The distinction between active relaxation and passive stiffness is central to understanding why the review’s cautious conclusion matters. Active relaxation is an energy-consuming process: after each heartbeat, calcium must be pumped back into the sarcoplasmic reticulum by SERCA2a, the sarco/endoplasmic reticulum calcium ATPase, and any residual calcium bound to the contractile proteins must be released so that cross-bridges detach and force declines. If calcium removal slows or myofilaments remain activated longer than they should, the ventricle begins to fill while it is still generating tension, and filling pressures rise. Passive stiffness, by contrast, is a property of the relaxed cell itself, determined largely by titin, the giant spring-like protein that spans from the Z-disc to the M-band of the sarcomere. Titin’s stiffness can be tuned by isoform switching, with the more compliant N2BA isoform giving way to the stiffer N2B isoform in some settings, and by phosphorylation of its elastic PEVK and N2B segments through kinases such as protein kinase A and protein kinase G. Hypophosphorylation of titin, oxidative modifications, and shifts in isoform ratio have all been proposed as mechanisms contributing to the elevated diastolic stiffness characteristic of HFpEF.

What makes the review’s framework particularly useful is its insistence on formal statistical testing of sex as a modifier. In experimental biology, it is common to report that females and males differ in some measured quantity, but a simple difference in a single endpoint does not establish that sex modifies the disease process. A true modifier effect requires a statistically significant interaction term, either sex by disease or sex by target, demonstrating that the effect of disease, or the response to an intervention, is itself different between the sexes. This is a much higher bar than demonstrating a baseline difference, and it is the appropriate standard when the clinical question is whether men and women should be classified or treated differently. By applying this standard systematically across the literature on calcium handling, myofilament function, titin, and mitochondrial bioenergetics, the authors converted a sprawling and often contradictory body of work into a much smaller set of defensible claims.

The result is striking in its sparseness. Among all the studies surveyed, the late sodium current emerged as the only active-relaxation-related cellular endpoint with a reported formal sex by disease interaction. The late sodium current is a small, sustained inward flow of sodium ions during the plateau phase of the cardiac action potential, and its pathological augmentation in disease states is thought to drive sodium and calcium overload through the sodium-calcium exchanger, contributing to diastolic tension and arrhythmogenic risk. The drug ranolazine, which suppresses the late current, has been tested clinically in the RALI-DHF trial for diastolic heart failure, making this target one of the few with a direct translational thread running from cellular electrophysiology to human intervention. Yet even here, the review notes that the reported sex interaction was electrophysiological rather than mechanical: the difference appeared in ionic current measurements, not in a demonstrated difference in how relaxation or stiffness responded. Without that mechanical link, the interaction remains an observation about membrane physiology rather than a guide to therapy.

The titin story illustrates a different kind of evidentiary gap. There is little doubt that titin modifications can change diastolic properties; interventions that alter titin phosphorylation or isoform expression have modified passive stiffness and filling in several HFpEF-like animal models, including models combining hypertension and metabolic stress such as the ZSF1 hybrid rat and models using L-NAME to induce nitric oxide synthase inhibition. Protein kinase G signaling, which phosphorylates titin and reduces its stiffness, has been a particularly attractive mechanistic target because it connects nitric oxide biology, cGMP signaling, and the phosphodiesterase pathways that have been explored pharmacologically in HFpEF. But the review’s systematic search found no experiment in which an independent laboratory replicated a sex-modified mechanical response to a titin-directed intervention. In other words, titin is clearly modifiable, and titin stiffness is clearly relevant to HFpEF, but the claim that women’s titin behaves differently from men’s titin in disease, in a way that would justify sex-specific treatment, has not been demonstrated under conditions that meet modern standards of rigor.

Mitochondrial bioenergetics and redox state occupy the connective position in this framework, and the review treats them accordingly. The energetic cost of relaxation is substantial: SERCA2a consumes a large fraction of the ATP generated by the cardiomyocyte, and any impairment of oxidative phosphorylation, NAD+ availability, or mitochondrial quality control can slow calcium reuptake and prolong contraction. Oxidative stress adds a second layer of vulnerability, because reactive oxygen species can modify ryanodine receptors, promote calcium leak, stiffen titin through oxidative cross-linking, and alter myofilament protein function. Pathways such as sirtuin 3, which depends on NAD+ and regulates mitochondrial protein acetylation, and calcium/calmodulin-dependent protein kinase II, which links calcium handling to oxidative stress, have each been implicated in diastolic dysfunction in experimental models. Interventions aimed at restoring NAD+ pools or reducing oxidative damage have improved diastolic phenotypes in some HFpEF-like settings. Yet here again, the review found no replicated demonstration that these bioenergetic interventions produce different mechanical benefits in females versus males, despite the plausible biological reasons to expect such differences, including known sex differences in mitochondrial function, estrogen-dependent regulation of energetics, and redox enzyme expression.

