Participants then evaluated nonverbal displays representing four types of social signal: prestige, dominance, neutral and smiling. Researchers assessed their perceptions of the targets’ dominance and prestige, alongside trait inferences about agency and communion. The study’s framework treats agency and communion as cognitive pathways theorized to underpin judgments of social rank.

The distinction between final judgments and the processing that produces them was central to the results. Testosterone had no significant main effect on the overall magnitude of explicit dominance and prestige ratings. Its detectable influence was narrower: for non-dominant signals, participants receiving testosterone showed reduced reliance on the pathway involving perceived communion, an affiliative trait.

Processing of dominance displays, which relied predominantly on agency, remained comparatively resistant to testosterone administration. The findings therefore indicate that testosterone’s measured role in social rank perception was limited and selective rather than a general upward or downward bias in status judgments. The authors characterize the effect as a subtle recalibration in the weighting of affiliative traits.

They also emphasize that the robustness of basic visual decoding means explicit verbal judgments of nonverbal displays may not be a sufficiently sensitive measure for detecting all effects of testosterone on social-cognitive processes. These results do not show that testosterone improves social judgment, changes behavior in actual social hierarchies or causes people to seek higher status. The experiment examined controlled displays in a sample restricted to healthy male participants, so its findings do not establish whether the same pattern would appear in women, other populations or real-world interactions.

Likewise, the study tested perception of dominance and prestige cues rather than whether administering testosterone alters an individual’s social position. The supported conclusion is narrower: under the study’s experimental conditions, testosterone selectively altered one component of the cognitive processing involved in interpreting non-dominant social signals without producing a broad change in explicit dominance or prestige ratings.

Subject of Research: Testosterone administration and cognitive processing of social rank cues in healthy men

Article Title: How testosterone administration affects social rank perceptions: A double-blind, placebo-controlled study

Article References: Ye, Y., Lei, X., Nan, Y., & Wu, Y. (2026). How testosterone administration affects social rank perceptions: A double-blind, placebo-controlled study. BMC Psychology. https://doi.org/10.1186/s40359-026-05508-z

Image Credits: AI Generated

DOI: 10.1186/s40359-026-05508-z

Keywords: testosterone, social rank, dominance perception, prestige perception, agency, communion, nonverbal cues, social cognition, double-blind study, placebo-controlled study, administration, affects

Sensitivity analyses comparing women receiving testosterone plus hormone therapy with women receiving hormone therapy alone also showed the same association. The study used data from the TriNetX US Collaborative Network and included postmenopausal women aged 45 years and older. Participants who initiated testosterone therapy were matched one to one with women without testosterone exposure.

The researchers applied a 12-month washout period, excluding women with any testosterone exposure during the 12 months before the index date, and they also excluded patients with prior cardiovascular disease. Mean follow-up was nearly three years. Propensity-score matching was used to balance measured characteristics, including demographics, smoking status, obesity, hysterectomy status, surgical menopause, baseline use of menopause hormone therapy or vaginal estrogen, vasomotor symptoms, premature ovarian insufficiency, diabetes, hypertension, dyslipidemia and other comorbidities associated with cardiovascular risk.

The composite outcome was broad: coronary artery disease, including angina, myocardial infarction and acute or chronic ischemic heart disease; cerebrovascular disease, including ischemic stroke or arterial occlusive disease; and heart failure. Qualifying events could occur from 30 days to five years after the index date. Because the analysis combined several cardiovascular conditions, its hazard ratio describes the association with the composite endpoint rather than the risk of each individual condition.

The findings also came from an observational cohort, so they demonstrate an association rather than establishing that testosterone therapy caused the cardiovascular events. Mean follow-up of nearly three years and the study design limit conclusions about longer-term risk. The findings identify a potential cardiovascular safety signal for a treatment whose long-term safety in postmenopausal women remains poorly characterized.

Testosterone therapy is sometimes prescribed off-label to address low libido and has proven effective for hypoactive sexual desire disorder, a persistent and distressing loss of interest in sex that is estimated to affect about 10% to 15% of postmenopausal women. There are currently no FDA-approved testosterone products for women in the United States, so healthcare professionals prescribing them for women generally use very low doses of male formulations, usually as a cream or gel. Higher doses have been associated with acne, increased facial hair, scalp hair thinning and a deepening of the voice.

Insufficient evidence also remains regarding testosterone for managing several other menopause symptoms, including fatigue, memory loss, weight gain and loss of bone density. Lead author Xuezhi Daniel Jiang, professor of obstetrics and gynecology at Drexel University College of Medicine, said the low absolute event rates and consistency across analyses warrant further prospective investigation. Stephanie Faubion, medical director for The Menopause Society, said studies of this kind are important because long-term safety data on testosterone use in women are lacking and clinicians must balance individualized risks and benefits when prescribing it.

The research did not evaluate a treatment strategy or demonstrate a clinical benefit from avoiding or discontinuing testosterone therapy.

Subject of Research: Association between testosterone therapy and incident composite cardiovascular disease in postmenopausal women

Article Title: Testosterone therapy may increase risk of cardiovascular disease in postmenopausal women

Article References: Testosterone therapy may increase risk of cardiovascular disease in postmenopausal women. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: testosterone therapy, postmenopausal women, cardiovascular disease, composite outcomes, hazard ratio, propensity matching, retrospective cohort, TriNetX, menopause, hypoactive sexual desire disorder, Testosterone, therapy

Investigators used dual-energy X-ray absorptiometry, or DEXA, to assess bone mineral density at the lumbar spine, femoral neck and hip. Measurements were taken at baseline, after participants had received estrogen therapy alone for at least one year, and after they had received estrogen plus testosterone for at least one year. The mean duration of estrogen-only therapy was 3.5 years, while the mean duration of combined estrogen and testosterone therapy was 3.1 years.

Across the study, participants were followed for an average of 4.1 years. The analysis compared T-scores at the three skeletal locations across these sequential treatment periods. Estrogen therapy alone did not produce a statistically significant increase in T-scores at the lumbar spine, femoral neck or hip.

In contrast, estrogen plus testosterone was associated with a significant increase in the lumbar spine T-score. The femoral neck and hip T-scores remained stable across both treatment periods, making the spine the only measured site where the researchers reported a significant increase after combined therapy. The release did not provide the numerical T-score changes, DEXA values, confidence intervals or other effect estimates, so the magnitude and precision of the observed association cannot be determined from the information supplied.

Based on the site-specific pattern, Davis and colleagues suggested that testosterone may have a synergistic effect with estrogen on trabecular bone, with the clearest measured association occurring at the spine. This was the investigators’ interpretation of the results rather than a separately demonstrated biological mechanism. The observational design and the sequence of estrogen-only and combined treatment mean that the findings establish an observed association, not a causal effect of adding testosterone.

Information about participant characteristics, adverse events and adherence was not included in the release. Bone density can decrease substantially during and after menopause as estrogen levels fall, and the release notes that women may lose 10% to 20% of their bone density in the first five to seven years after menopause. This rapid thinning raises the risk of osteopenia, described as low bone mass, and osteoporosis, characterized by weak, brittle bones that are prone to fracture.

Estrogen therapy has historically been prescribed to lower the risk of spine and hip fractures, while weight-bearing and resistance exercise, adequate calcium and vitamin D intake and hormone therapy are described as proven methods for protecting bone health. The present findings do not report a fracture outcome, and Davis said further research is needed to determine how testosterone could be used safely and effectively in individualized menopausal care. Stephanie Faubion, medical director of The Menopause Society, similarly emphasized the need for more studies exploring options that may help protect women’s bones during and after menopause.

