Bethea M, Cook T, Stafford P
… +14 more, Knaub L, Martinez ME, Schniedewind B, Christians U, Hendrix JJ, Mestroni L, Graw S, Karimpour-Fard A, Taylor MRG, Vagnozzi RJ, Hernandez A, Scalzo R, A Sandoval D, da Silva Teixeira S
Endocrinology
· 2026 Jan · PMID 41388537
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Thyroid hormone (TH) is essential for cardiovascular function, and women are disproportionately affected by TH disorders and experience worse outcomes following myocardial infarction (MI). However, the role of sex-specif...Thyroid hormone (TH) is essential for cardiovascular function, and women are disproportionately affected by TH disorders and experience worse outcomes following myocardial infarction (MI). However, the role of sex-specific TH regulation in post-MI cardiac recovery remains poorly understood. We investigated TH homeostasis and type 3 deiodinase (D3) activity, an enzyme that inactivates TH, in male and female C57BL/6 mice following MI. Using cardiomyocyte-specific D3-deficient (Dio3ΔHeart) mice, we investigated how impaired TH inactivation influences cardiac function and mitochondrial respiration. We also examined DIO3 messenger RNA expression, which encodes the D3 enzyme, in left ventricular (LV) tissue from human donors with nonfailing (NF) hearts or ischemic cardiomyopathy (ICM). Four weeks post MI, wild-type female mice exhibited sustained cardiac D3 activity, which effectively limited 3,5,3'-triiodothyronine (T3) levels in the LV. In contrast, Dio3ΔHeart females, lacking cardiomyocyte D3, showed impaired systolic recovery, elevated LV thyroxine and T3 levels, and reduced fatty acid-supported mitochondrial respiration, effects not observed in Dio3ΔHeart males. Similarly, DIO3 expression was selectively upregulated in LV tissue from women with ICM, but not in men. These findings identify DIO3 as a key protective mechanism in females that limits T3-induced metabolic stress and preserves mitochondrial function after MI, revealing a sex-dependent pathway with therapeutic relevance for cardiac recovery.
Currently, worldwide millions of individuals, athletes, and non-athletes, of different ages and probably of all social genders (cisgender males and females, male to female (MtF) and female to male (FtM) transgenders, etc...Currently, worldwide millions of individuals, athletes, and non-athletes, of different ages and probably of all social genders (cisgender males and females, male to female (MtF) and female to male (FtM) transgenders, etc.), are current or former androgenic anabolic steroids (AAS) abusers. AAS abuse is associated with seriously increased short- and long-term risks for general, reproductive and sexual health. Indeed, to improve the knowledge and health of the population at risk of AAS misuse and standardize the current clinical practice concerning the health risks of such abuse, it is essential to also prevent, detect, diagnose, and treat all reproductive and sexual sequelae of non-therapeutic AAS assumption. The main AAS-related pathways and factors influencing reproduction and sexuality in humans, the possible reproductive and sexual signs and symptoms associated with AAS abuse and to AAS withdrawal, and the major concerns in the diagnosis and management of such clinical conditions are reported. The scientific literature has mainly evaluated male AAS abusers, but, we tried to describe/hypothesize all the possible reproductive and sexual side effects and concerns of AAS abuse also in other genders.
BACKGROUND: Papillary thyroid carcinoma (PTC) has classically been considered a sporadic carcinoma. However, a subgroup with familial clustering has been observed, which appears to present a poorer prognosis than the spo...BACKGROUND: Papillary thyroid carcinoma (PTC) has classically been considered a sporadic carcinoma. However, a subgroup with familial clustering has been observed, which appears to present a poorer prognosis than the sporadic form. The aim of this study is to analyze the recurrence rates and prognostic factors for familial PTC (FPTC) treated with curative intent. METHODS: Multicenter national study, endorsed by the Spanish Association of Surgeons. Study population: patients with FPTC (families who have at least 2 first-degree relatives with a confirmed PTC) who meet cure criteria after the treatment. Study endpoints: recurrence rate and risk factors for recurrence. Statistical analysis: Cox regression analysis and survival analysis. RESULTS: The study included 252 cases with a mean follow-up of 90±68,9 months, recurrence in 26.9% (N.=68) and a disease-free survival of 183,46±7,8 months. In the multivariate analysis, the independent factors for the risk of recurrence were: 1) the number of patients with FPTC in the family (OR 1.165); 2) the multifocality (OR 2.525); 3) the vascular invasion (OR 2.770); and 4) TNM staging system (OR 5.128). In the reanalysis that included the American Thyroid Association (ATA) risk of recurrence, this variable was highly predictive of recurrence (OR 12.048). CONCLUSIONS: FPTC presents a high recurrence rate, which is related to the number of cases of FPTC in the family, the presence of multifocality and vascular invasion, the TNM staging system and the ATA recurrence risk assessment.
