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Introduction: Melasma is a common acquired disorder of melanogenesis that predominately affects women and presents as hyperpigmented skin lesions mainly located on the face. The study aims to investigate the epidemiologic characteristics and hormonal profiles in melasma patients. Methods: One hundred fifty patients were enrolled in this study in a tertiary care hospital. Clinical patterns, pigment depth, disease severity, underlying conditions, and heredity were recorded. Endocrinologic profile and vitamin D levels were assessed. Results: On clinical examination, the condition indicated a centrofacial localization in 74% of the patients. Extra facial melasma was noticed in 10 patients who had centrofacial melasma to begin with. Wood's lamp examination showed the dermal type as the most common. A family history of melasma was noted in 38% of the patients. Melasma Area and Severity Index (MASI) score ranged from 0.3 to 10.8, with a mean score of 4.12 ± 2.06. Pregnancy-induced melasma was reported in 36.1% of the patients. In 17.4% of women, melasma was related to using oral contraceptives. In 22% of patients, mild vitamin D deficiency was detected, while 21% had thyroid disorders. Conclusion: There is a strong correlation between family history and prevalence of melasma. Sun exposure is a major precipitating factor and should be carefully addressed in Mediterranean countries like Greece. However, other factors such as concomitant medication, multiple pregnancies, use of oral contraceptives, thyroid disorders and vitamin D deficiency might precipitate melasma. [ABSTRACT FROM AUTHOR]

Context Women with hypopituitarism remain at increased risk of morbidity and mortality. Insufficient replacement of sex steroids has been suggested as a contributing factor, but sex steroid levels in women with hypopituitarism have not been comprehensively mapped. Objective To quantify sex steroids in women with hypopituitarism by a high-sensitivity assay. Methods Using a combination of clinical and biochemical criteria, women with hypopituitarism (n = 104) who started GH replacement in 1995 to 2014 at a single center were categorized as eugonadal or having hypogonadotropic hypogonadism (HH). A population-based cohort of women (n = 288) served as controls. Eugonadal women and controls were categorized as pre-/postmenopausal and HH women as younger/older (≤ or >52 years). Dehydroepiandrosterone (DHEA), androstenedione, testosterone, dihydrotestosterone, progesterone, 17αOH-progesterone, estradiol, and estrone were analyzed by a validated liquid chromatography-tandem mass spectrometry assay. Results Among both premenopausal/younger and postmenopausal/older women, women with HH had lower levels of sex steroid precursors (DHEA, androstenedione) and androgens (testosterone and dihydrotestosterone) than controls. Progesterone, 17αOH-progesterone, estrone, and estradiol showed similar patterns. Women with HH and ACTH deficiency had markedly lower concentrations of all sex hormones than those without ACTH deficiency. Conclusion This study demonstrates for the first time a broad and severe sex steroid deficiency in both younger and older women with HH, particularly in those with combined gonadotropin and ACTH deficiency. The health impact of low sex steroid levels in women with hypopituitarism requires further study, and women with combined gonadotropin and ACTH deficiency should be a prioritized group for intervention studies with sex hormone replacement. [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes (T2D) are widespread metabolic disorders that significantly impact global health today, affecting approximately 17% of adults worldwide with obesity and 9.3% with T2D. Both conditions are closely linked to disruptions in lipid metabolism, where peroxisomes play a pivotal role. Mitochondria and peroxisomes are vital organelles responsible for lipid and energy regulation, including the β-oxidation and oxidation of very long-chain fatty acids (VLCFAs), cholesterol biosynthesis, and bile acid metabolism. These processes are significantly influenced by estrogens, highlighting the interplay between these organelles' function and hormonal regulation in the development and progression of metabolic diseases, such as obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and T2D. Estrogens modulate lipid metabolism through interactions with nuclear receptors, like peroxisome proliferator-activated receptors (PPARs), which are crucial for maintaining metabolic balance. Estrogen deficiency, such as in postmenopausal women, impairs PPAR regulation, leading to lipid accumulation and increased risk of metabolic disorders. The disruption of peroxisomal–mitochondrial function and estrogen regulation exacerbates lipid imbalances, contributing to insulin resistance and ROS accumulation. This review emphasizes the critical role of these organelles and estrogens in lipid metabolism and their implications for metabolic health, suggesting that therapeutic strategies, including hormone replacement therapy, may offer potential benefits in treating and preventing metabolic diseases. [ABSTRACT FROM AUTHOR]

Estrogens, widely used for therapeutic or contraceptive purposes, act as endocrine disruptors in aquatic systems and have adverse effects on a wide range of living organisms. Wastewater insufficiently treated by conventional methods is the main way for estrogens to enter aquatic systems. Therefore, the purpose of this paper is to develop a novel photocatalytic system for the removal of the estrogenic mixture estradiol valerate/norgestrel from wastewater. The photocatalytic modules are operated in a plug flow reactor system under a UV-A radiation field, and the photocatalyst (TiO2, ZnO or TiO2/ZnO) is immobilized on an inert support of glass balls that are strung on stainless-steel wire and arranged in rows along the photocatalytic modules. The photocatalysts were synthesized by the sol–gel method and then deposited on the inert glass support by the hot method, after which it was calcined for two hours at a temperature of 500 °C. The experimental results showed that the efficiency of photocatalytic degradation largely depends on the dose of photocatalyst. The dose of photocatalyst can be adjusted by adding or removing photocatalytic modules, each of which have an approximately equal amount of photocatalyst. The best result was obtained for the TiO2/ZnO photocatalyst, the organic substrate being practically mineralized in 120 min, for which only two photocatalytic modules are needed. [ABSTRACT FROM AUTHOR]

Simple Summary: As women transition to menopause (i.e., perimenopause), they become more susceptible to hypertension. Animal studies using a mouse model of peri-menopause (peri-AOF) have revealed that hypertension susceptibility is associated with increased postsynaptic glutamatergic NMDA receptor plasticity in the paraventricular hypothalamic nucleus (PVN), a brain area critical for blood pressure regulation. The aim of this study was to determine if presynaptic NMDA receptors also play a role in neural plasticity in peri-AOF hypertension susceptibility. For comparison, males were also studied. Following slow pressor Angiotensin II (AngII), both peri-AOF and male mice became hypertensive; however, peri-AOF females showed higher cytoplasmic NMDA receptor levels. To determine the involvement of estrogen signaling in AngII-induced hypertension, an estrogen receptor beta (ERß) agonist was co-administered. In peri-AOF females, but not males, activation of ERß blocked hypertension and increased NMDA receptors on the membrane of axon terminals where it would be more available for binding of glutamate. These results indicate that sex-dependent recruitment of presynaptic NMDA receptors in the PVN is influenced by ERß signaling in a mouse model of perimenopause. Women become susceptible to hypertension as they transition to menopause (i.e., perimenopause); however, the underlying mechanisms are unclear. Animal studies using an accelerated ovarian failure (AOF) model of peri-menopause (peri-AOF) demonstrate that peri-AOF hypertension is associated with increased postsynaptic NMDA receptor plasticity in the paraventricular hypothalamic nucleus (PVN), a brain area critical for blood pressure regulation. However, recent evidence indicates that presynaptic NMDA receptors also play a role in neural plasticity. Here, using immuno-electron microscopy, we examine the influence of peri-AOF hypertension on the subcellular distribution of the essential NMDA GluN1 receptor subunit in PVN axon terminals in peri-AOF and in male mice. Hypertension was produced by 14-day slow-pressor angiotensin II (AngII) infusion. The involvement of estrogen signaling was investigated by co-administering an estrogen receptor beta (ERß) agonist. Although AngII induced hypertension in both peri-AOF and male mice, peri-AOF females showed higher cytoplasmic GluN1 levels. In peri-AOF females, activation of ERß blocked hypertension and increased plasmalemmal GluN1 in axon terminals. In contrast, stimulation of ERß did not inhibit hypertension or influence presynaptic GluN1 localization in males. These results indicate that sex-dependent recruitment of presynaptic NMDA receptors in the PVN is influenced by ERß signaling in mice during early ovarian failure. [ABSTRACT FROM AUTHOR]