Subject of Research: Bone mineral density during sequential estrogen and combined estrogen-testosterone therapy in postmenopausal women

Article Title: Combined estrogen and testosterone therapy increases lumbar spine bone mineral density

Article References: Combined estrogen and testosterone therapy increases lumbar spine bone mineral density. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: postmenopausal women, bone mineral density, estrogen therapy, testosterone therapy, lumbar spine, osteoporosis, menopause, DEXA, Combined, estrogen, testosterone, therapy

The study arrives at a politically charged moment. Recent eligibility frameworks in women’s sport, including proposals for sex-determining region Y (SRY) gene screening, have focused attention on single biological markers as the basis for classification. Yet the relationship between such markers and sport-specific performance has remained poorly documented, particularly for athletes with DSD, an umbrella term covering congenital conditions in which chromosomal, gonadal, endocrine and anatomical sex characteristics do not align in typical patterns. The researchers argue that no single genetic or hormonal measurement can reliably predict how fast, strong or enduring an athlete will be on the pitch.

The participant, a 20-year-old competing at national-team level in women’s football, had never undergone formal genetic assessment before enrolling in the study. She reported no chronic disease, no medication or supplement use, and her only relevant medical history was a knee ligament strain that did not restrict testing. To protect her identity, the authors withheld her club, playing position and other potentially identifying details. Every planned assessment was completed without adverse events, and no therapeutic intervention was administered; the investigation was purely observational and cross-sectional.

Whole-genome sequencing, performed on the MGI DNBSEQ-T1x platform at an average depth of 51.3-fold, revealed a 46,XY chromosomal complement with the SRY locus present. Crucially, the analysis also identified a homozygous missense variant in the SRD5A2 gene, c.578A>G (p.Asn193Ser), classified as pathogenic in ClinVar and predicted deleterious by multiple computational tools. This gene encodes 5α-reductase type 2, the enzyme responsible for converting testosterone into dihydrotestosterone (DHT), the more potent androgen that drives many aspects of male-typical development. Genome-wide screening flagged six pathogenic or likely pathogenic variants in total, but only the SRD5A2 variant related to the athlete’s clinical picture; targeted evaluation of two published DSD gene panels, covering 171 and 267 genes respectively, found nothing else of significance.

The endocrine profile told a consistent biochemical story. Total testosterone measured 23.6 nmol per litre, well above typical female reference intervals, while DHT was only 0.80 nmol per litre, producing a testosterone-to-DHT molar ratio of 29.5:1. That disproportionate ratio is the biochemical signature of impaired 5α-reductase activity, confirming the molecular diagnosis. Luteinizing hormone and follicle-stimulating hormone were also elevated, a pattern seen when downstream androgen signalling is blunted. Yet the athlete’s oestradiol, progesterone and androstenedione levels, along with her sex hormone-binding globulin, painted a more nuanced picture that aligned with neither a typical female endocrine profile nor a eugonadal male one.

Physical testing exposed the mismatch between biology and performance. Countermovement jump height of 41.9 centimetres exceeded the means of both under-18 (30.0 centimetres) and first-team (32.3 centimetres) elite female football squads by large margins, corresponding to z-scores of 4.25 and 2.82, while remaining well below male position-specific references. Her best 30-metre sprint time was faster than both elite female reference groups and closely aligned with professional male first-division values. In sharp contrast, maximal isometric knee-extensor torque of 203 newton-metres was almost identical to the cisgender female comparator mean and below both cisgender male and transgender female cohort means. Isokinetic strength results fluctuated by contraction mode and velocity, sometimes matching female squad averages and sometimes falling well short of them.

Aerobic and respiratory measures continued the pattern of heterogeneity. Relative VO2max of 48.7 millilitres per kilogram per minute, measured directly by breath-by-breath gas analysis during a treadmill ramp test, sat slightly above elite female football reference means but far below male position-specific values, with z-scores between roughly minus three and minus four. Forced vital capacity and forced expiratory volume in one second were lower than every comparator group in absolute terms, corresponding to 85 and 90 percent of predicted values, although the elevated FEV1/FVC ratio of 0.94 indicated preserved expiratory flow. On the field, she covered 440 metres on the Yo-Yo Intermittent Recovery Test Level 2, within the reported range for elite female cohorts and below male references, under moderate heat stress recorded at a wet-bulb globe temperature of 27.79 degrees Celsius.

Body composition added further nuance. Dual-energy X-ray absorptiometry on a Hologic Horizon scanner showed elevated lumbar spine bone mineral density of 1.37 grams per square centimetre, low adiposity with 11.6 kilograms of fat mass, and an intermediate fat-free mass of 48.7 kilograms. Cross-calibration equations, applied because comparator groups were scanned on a GE Lunar Prodigy system, strengthened rather than reversed these findings. Against published elite female football data, her bone density, body fat percentage and lean mass all fell within reported ranges, while relative to elite male squads she showed higher body fat and lower absolute lean mass. The authors note that her self-reported training volume of 9,813 MET-minutes per week, roughly 2.3 to 2.4 times that of the recreationally active in-house comparator groups, likely contributes to some laboratory advantages, though core performance benchmarks came from training-matched elite cohorts.

The research team is careful about what the case can and cannot show. A single-athlete, cross-sectional design cannot establish that 46,XY DSD, the SRD5A2 variant or the endocrine profile caused any element of the performance phenotype. The z-scores are descriptive comparisons sensitive to the means and sample sizes of source datasets drawn from Finnish, Norwegian, English and German cohorts collected between 1998 and 2023, differing in era, competition level and testing conditions. Family history and psychosocial data were not collected, and the authors acknowledge a residual risk of deductive re-identification given the rarity of the condition, which constrained how much detail could be published. They explicitly state that the data do not allow inference that the endocrine profile explains the observed differences between sprint, strength and aerobic outcomes.

Still, the implications for policy are pointed. As governing bodies move toward genetic screening, the case demonstrates that genotype, endocrine status and sport-specific performance phenotype may diverge substantially within a single athlete, and that football performance depends on multiple interacting domains rather than one trait. The athlete herself consented voluntarily and expressed hope that such studies would contribute to a more evidence-based understanding of DSD in sport. The authors call for the systematic accumulation of multidimensional, sport-specific physiological datasets, arguing that this rare kind of natural biological variation deserves the same scientific scrutiny that human-performance research traditionally reserves for training, technology and pharmacology. Until such datasets exist, they contend, isolated markers like an SRY result reveal far less about athletic capability than the biology of performance itself.