Horrmann A, Travadi Y, Mallery K
… +11 more, Schaap G, Kamalanathan KJ, Bristow NR, Galeano-Garces C, Bae SY, Ball H, Hesch AR, Pederson S, Konety BR, Olimpiadi Y, Drake JM
Endocrinology
· 2026 Feb · PMID 41354060
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Despite the widespread use of mammography as the standard of care for breast cancer screening, its accuracy remains limited for select patient populations, such as women with high breast density. Liquid biopsy-based test...Despite the widespread use of mammography as the standard of care for breast cancer screening, its accuracy remains limited for select patient populations, such as women with high breast density. Liquid biopsy-based tests offer an accessible complement to conventional screening methods. Here, we conducted a case-control study to develop a plasma-based protein classifier to distinguish between those with early-stage breast cancer and healthy individuals. A total of 335 women, comprising 116 patients with newly diagnosed, treatment-naïve breast cancer (stage 0-2) and 219 healthy controls, had plasma samples collected and processed in a blinded manner using a sample preparation method coupled with semiquantitative, label-free mass spectrometry-based analysis. The median number of proteins detected per patient across breast cancer and healthy individuals was 6991 and 6818, respectively. A machine learning-based classifier was trained and validated on patient proteome profiles using a leave-one-out cross-validation approach to identify patients with breast cancer. The classifier achieved an area under the curve of 0.96 (95% CI, 0.93-0.97), with a sensitivity of 86.2% (95% CI, 78.8-91.3%) and a specificity of 90.4% (95% CI, 85.8-93.6%). In patients with breast cancer, the classifier retained >85% sensitivity regardless of breast density (low density: 87.2%, high density: 90.2%) at 90% specificity. Our workflow demonstrates the potential of plasma proteomics as a potent diagnostic tool in early-stage breast cancer screening.
Many diseases, including breast cancer, increase in women after menopause and with obesity. This Review addresses novel insights that link obesity, oestrogens, inflammation and breast cancer. Adipose tissue is chronicall...Many diseases, including breast cancer, increase in women after menopause and with obesity. This Review addresses novel insights that link obesity, oestrogens, inflammation and breast cancer. Adipose tissue is chronically inflamed in obesity owing to pre-adipocyte expansion and activation of nuclear factor-κB (NF-κB), which upregulate pro-inflammatory cytokines. Obesity also impairs immunosurveillance. Emerging data indicate that the major oestrogens before and after menopause have opposing effects on inflammation. In contrast to the anti-inflammatory properties of premenopausal 17β-oestradiol, the dominant postmenopausal oestrogen, oestrone, is pro-inflammatory. Oestrone is synthesized in adipocytes, therefore the expanded adipose tissue biomass in obesity increases oestrone levels in both men and women, promoting NF-κB-driven inflammation. These pro-inflammatory effects of oestrone are also oncogenic, promoting breast cancer progression in laboratory models. The dominance of oestrone and loss of 17β-oestradiol might underlie the increased prevalence of hormone-responsive breast cancer after menopause, particularly in the context of obesity. Although oestrogens account for much of the excess breast cancer risk with obesity, data on 17β-oestradiol and oestrone levels in the breast and circulation in postmenopausal women, whether or not obesity is present, are limited. Weight loss is associated with reduced breast cancer risk and improved outcomes. The opportunity to use potent weight loss drugs as adjuncts to cancer therapy is discussed.
The role of physical activity and exercise training in preventing the development of chronic disease and reducing mortality is increasingly recognized. A substantial body of evidence indicates that exercise confers these...The role of physical activity and exercise training in preventing the development of chronic disease and reducing mortality is increasingly recognized. A substantial body of evidence indicates that exercise confers these benefits to subsequent generations. This Review examines the effects of parental exercise, focusing on findings published within the past 10 years and related to mechanisms of transmission and sex-specific differences in both parents and offspring. Epigenetic modifications, including DNA methylation, histone modification and small non-coding RNAs, are crucial in how parental exercise influences offspring development. Paternal exercise alters the small RNA pool and methylation profiles in sperm, whereas maternal exercise affects both the in utero environment and postnatal lactation factors. Notably, male offspring show enhanced metabolic benefits, whereas female offspring exhibit greater cardiac improvements than male offspring. These findings highlight the sex-dependent nature of the generational effects of exercise and emphasize the need for further research into the molecular underpinnings and long-term implications for both male and female offspring.