The confounding landscape surrounding this literature is unusually dense, and the review is careful to enumerate it. Findings varied with the animal model employed, the genetic strain, the age of the animals, their reproductive state, the specific disease driver used to induce the HFpEF phenotype, the stage of disease at which measurements were made, and the assay used to assess function. Each of these variables can plausibly interact with sex. Reproductive state is especially important in females, since estrogen status influences calcium handling proteins, mitochondrial enzymes, and titin phosphorylation, and ovariectomy versus intact status can change experimental outcomes. Age interacts with both sex and disease, because HFpEF is predominantly a disease of older adults and many animal models study young animals. Disease drivers matter because hypertension-driven, metabolic-driven, and anemia-driven HFpEF models produce overlapping but distinct cellular phenotypes. A sex difference observed in one combination of these variables may simply not generalize to another, which is precisely the pattern the review documents.

Human evidence, which would ideally anchor the field, is itself fragmented. Studies of ventricular tissue from patients with HFpEF have documented slowed active relaxation, elevated passive stiffness, and metabolic remodeling, including shifts in substrate utilization and mitochondrial protein expression. But these findings come from separate cohorts, often with small sample sizes, and the role of sex within each finding remains unresolved. Human myocardial tissue is difficult to obtain, typically available only from surgical procedures such as valve replacement or from transplant and autopsy material, and the underlying disease etiologies of donors vary widely. Direct comparisons of women and men using the same cellular assays on matched tissue are rare. This means that even the well-documented cellular abnormalities of HFpEF cannot currently be assigned a sex-specific prevalence or magnitude with confidence.

The review also draws a useful methodological distinction among the kinds of comparisons that would actually advance the field. One question is whether disease affects females and males differently, which requires comparing each sex against its own healthy control. A second question is whether a molecular target functions differently within diseased hearts of each sex, which requires testing the target’s contribution in both sexes under disease conditions. A third question is whether any observed difference is specific to disease rather than a baseline sex difference that exists independently of pathology. Many published studies conflate these questions, reporting sex differences without the appropriate controls to determine what kind of difference has been found. Prespecifying sex comparisons and linking them to a relevant functional endpoint, such as relaxation kinetics or passive force, would allow future studies to distinguish genuine modifier effects from incidental observations.

The clinical implications of this cautious conclusion deserve emphasis. If sex alone cannot define calcium-dominant or titin-dominant HFpEF endotypes, then treatment selection based on a patient’s sex would currently lack a mechanistic foundation. This does not mean sex is irrelevant to HFpEF; the epidemiological preponderance of women, differences in ventricular remodeling patterns, and known hormonal influences on cardiovascular physiology all remain real and clinically important. It means instead that the cellular mechanisms underlying any sex-related clinical differences have not been pinned down with the specificity needed to guide endotyping. The practical path forward suggested by the review is to treat sex as a hypothesis-generating variable to be tested in defined experimental and clinical settings, rather than as a classification tool. Until replicated, sex-stratified, mechanically anchored evidence accumulates, the heterogeneous reality of HFpEF, in which multiple cellular defects coexist and vary with context, remains the best available description of the disease for both women and men.

Subject of Research: Sex differences in cardiomyocyte relaxation mechanisms in heart failure with preserved ejection fraction

Article Title: Evaluating sex as a modifier of cardiomyocyte relaxation in heart failure with preserved ejection fraction: calcium handling, titin, and bioenergetics

Article References: Wang, B., & Dai, X.-C. (2026). Evaluating sex as a modifier of cardiomyocyte relaxation in heart failure with preserved ejection fraction: calcium handling, titin, and bioenergetics. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00993-8

Image Credits: AI Generated

DOI: 10.1186/s13293-026-00993-8

Keywords: HFpEF, cardiomyocyte relaxation, calcium handling, titin, passive stiffness, mitochondrial bioenergetics, sex differences, late sodium current, NAD+, diastolic dysfunction, heart failure, Biology of Sex Differences

The research team, led by Yumnah T. Khan of the Autism Research Centre in the Department of Psychiatry, together with colleagues including Alex Tsompanidis, Carrie Allison, neonatologist Topun Austin, and Simon Baron-Cohen, tested 130 newborns, 67 males and 63 females, at a mean age of just 33 hours after birth. That extraordinarily tight window is the study’s methodological centrepiece. Infants tested at 33 hours of life have experienced almost none of the social world: no extended eye contact, no named gender, no toys, no language, and no deliberate socialisation. Any behavioural difference observed at this stage, the researchers argue, is far harder to attribute to learning than differences measured in older babies, toddlers, or children.