Subject of Research: Integrated genetic, endocrine and sport-specific performance profiling of an elite footballer with 46,XY differences of sex development

Article Title: Case Report: Integrated physiological and performance profiling of an elite athlete with differences of sex development

Article References: Hu, K., Huang, K., Xu, X., Hamilton, B. R., Rozenštoka, S., Pigozzi, F., Ling, S. K.-K., Cheung, A. S., Vilain, E., & Pitsiladis, Y. P. (2026). Case Report: Integrated physiological and performance profiling of an elite athlete with differences of sex development. Frontiers in Sports and Active Living, 8, Article 1906817. https://doi.org/10.3389/fspor.2026.1906817

Image Credits: AI Generated

DOI: 10.3389/fspor.2026.1906817

Keywords: differences of sex development, DSD, SRD5A2, testosterone, dihydrotestosterone, athlete eligibility, whole-genome sequencing, VO2max, sprint performance, women's football, sports physiology, SRY gene testing

The research team, led by Robin Kruger and senior author Ariella Shikanov, set out to answer a question that clinical studies have struggled to resolve: does testosterone worsen, mitigate, or simply modify the consequences of ovarian hormone loss? Human studies of exogenous testosterone administration show inconsistent effects on lipid profiles, insulin sensitivity, body weight, and blood pressure, and they are often constrained by retrospective designs, heterogeneous hormone regimens, and confounding variables such as participant age and baseline metabolic status. Crucially, none of these studies have examined potential differences in outcomes between patients with and without endogenous ovaries. A controlled animal model offered a way to isolate the direct physiological effects of testosterone and ovarian hormone loss on metabolism and the skeleton.

The experiment was elegantly simple in design. Eight-week-old adult female CD-1 mice underwent either sham surgery or ovariectomy, and at the same time were implanted subcutaneously with silastic capsules containing either 10 milligrams of testosterone powder or empty control capsules. This produced four experimental groups: intact mice with empty capsules, ovariectomized mice with empty capsules, intact mice with testosterone, and ovariectomized mice with testosterone, with seven to eight animals per group. After six weeks of treatment, the researchers measured fasting glucose, glucose tolerance, serum lipids, insulin, reproductive hormones, fat pad weights, adipocyte size, heart and liver phenotypes, and bone density and strength. Serum testosterone rose to the range typically observed in male mice in both testosterone-treated groups, confirming that the treatment produced a genuinely hyperandrogenic hormonal milieu.

The most dramatic result concerned glucose metabolism. Mice that lost their ovaries without testosterone replacement developed hyperglycemia and impaired glucose tolerance, consistent with previous studies of ovariectomy-induced metabolic dysfunction. Yet ovariectomized mice receiving testosterone retained entirely normal glucose function, indistinguishable from intact controls. Testosterone treatment was sufficient to prevent the ovariectomy-induced glucose metabolism defects, even though fasting insulin levels did not change proportionally. This suggests that testosterone supplementation alone can maintain glucose homeostasis in the absence of ovarian hormones, a finding with direct implications for how clinicians might think about metabolic risk after estradiol depletion.

Bone told an equally compelling story. Using nano-computed tomography of the femur and three-point bending tests of the radius, the team found that testosterone increased trabecular bone number, reduced trabecular spacing, and raised bone density measures regardless of whether the ovaries were present. Both testosterone-treated groups showed congruent trends toward greater maximum load and bending stiffness in mechanical testing. Interestingly, trabecular thickness was not increased despite the greater number of trabeculae, consistent with previous reports in mice and humans that testosterone induces formation of more but thinner trabeculae. Testosterone had minimal impact on cortical bone, supporting clinical evidence that cortical microstructure is not as strongly regulated by androgen signaling. Together, these data demonstrate that elevated testosterone is sufficient not only to prevent ovariectomy-associated bone loss but to raise trabecular bone density above baseline even without endogenous gonads.

But the story was not uniformly rosy. Testosterone could not prevent dyslipidemia in the absence of ovaries. Both ovariectomized groups, whether treated with testosterone or not, displayed elevated fasting total cholesterol and HDL cholesterol levels compared with intact mice. In mice, which carry most plasma cholesterol in HDL particles, elevated HDL more likely reflects overall hypercholesterolemia rather than a protective phenotype as it might in humans. Similarly, ovariectomy increased adipocyte size in both inguinal and perigonadal fat pads regardless of testosterone treatment, indicating adipocyte hypertrophy persisted despite the androgen excess. In contrast, testosterone-treated mice with intact ovaries showed decreased fat pad weight and smaller median adipocyte size, a pattern aligning with sexual dimorphism in body composition where males carry lower adiposity than females. The researchers concluded that lipid metabolism is more sensitive to estradiol levels than to testosterone levels, and that testosterone aromatized in non-ovarian tissues is not sufficient to maintain lipid homeostasis in females.

The heart added another layer of complexity. Testosterone treatment significantly increased heart weight in both ovary-intact and ovariectomized mice compared with untreated controls, supported by congruent trends toward increased heart longitudinal area and left ventricular cardiomyocyte size. Neither testosterone nor ovariectomy significantly impacted heart fibrosis, liver weight, collagen deposition, or hepatic lipid content over the six-week period. The researchers argue that these changes are more likely direct androgenic effects rather than consequences of reduced estradiol, because ovariectomized mice without testosterone did not exhibit the same phenotypes. This premise is consistent with prior studies showing that males generally have greater heart mass and higher triglyceride levels than females, and that testosterone can induce cardiomyocyte hypertrophy in vitro through androgen receptor signaling.

One of the most intriguing findings involved the uterus. Testosterone-treated mice with intact ovaries showed increased uterine weight and cross-sectional area, a uterotrophic effect suggesting significant aromatization of testosterone into estradiol and estrogenic signaling, despite the cessation of estrous cycling. Meanwhile, ovariectomized mice without testosterone showed the expected uterine regression. Remarkably, the uteri of testosterone-treated ovariectomized mice were indistinguishable from intact controls, avoiding both testosterone-induced hypertrophy and ovariectomy-induced atrophy. If the uterotrophic effect comes from aromatization into estradiol, this would indicate that peripheral tissues alone can generate bioactive levels of estradiol to sustain uterine morphology. Alternatively, the effect could reflect direct androgen receptor signaling in uterine tissue. Either mechanism suggests that testosterone treatment and ovariectomy do not produce identical hormonal environments, despite similar repression of estrous cycling, and such differences in estrogenic activity may explain how testosterone-treated intact mice differ from ovariectomized groups in metabolic outcomes such as adiposity and cholesterol.

The study faces limitations, particularly in determining the mechanisms governing the observed metabolic changes. A primary shortcoming is the inability to distinguish which effects of testosterone administration result from androgen signaling and which may be due to aromatization of testosterone into estradiol. Many peripheral tissues express aromatase, and this mechanism is undoubtedly at play even in ovariectomized animals. Previous studies have shown that aromatization is critical for the beneficial effects of androgen administration on rodent metabolism and skeletal health. Future studies may employ aromatase inhibition or androgen receptor knockout models to separate these two pathways, along with insulin tolerance testing, estradiol measurements, and quantification of metabolic gene expression. It is also worth noting that several metabolic endpoints, including fasting insulin, metabolic tissue fibrosis, and hepatic lipid accumulation, were unaffected by either testosterone or ovary status, likely reflecting the resistance of CD-1 mice to hepatic steatosis on a standard diet and highlighting the importance of genetic background and diet in determining susceptibility to reproductive hormone-associated metabolic disease.

Clinically, these distinctions matter enormously. For women with conditions characterized by high testosterone levels, including polyendocrine metabolic ovarian syndrome, congenital adrenal hyperplasia, environmental exposure, or androgen-producing tumors, several of which are common comorbidities with metabolic syndrome and obesity that worsen in peri-menopause, this study may inform which metabolic disease factors are likely to increase in risk after estradiol depletion and which may be compensated by high testosterone. The findings are also directly relevant to transmasculine patients receiving testosterone gender-affirming hormone therapy, especially those considering gender-affirming oophorectomy. The results suggest that testosterone therapy is sufficient to maintain normal glucose metabolism and bone density after oophorectomy, but that gonad retention may be protective with respect to lipid and adipose tissue regulation. Further research investigating the mechanisms of interaction between endogenous and exogenous hormones, effects in individuals with existing disease states such as obesity, diabetes, and cardiovascular disease, and potential mitigation strategies for metabolic risk factors will be crucial to support the health of hyperandrogenic patients.

