Are young men attempting to achieve paternity through intracytoplasmic sperm injection candidates for general health screenings?
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Transgenerational inheritance of diabetes susceptibility in male offspring with maternal androgen exposure
Androgen exposure (AE) poses a profound health threat to women, yet its transgenerational impacts on male descendants remain unclear. Here, employing a large-scale mother-child cohort, we show that maternal hyperandrogenism predisposes sons to β-cell dysfunction. Male offspring mice with prenatal AE exhibited hyperglycemia and glucose intolerance across three generations, which were further exacerbated by aging and a high-fat diet. Mechanistically, compromised insulin secretion underlies this transgenerational susceptibility to diabetes. Integrated analyses of methylome and transcriptome revealed differential DNA methylation of β-cell functional genes in AE-F1 sperm, which was transmitted to AE-F2 islets and further retained in AE-F2 sperm, leading to reduced expression of genes related to insulin secretion, including Pdx1, Irs1, Ptprn2, and Cacna1c. The methylation signatures in AE-F1 sperm were corroborated in diabetic humans and the blood of sons with maternal hyperandrogenism. Moreover, caloric restriction and metformin treatments normalized hyperglycemia in AE-F1 males and blocked their inheritance to offspring by restoring the aberrant sperm DNA methylations. Our findings highlight the transgenerational inheritance of impaired glucose homeostasis in male offspring from maternal AE via DNA methylation changes, providing methylation biomarkers and therapeutic strategies to safeguard future generations’ metabolic health.
What makes a man unmanly? The global concept of ‘unmanliness’
This paper presents the findings of a multi-national study that led to the development of a new analytical framework in masculinity research—the Global Concept of ‘Unmanliness’ (GCU). Drawing on three key theories—hegemonic masculinity, precarious manhood and masculinity threat, and emasculation—we conducted an innovative study across 15 countries (selected from an initial pool of 62) to examine cultural perceptions of ‘unmanliness.’ Participants provided open-ended responses to identify traits and behaviors considered unmanly within their cultural contexts. By analyzing common themes expressed by young men, we propose the Global Concept of ‘Unmanliness’ as a framework for understanding how societies define and enforce masculinity norms. Furthermore, comparing these findings with the Global Gender Gap Index (GGGI) revealed a key distinction in how ‘unmanliness’ is characterized across different levels of gender emancipation. In countries with high GGGI rankings (e.g., Norway, Ireland, Germany), ‘unmanliness’ is more often associated with physical traits and behaviors linked to femininity (e.g., clothing, makeup). Conversely, in countries with low GGGI rankings (e.g., Pakistan, Morocco, Nigeria), it is more commonly defined by acts such as violence against women. Our study highlights how cultural and structural gender dynamics shape the boundaries of masculinity and offers a new lens for cross-cultural research on gender norms.
Comparing vasectomy techniques, recovery and complications: tips and tricks
Vasectomies are safe and effective, achieving up to 99.7% in sterilization, with complication rates around 1–2%. As vasectomy uptake rises, physicians should stay informed about counseling, isolation and occlusion techniques, post-op recovery, and associated risks and complications. Historically, pre-vasectomy counseling has been performed in-person, but recent literature has shown that telehealth is a viable alternative, and a physical exam may not be necessitated. With regard to vas isolation and occlusion, current international guidelines support a minimally invasive approach such as no-scalpel vasectomy with mucosal cautery and fascial interposition, as they are the most effective in achieving vasectomy success and have the lowest complication rates. After a vasectomy, patients should undergo a post-vasectomy semen analysis 8–16 weeks after the procedure to ensure severe non-motile oligozoospermia (≤100,000 non-motile sperm/mL) or azoospermia. While risks and complications from vas isolation and occlusion are rare, patients should be informed about the potential for hematomas, infections, postoperative pain, and vas recanalization. In the U.S, vasectomies have increased in utilization from previous years, likely in the setting of increased access to telehealth and restricted female reproductive access. This trend raises questions about future fertility options such as vasectomy reversals and highlights the need for informed decision-making.
Age-dependent differences in breast tumor microenvironment: challenges and opportunities for efficacy studies in preclinical models
Immunity suffers a function deficit during aging, and the incidence of cancer is increased in the elderly. However, most cancer models employ young mice, which are poorly representative of adult cancer patients. We have previously reported that Triple-Therapy (TT), involving antigen-presenting-cell activation by vinorelbine and generation of TCF1+-stem-cell-like T cells (scTs) by cyclophosphamide significantly improved anti-PD-1 efficacy in anti-PD1-resistant models like Triple-Negative Breast Cancer (TNBC) and Non-Hodgkin’s Lymphoma (NHL), due to T-cell-mediated tumor killing. Here, we describe the effect of TT on TNBC growth and on tumor-microenvironment (TME) of young (6–8w, representative of human puberty) versus adult (12 m, representative of 40y-humans) mice. TT-efficacy was similar in young and adults, as CD8+ scTs were only marginally reduced in adults. However, single-cell analyses revealed major differences in the TME: adults had fewer CD4+ scTs, B-naïve and NK-cells, and more memory-B-cells. Cancer-associated-fibroblasts (CAF) with an Extracellular Matrix (ECM) deposition-signature (Matrix-CAFs) were more common in young mice, while pro-inflammatory stromal populations and myofibroblasts were more represented in adults. Matrix-CAFs in adult mice displayed decreased ECM-remodeling abilities, reduced collagen deposition, and a different pattern of interactions with the other cells of the TME. Taken together, our results suggest that age-dependent differences in the TME should be considered when designing preclinical studies.
Risk prediction score and equation for progression of arterial stiffness using Japanese longitudinal health examination data
The brachial-ankle pulse wave velocity (baPWV) is useful for evaluating arterial stiffness. No longitudinal studies have examined the association between multiple arterial stiffness risk factors and increased baPWV. We sought to identify factors associated with baPWV ≥1400 cm/s within 5 years and create an equation and simple risk score to predict its occurrence, using data from a large-scale Japanese health examination database. Of 10,284 participants aged 30–69 years for whom follow-up data were available over a 5-year period, 3394 men and 2710 women with baseline baPWV<1400 cm/s were analyzed. We used age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), fasting blood sugar (FBS), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), estimated glomerular filtration rate (eGFR), habitual exercise, habitual drinking, and smoking history as variables. In the multivariate logistic regression analysis, baPWV≥1400 cm/s was associated significantly with age, BMI, SBP, DBP, HR, FBS, and TG in men and age, SBP, DBP, HR, and smoking history in women. A prediction score based on these factors yielded an area under the curve (AUC) for the 5-year incidence of baPWV≥1400 cm/s of 0.68 for men and 0.71 for women. Furthermore, a risk prediction equation for the 5-year incidence of baPWV≥1400 cm/s showed an AUC = 0.71 for men and 0.77 for women. The prediction equation and a simple prediction score are easy to implement clinically. The predictive ability of these scores and equations for arterial stiffness should be validated in prospective studies.
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