Park JW, Cortes LR, Sandoval NP
… +12 more, Vree AR, Baron AG, Vranich K, Fideles HJ, Martinez RM, Dilday EA, Hansen MR, Budek W, Lopez JI, Kammel LG, van Veen JE, Correa SM
Endocrinology
· 2025 Dec · PMID 41315012
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Estrogens have considerable effects on energy homeostasis and metabolic health. In mice, signaling through estrogen receptor α (ERα) alters energy intake and expenditure, effects that may be mediated by specific regions...Estrogens have considerable effects on energy homeostasis and metabolic health. In mice, signaling through estrogen receptor α (ERα) alters energy intake and expenditure, effects that may be mediated by specific regions or cellular subpopulations of the hypothalamus. This study investigates the function of ERα signaling in the lineage that expresses Rprm (reprimo), a gene we previously linked to thermoregulation in females. Here, we engineered a novel ReprimoCre mouse to selectively knock out ERα in Rprm lineage cells (Reprimo-specific ERα knockout [KO]; RERKO). We report modest changes in core temperature, higher brown adipose tissue (BAT) mass, elevated BAT temperature during the light phase, and lower tail temperature during the light phase in RERKO females relative to controls. RERKO females also exhibited a subtle difference in locomotion and no differences in feeding or body mass. These phenotypes suggest sex-specific effects on the patterns of body temperature instead of overall increases or decreases in heat generation or dissipation. Labeling of the Rprm lineage was detected in the brain, but not in BAT or white adipose, suggesting that temperature changes may be mediated by the nervous system. To test for centrally mediated effects on temperature, we ablated Rprm-expressing cells in the mediobasal hypothalamus. Although this approach eliminates the cells entirely instead of selectively eliminating ERα in Rprm-expressing cells, we observed a phenotype similar to RERKO mice, with effects on core temperature and BAT mass. Together, these results indicate that estrogen signaling in the Rprm lineage is important for thermoregulation in female, but not male, mice.
Hypophysitis is defined by inflammation of the pituitary gland and/or infundibulum. It can cause headaches and symptoms due to hypopituitarism. Diagnosis is based on a combination of hormonal and imaging parameters but c...Hypophysitis is defined by inflammation of the pituitary gland and/or infundibulum. It can cause headaches and symptoms due to hypopituitarism. Diagnosis is based on a combination of hormonal and imaging parameters but can, in individuals with an uncertain diagnosis, require a transsphenoidal biopsy. While the risk of immune checkpoint inhibitor-induced hypophysitis is well known, several aetiologies of secondary hypophysitis have been identified and hypophysitis can also occur in relation to pregnancy. Primary hypophysitis is defined by the absence of a secondary cause of hypophysitis. Although each subtype can present with distinct clinical, endocrine and radiological features, extensive overlap makes the aetiological diagnosis difficult. Management of hypophysitis is another challenging task. Whereas some studies have suggested that high-dose glucocorticoids can improve pituitary function and alleviate symptoms, others have found limited benefit. Immunosuppressive agents have also been used as targeted therapy for the underlying condition or in individuals with aggressive hypophysitis, potentially improving both clinical presentation and hormonal function. These therapeutic approaches, used alone or in combination, can be considered in selected patients with primary, pregnancy-related or secondary hypophysitis. The aim of this comprehensive Review is to critically analyse the positive and aetiological diagnostic steps and the management of all subtypes of hypophysitis.
BACKGROUND: Treatment of type 2 diabetes mellitus (T2DM) relies on diverse glucose-lowering medications, championing sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists as via...BACKGROUND: Treatment of type 2 diabetes mellitus (T2DM) relies on diverse glucose-lowering medications, championing sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists as viable options to address concurrent cardiovascular risk. An oral formulation of semaglutide (Rybelsus, Novo Nordisk) has been recently introduced to clinical use for managing T2DM. Accordingly, there is a paucity of practice evidence while building experience on its combination with SGLT2i. METHODS: In this observational, single-arm, retrospective study, data collected from 142 T2DM patients (66% males, 68% older than 60 years, 85% overweight/obese) treated with oral semaglutide in combination with SGLT2i were analyzed. RESULTS: After 6.8±2.6 months of treatment, both glycosylated hemoglobin (HbA1c) and fasting plasma glucose levels significantly improved: 39.6% of patients achieved HbA1c<inf>DCCT</inf> ≤7% (HbA1c<inf>IFCC</inf> ≤53.0 mmol/mol) and 18.8% experienced both a decrease of HbA1c ≥1% and a weight loss ≥5%. In addition, body weight, body mass index, waist circumference, triglycerides, and total cholesterol levels were significantly reduced. Regarding safety, 94.7% of reported adverse events were non-serious gastrointestinal symptoms and 1 patient experienced hypoglycemia. CONCLUSIONS: The herein presented real-world data suggest that oral semaglutide can be regarded as safe and effective, when used as add-on medication for uncontrolled T2DM on background SGLT2i.