It has now been about a century since a flurry of discoveries identified first the pituitary, then more specifically the anterior pituitary and soon thereafter the central nervous system as components regulating gonadal and downstream reproductive functions. This was an era of ablation/replacement designs using at first rudimentary and then increasingly pure preparations of gonadal and pituitary "activities" or transplanting actual glands, whole or homogenized, among subjects. There was, of course, controversy as is typical of lively and productive scientific debates to this day. The goals of this commentary are to briefly review the history of this work and how the terms referring to interactions among the components of the hypothalamo (as the central neural component was soon associated with)–pituitary–gonadal (HPG) axis evolved, and then to question if the current terms used have kept up with our understanding of the system. The focus in this review will be the actions of estradiol primarily upon the hypothalamus. Important actions of progesterone on the hypothalamus as well as both steroids on the pituitary response to hypothalamic factors are both acknowledged and largely ignored in this document, as are any sex differences as we focus on females. [ABSTRACT FROM AUTHOR]

The estrous cycle regulates rhythms of locomotor activity, body temperature, and circadian gene expression. In female mice, activity increases on the night of proestrus, when elevated estrogens cause ovulation. Exogenous estradiol regulates eating behavior rhythms in female mice fed a high-fat diet, but it is unknown whether endogenous estrogens regulate eating rhythms. In this study, we investigated whether diurnal and circadian eating behavior rhythms change systematically across the estrous cycle. We first studied diurnal eating behavior rhythms in female C57BL/6J mice in 12L:12D. Estrous cycle stages were determined by vaginal cytology while eating behavior and wheel revolutions were continuously measured. The mice had regular 4- to 5-day estrous cycles. Consistent with prior studies, the greatest number of wheel revolutions occurred on the night of proestrus into estrus when systemic levels of estrogens peak. The amplitude, or robustness, of the eating behavior rhythm also fluctuated with 4- to 5-day cycles and peaked primarily during proestrus or estrus. The phases of eating behavior rhythms fluctuated, but not at 4- or 5-day intervals, and phases did not correlate with estrous cycle stages. After ovariectomy, the eating behavior rhythm amplitude fluctuated at irregular intervals. In constant darkness, the amplitude of the circadian eating behavior rhythm peaked every 4 or 5 days and coincided with the circadian day that had the greatest number of wheel revolutions, a marker of proestrus. These data suggest that fluctuations of ovarian hormones across the estrous cycle temporally organize the robustness of circadian eating behavior rhythms so that it peaks during ovulation and sexual receptivity. [ABSTRACT FROM AUTHOR]

Purpose: Functional hypothalamic amenorrhea (FHA) is characterized by an estrogen deficiency which in turn can cause vascular dysfunction. The aim of this study is to evaluate any changes in the chorio-retinal circulation in patients affected by FHA. 24 patients with FHA and 24 age-matched controls underwent a gynecological evaluation and an OCT angiography (OCTA) to study chorio-retinal vascularization. Results: OCTA in FHA patients showed an increase in vessel density in the choriocapillaris (CC) layer (both in the fovea area, at 5% p value = 0.037 and in the whole area, at 5% p value = 0.028) and an increase in vascular density in the deep fovea (DVP) (at 10% p value = 0.096) in the whole district compared to controls. Simple linear regressions show a significant negative association between CC vessel density and insulin (p = 0.0002) and glucose values (p = 0.0335) for the fovea district and a negative association between DVP vessel density and endometrial thickness (at 10%, p value: 0.095) in the whole district. Conclusion: Our study shows that CC vessel density is increased in women affected by FHA. This could represent a compensation effort to supply the vascular dysfunction caused by estrogen deficiency. We also found an increasing trend in vascular density in DVP associated with the decrease of endometrial thickness, an indirect sign of estrogenization. Considering that these changes occur in absence of visual defects, they could be used as a biomarker to estimate hypoestrogenism-induced microcirculation changes before clinical appearance. [ABSTRACT FROM AUTHOR]

Background: The mechanisms underlying alcohol‐induced breast carcinogenesis are not fully understood but may involve hormonal changes. Methods: Cross‐sectional associations were investigated between self‐reported alcohol intake and serum or plasma concentrations of estradiol, estrone, progesterone (in premenopausal women only), testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone binding globulin (SHBG) in 45 431 premenopausal and 173 476 postmenopausal women. Multivariable linear regression was performed separately for UK Biobank, European Prospective Investigation into Cancer and Nutrition, and Endogenous Hormones and Breast Cancer Collaborative Group, and meta‐analyzed the results. For testosterone and SHBG, we also conducted Mendelian randomization and colocalization using the ADH1B (alcohol dehydrogenase 1B) variant (rs1229984). Results: Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in premenopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal estradiol to 6.6% for postmenopausal dehydroepiandrosterone sulfate. There was an inverse association of alcohol with SHBG in postmenopausal women but a small positive association in premenopausal women. Two‐sample randomization identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI, 0.6–7.6) and free testosterone (7.8%; 4.1–11.5), and an inverse association with SHBG (–8.1%; –11.3% to –4.9%). Colocalization suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (posterior probability for H4, 0.81 and 0.97, respectively). Conclusions: Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk. Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions. Sex hormones are therefore likely to be part of the mechanism through which alcohol increases breast cancer risk. [ABSTRACT FROM AUTHOR]

Mounting evidence indicates that whereas some fundamental aspects of bone cell differentiation and function are similar in females and males, there is a clear contribution of sex/gender on the effects of signaling molecules on bone mass and strength and, consequently, on the effects of pharmacologic approaches to treat skeletal disorders. However, until recently, most studies were designed and performed using only 1 sex, resulting in a scarcity of published information on sexual dimorphism of the musculoskeletal system, including the mandible/masticatory muscles and the axial and appendicular bones and skeletal muscles. Further, it is now recognized that scientific rigor requires the study of both males and females. Therefore, there is an increasing need to understand the molecular and cellular basis for the differential outcomes of genetic manipulations and therapeutic agent administration depending on the sex of the experimental animals. Studies have shown higher muscle mass, cancellous bone mass, and long bone width in males compared with females as well as different traits in the pelvis and the skull, which are usually used for gender identification in forensic anthropology. Yet, most reports focus on the role of sex hormones, in particular, the consequences of estrogen deficiency with menopause in humans and in ovariectomized animal models. In addition, emerging data is starting to unveil the effects of gender-affirming hormonal therapy on the musculoskeletal system. We summarize here the current knowledge on the sex/gender-dependent phenotypic characteristics of the bone and skeletal muscles in humans and rodents, highlighting studies in which side by side comparisons were made. [ABSTRACT FROM AUTHOR]

Fish are exposed to increased water temperatures and aquatic pollutants, including endocrine-disrupting compounds (EDCs). Although each stressor can disturb fish liver metabolism independently, combined effects may exist. To unveil the molecular mechanisms behind the effects of EDCs and temperature, fish liver cell lines are potential models needing better characterisation. Accordingly, we exposed the rainbow trout RTL-W1 cells (72 h), at 18 °C and 21 °C, to ethynylestradiol (EE2), levonorgestrel (LNG), and a mixture of both hormones (MIX) at 10 µM. The gene expression of a selection of targets related to detoxification (CYP1A, CYP3A27, GST, UGT, CAT, and MRP2), estrogen exposure (ERα, VtgA), lipid metabolism (FAS, FABP1, FATP1), and temperature stress (HSP70b) was analysed by RT-qPCR. GST expression was higher after LNG exposure at 21 °C than at 18 °C. LNG further enhanced the expression of CAT, while both LNG and MIX increased the expressions of CYP3A27 and MRP2. In contrast, FAS expression only increased in MIX, compared to the control. ERα, VtgA, UGT, CYP1A, HSP70b, FABP1, and FATP1 expressions were not influenced by the temperature or the tested EDCs. The RTL-W1 model was unresponsive to EE2 alone, sensitive to LNG (in detoxification pathway genes), and mainly insensitive to the temperature range but had the potential to unveil specific interactions. [ABSTRACT FROM AUTHOR]

Estrogens in river systems can significantly impact aquatic ecosystems. This study aimed to investigate the multiphase partitioning of estrogens in Wulo Creek, Taiwan, which receives animal feedlot wastewater, to understand their distribution and potential environmental implications. Water samples were separated into suspended particulate matter (SPM), colloidal, and soluble phases using centrifugation and cross-flow ultrafiltration. Concentrations of estrone (E1), 17β-estradiol (E2), and estriol (E3) in each phase were analyzed using LC/MS/MS. Partition coefficients were calculated to assess estrogen distribution among phases. Estrogens were predominantly found in the soluble phase (85.8–87.3%). The risk assessment of estrogen equivalent (EEQ) values suggests that estrogen concentration in water poses a higher risk compared to SPM, with a majority of the samples indicating a high risk to aquatic organisms. The colloidal phase contained 12.7–14.2% of estrogens. The log KCOC values (4.72–4.77 L/kg-C) were significantly higher than the log KOC and log KPOC values (2.02–3.40 L/kg-C) for all estrogens. Colloids play a critical role in estrogen distribution in river systems, potentially influencing their fate, transport, and biotoxicity. This finding highlights the importance of considering colloidal interactions in assessing estrogen behavior in aquatic environments. [ABSTRACT FROM AUTHOR]

