality in women, necessitating innovative primary prevention strategies. Contemporary guidelines on primary prevention of CVD highlight the increasing prevalence of CVD risk factors and emphasize the significance of female-specific risk enhancers that substantially augment the future risk of CVD. These risk factors occur throughout a woman's life cycle, such as hormonal contraception, hypertensive disorders of pregnancy, and menopause, all of which confer an added layer of risk in women beyond the conventional risk factors. Despite this, current methods may not fully capture the nuanced vulnerabilities in women that increase their risk of CVD. In this review, we highlight gender-specific risk enhancers and subsequent prevention as well as strategies to improve primary prevention of CVD in women.
Topics: Pregnancy; Female; Humans; Cardiovascular Diseases; Hypertension; Menopause; Risk Factors; Primary Prevention
PubMed: 38495667
DOI: 10.14797/mdcvj.1313 -
Frontiers in Endocrinology 2023The number of primordial follicles (PFs) in mammals determines the ovarian reserve, and impairment of primordial follicle formation (PFF) will cause premature ovarian...
INTRODUCTION
The number of primordial follicles (PFs) in mammals determines the ovarian reserve, and impairment of primordial follicle formation (PFF) will cause premature ovarian insufficiency (POI).
METHODS
By analyzing public single-cell RNA sequencing performed during PFF on mice and human ovaries, we identified novel functional genes and novel ligand-receptor interaction during PFF. Based on immunofluorescence and in vitro ovarian culture, we confirmed mechanisms of genes and ligand-receptor interaction in PFF. We also applied whole exome sequencing (WES) in 93 cases with POI and whole genome sequencing (WGS) in 465 controls. Variants in POI patients were further investigated by in silico analysis and functional verification.
RESULTS
We revealed ANXA7 (annexin A7) and GTF2F1 (general transcription factor IIF subunit 1) in germ cells to be novel potentially genes in promoting PFF. Ligand Mdk (midkine) in germ cells and its receptor Sdc1 (syndecan 1) in granulosa cells are novel interaction crucial for PFF. Based on immunofluorescence, we confirmed significant up-regulation of ANXA7 in PFs compared with germline cysts, and uniform expression of GTF2F1, MDK and SDC1 during PFF, in 25 weeks human fetal ovary. In vitro investigation indicated that Anxa7 and Gtf2f1 are vital for mice PFF by regulating Jak/Stat3 and Jnk signaling pathways, respectively. Ligand-receptor (Mdk-Sdc1) are crucial for PFF by regulating Pi3k-akt signaling pathway. Two heterozygous variants in GTF2F1, and one heterozygous variants in SDC1 were identified in cases, but no variant were identified in controls. The protein level of GTF2F1 or SDC1 in POI cases are significantly lower than that of controls, indicating the pathogenic effects of the two genes on ovarian function were dosage dependent.
DISCUSSION
Our study identified novel genes and novel ligand-receptor interaction during PFF, and further expanding the genetic architecture of POI.
Topics: Female; Humans; Animals; Mice; Exome Sequencing; Phosphatidylinositol 3-Kinases; Ligands; Single-Cell Gene Expression Analysis; Ovarian Follicle; Primary Ovarian Insufficiency; Menopause, Premature; Mammals
PubMed: 38149096
DOI: 10.3389/fendo.2023.1285667 -
The Journal of Clinical Endocrinology... Oct 2023Perturbations to the hypothalamic-pituitary-adrenal (HPA) axis have been hypothesized to increase postmenopausal cardiometabolic risk. Although sleep disturbance, a...
CONTEXT
Perturbations to the hypothalamic-pituitary-adrenal (HPA) axis have been hypothesized to increase postmenopausal cardiometabolic risk. Although sleep disturbance, a known risk factor for cardiometabolic disease, is prevalent during the menopause transition, it is unknown whether menopause-related sleep disturbance and estradiol decline disturb the HPA axis.
OBJECTIVE
We examined the effect of experimental fragmentation of sleep and suppression of estradiol as a model of menopause on cortisol levels in healthy young women.
METHODS
Twenty-two women completed a 5-night inpatient study during the mid-to-late follicular phase (estrogenized). A subset (n = 14) repeated the protocol after gonadotropin-releasing hormone agonist-induced estradiol suppression. Each inpatient study included 2 unfragmented sleep nights followed by 3 experimental sleep fragmentation nights. This study took place with premenopausal women at an academic medical center. Interventions included sleep fragmentation and pharmacological hypoestrogenism, and main outcome measures were serum bedtime cortisol levels and cortisol awakening response (CAR).
RESULTS
Bedtime cortisol increased 27% (P = .03) and CAR decreased 57% (P = .01) following sleep fragmentation compared to unfragmented sleep. Polysomnographic-derived wake after sleep-onset (WASO) was positively associated with bedtime cortisol levels (P = .047) and negatively associated with CAR (P < .01). Bedtime cortisol levels were 22% lower in the hypoestrogenized state compared to the estrogenized state (P = .02), while CAR was similar in both estradiol conditions (P = .38).
CONCLUSION
Estradiol suppression and modifiable menopause-related sleep fragmentation both independently perturb HPA axis activity. Sleep fragmentation, commonly seen in menopausal women, may disrupt the HPA axis, which in turn may lead to adverse health effects as women age.
Topics: Humans; Female; Estradiol; Hydrocortisone; Sleep Deprivation; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Menopause; Sleep; Saliva
PubMed: 37207451
DOI: 10.1210/clinem/dgad285