BACKGROUND: Serum uric acid (UA), the end product of purine metabolism, has been implicated in metabolic and cardiovascular diseases. While obesity, particularly visceral fat accumulation, is related with hyperuricemia,...BACKGROUND: Serum uric acid (UA), the end product of purine metabolism, has been implicated in metabolic and cardiovascular diseases. While obesity, particularly visceral fat accumulation, is related with hyperuricemia, limited studies have explored the association between serum UA levels and the visceral-to-subcutaneous fat ratio as a novel marker of cardiometabolic risk. This study investigates the relationship between serum UA levels and abdominal fat distribution, focusing on the visceral-to-subcutaneous fat ratio in Korean men. METHODS: This retrospective, cross-sectional study analyzed 5114 male participants who underwent serum UA measurement and abdominopelvic computed tomography (CT) as part of health examinations from 2014 to 2019. Visceral and subcutaneous fat areas were quantified using CT imaging, and the visceral-to-subcutaneous fat ratio was calculated. Participants were stratified into quartiles based on serum UA levels. Univariate and multivariate analyses were performed to assess the association between serum UA levels and abdominal fat area and visceral fat/subcutaneous fat ratio were evaluated using univariate and multivariate analyses. RESULTS: Higher serum UA levels were significantly associated with increased visceral fat area, subcutaneous fat area, and visceral-to-subcutaneous fat ratio in both univariate and multivariate analyses. Participants in the highest UA quartile demonstrated the greatest visceral fat accumulation and the highest visceral-to-subcutaneous fat ratios. Multivariate analyses revealed that the association between serum UA and the visceral-to-subcutaneous fat ratio remained significant after adjusting for covariates. CONCLUSIONS: This study demonstrated a positive correlation between serum UA levels and both visceral fat area and subcutaneous fat areas in Korean men. Furthermore, higher serum UA levels were positively correlated with the visceral-to-subcutaneous fat ratio, offering insights into its potential contribution to elevated cardiometabolic and cardiovascular risk.
Endocrinology
· 2025 Dec · PMID 41292460
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Polycystic ovary syndrome (PCOS) is associated with a high prevalence of insulin resistance (IR) and obesity. Adiponectin, an insulin-sensitizing hormone, is reduced in PCOS and inversely correlated with IR and obesity....Polycystic ovary syndrome (PCOS) is associated with a high prevalence of insulin resistance (IR) and obesity. Adiponectin, an insulin-sensitizing hormone, is reduced in PCOS and inversely correlated with IR and obesity. This study tested whether androgens reduce adiponectin, and if the adiponectin receptor agonist AdipoRon improves IR and obesity in a PCOS model. Four-week-old female Sprague Dawley rats were implanted with dihydrotestosterone (DHT) or control Silastic tubes for 12 weeks. After 6 weeks of DHT treatment, rats received AdipoRon or vehicle in their food for 6 weeks. DHT increased body weight, fat and lean mass, food intake, serum leptin, adipose mitochondrial oxidative stress, inflammatory markers, HOMA-IR, adipocyte size, and decreased serum adiponectin levels. DHT upregulated GLUT4, PPARγ, and adiponectin mRNA expression in subcutaneous adipose tissue (SAT), while PPARγ was downregulated in visceral adipose tissue (VAT). DHT also reduced Akt protein expression in SAT and p(S473)-Akt phosphorylation in VAT and caused a depot-specific effect on androgen receptor expression. AdipoRon reduced body weight, fat, and lean mass, food intake, serum leptin, adipocyte size, and IR markers in DHT-treated rats. AdipoRon upregulated Akt, AMPK, and AdipoR1 mRNA expression in SAT and increased p(S473)-Akt phosphorylation in both white adipose tissue (WAT) depots. AdipoRon also reduced mitochondrial oxidative stress in both WAT depots and decreased androgen receptor expression in VAT. AdipoRon attenuates hyperandrogenemia-induced adiposity and IR in a PCOS model by improving adipose insulin and adiponectin signaling, reducing mitochondrial oxidative stress and food intake, supporting its therapeutic potential in managing IR and obesity in PCOS women.
The intricate processes of feto-placental development are regulated by both genetics and the nutritional environment. The placenta mediates nutrient transfer to the fetus and waste transfer to the maternal circulation to...The intricate processes of feto-placental development are regulated by both genetics and the nutritional environment. The placenta mediates nutrient transfer to the fetus and waste transfer to the maternal circulation to facilitate proper fetal cell fate specification. Disruptions in these fate-regulatory programmes can lead to maternal and fetal complications. We explore how metabolic-epigenetic mechanisms programme feto-placental development, discussing the roles of metabolic sensing mechanisms. This Review covers the roles of nutrient metabolite-dependent protein modifications, lipid signalling, steroid signalling and oxygen signalling in regulating particular phases and lineages of feto-placental development. Understanding these environmental-genetic interactions is crucial for elucidating the limits of developmental plasticity, the pathogenesis of pregnancy-related disorders and the potential therapeutic windows we can leverage to improve maternal and fetal outcomes.