17 β‐Estradiol is produced by animals, and humans and excreted through excreta, and has endocrine‐disrupting activity. Bacterial degradation is one of the suitable methods used for the removal of 17 β‐estradiol (E2) from the natural environment. In this study, E2‐degrading bacteria were screened from the enriched sediment sample from the wastewater environment. Two bacterial strains of E2‐degrading bacteria (Stenotrophomonas maltophilia MN08 and Pseudomonas aeruginosa KL10) were determined and >70% of E2‐degradation was achieved. The strain MN08 could rapidly remove approximately 86.5% ± 1.3% of E2 within 7 days of treatment. In addition, the strain KL10 removed 79.5% ± 1% of E2 within the same period. Optimized culture temperature and pH of the medium could improve E2‐degradation. The results demonstrated that the strain MN08 exhibited maximum E2‐degradation activity at 35°C, and pH 8.0. The optimal pH for strain KL10 to degrade E2 ranged from 7.0 to 9.0. The E2‐degradation level for the mixture culture systems can exhibit synergistic E2‐degradation activity. The degradation of the MN08 and KL10 individual strains was 87.3% ± 1.2% and 81.4% ± 1.5%, respectively. The E2‐degradation potential for the mixed culture system was 91.3% ± 2.9% under optimized conditions in which 100 mg/L of E2 served as the sole source of carbon and energy. The present finding demonstrates that the co‐culture of S. maltophilia MN08 and P. aeruginosa KL10 may provide a promising bio‐treatment strategy for the removal of steroids from wastewater. [ABSTRACT FROM AUTHOR]

Abstract Introduction Melasma is a common acquired disorder of melanogenesis that predominately affects women and presents as hyperpigmented skin lesions mainly located on the face. The study aims to investigate the epidemiologic characteristics and hormonal profiles in melasma patients. Methods One hundred fifty patients were enrolled in this study in a tertiary care hospital. Clinical patterns, pigment depth, disease severity, underlying conditions, and heredity were recorded. Endocrinologic profile and vitamin D levels were assessed. Results On clinical examination, the condition indicated a centrofacial localization in 74% of the patients. Extra facial melasma was noticed in 10 patients who had centrofacial melasma to begin with. Wood's lamp examination showed the dermal type as the most common. A family history of melasma was noted in 38% of the patients. Melasma Area and Severity Index (MASI) score ranged from 0.3 to 10.8, with a mean score of 4.12 ± 2.06. Pregnancy-induced melasma was reported in 36.1% of the patients. In 17.4% of women, melasma was related to using oral contraceptives. In 22% of patients, mild vitamin D deficiency was detected, while 21% had thyroid disorders. Conclusion There is a strong correlation between family history and prevalence of melasma. Sun exposure is a major precipitating factor and should be carefully addressed in Mediterranean countries like Greece. However, other factors such as concomitant medication, multiple pregnancies, use of oral contraceptives, thyroid disorders and vitamin D deficiency might precipitate melasma.

Pathologic pain is a serious chronic disease, including inflammatory pain, neuropathic pain and cancer pain. Previous studies have proved a close correlation of estrogen and its receptors with pathologic pain, which plays an important role in its occurrence and development, therefore, it has attracted the attention of many researchers at home and abroad. Combining the relevant literature at home and abroad in recent years, this paper reviews the relevant research progress of the mechanism of estrogen and its receptors in pathologic pain, in order to provide a theoretical basis for the prevention and treatment of pathologic pain, as well as the guidance for future research.

Aim: systemically assessed characteristics of intestinal microbiota taxonomic composition in relation to parameters of hormonal and immune status in patients with external genital endometriosis (EGE).Materials and Methods. The controlled cross-sectional study included 33 patients with EGE comprising main group, and 30 healthy women enrolled to control group. All women underwent assessment of hormonal status and cytokine expression levels in peripheral blood. Level of blood hormones estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL) was carried out using enzyme-linked immunosorbent and chemiluminescent assays. Expression levels of cytokines such as interleukin (IL) IL-6, IL-8, tumor necrosis factor alpha (TNF-α) were analyzed by an enzyme-linked immunosorbent assay. Taxonomic composition of intestinal microbiota at the level of phyla and genera was carried out by 16S ribosomal RNA gene sequencing. Microbial community a-diversity, the Chao1, ACE, and Sobs indices were used.Results. The concentration of blood E2 in main group was significantly higher compared to control group. Also, women with EGE had higher plasma concentrations for IL-6, IL-8, IL-17 and TNF-a compared to those in control group (p < 0.001). While analyzing bacterial community a-diversity in main group, Chao1 index was found to be significantly decreased. At the phylum level, the Firmicutes/Bacteroidetes ratio was increased in patients with EGE compared with that in control group. Among the 20 largest genera in patients with EGE, significant abundance was observed for Lachnospira, Blautia, Dorea, Streptococcus, Eubacterium hallii_group paralleled with significant decline in Bifidobacterium and Eubacterium eligens_group. A positive correlation was obtained between estrogen levels and the number of representatives from the genera Eubacterium hallii_group and Streptococcus, IL-8 and Streptococcus, TNF-α and Streptococcus and Lachnospira, as well as a negative correlation between TNF-α and Bifidobacterium.Conclusion. A relation between dysbiotic intestinal alterations and developing endometriosis was found. The identified correlations between altered taxonomic composition of the intestinal microflora and parameters of hormonal and immune status in patients with EGE suggest that intestinal microbiota is involved in pathophysiology of endometriosis.

17α-Estradiol (17αE2), a less-feminising enantiomer of 17β-estradiol, has been shown to prolong lifespan and improve metabolic health in a sex-specific manner in male, but not in female mice. Recent studies have demonstrated the pivotal role of estrogen receptor α (ERα) in mediating the effects of 17αE2 on metabolic health. However, the specific tissues and/or neuronal signalling pathways that 17αE2 acts through remain to be elucidated. ERα expression in glutamatergic and GABAergic neurons (principal excitatory and inhibitory neurons respectively) in the hypothalamus is essential for estradiol signalling. Therefore, we hypothesised that knocking out ERα from one of these neuronal populations would attenuate the established beneficial metabolic effects of 17αE2 in male mice exposed to a high fat diet. To test this hypothesis we used two established brain specific ERα KO models, targeting either glutamatergic or GABAergic neurons (Vglut2/Vgat-ERαKO). We show that both of these ERα KO models exhibit a strong reduction in ERα expression in the arcuate nucleus of the hypothalamus, a control centre for metabolic regulation. Deletion of ERα from GABAergic neurons significantly diminished the effect of 17αE2 on body weight relative to controls, although these animals still show metabolic benefits with 17αE2 treatment. The response to 17αE2 was unaffected by ERα deletion in glutamatergic neurons. Our results support a benefit of 17αE2 treatment in protection against metabolic dysfunction, but these effects do not depend on exclusive ERα expression in glutamatergic and GABAergic neurons and persist when ERα expression is strongly reduced in the arcuate nucleus of the hypothalamus. [ABSTRACT FROM AUTHOR]

This review thoroughly explores the multifaceted roles of sexual hormones, emphasizing their impact beyond reproductive functions and underscoring their significant influence on cardiometabolic regulation. It analyzes the broader physiological implications of estrogen, testosterone, and progesterone, highlighting their effects on metabolic syndrome, lipid metabolism, glucose homeostasis, and cardiovascular health. Drawing from diverse molecular, clinical, and therapeutic studies, the paper delves into the intricate interplay between these hormones and cardiometabolic processes. By presenting a comprehensive analysis that goes beyond traditional perspectives, and recognizing sexual hormones as more than reproductive agents, the review sheds light on their broader significance in health and disease management, advocating for holistic and personalized medical approaches.