Subject of Research: Endocrinology

Article Title: Testosterone treatment prevents most gonadectomy-induced metabolic and skeletal deficiencies in female mice

Article References: Kruger, R. E., Yohannes, H., Cho, E., Eisner, L., Pfau, D. R., Chan-Sui, R. K., Migotsky, N., Monteiro da Rocha, A., Killian, M. L., Moravek, M. B., Padmanabhan, V., & Shikanov, A. (2026). Testosterone treatment prevents most gonadectomy-induced metabolic and skeletal deficiencies in female mice. Frontiers in Endocrinology, 17, Article 1940100. https://doi.org/10.3389/fendo.2026.1940100

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1940100

Keywords: testosterone, ovariectomy, female mice, glucose metabolism, bone density, trabecular bone, dyslipidemia, adipocyte hypertrophy, estrogen, aromatization, hyperandrogenism, gender-affirming hormone therapy

The scale of the market illustrates how quickly this sector has grown. In 2024, the UK testosterone replacement market was valued at around 205 million dollars, with projections suggesting it could reach 365 million dollars by 2032. Official NHS figures show that community dispensing of testosterone increased by 52 percent between 2020/21 and 2024/25. Alongside this, there was a ten-fold rise in testosterone gel prescriptions for women aged 50 and older in England between 2015 and 2022, reflecting growing off-label use of the hormone for menopausal symptoms.

One of the central problems, the authors explain, is that private prescriptions are not recorded in any national system, so the true scale of private testosterone provision is unknown. Nevertheless, several indicators point to rapid growth. There has been a proliferation of private and online clinics offering testosterone services, many built around subscription pricing models ranging from 100 to 375 pounds a month. These subscriptions typically cover ongoing monitoring, remote consultations, and home-delivered medication. Heavy marketing through social media platforms, influencers, and outdoor advertising has amplified demand, targeting men who may simply be experiencing the natural effects of ageing.

The potential market is substantial. Declining testosterone levels and reduced libido are natural aspects of ageing, and up to a fifth of men over 50 may report symptoms consistent with deficiency. Yet fewer than 1 percent of these men receive treatment through the NHS, where prescribing is reserved for those with confirmed clinical need. This gap between symptom prevalence and NHS treatment rates represents the commercial opportunity that private providers are increasingly moving to fill, often with diagnostic and monitoring standards that differ from those applied in conventional medical practice.

Diagnosing genuine testosterone deficiency is not a simple matter. It requires time, careful clinical assessment, and repeated testing to confirm consistently low levels alongside characteristic symptoms. The authors note that it is not established how consistently private providers follow this rigorous process. They warn that rapid-access subscription models built around marketing to non-specific symptoms are unsuitable to handle the complexity of the diagnostic process, and that such models risk unnecessary lifelong treatment and a resulting NHS monitoring burden. Fatigue, low mood, and reduced libido, the symptoms most commonly marketed in advertising campaigns, can have many causes and do not by themselves justify hormone replacement.

Another layer of complexity arises from the absence of a single unified standard for treatment. For testosterone therapy in men, clinicians rely on professional society guidance that uses differing thresholds for diagnosis and treatment initiation. This inconsistency means that NHS clinicians may encounter patients who have already started taking testosterone prescribed against a more permissive private threshold, creating difficult decisions about whether to continue, adjust, or withdraw treatment that was initiated outside NHS pathways. The lack of harmonised criteria complicates continuity of care and makes it harder to evaluate whether individual patients are receiving appropriate therapy.

The long-term risks of testosterone therapy add further weight to these concerns. Treatment can be associated with heart and kidney problems that require ongoing monitoring, and the authors argue that this follow-up work will likely fall to the NHS regardless of where treatment began. There are also growing concerns about private off-label testosterone prescribing for women, mainly for low libido associated with menopause. While testosterone can be a valuable treatment for carefully selected patients of both sexes, the expansion of commercial prescribing raises questions about whether selection criteria and safety monitoring are being applied consistently across the private sector.

Responsibility for care is another flashpoint. As stated in official guidance, the responsibility of care rests exclusively with any private sector clinician who initiates treatment, unless an NHS GP formally agrees to a shared care arrangement. In practice, however, patients who started treatment privately may return to their GP informally for blood tests or help with managing side effects. This informal transfer creates a situation in which the NHS absorbs the workload without any formal agreement, shouldering the clinical and administrative consequences of prescribing decisions made elsewhere. GPs are left managing the downstream effects of treatment they did not initiate, often without complete records of dosing, monitoring history, or the original diagnostic rationale.

The authors stress that testosterone replacement remains a valuable treatment for carefully selected patients, and their criticism is not of the therapy itself but of the commercial structures growing around it. They call for national data to close the evidence gap on private prescribing of testosterone, arguing that without systematic information, neither regulators nor the NHS can accurately assess the scale of the issue or its impact on patient safety and health service resources. Reliable data would allow policymakers to distinguish between appropriate private provision and practices that generate avoidable harm.

To address the gap, Atkin and Kilpatrick propose a concrete solution. A reporting framework for private prescribers and dispensing pharmacies could capture indications, patient numbers, monitoring, and transfers of care, they write. Such a framework would lead to transparent prescribing and demonstrable adherence to evidence-based care, protecting patients while preserving access to effective treatment. As the private testosterone market continues its projected growth toward 365 million dollars by 2032, the authors argue that establishing robust oversight now, before the sector expands further, is essential to prevent a widening divide between commercial incentives and clinical standards, and to ensure the NHS is not left carrying the consequences of a trade it neither authorised nor recorded.

Subject of Research: Commercial and private testosterone prescribing in the UK and its implications for the NHS

Article Title: Rise in private testosterone prescribing risks overtreatment and more strain on the NHS

Article References: Rise in private testosterone prescribing risks overtreatment and more strain on the NHS. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: testosterone, testosterone replacement therapy, private prescribing, NHS, The BMJ, hypogonadism, menopause, off-label prescribing, health policy, patient safety, hormone therapy, UK healthcare

Energy homeostasis is governed centrally by the brain, which integrates nutritional, hormonal, and environmental signals to decide how calories are spent. In vertebrates, hypothalamic neuropeptides coordinate feeding behavior, energy expenditure, and lipid metabolism, and this coordination becomes especially visible in species that respond to seasonal cues. Reproduction is among the most energetically expensive events in an animal’s life cycle, and the onset of sexual maturation demands a coordinated redistribution of resources from growth and storage toward gonadal development. Yet the specific hypothalamic factors that decide whether energy flows into fat reserves or reproductive tissue have remained poorly defined, particularly in birds, where some neuropeptides act in ways that differ from their roles in mammals.

NPGM was first identified as a novel secretory protein in the chicken hypothalamus, and its gene is conserved across vertebrates including chickens, quails, rats, and humans. In Japanese quail, NPGM-expressing cells sit in the medial mammillary nucleus and project neural fibers to the median eminence. Previous work showed that chronic central administration of NPGM induced fat accumulation without overeating in neonatal chicks, while in mice, acute injection of NPGM or stimulation of NPGM-expressing neurons promoted feeding. NPGM has a paralogous gene, NPGL, encoding neurosecretory protein GL; chronic administration or hypothalamic overexpression of NPGL induces obesity in chicks and rodents, whereas double knockout of both genes produces lean mice with reduced food intake and elevated energy expenditure. Together, the two proteins appear to constitute an independent peptide family central to energy regulation.