This work examined the potential benefit of curcumin in breast cancer patients as a supplementary drug in ER-positive cancers. The results indicated that in the MCF-7 human breast cancer cell line, E2 and curcumin decreased cell proliferation and the colony-forming capacity and down-regulated protein expression as well as important molecules associated with cell proliferation, such as PCNA and estrogen receptor alpha; genes associated with the epithelial-mesenchymal transition, such as β-catenin, Vimentin, and E-cadherin; and molecules associated with apoptosis. Clinical studies in bioinformatics have indicated a positive correlation between ESR1 and either CCND1 or BCL2 gene expression in all breast cancer patients. Thus, curcumin could become a potential natural adjuvant treatment for patients with estrogen receptor alpha-positive breast cancer and those with resistance or a poor response to endocrine therapy since the reactivation of estrogen receptor alpha is inevitable. [ABSTRACT FROM AUTHOR]

In 2024, the Centers for Disease Control and Prevention (CDC) in the U.S. published two essential documents that update recommendations for contraceptive use: U.S. Selected Practice Recommendations for Contraceptive Use and U.S. Medical Eligibility Criteria for Contraceptive Use. These guidelines, along with recommendations from the European Medicines Agency and recent studies, outline a detailed approach to contraceptive options. They emphasize the need for personalized counseling, tailored to patients’ preferences, taking into account their health status, comorbidities, and lifestyle. The paper presents criteria for selecting contraceptive methods and discusses specific aspects of contraception in women with obesity, migraines, cardiovascular conditions, or during the postpartum period. Contraceptive methods are diverse and may offer additional benefits, such as reducing symptoms of endometriosis and providing protection against certain types of cancer. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the risk of osteoarthritis associated with menopausal hormone therapy (MHT). Methods: This population-based retrospective cohort study used a database of Korean health insurance claims (2007--2020). Females aged ≥ 40 who initiated menopause-related healthcare visits between 2011 and 2014 were identified. The MHT group comprised females aged ≥ 40 who initiated MHT for ≥ 6 months during this period. The non-MHT group comprised females aged ≥ 40 who attended menopause-related healthcare visits but did not receive MHT. To account for potential confounding factors, the two groups were matched at a 1:1 ratio using propensity score matching. Results: A cohort of 453,040 postmenopausal females aged ≥ 40 years was identified, with 26,354 assigned to either the MHT or non- MHT group after propensity matching. The median age was 49 years, and the median follow-up was 8.2 years. The Cox proportional hazards model demonstrated an elevated risk of osteoarthritis with MHT (hazard ratio [HR], 1.154; 95% confidence interval [CI], 1.117--1.193) for knee (HR, 1.148; 95% CI, 1.102--1.195) and other arthritis (HR, 1.205; 95% CI, 1.151--1.261), although not statistically significant for hip arthritis. Tibolone (HR, 1.211; 95% CI, 1.161--1.263), estrogen--progestogen therapy (EPT) (HR, 1.092; 95% CI, 1.048-- 1.137), and estrogen therapy (ET) (HR, 1.235; 95% CI, 1.148--1.329) were associated with a higher risk of osteoarthritis compared to non- MHT users. Conclusions: MHT was associated with an increased risk of osteoarthritis, consistently observed across tibolone, EPT, and ET, particularly affecting joints other than the hip, with a trend toward an elevated risk of hip osteoarthritis. [ABSTRACT FROM AUTHOR]

Declines in estrogen levels occur in women transitioning to menopause. Estrogen hormones play important roles in multiple systems of the body, and estrogen loss is associated with a variety of symptoms that can decrease quality of life. The gut microbiota is involved in regulating endogenous estrogen levels. A portion of estrogen glucuronides can be reactivated in the gut by the microbial enzyme β-glucuronidase, and the resulting free estrogens can return to the bloodstream. Here, we carried out in vitro screening of β-glucuronidase activities for 84 strains belonging to 16 different species of lactic acid bacteria and bifidobacteria and found that one and three strains of Levilactobacillus brevis and Lacticasebacillus rhamnosus, respectively, can deconjugate estrogens. Among these strains, L. brevis KABP052 had the highest β-glucuronidase activity. Moreover, in an exploratory, randomized, double-blind, placebo-controlled trial, we demonstrated that serum estrogen levels in healthy peri- and postmenopausal women given a probiotic formula containing KABP052 were maintained over time, whereas levels significantly decreased in the group given a placebo. Significantly higher levels of estradiol (31.62 ± 7.97 pg/mL vs. 25.12 ± 8.17 pg/mL) and estrone (21.38 ± 8.57 pg/mL vs. 13.18 ± 8.77 pg/mL) were observed in the probiotic versus placebo group after 12 weeks of intervention. This clinical study demonstrated for the first time the estrogen modulation capacity of a probiotic formula containing a bacterial strain having β-glucuronidase activity in women during the menopausal transition and formed the basis for future investigations using probiotics in the menopausal population. [ABSTRACT FROM AUTHOR]

Sexual dimorphism among mammals includes variations in the pain threshold. These differences are influenced by hormonal fluctuations in females during the estrous and menstrual cycles of rodents and humans, respectively. These physiological conditions display various phases, including proestrus and diestrus in rodents and follicular and luteal phases in humans, distinctly characterized by varying estrogen levels. In this study, we evaluated the capsaicin responses in male and female mice at different estrous cycle phases, using two murine acute pain models. Our findings indicate that the capsaicin-induced pain threshold was lower in the proestrus phase than in the other three phases in both pain assays. We also found that male mice exhibited a higher pain threshold than females in the proestrus phase, although it was similar to females in the other cycle phases. We also assessed the mRNA and protein levels of TRPV1 in the dorsal root and trigeminal ganglia of mice. Our results showed higher TRPV1 protein levels during proestrus compared to diestrus and male mice. Unexpectedly, we observed that the diestrus phase was associated with higher TRPV1 mRNA levels than those in both proestrus and male mice. These results underscore the hormonal influence on TRPV1 expression regulation and highlight the role of sex steroids in capsaicin-induced pain. [ABSTRACT FROM AUTHOR]

A novel magnetic dispersive solid phase extraction (MDSPE) procedure based on the deep eutectic solvent (DES) modified magnetic graphene oxide/metal organic frameworks nanocomposites (MGO@ZIF-8@DES) was established and used for the efficient enrichment of estradiol, estrone, and diethylstilbestrol in cosmetics (toner, lotion, and cream) for the first time. Then, the three estrogens were separated and determined by UHPLC-UV analysis method. In order to study the features and morphology of the synthesized adsorbents, various techniques such as FT-IR, SEM, and VSM measurements were executed. The MGO@ZIF-8@DES nanocomposites combine the advantages of high adsorption capacity, adequate stability in aqueous solution, and convenient separation from the sample solution. To achieve high extraction recoveries, the Box-Behnken design and single factor experiment were applied in the experimental design. Under the optimum conditions, the method detection limits for three estrogens were 20–30 ng g−1. This approach showed a good correlation coefficient (r more than 0.9998) and reasonable linearity in the range 70–10000 ng g−1. The relative standard deviations for intra-day and inter-day were beneath 7.5% and 8.9%, respectively. The developed MDSPE-UHPLC-UV method was successfully used to determine three estrogens in cosmetics, and acceptable recoveries in the intervals of 83.5–95.9% were obtained. Finally, three estrogens were not detected in some cosmetic samples. In addition, the Complex GAPI tool was used to evaluate the greenness of the developed pretreatment method. The developed MDSPE-UHPLC-UV method is sensitive, accurate, rapid, and eco-friendly, which provides a promising strategy for determining hormones in different complex samples. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder that primarily manifests itself by progressive memory loss and cognitive decline, thus significantly affecting memory functions and quality of life. In this review, we proceed from the understanding that the canonical amyloid‐β hypothesis, while significant, has faced setbacks, highlighting the need to adopt a broader perspective considering the intricate interplay of diverse pathological pathways for effective AD treatments. Sex differences in AD offer valuable insights into a better understanding of its pathophysiology. Fluctuation of the levels of ovarian sex hormones during perimenopause is associated with changes in glucose metabolism, as a possible window of opportunity to further understand the roles of sex steroid hormones and their associated receptors in the pathophysiology of AD. We review these dimensions, emphasizing the potential of estrogen receptors (ERs) to reveal mitochondrial functions in the search for further research and therapeutic strategies for AD pharmacotherapy. Understanding and addressing the intricate interactions of mitochondrial dysfunction and ERs potentially pave the way for more effective approaches to AD therapy. [ABSTRACT FROM AUTHOR]