To probe NPGM’s role during puberty, the team turned to Japanese quail, which reach sexual maturity rapidly under simple photoperiod manipulation and retain seasonal migratory behavior, making them an ideal model. Five-week-old quails at the onset of puberty received continuous intracerebroventricular infusion of synthetic NPGM at 15 nanomoles per day for 13 days via osmotic pumps connected to cannulas targeting the lateral ventricle. The researchers monitored body mass, food intake, and water intake daily, then measured tissue and organ masses, serum metabolites including glucose, fatty acids, triglycerides, testosterone, and 17β-estradiol, hepatic triglyceride content, and gene expression profiles across the hypothalamus, liver, and abdominal fat.

The results in males were striking. NPGM infusion significantly increased body mass gain, cumulative food intake, and cumulative water intake, and enlarged subcutaneous, abdominal, and gizzard fat depots. The liver, pancreas, and heart were heavier in treated males, although muscle masses were unchanged. Crucially, testicular mass relative to body mass fell significantly, and serum testosterone dropped while serum and hepatic triglycerides rose. Gene expression analysis revealed a corresponding molecular signature: hepatic SCD1, a lipogenic enzyme, was upregulated, while CGI-58, PPARγ, SLC2A2, and CD36 were downregulated. In abdominal fat, LPL expression decreased significantly. These patterns suggest that NPGM-induced fat gain in males stems not from enhanced fatty acid uptake but from suppressed lipid mobilization and utilization, compounded by reduced testosterone, which in humans and rodents is a recognized risk factor for visceral fat accumulation.

Females told a different story. NPGM-treated females accumulated subcutaneous and abdominal fat without any increase in food intake, body mass gain, or hepatic triglyceride content. Ovarian mass showed a decreasing trend relative to body mass, and serum 17β-estradiol levels fell. In the liver, expression of VTG2 and APOV1, genes encoding yolk protein precursors produced in response to estrogen, was significantly reduced. In abdominal fat, the lipolytic and transport genes ATGL, LPL, and FATP were all downregulated. The authors interpret this as a shift in lipid allocation: with yolk precursor synthesis dampened, lipids that would normally be routed to developing follicles are instead retained in adipose tissue. This fits with observations that visceral fat mass normally declines in laying hens as lipids are redirected toward yolk production.

Hypothalamic gene expression added another layer of intrigue. NPGM administration reduced expression of AGRP, an orexigenic neuropeptide, in both sexes, while NPY was additionally reduced in females. Notably, expression of GnRH and GnIH, the two key hypothalamic neuropeptides controlling reproductive function, remained unchanged in both sexes, suggesting that NPGM’s effects on gonads and sex hormones are not mediated through direct regulation of the canonical reproductive axis. The downstream signaling pathway of NPGM remains unclear, although GPR83 has been proposed as a candidate receptor based on in vitro binding assays, and NPGM appears to be co-expressed in a subset of AgRP neurons in mice.

The sex-specific responses raise broader questions about how hypothalamic feeding circuits are wired differently in males and females. In mammals, the orexigenic actions of NPY and AgRP are modulated by sex hormones, particularly estradiol, and anorexigenic POMC neurons show enhanced activity in females. Similar sex differences in feeding-related gene expression have been documented in chickens. Because basal NPGM expression does not differ between male and female quails, the authors suggest that the divergent effects likely reflect differences in the neural networks or hormonal environments through which NPGM acts, rather than differences in the peptide itself. Interestingly, while NPGM gene expression responds to fasting in both birds and mammals, pharmacological administration has produced opposite effects on feeding in the two groups, in chicks suppressing intake and in mice stimulating it, a puzzle the authors flag for future evolutionary study.

The study has limitations the authors acknowledge. Male and female experiments were conducted independently, precluding direct statistical comparison between sexes, and the work relied on chronic administration of exogenous NPGM, leaving the physiological role of endogenous NPGM unresolved. Future studies using avian adeno-associated virus-mediated overexpression and genome editing to generate loss-of-function models in quail are planned. Moreover, because quail are long-day breeders with strong photoperiodic responses, and the experiments were run exclusively under long-day conditions, it remains unknown whether NPGM’s actions hold under short-day states. Given that seasonally breeding species enhance fat deposition after the breeding season to prepare for migration or overwintering, NPGM may prove to be a seasonal gatekeeper coordinating energy allocation among storage, reproduction, and migration.

For now, the study delivers a clear message: a single hypothalamic microprotein can reorganize an animal’s metabolic priorities at puberty, pushing resources into fat depots at the expense of gonadal maturation, and doing so through distinct molecular routes in each sex. As obesity research increasingly looks to the brain’s energy-allocation circuitry, NPGM and its paralog NPGL offer a fresh and evolutionarily conserved entry point into one of biology’s oldest trade-offs.

Subject of Research: Role of hypothalamic neurosecretory protein GM in energy allocation, fat deposition, and gonadal hormone regulation during sexual maturation in Japanese quail

Article Title: Hypothalamic neurosecretory protein GM causes fat deposition and affects gonadal hormones in Japanese quail

Article References: Kato, M., Iwakoshi-Ukena, E., Furumitsu, M., Narimatsu, Y., Yatsuda, C., Nakamura, Y., & Ukena, K. (2026). Hypothalamic neurosecretory protein GM causes fat deposition and affects gonadal hormones in Japanese quail. Frontiers in Neuroscience, 20, Article 1980898. https://doi.org/10.3389/fnins.2026.1980898

Image Credits: AI Generated

DOI: 10.3389/fnins.2026.1980898

Keywords: NPGM, hypothalamus, Japanese quail, fat deposition, sexual maturation, testosterone, 17β-estradiol, lipid metabolism, neuropeptide, energy homeostasis, reproduction, neuroendocrinology

The story begins with a simple observation. When the researchers profiled rat testicular tissue at 2, 6, 12, and 18 months of age, they found that both overall DNA methyltransferase activity and circulating testosterone levels followed strikingly parallel trajectories, with a pronounced concurrent decline beginning at 12 months. The enzymes that actually build testosterone—CYP11A1, CYP17A1, and the cholesterol transporter StAR—mirrored this drop precisely. Intriguingly, when the team mined existing human multi-tissue transcriptomic datasets, they discovered that DNMT1, the principal maintenance methyltransferase responsible for preserving genomic methylation patterns during cell division, is preferentially and abundantly expressed in the testis compared with 31 other human tissues. This positioned DNMT1 as a prime candidate regulator of testicular function, and indeed, complementary RT-qPCR, Western blotting, and immunohistochemical staining all confirmed a progressive age-related decline in DNMT1 expression in rat testes.

To isolate the cell-intrinsic relationship between DNMT1 and testosterone production without the confounding influences of the living organism, the researchers established an in vitro aging model using primary Leydig cells—the specialized interstitial cells that serve as the testis’s sole source of testosterone. Isolated from juvenile rats and serially passaged to induce replicative senescence, these cells developed a robust aged phenotype, with more than 70 percent staining positive for senescence-associated β-galactosidase. They also upregulated the senescence marker p16 and secreted elevated levels of inflammatory SASP factors including TNF-α, IL-1β, and IL-6. Crucially, these senescent Leydig cells produced markedly less testosterone and expressed significantly less DNMT1, recapitulating the age-related declines observed in living animals and supporting DNMT1 as a cell-intrinsic correlate of Leydig cell functional aging.