Background: A woman's entry into the menopause period is associated with a number of changes in the body, including those related to the immune system. Immune aging is a consequence of age-related changes in the function of immune cells and the composition of their subpopulations. Menopausal hormone therapy (MHT) is thought to partially neutralize the negative effects of aging on the immune system. Objective: We aimed to evaluate the effect of oral and transdermal MHT on cellular immunity parameters and cytokine profile in menopausal women. Methods: Fifty peri- and early postmenopausal women were included. Immune parameters were assessed by flow cytometry and multiplex analysis. Results: We showed that different routes of MHT administration led to significant changes in monocyte phenotype and a decrease in monocyte chemoattractant protein-1 (MCP-1) level in menopausal patients. In addition, oral MHT resulted in a significant increase in NK and B cells. A significant increase in the number of T-helper cells was observed with transdermal MHT. In addition, oral MHT resulted in a significant decrease in IL-1β level. Conclusions: We have demonstrated for the first time that oral therapy, in contrast to transdermal therapy, has a more pronounced effect on specific immune subpopulations of blood cells in menopausal women. This effect is likely to be responsible for its anti-aging properties in the context of immune aging as well as its protective effects in infectious diseases. Perhaps testing blood immune parameters or assessing immune status before prescribing MHT could become a routine step in clinical practice before choosing a patient management strategy. [ABSTRACT FROM AUTHOR]

The role of estrogens in prostate cancer (PCa) is shrouded in mystery, with its actions going from angelic to devilish. The findings by Huggins and Hodges establishing PCa as a hormone-sensitive cancer have provided the basis for using estrogens in therapy. However, despite the clinical efficacy in suppressing tumor growth and the panoply of experimental evidence describing its anticarcinogenic effects, estrogens were abolished from PCa treatment because of the adverse secondary effects. Notwithstanding, research work over the years has continued investigating the effects of estrogens, reporting their pros and cons in prostate carcinogenesis. In contrast with the beneficial therapeutic effects, many reports have implicated estrogens in the disruption of prostate cell fate and tissue homeostasis. On the other hand, epidemiological data demonstrating the lower incidence of PCa in Eastern countries associated with a higher consumption of phytoestrogens support the beneficial role of estrogens in counteracting cancer development. Many studies have investigated the effects of phytoestrogens and the underlying mechanisms of action, which may contribute to developing safe estrogen-based anti-PCa therapies. This review compiles the existing data on the anti- and protumorigenic actions of estrogens and summarizes the anticancer effects of several phytoestrogens, highlighting their promising features in PCa treatment. [ABSTRACT FROM AUTHOR]

A novel ferrofluid prepared from a hydrophobic deep eutectic solvent (DES) and Fe3O4@graphite composite materials was introduced as a green microextraction medium for the separation and enrichment of trace estrogens in real samples. It was found that the ferrofluid greatly improved the capacity and selectivity of target analytes, benefiting from the enrichment of both DES and Fe3O4@graphite composite materials. Using a combination of high-performance liquid chromatography–fluorescence detection (HPLC-FLD) and vortex-assisted liquid–liquid microextraction (VALLME), a new method was established for simultaneous rapid processing and accurate determination of three estrogens (estradiol [E2], estriol [E3], and ethinyl estradiol [EE2]) in environmental water and urine samples. Key parameters affecting the extraction efficiency were optimized using a single-factor approach and response surface methodology. Under optimal conditions, this method yielded a low limit of detection (1.01 ng L−1, 3.03 ng L−1, and 25.0 ng L−1 for EE2, E2, and E3, respectively), wide linear range (3–200,000 ng L−1), high enrichment factors (9.81–47.2), and satisfactory recovery (73.8–129.0%). Compared with traditional analytical techniques, this method avoids the use of volatile toxic organic extraction solvents and cumbersome phase separation operations. [ABSTRACT FROM AUTHOR]

Purpose: The aromatase inhibitor letrozole and the aromatase inactivator exemestane are two of the most pivotal cancer drugs used for endocrine treatment of ER-positive breast cancer in all phases of the disease. Although both drugs inhibit CYP19 (aromatase) and have been used for decades, a direct head-to-head, intra-patient-cross-over comparison of their ability to decrease estrogen synthesis in vivo is still lacking. Methods: Postmenopausal breast cancer patients suitable for neoadjuvant endocrine therapy were randomized to receive either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) for an initial treatment period, followed by a second treatment period on the alternative drug (intra-patient cross-over study design). Serum levels of estrone (E1), estradiol (E2), letrozole, exemestane, and 17-hydroxyexemestane were quantified simultaneously using a novel, ultrasensitive LC–MS/MS method established in our laboratory. Results: Complete sets of serum samples (baseline and during treatment with letrozole or exemestane) were available from 79 patients, including 40 patients starting with letrozole (cohort 1) and 39 with exemestane (cohort 2). Mean serum estrone and estradiol levels in cohort 1 were 174 pmol/L and 46.4 pmol/L at baseline, respectively. Treatment with letrozole suppressed serum E1 and E2 to a mean value of 0.2 pmol/L and 0.4 pmol/L (P < 0.001). After the cross-over to exemestane, mean serum levels of E1 and E2 increased to 1.4 pmol/L and 0.7 pmol/L, respectively. In cohort 2, baseline mean serum levels of E1 and E2 were 159 and 32.5 pmol/L, respectively. Treatment with exemestane decreased these values to 1.8 pmol/L for E1 and 0.6 pmol/L for E2 (P < 0.001). Following cross-over to letrozole, mean serum levels of E1 and E2 were significantly further reduced to 0.1 pmol/L and 0.4 pmol/L, respectively. Serum drug levels were monitored in all patients throughout the entire treatment and confirmed adherence to the protocol and drug concentrations within the therapeutic range for all patients. Additionally, Ki-67 values decreased significantly during treatment with both aromatase inhibitors, showing a trend toward a stronger suppression in obese women. Conclusion: To the best of our knowledge, we present here for the first time a comprehensive and direct head-to-head, intra-patient-cross-over comparison of the aromatase inhibitor letrozole and the aromatase inactivator exemestane concerning their ability to suppress serum estrogen levels in vivo. All in all, our results clearly demonstrate that letrozole therapy results in a more profound suppression of serum E1 and E2 levels compared to exemestane. [ABSTRACT FROM AUTHOR]

Background:d-Chiro-inositol is a natural molecule that, in association with its well-studied isomer myo-inositol, may play a role in treating various metabolic and gynecological disorders. Objectives: This perspective seeks to explore the mechanisms and functions of d-chiro-inositol, laying the foundations to discuss its use in clinical practice, across dysmetabolism, obesity, and hormonal dysregulation. Methods: A narrative review of all the relevant papers known to the authors was conducted. Outcome:d-Chiro-inositol acts through a variety of mechanisms, acting as an insulin sensitizer, inhibiting the transcription of aromatase, in addition to modulating white adipose tissue/brown adipose tissue transdifferentiation. These different modes of action have potential applications in a variety of therapeutic fields, including PCOS, dysmetabolism, obesity, hypoestrogenic/hyperandrogenic disorders, and bone health. Conclusions:d-Chiro-inositol mode of action has been studied in detail in recent years, resulting in a clear differentiation between d-chiro-inositol and its isomer myo-inositol. The insulin-sensitizing activities of d-chiro-inositol are well understood; however, its potential applications in other fields, in particular obesity and hyperestrogenic/hypoandrogenic disorders in men and women, represent promising avenues of research that require further clinical study. [ABSTRACT FROM AUTHOR]

A large body of evidence indicates that vasopressin (AVP) and steroid hormones are frequently secreted together and closely cooperate in the regulation of blood pressure, metabolism, water–electrolyte balance, and behavior, thereby securing survival and the comfort of life. Vasopressin cooperates with hormones of the hypothalamo–pituitary–adrenal axis (HPA) at several levels through regulation of the release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and multiple steroid hormones, as well as through interactions with steroids in the target organs. These interactions are facilitated by positive and negative feedback between specific components of the HPA. Altogether, AVP and the HPA cooperate closely as a coordinated functional AVP-HPA system. It has been shown that cooperation between AVP and steroid hormones may be affected by cellular stress combined with hypoxia, and by metabolic, cardiovascular, and respiratory disorders; neurogenic stress; and inflammation. Growing evidence indicates that central and peripheral interactions between AVP and steroid hormones are reprogrammed in cardiovascular and metabolic diseases and that these rearrangements exert either beneficial or harmful effects. The present review highlights specific mechanisms of the interactions between AVP and steroids at cellular and systemic levels and analyses the consequences of the inappropriate cooperation of various components of the AVP-HPA system for the pathogenesis of cardiovascular and metabolic diseases. [ABSTRACT FROM AUTHOR]

This study aimed to assess the correlation between glycemic status (prediabetes and type 2 diabetes mellitus) and the risk of gastric cancer according to menopausal status. A total of 982,559 pre/peri-menopausal and 1445,419 postmenopausal women aged ≥ 40, who underwent the Korean national health screening in 2009, were included and followed up until 2018. Hazard ratio (HR) and 95% confidence interval (CI) were calculated for development of gastric cancers according to hyperglycemic status in both groups using Cox proportional hazards models. Over a mean follow-up period of 8.3 years, 3259 (0.33%) pre/peri-menopausal women and 13,245 (0.92%) postmenopausal women were diagnosed with gastric cancer. In postmenopausal women, only diabetes mellitus conferred a higher risk of gastric cancer compared to normal glycemic status (HR, 1.15; 95% CI, 1.09–1.20), with an increasing trend of gastric cancers from prediabetes to diabetes (P for trend < 0.001) observed regardless of menopausal status. Obesity, smoking, and heavy alcohol consumption was associated with increased gastric cancer risk mainly in the postmenopausal period. The risk of gastric cancer escalates with deteriorating glycemic status in a dose-response manner. Diabetes mellitus is linked with an elevated risk of gastric cancer in postmenopausal women. [ABSTRACT FROM AUTHOR]

Brain lipid homeostasis is an absolute requirement for proper functionality of nerve cells and neurological performance. Current evidence demonstrates that lipid alterations are linked to neurodegenerative diseases, especially Alzheimer's disease (AD). The complexity of the brain lipidome and its metabolic regulation has hampered the identification of critical processes associated with the onset and progression of AD. While most experimental studies have focused on the effects of known factors on the development of pathological hallmarks in AD, e.g., amyloid deposition, tau protein and neurofibrillary tangles, neuroinflammation, etc., studies addressing the causative effects of lipid alterations remain largely unexplored. In the present study, we have used a multifactor approach combining diets containing different amounts of polyunsaturated fatty acids (PUFAs), estrogen availabilities, and genetic backgrounds, i.e., wild type (WT) and APP/PS1 (FAD), to analyze the lipid phenotype of the frontal cortex in middle-aged female mice. First, we observed that severe n-3 PUFA deficiency impacts the brain n-3 long-chain PUFA (LCPUFA) composition, yet it was notably mitigated by hepatic de novo synthesis. n-6 LCPUFAs, ether-linked fatty acids, and saturates were also changed by the dietary condition, but the extent of changes was dependent on the genetic background and hormonal condition. Likewise, brain cortex phospholipids were mostly modified by the genotype (FAD>WT) with nuanced effects from dietary treatment. Cholesterol (but not sterol esters) was modified by the genotype (WT>FAD) and dietary condition (higher in DHA-free conditions, especially in WT mice). However, the effects of estrogen treatment were mostly observed in relation to phospholipid remodeling in a genotype-dependent manner. Analyses of lipid-derived variables indicate that nerve cell membrane biophysics were significantly affected by the three factors, with lower membrane microviscosity (higher fluidity) values obtained for FAD animals. In conclusion, our multifactor analyses revealed that the genotype, diet, and estrogen status modulate the lipid phenotype of the frontal cortex, both as independent factors and through their interactions. Altogether, the outcomes point to potential strategies based on dietary and hormonal interventions aimed at stabilizing the brain cortex lipid composition in Alzheimer's disease neuropathology. [ABSTRACT FROM AUTHOR]

There is a need to fully know the physiology of Eurasian beaver due to its essential role in environmental homeostasis. However, a "human factor" impacts this, including stress conditions and environmental pollution. Adrenal glands protect these all. The regulation of endocrine processes by nonclassical androgen and estrogen signaling, the first and fastest control, is still a matter of research. The specific analyses performed here in mature female and male beaver adrenals contained: anatomical and histological examinations, expression and localization of membrane androgen receptor (zinc transporter, Zinc‐ and Iron‐like protein 9; ZIP9) and membrane estrogen receptor coupled with G protein (GPER), and measurement of zinc (Zn2+) and copper (Ca2+) ion levels and corticosterone levels. We revealed normal anatomical localization, size, and tissue histology in female and male beavers, respectively. Equally, ZIP9 and GPER were localized in the membrane of all adrenal cortex cells. The protein expression of these receptors was higher (p < 0.001) in male than female adrenal cortex cells. Similarly, Zn2+ and Ca2+ ion levels were higher (p < 0.05, p < 0.01) in male than female adrenal cortex. The increased corticosterone levels (p < 0.001) were detected in the adrenal cortex of females when compared to males. The present study is the first to report the presence of nonclassical androgen and estrogen signaling and its possible regulatory function in the adrenal cortex of Eurasian beavers. We assume that this first‐activated and fast‐transmitted regulation can be important in the context of the effect of environmental physical and chemical stressors especially on adrenal cortex cells. The beaver adrenals may constitute an additional supplementary model for searching for universal mechanisms of adrenal cortex physiology and diseases. Highlights: There are no sex‐specific changes in the anatomy and histology of Eurasian beavers.Expression of ZIP9 and GPER is higher in males.Zn2+ and Ca2+ levels were higher in males.The corticosterone levels are higher in females. [ABSTRACT FROM AUTHOR]

Purpose: Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways. Methods: This analysis included 1208 women from a case–cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex-hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders. Results: Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI 1.03 to 1.44), androstenedione (RR 1.20, 95% CI 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI 0.98 to 1.28), estrone (RR 1.21, 95% CI 0.99 to 1.48), total estradiol (RR 1.19, 95% CI 1.02 to 1.39) and free estradiol (RR 1.22, 95% CI 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR 0.83, 95% CI 0.66 to 1.05). Conclusion: Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex-hormone-driven nature of postmenopausal breast cancer. [ABSTRACT FROM AUTHOR]

This narrative review delves into the area of endogenous hormones and their impact on cognitive function, with a focus on women transitioning through perimenopause. While artificial intelligence technologies have revolutionized cognitive research, the inclusion of hormonal biomarkers remains sparse. The review synthesizes findings from diverse studies exploring the relationships between estrogen, progesterone, testosterone, other sex hormones, and cognitive performance. The research question explores the potential for monitoring endogenous hormonal levels during perimenopause to predict cognitive decline and inform preventive strategies. An analysis of relevant studies reveals a complex relationship, with varying impacts on cognitive domains. Thus, high E2 levels correlate positively with verbal memory and retrieval efficiency, contrasting with lower levels associated with enhanced visual memory, and testosterone shows positive links to verbal fluency. The limitations of existing research, including heterogeneous methodologies and a dearth of premenopausal representation, emphasize the necessity for future studies. To achieve this objective, it is important to leverage data from studies implementing standardized methodologies for tracking endogenous hormonal levels while accounting for cycle phases and menopausal transition stages. Additionally, employing standardized assessments for cognitive decline and analyzing extensive datasets derived from real-world sources, such as hospital or outpatient clinic chains, and digital apps, is crucial. [ABSTRACT FROM AUTHOR]

Sex differences in colorectal cancer (CRC) has received considerable research attention recently, particularly regarding the influence of sex hormones and the intestinal microbiota. Estrogen, at the genetic and epigenetic levels, directly inhibits CRC cell proliferation by enhancing DNA mismatch repair, regulating miRNAs, blocking the cell cycle, and modulating ion channels. However, estradiol’s activation of GPER promotes oncogene expression. Conversely, androgen contributes to epigenetic dysregulation and CRC progression via nuclear receptors while inducing apoptosis through membrane receptors. Specific gut microorganisms produce genotoxins and oncogenic metabolites that damage colonic cell DNA and contribute to cancer induction. Regarding the tumor microenvironment, estrogen mitigates intestinal inflammation, reverses immunosuppression, increases gut microbiome diversity and commensal bacteria abundance, and decreases pathogen enrichment. On the contrary, androgen disrupts intestinal microecology, diminish immunotherapy efficacy, and exacerbate colonic inflammation and tumor growth. The impact of estrogen and androgen is closely tied to their receptor status, elucidating their dual roles in CRC pathogenesis. This review comprehensively discusses the direct and indirect effects of sex hormones and the intestinal microbiota on CRC, considering environmental factors such as diet and lifestyle to propose novel prevention and treatment strategies.