Gain- and loss-of-function experiments then established DNMT1 as a genuine positive regulator of steroidogenesis rather than a mere bystander. When the researchers knocked down DNMT1 using lentiviral shRNA, testosterone secretion into the culture medium plummeted, and the protein expression of CYP11A1, CYP17A1, and StAR all fell in concert. Conversely, overexpressing DNMT1 produced the reciprocal phenotype, elevating testosterone output and upregulating the same rate-limiting enzymes. DNMT1 knockdown also drove Leydig cells toward senescence, increasing the proportion of β-galactosidase-positive cells and upregulating p16 and SASP factors. Overexpression of DNMT1 in already-senescent cells reversed this program, reducing senescence markers and restoring testosterone secretion. Together, these findings position DNMT1 as an epigenetic safeguard against the functional decay of the aging testis.

The real surprise came when the team performed RNA sequencing on DNMT1-deficient Leydig cells to identify what DNMT1 actually controls. Among the altered transcripts, the mRNA encoding FTO—the fat mass and obesity-associated protein, better known as a demethylase that erases N6-methyladenosine (m6A) marks from messenger RNA—was significantly upregulated when DNMT1 was silenced. Methylation-specific PCR revealed that the Fto promoter became significantly hypomethylated following DNMT1 knockdown, and chromatin immunoprecipitation coupled with qPCR confirmed that DNMT1 physically binds to the CpG island within the Fto promoter, enriching approximately 398-fold over a control antibody. In other words, DNMT1 normally keeps FTO switched off by methylating its promoter, and when DNMT1 levels fall with age, FTO is derepressed and begins to accumulate.

FTO, it turns out, is not a benign consequence of DNMT1 loss but an active agent of decline. When the researchers overexpressed FTO in Leydig cells, testosterone production dropped and the steroidogenic enzymes CYP11A1, CYP17A1, and StAR were all downregulated—phenocopying the effect of DNMT1 knockdown. Dual knockdown experiments then established the direction of causality: silencing FTO in DNMT1-deficient cells rescued testosterone production and restored enzyme expression, whereas silencing DNMT1 in FTO-deficient cells produced the opposite outcome. Notably, FTO overexpression did not feed back to alter DNMT1 levels, confirming that the regulatory axis is unidirectional, with DNMT1 upstream and FTO downstream.

To find FTO’s actual target, the team turned to computational prediction and RNA immunoprecipitation. Using the catRAPID protein-RNA interaction database, they identified Hsp90aa1—the gene encoding heat shock protein 90α, a molecular chaperone that stabilizes and activates the pro-survival kinase AKT—as the transcript with the highest binding propensity for FTO. RIP-qPCR using an FTO-specific antibody confirmed that Hsp90aa1 mRNA is a direct binding substrate of FTO. MeRIP-qPCR then showed that FTO overexpression reduced the m6A modification level of Hsp90aa1 transcripts, and this demethylation was accompanied by downregulation of Hsp90aa1 mRNA and HSP90AA1 protein. Conversely, FTO knockdown elevated both m6A marks and HSP90AA1 abundance. Importantly, DNMT1 knockdown did not alter the DNA methylation status of the Hsp90aa1 promoter, yet it still reduced HSP90AA1 expression—and this reduction was rescued by concurrent FTO knockdown. The message is clear: DNMT1 regulates HSP90AA1 indirectly, through the FTO-mediated m6A axis, rather than through direct promoter methylation.

The downstream consequences of losing HSP90AA1 are what ultimately kill testosterone production. HSP90AA1 overexpression increased testosterone output and upregulated the steroidogenic enzymes, while simultaneously raising the levels of phosphorylated AKT and the anti-apoptotic protein BCL-2 and lowering the pro-apoptotic protein BAX. Pharmacological inhibition of HSP90AA1 with 17-AAG produced the opposite effects, reducing testosterone secretion, suppressing AKT phosphorylation, and tipping the balance toward cell death. Rescue experiments confirmed the hierarchical architecture of the pathway: FTO knockdown reversed the inhibitory effects of DNMT1 deficiency on HSP90AA1 expression, AKT phosphorylation, and testosterone production, whereas HSP90AA1 overexpression rescued the functional impairments induced by FTO overexpression. TUNEL staining corroborated these molecular findings, confirming that the DNMT1–FTO–HSP90AA1–AKT axis exerts hierarchical control over Leydig cell apoptosis.

When the researchers examined how this axis behaves during natural aging, the picture became even more coherent. In testicular tissue from 18-month-old rats, the Fto promoter was significantly hypomethylated compared with 2-month-old controls, FTO binding to Hsp90aa1 mRNA was markedly enhanced, and the m6A modification level of Hsp90aa1 transcripts was significantly reduced. FTO expression rose progressively with age while HSP90AA1 fell, and immunohistochemical staining revealed elevated FTO, reduced HSP90AA1, and increased pro-apoptotic Caspase-3 in aged testicular sections. TUNEL staining verified a significant age-dependent increase in apoptotic cells, and Western blot analysis showed that phosphorylated AKT and BCL-2 were significantly decreased while BAX was markedly upregulated. Senescent Leydig cells in vitro recapitulated every one of these molecular alterations, and primary Leydig cells isolated from aged rats displayed the same reduced Fto promoter methylation, reduced m6A modification of Hsp90aa1, and impaired AKT signaling.

To validate the pathway in a living organism, the team delivered adeno-associated virus serotype 9 carrying a Dnmt1-targeting construct directly into rat testes via local intratesticular injection. Three weeks later, serum testosterone levels were significantly reduced, the steroidogenic enzymes CYP11A1, CYP17A1, and StAR were downregulated, Fto promoter methylation was decreased, FTO was upregulated, HSP90AA1 was downregulated, and apoptotic cells within the testicular interstitium were markedly increased. Phosphorylated AKT and BCL-2 fell while BAX rose, and senescence markers including p16 and SASP factors were elevated. These in vivo observations mirror the in vitro findings almost exactly, confirming that the DNMT1–FTO–HSP90AA1–AKT cascade operates as a genuine regulatory circuit in the aging testis rather than an artifact of cell culture.

The implications of this work extend well beyond basic reproductive biology. Testosterone replacement therapy, currently the most widely applied intervention for age-related hypogonadism, carries notable contraindications and adverse effects including polycythemia, cardiovascular events, and prostate-related morbidity, and its efficacy remains suboptimal. The DNMT1–FTO–HSP90AA1 axis offers a mechanistic alternative: rather than supplying testosterone from outside the body, it suggests that pharmacological strategies aimed at preserving DNMT1 activity, restraining FTO expression, or sustaining HSP90AA1-dependent AKT signaling could enhance endogenous testosterone synthesis from within. Selective small-molecule inhibitors targeting DNMT1 and m6A modifiers provide feasible therapeutic entry points, and the identification of Leydig cells as among the earliest testicular cell types to undergo senescence makes them a particularly attractive target for interventions designed to postpone reproductive aging. The authors acknowledge several limitations, including the fact that the precise m6A residues on Hsp90aa1 transcripts have not yet been mapped, that the MSP assay lacked certain positive controls, and that the findings have not yet been validated in human testicular samples. Nevertheless, the study establishes a comprehensive molecular model in which the slow erosion of a single epigenetic enzyme—DNMT1—triggers a cascade of RNA-level changes that ultimately silence the testis’s capacity to produce its own testosterone, and it identifies the DNMT1–FTO–HSP90AA1–AKT axis as a promising therapeutic target for enhancing endogenous steroidogenesis during aging.