The expression of BDNF in both neuronal and non-neuronal cells is influenced by various stimuli, including prenatal developmental factors and postnatal conditions such as estrogens, dietary habits, and lifestyle factors like obesity, blood pressure, and aging. Central BDNF plays a crucial role in modulating how target tissues respond to these stimuli, influencing the pathogenesis of hypertension, mitigating obesity, and protecting neurons from aging. Thus, BDNF serves as a dynamic mediator of environmental influences, reflecting an individual's unique history of exposure. Estrogens, on the other hand, regulate various processes to maintain overall physiological well-being. Through nuclear estrogen receptors (ERα, ERβ) and the membrane estrogen receptor (GPER1), estrogens modulate transcriptional processes and signaling events that regulate the expression of target genes, such as ERα, components of the renin-angiotensin system (RAS), and hormone-sensitive lipase. Estrogens are instrumental in maintaining the set point for blood pressure and energy balance. BDNF and estrogens work cooperatively to prevent obesity by favoring lipolysis, and counteractively regulate blood pressure to adapt to the environment. Estrogen deficiency leads to menopause in women with low central BDNF level. This review delves into the complex mechanisms involving BDNF and estrogen, especially in the context of hypertension and obesity, particularly among postmenopausal women. The insights gained aim to inform the development of comprehensive therapeutic strategies for these prevalent syndromes affecting approximately 68% of adults.

Background & Aims: The loss of ovarian functions defining menopause leads to profound metabolic changes and heightens the risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). Although estrogens primarily act on the female liver through estrogen receptor alpha (ERα), the specific contribution of impaired ERα signaling in triggering MASLD after menopause remains unclear. Methods: To address this gap in knowledge, we compared the liver transcriptomes of sham-operated (SHAM) and ovariectomized (OVX) control and liver ERα knockout (LERKO) female mice by performing RNA-Seq analysis. Results: OVX led to 1426 differentially expressed genes (DEGs) in the liver of control mice compared to 245 DEGs in LERKO mice. Gene ontology analysis revealed a distinct ovariectomy-induced modulation of the liver transcriptome in LERKO compared with controls, indicating that hepatic ERα is functional and necessary for the complete reprogramming of liver metabolism in response to estrogen depletion. Additionally, we observed an ovariectomy-dependent induction of male-biased genes, especially in the liver of control females, pointing to hepatic ERα involvement in the masculinization of the liver after estrogen loss. To investigate the translational relevance of such findings, we assessed liver samples from a cohort of 60 severely obese individuals (51 women; 9 men). Notably, a shift of the liver transcriptome toward a male-like profile was also observed only in obese women with MASLD (n = 43), especially in women ≥51 years old (15/15), suggesting that masculinization of the female liver contributes to MASLD development in obese women. Conclusions: These results highlight the role of hepatic ERα in driving masculinization of the liver transcriptome following menopause, pointing to this receptor as a potential pharmacological target for preventing MASLD in post-menopausal women. Impact and implications:: Despite the increased risk of developing MASLD after menopause, the specific contribution of impaired hepatic estrogen signaling in driving MASLD in females has not been a major research focus, and, thus, has limited the development of tailored strategies that address the specific mechanisms underlying MASLD in post-menopausal women. This study reveals the functional role of hepatic ERα in mediating liver metabolic changes in response to estrogens loss, leading to a shift in the liver transcriptome towards a male-like profile. In women with obesity, this shift is associated with the development of MASLD. These findings underscore the potential of targeting hepatic ERα as a promising approach for developing effective, sex-specific treatments to preserve liver health and prevent or limit the development and progression of MASLD in post-menopausal women.

This narrative review delves into the area of endogenous hormones and their impact on cognitive function, with a focus on women transitioning through perimenopause. While artificial intelligence technologies have revolutionized cognitive research, the inclusion of hormonal biomarkers remains sparse. The review synthesizes findings from diverse studies exploring the relationships between estrogen, progesterone, testosterone, other sex hormones, and cognitive performance. The research question explores the potential for monitoring endogenous hormonal levels during perimenopause to predict cognitive decline and inform preventive strategies. An analysis of relevant studies reveals a complex relationship, with varying impacts on cognitive domains. Thus, high E2 levels correlate positively with verbal memory and retrieval efficiency, contrasting with lower levels associated with enhanced visual memory, and testosterone shows positive links to verbal fluency. The limitations of existing research, including heterogeneous methodologies and a dearth of premenopausal representation, emphasize the necessity for future studies. To achieve this objective, it is important to leverage data from studies implementing standardized methodologies for tracking endogenous hormonal levels while accounting for cycle phases and menopausal transition stages. Additionally, employing standardized assessments for cognitive decline and analyzing extensive datasets derived from real-world sources, such as hospital or outpatient clinic chains, and digital apps, is crucial.

Estrogens are hormones that play an important role in the digestive tract, including in men. Letrozole is an inhibitor of cytochrome P450 aromatase, an enzyme converting androgens to estrogens. The use of letrozole may cause oxidative stress and endoplasmic reticulum stress in the cells. Factors modulating cellular stress may include vitamin C. The purpose of this study was to examine whether letrozole and/or vitamin C supplementation can affect the morphology of the small intestine, the parameters of endoplasmic reticulum stress, programmed cell death markers, and oxidative damage. Three-month-old male rats were divided into four groups and treated with the following: (I) CTRL—water; (II) CTRL+C—L-ascorbic acid; (III) LET—letrozole; and (IV) LET+C—letrozole + L-ascorbic acid. The morphometrical measurements included epithelial thickness, crypt and lumen area, crypt perimeter, nuclei number in the crypt, and the cell size of crypts. The expression levels of PERK, caspase-3, and catalase were determined. Significant differences in the morphometrical measurements and immunoexpression were observed. This may indicate that chronic treatment with letrozole can affect morphology and induce ER stress, oxidative stress, and programmed cell death in the epithelial cells of the small intestine of adult male rats. Vitamin C supplementation exerts an effect on some parameters of the molecular processes.

Objective: The significance of the onset of seizure based on the medical and social aspects of epilepsy. The aim of this study was to investigate the age of seizure onset based on the specific characteristics of each age of seizure onset in many epilepsy syndromes to make an appropriate diagnosis. Methods: The age at epilepsy was retrospectively studied in 155 women aged between 16 and 45 years with a verified diagnosis of epilepsy. The epidemiological method revealed the age at epilepsy onset, and females were divided into three groups: pre-puberty (10-11 years old), puberty (10-18 years old), and post-puberty (18+ years old). A correlation study of the frequency of onset with the periods of formation and function of the female reproductive tract was conducted. Results: A statistically significant quantitative predominance of females with epilepsy onset during puberty (p

Context: Echinacea purpurea, a well-known herbal remedy, is believed to possess immunomodulatory properties and has been traditionally utilized for a wide range of health benefits. However, its antiviral activities, particularly against SARS-CoV-2, and its modulation of reproductive hormones remain unknown. Aims: To investigate the utilization of E. purpurea herbal preparations as an antiviral by evaluating the Transmembrane Serine Protease 2 (TMPRSS2) expression and investigating its effect on reproductive hormones by measuring androgen in males and estrogen in females. Methods: Forty male and female participants were randomly assigned to different groups. Daily administration of 400 mg of E. purpurea herbal preparations for 28 days constituted the intervention. The gathering of demographic data was documented. Before and after the intervention, samples were collected for investigation, which included the ELISA-based assessment of androgen, estrogen, and TMPRSS2 expression. Results: This study indicated that administration of E. purpurea can significantly down-regulate TMPRSS2 expression in both males (8.39 ± 1.13 to 4.16 ± 1.53; p=0.000) and females (14.18 ± 1.93 to 5.25 ± 1.13; p=0.000). The androgen was also significantly down-regulated in the male intervention group (22.73 ± 1.75 to 12.72 ± 2.26; p=0.000). In addition, estrogen levels were also significantly up-regulated in the female intervention group (72.33 ± 11.12 to 161.14 ± 35.13; p=0.000). Conclusions: E. purpurea may be capable of down-regulating androgen in males, up-regulating estrogen in females, and down-regulating TMPRSS2 expression. This study contributes to the growing body of literature exploring the effects of E. purpurea as an antiviral property, especially for SARS-CoV-2, and its effect on reproductive hormones.