Subject of Research: Epigenetics and Reproductive Aging

Article Title: DNMT1 Regulates Testosterone Synthesis in Aged Rat Leydig Cells via FTO‐Mediated HSP90AA1 m6A Levels

Article References: Li, Y., Duan, Y., Tian, Z., Gao, Y., Qiao, Y., Zhao, S., Li, W., Gao, Z., & Niu, S. (2026). DNMT1 Regulates Testosterone Synthesis in Aged Rat Leydig Cells via FTO ‐Mediated HSP90AA1 m 6 A Levels. Aging Cell, 25(10), Article e70760. https://doi.org/10.1111/acel.70760

Image Credits: AI Generated

DOI: 10.1111/acel.70760

Keywords: DNMT1, FTO, HSP90AA1, m6A, testosterone, Leydig cells, epigenetics, aging, AKT signaling, reproductive biology, Regulates, Synthesis

The research team, led by investigators at S.D. Asfendiyarov Kazakh National Medical University in Almaty, analyzed data from a WHO STEPS survey conducted between May and October 2025. Of 3,198 eligible men, 3,083 had testosterone measurements suitable for analysis, and the investigators applied survey weights, stratification, and clustering to ensure their estimates reflected the true structure of the Kazakh male population. The primary outcome was a total testosterone concentration below 8 nmol/L, a cutoff frequently used to flag biochemical hypogonadism, with additional sensitivity analyses at 10 and 12 nmol/L to test whether the associations held at different thresholds. This design-based approach matters because naive analyses of survey data can produce misleading confidence intervals and prevalence estimates.

The headline numbers are straightforward. The observed proportion of men with testosterone below 8 nmol/L was 5.1 percent, or 156 of 3,083 participants, and after weighting the survey-adjusted prevalence came in at 5.3 percent, with a 95 percent confidence interval of 4.4 to 6.2 percent. That figure is lower than some clinic-based estimates from other regions, a reminder that men who walk into endocrinology clinics are not typical of the population at large. But the raw prevalence tells only part of the story. The heart of the paper lies in its regression models, which disentangle the independent contributions of body size, glycemic status, and age to the probability of low testosterone.

In the primary logistic model, which included 2,959 men and adjusted for age, body mass index, and glycated hemoglobin, or HbA1c, the metabolic signals were strong and consistent. Overweight men had roughly double the odds of low testosterone compared with men of normal weight, with an adjusted odds ratio of 2.05. Men with obesity fared far worse still: their odds were more than four and a half times higher, at 4.58, than those of their lean counterparts. Glycemic status showed a parallel gradient. Men whose HbA1c fell in the prediabetes range had 2.39 times the odds of low testosterone, while those in the diabetes range had 3.49 times the odds. In other words, both the degree of adiposity and the severity of dysglycemia tracked closely with the likelihood of biochemical testosterone deficiency.

When testosterone was analyzed as a continuous variable after logarithmic transformation, the same pattern emerged in proportional terms. Overweight was associated with testosterone levels 15.0 percent lower than in normal-weight men, and obesity with levels 24.8 percent lower. Prediabetes-range HbA1c corresponded to levels 19.0 percent lower, and diabetes-range HbA1c to levels 24.5 percent lower. These continuous estimates are informative because they suggest a dose-response relationship rather than a binary cliff: the worse the metabolic profile, the lower the circulating hormone. Importantly, the associations with obesity and dysglycemia remained positive even when the researchers relaxed the diagnostic threshold to 10 or 12 nmol/L, indicating that the findings are not an artifact of one particular cutoff.

Perhaps the most scientifically intriguing result concerns age. Taken on its own, aging appeared to raise the risk: men aged 60 to 69 had 1.84 times the odds of low testosterone compared with men aged 18 to 29. Yet once body mass index and HbA1c were factored in, the direction of the association flipped, yielding an adjusted odds ratio of 0.65, and the effect was no longer statistically significant. The authors interpret this reversal as evidence that the apparent age-related decline in testosterone within this population may be substantially mediated by metabolic factors. Older men in the survey tended to be heavier and more dysglycemic, and it is those characteristics, rather than chronological age itself, that appear to drive much of the association with low testosterone.

This finding resonates with a broader mechanistic literature on the hypothalamic-pituitary-gonadal axis and metabolism. Adipose tissue, particularly visceral fat, is metabolically active: the enzyme aromatase converts testosterone into estradiol, the hypothalamic-pituitary feedback loop responds by suppressing gonadotropin release, and leptin and inflammatory cytokines secreted by fat cells further dampen gonadal steroidogenesis. Hyperglycemia and insulin resistance compound these effects, and the testosterone-glucose relationship is often described as bidirectional, since low testosterone itself can promote insulin resistance and central fat deposition. The Kazakh data cannot establish causation, being cross-sectional, but the strength and consistency of the adiposity and glycemia signals align closely with what these physiological models predict.

The study carries significant public health implications for Kazakhstan and the wider Central Asian region, where population-based endocrine data have historically been scarce. Funded by Kazakhstan’s Ministry of Healthcare under a grant on epigenetics and non-communicable disease prevention, and registered as clinical trial NCT06953180, the survey demonstrates how the standardized WHO STEPS framework can be extended from its traditional focus on cardiovascular risk factors to hormone health. If excess adiposity and dysglycemia are the dominant modifiable correlates of low testosterone, then strategies targeting obesity and prediabetes prevention may carry hormonal benefits alongside their well-established cardiovascular ones. For a country confronting the global epidemic of metabolic disease, the overlap between these two health burdens is a compelling argument for integrated prevention programs.

The authors are careful to draw a crucial clinical boundary: a biochemical reading below 8 nmol/L is not, by itself, a diagnosis of clinical hypogonadism. True hypogonadism requires compatible symptoms, such as reduced libido, fatigue, or loss of muscle mass, together with confirmatory testing, typically including repeated morning measurements and assessment of the hypothalamic-pituitary axis. Cross-sectional biochemical associations describe the population’s hormonal landscape; they do not tell clinicians which individual men need treatment. This caution is especially important in an era when testosterone testing and therapy are increasingly marketed directly to consumers, and it underscores why large, methodologically rigorous population surveys are needed to ground clinical practice in representative evidence.

As an early-access, open-access publication carrying a permanent DOI, the study invites both replication and extension. Future work could follow men over time to test whether weight loss and glycemic control raise testosterone levels, examine free and bioavailable testosterone rather than total concentrations alone, and probe whether behavioral factors measured in STEPS surveys, such as physical activity and alcohol intake, modify the metabolic associations. For now, the message from Kazakhstan is clear and quantifiable: in a nationally representative sample of men, low circulating testosterone clustered tightly around the two great metabolic risk factors of our time, and age, once those factors were accounted for, lost much of its apparent grip. The study reframes male hormone health not as an inevitable consequence of growing older, but as a mirror of metabolic health, one that may be more malleable than conventional wisdom suggests.

Subject of Research: Metabolic correlates of low total testosterone among men in a national Kazakhstan WHO STEPS survey

Article Title: Metabolic correlates of biochemically low total testosterone among men participating in a national WHO STEPS survey in Kazakhstan

Article References: Gizat, D., Shamsutdinova, A., Ibrayeva, A., Ismoldayev, Y., Alchinbayev, M., Shoranov, M., Tanabayeva, S., & Fakhradiyev, I. (2026). Metabolic correlates of biochemically low total testosterone among men participating in a national WHO STEPS survey in Kazakhstan. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02659-3

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02659-3

Keywords: testosterone, hypogonadism, obesity, dysglycemia, HbA1c, Kazakhstan, WHO STEPS survey, endocrinology, metabolic syndrome, cross-sectional study, men's health, public health

The research team, led by Hejing Zhang and Yina Ma of Beijing Normal University, analyzed behavior from 528 participants engaged in a real-time offender-defender game. Participants were organized into six-person same-sex groups, with three-person offense teams attempting to extract resources from a three-person defense team. Over 24 rounds, each participant independently decided how many tokens to contribute to their group pool. The payoff structure was deliberately asymmetric: if the offensive group’s total contribution exceeded the defensive group’s total, the attackers retained their own uninvested tokens and equally shared the defenders’ remaining unspent tokens, while defenders earned zero for that round. If the defensive total matched or exceeded the offensive total, the attack failed and all participants retained only their own uninvested tokens. This design distilled offense and defense into their core strategic problems: acquiring resources under uncertainty versus protecting resources under threat.

To quantify the strategies participants used, the researchers computed two indices from the trial-by-trial contribution data. Behavioral variability, indexing strategic unpredictability, was defined as the intra-individual variance of contributions across the 24 rounds. Strategic tracking, indexing state estimation, was measured as the extent to which an individual’s contributions changed in response to the opponent group’s previous actions, calculated using a lagged regression model. The results revealed a robust complementary pattern: behavioral variability was positively associated with success in offensive roles (r = 0.361, p < 0.001) but negatively associated with success in defensive roles (r = -0.179, p = 0.003). In contrast, strategic tracking predicted higher success in defense (r = 0.277, p < 0.001) but was unrelated to success in offense.

The researchers went further, decomposing variability into its behavioral components to rule out a pure noise account. High variability was driven by a pulsed pattern: combining high non-zero contribution levels when engaging, interspersed with intermittent zero-contribution rounds. Both engagement intensity and zero-contribution rate were independently associated with offensive success. Zero-contribution rounds were systematically linked to lower defensive resistance, greater average spoils on successful offensive rounds, and greater resource-extraction efficiency. This pattern argues against random fluctuation and instead suggests a temporally pulsed mode of offensive engagement: larger active-round contributions were linked to successful attack, whereas intermittent disengagement was associated with lower defensive investment and more efficient resource capture when offense succeeded.

When the researchers examined whether these strategic optima aligned with sex-differentiated behavioral priors, a clear pattern emerged. Across roles, males showed significantly higher behavioral variability than females (20.580 versus 15.510; p < 0.001), and this effect remained significant after controlling for opponent average contribution. Decomposing the variability effect revealed that males showed higher non-zero contribution levels than females (9.686 versus 8.272; p < 0.001), and in covariate-adjusted sensitivity analyses, males also showed higher zero-contribution frequency. This suggests that the male strategy is characterized by pulsed, high-intensity engagement that generates unpredictability, rather than simple differences in effort.

Females, in contrast, exhibited a role-specific bias toward adaptive tracking. A significant sex-by-role interaction emerged for the tracking index (p < 0.001). In the defensive role, female defenders showed significantly stronger positive opponent-contingent tracking than male defenders (0.223 versus 0.120; p = 0.011). In the offensive role, female offenders showed more negative opponent-contingent coupling than male offenders (-0.200 versus -0.107; p = 0.021). This interaction remained significant after controlling for opponent average contribution. Thus, females showed stronger opponent-contingent adjustment than males in both roles, but this adjustment was expressed in opposite directions: positive tracking in defense and more negative coupling in offense.

These strategic biases translated into measurable performance asymmetries. Males outperformed females in offensive roles, achieving higher success rates (0.259 versus 0.189; p < 0.001) and making decisions closer to the theoretical optimum. In contrast, females outperformed males in defensive roles, achieving higher success rates (0.811 versus 0.741; p < 0.001) and earning substantially more (9.985 versus 8.485; p < 0.001). Crucially, process measures indicated that the female defensive advantage was underpinned by greater cognitive efficiency: female defenders not only made more rational decisions but also responded significantly faster than male defenders. These patterns remained robust in supplementary analyses controlling for the opponent behavioral environment.

The researchers also explored whether individual differences in salivary testosterone were related to these role-aligned behavioral patterns. In male offenders, higher log-transformed testosterone values were associated with greater behavioral variability both before and after the task, with post-task testosterone also covarying with offensive success. In female defenders but not female offenders, higher salivary testosterone values were associated with stronger strategic tracking. These findings are presented as preliminary associations within each sex rather than as tests of male-female differences in mean testosterone levels, and the authors caution that estimates from cotton-collected salivary immunoassays can depend on both the collection procedure and the analytical method, particularly at the lower testosterone concentrations typically observed in women. Replication using more precise serum-based measures will be needed to establish the robustness of these associations.

Why do the sexes diverge along these specific strategic lines? The authors interpret these patterns as average, role-congruent tendencies under the asymmetric demands of the task, rather than fixed sex-specific specializations. Males, who have historically faced higher variance in reproductive payoffs, appear to encode a high-volatility prior, enduring the costs of variable engagement to maximize the probability of high-stakes returns. Females, incurring higher costs of injury and parental investment, appear to encode a precision prior, prioritizing error minimization and sensitivity to social cues. This account also accommodates the possibility that female competition is active and strategic rather than passive: work on competitive gossip and informational competition emphasizes monitoring rivals, updating socially relevant information, and using such information to manage competitive threats. Such information-sensitive strategies may fit the defensive demands of the present task, where success depended on tracking opponent behavior and adjusting contributions accordingly.

Importantly, the data indicate that these sex-differentiated priors reflect functional competence rather than impulsivity. The male advantage in offense and the female advantage in defense were accompanied by higher decision rationality and greater economic efficiency, implying that the male tendency toward variability is a potentially functional tactic to capitalize on uncertainty, while the female tendency toward tracking reflects an efficient heuristic for threat management. The present data cannot determine whether these tendencies reflect evolved affordances, contemporary gendered socialization, prior competitive experience, or their interaction. A key question for future research is how these distinct priors interact in direct cross-sex competition: whether the high-variability offense of males overwhelms the tracking capacity of female defenders, or whether female vigilance effectively decodes and neutralizes that variability. The study nonetheless provides a compelling framework for understanding sex- and role-related variation in intergroup decision-making, revealing that human conflict relies on a dissociated strategy architecture in which unpredictability generation and opponent tracking serve as specialized tools for acquisition and protection.

Subject of Research: Behavioral science

Article Title: Offensive unpredictability and defensive tracking in intergroup conflict show sex-differentiated patterns

Article References: Zhang, H., Zhang, C., Widjaja, A., & Ma, Y. (2026). Offensive unpredictability and defensive tracking in intergroup conflict show sex-differentiated patterns. iScience, 29(11), Article 117887. https://doi.org/10.1016/j.isci.2026.117887

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117887

Keywords: intergroup conflict, sex differences, unpredictability, strategic tracking, testosterone, game theory, evolutionary psychology, defense, offense, decision-making, Offensive, defensive