Endometriosis is a common estrogen-dependent inflammatory disease with a chronic course and a tendency to recur. The association between endometriosis and cancer has been studied for several years. Numerous reports have demonstrated a strong association between specific ovarian malignancies and endometriotic lesions. Atypical endometriosis has been widely described as a malignant precursor to ovarian epithelial tumors, particularly clear cell carcinomas and endometrioid carcinomas. These histological types associated with endometriosis develop predominantly in the ovary rather than in extragonadal sites. The detailed molecular mechanism of etiology remains unclear. Recent studies have analyzed the genetic and molecular mechanisms involved in endometriosis-associated ovarian cancer. A critical role appears to be played by a carcinogenic model based on iron-induced oxidative stress, which is typical of the endometriosis microenvironment. It has been hypothesized that trans-tubal reflux of blood, endometrial cells and associated iron-induced oxidative stress underlie the development of endometriosis-associated ovarian cancer. However, the multifactorial mechanisms of this malignant transformation are not fully understood. The aim of this review is to summaries the current epidemiological, histopathological, genetic and molecular findings in the progression of endometriosis-associated ovarian cancer.

There are fewer investigations conducted on human primary endometrial epithelial cells (HPEECs) compared to human primary endometrial stromal cells (HPESCs). One of the main reasons is the scarcity of protocols enabling prolonged epithelial cell culture. Even though it is possible to culture HPEECs in 3D over a longer period of time, it is technically demanding. In this study, we successfully established a highly pure, stable, and long-term viable human conditionally reprogrammed endometrial epithelial cell line, designated as eCRC560. These cells stained positive for epithelial markers, estrogen and progesterone receptors, and epithelial cell–cell contacts but negative for stromal and endothelial cell markers. Estradiol (ES) reduced the abundance of ZO-1 in a time- and dose-dependent manner, in contrast to the dose-dependent increase with the progestin dienogest (DNG) when co-cultured with HPESCs. Moreover, ES significantly increased cell viability, cell migration, and invasion of the eCRC560 cells; all these effects were inhibited by pretreatment with DNG. DNG withdrawal led to a significantly disrupted monolayer of eCRC560 cells in co-culture with HPESCs, yet it markedly increased the adhesion of eCRC560 to the human mesothelial MeT-5A cells. The long-term viable eCRC560 cells are suitable for in vitro analysis of HPEECs to study the epithelial compartment of the human endometrium and endometrial pathologies. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea, a common form of sleep-disordered breathing, is characterized by intermittent cessations of breathing that reduce blood oxygen levels and contribute to the development of hypertension. Hypertension is a major complication of obstructive sleep apnea that elevates the risk of end-organ damage. Premenopausal women have a lower prevalence of obstructive sleep apnea and cardiovascular disease than men and postmenopausal women, suggesting that sex hormones play a role in the pathophysiology of sleep apnea-related hypertension. The lack of protection in men and postmenopausal women implicates estrogen and progesterone as protective agents but testosterone as a permissive agent in sleep apnea-induced hypertension. A better understanding of how sex hormones contribute to the pathophysiology of sleep apnea-induced hypertension is important for future research and possible hormone-based interventions. The effect of sex on the pathophysiology of sleep apnea and associated intermittent hypoxia-induced hypertension is of important consideration in the screening, diagnosis, and treatment of the disease and its cardiovascular complications. This review summarizes our current understanding of the impact of sex hormones on blood pressure regulation in sleep apnea with a focus on sex differences. [ABSTRACT FROM AUTHOR]

BACKGROUND: Arterial stiffness is a cardiovascular risk factor and dramatically increases as women transition through menopause. The current study assessed whether a mouse model of menopause increases arterial stiffness in a similar manner to aging and whether activation of the G-protein–coupled estrogen receptor could reverse stiffness. METHODS: Female C57Bl/6J mice were ovariectomized at 10 weeks of age or aged to 52 weeks, and some mice were treated with G-protein–coupled estrogen receptor agonists. RESULTS: Ovariectomy and aging increased pulse wave velocity to a similar extent independent of changes in blood pressure. Aging increased carotid wall thickness, while ovariectomy increased material stiffness without altering vascular geometry. RNA-sequencing analysis revealed that ovariectomy downregulated smooth muscle contractile genes. The enantiomerically pure G-protein–coupled estrogen receptor agonist, LNS8801, reversed stiffness in ovariectomy mice to a greater degree than the racemic agonist G-1. In summary, ovariectomy and aging induced arterial stiffening via potentially different mechanisms. Aging was associated with inward remodeling, while ovariectomy-induced material stiffness independent of geometry and a loss of the contractile phenotype. CONCLUSIONS: This study enhances our understanding of the impact of estrogen loss on vascular health in a murine model and warrants further studies to examine the ability of LNS8801 to improve vascular health in menopausal women. [ABSTRACT FROM AUTHOR]

A subset of bacterial species that holds genes encoding for β-glucuronidase and β-galactosidase, enzymes involved in the metabolism of conjugated estrogens, is called the "estrobolome." There is an emerging interest embracing this concept, as it may exert a selective impact on a number of pathologies, including oral cancer. Although the estrobolome bacteria are typically part of the gut microbiota, recent experimental pieces of evidence have suggested a crosstalk among oral and gut microbiota. In fact, several oral bacterial species are well represented also in the gut microbiota, and these microbes can effectively induce the estrobolome activation. The main pathways used for activating the estrobolome are based on the induction of the expression patterns for 2 bacterial enzymes: β-glucuronidase and aromatase, both involved in the increase of estrogen released in the bloodstream and consequently in the salivary compartment. Mechanistically, high estrogen availability in saliva is responsible for an increase in oral cancer risk for different reasons: briefly, 1) estrogens directly exert biological and metabolic effects on oral mucosa cells; 2) they can modulate the pathological profile of some bacteria, somewhere associated with neoplastic processes (i.e., Fusobacterium spp., Parvimonas ssp.); and 3) some oral bacteria are able to convert estrogens into carcinogenic metabolites, such as 4-hydroxyestrone and 16α-hydroxyestrone (16α-OHE), and can also promote local and systemic inflammation. Nowadays, only a small number of scientific studies have taken into consideration the potential correlations among oral dysbiosis, alterations of the gut estrobolome, and some hormone-dependent cancers: this lack of attention on such a promising topic could be a bias affecting the full understanding of the pathogenesis of several estrogen-related oral pathologies. In our article, we have speculated on the activity of an oral–gut–estrobolome axis, capable of synergizing these 2 important microbiotas, shedding light on a pilot hypothesis requiring further research. [ABSTRACT FROM AUTHOR]

The importance of management in women in menopause and postmenopause is not diminishing, but only gaining relevance. It is estimated that by 2050, more than 1.6 billion women worldwide will reach this age, compared to 1 billion in 2020. Vasomotor symptoms (VMS) are the most common symptoms of menopause and affect more than 70% of women. They are diagnosed in 35-50% of women in perimenopause and 30-80% women in postmenopause. Most of these symptoms persist less than 7 years after the last menstrual period, but one in four women may experience them up to 10 years, and one in ten women may experience them after 10 years. They are based on complex endocrine, neuroendocrine and epigenetic mechanisms. This article is a review of scientific literature publications aimed at determining the impact of VMSs on women’s future life based on the analysis of published modern studies. VMSs not only have a negative impact on a woman’s quality of life, but also have potential importance for cardiovascular health. The increased risk of cardiovascular diseases (CVD) after menopause is attributed to a sharp decrease of endogenous estrogen levels, which indicates its potential cardioprotective effect in premenopausal women. It has been established that VMSs are a risk factor for coronary heart disease and diabetes mellitus. The presence of non-alcoholic fatty liver disease is also significantly associated with an increased risk of early and severe forms of VMSs among perimenopausal women. Taking into account that women spend a third of their lives in the postmenopausal period, it is important to analyze the experience of their management during this difficult period. It is based on focusing on a healthy lifestyle as part of primary prevention, including regular physical activity, calcium/vitamin D intake, maintaining an optimal body weight, avoiding stress, etc. Menopausal hormone therapy (MHT) is considered as a first-line treatment for VMSs in menopause and perimenopause. Its use should be individualized, and initiation and discontinuation should not be based only on a woman’s age. Assessment of baseline CVD risk, age and period since menopause are important. It is considered a priority for women with menopause before 10 years or under 60 years of age who have no contraindications to MHT. Hormone therapy is not indicated only for the prevention of CVD. However, it has the potential to improve cardiovascular risk profile due to its beneficial effects on vascular function, lipid levels, glucose metabolism, and reduction of diabetes mellitus. Non-hormonal VMS treatment has sufficient experience of use when there are medical contraindications to hormonal therapy or a woman’s personal choice. However, MHT remains the most effective for VMS treatment. [ABSTRACT FROM AUTHOR]