The experimental design was deliberately minimal. Each newborn was presented simultaneously with a video of a human face and a video of a non-social object, while gaze-tracking equipment recorded precisely where the infant looked and for how long. The stimuli were matched in their presentation, and the infants’ spontaneous looking behaviour served as the sole measure. Eye-tracking is the gold standard for interrogating early attention because newborns cannot follow verbal instructions, and their visual behaviour is one of the few channels through which the hidden architecture of their emerging cognition can be observed at all.

The results split into two revealing layers. When the researchers analysed percentage looking time — the proportion of total looking devoted to the face rather than the object — female newborns on average allocated a greater percentage of their attention to the face than male newborns did. The effect size was moderate, at Cohen’s d of 0.40, a magnitude that is meaningful in behavioural science without being dramatic. When the analysis shifted to absolute looking times, an equally nuanced pattern appeared: females showed a genuine preference, looking longer at the face than at the non-social object, whereas males showed no preference for either stimulus.

Crucially, however, the team found no statistically significant differences between the sexes in the absolute amount of time each group spent looking at the face, or at the object. That absence is what elevates the study above a simple headline. The sex difference is not that girls look more at faces in total, nor that boys look less; it is that girls distribute their attention differently between the two types of stimuli. Sex differences in this experiment live in the relative allocation of attention — in the internal comparison an infant appears to make between a social signal and a non-social one — rather than in raw visual appetite.

The significance of that distinction extends to how scientists interpret the causes of behavioural sex differences more broadly. Decades of research have documented on-average psychological differences between males and females, from interests and social orientation to the prevalence of particular neurodevelopmental conditions. But the scientific community remains divided over the engines of those differences. One camp emphasises gender socialisation: from birth, children are treated, spoken to, and encouraged differently depending on their sex, and any observed divergence could in principle be the residue of that immersion. The other camp allows for partial biological contributions, notably prenatal sex hormones such as testosterone, which differ systematically between male and female foetuses and are known to influence brain development.

Newborns are among the very few human populations capable of adjudicating between these accounts, at least in principle. Because infants at 33 hours have had negligible postnatal social experience, a reliable behavioural difference at this age suggests that something occurring before or at birth — prenatal hormones, genetic factors, or differences in maturational tempo — may contribute to the earliest organisation of social attention. The Cambridge team is careful, in its published abstract and plain-language summary, to frame prenatal sex hormones as one possible explanation rather than a proven cause. They also name two credible alternatives that the current design cannot fully exclude.

The first alternative concerns maturation. Male and female foetuses develop on slightly different schedules, and differences in the maturity of visual or attentional systems at birth could produce divergent looking patterns without any specifically social mechanism being involved. A less visually mature infant might, for instance, engage more diffusely with both stimuli, diluting any face preference. The second alternative concerns the stimuli themselves. Low-level visual properties — contrast, motion, complexity, colour, luminance — can drive infant looking independently of whether a stimulus is social. If the face video happened to possess visual features that interact differently with male and female early visual systems, the observed effect could reflect those properties rather than the face’s social meaning. The authors present these explanations not as disqualifiers but as honest boundary conditions on interpretation.

Context strengthens the new findings considerably. Previous research on neonatal sex differences in face preference is described by the team as extremely limited, with the small number of existing studies yielding mixed results, raising methodological concerns, and remaining unreplicated. The new work, with a sample of 130 neonates — large by the demanding standards of newborn research, where recruiting families within hours of birth is logistically fraught — represents one of the most rigorous attempts to date to re-evaluate the question. Conducted at the Rosie Hospital in Cambridge with NHS Research Ethics Committee approval and written informed maternal consent, the study benefits from a controlled protocol, objective eye-tracking measurement, and a sample size that gives the moderate effect observed some statistical credibility.

The longer-term stakes reach into psychiatry and neurodevelopmental medicine. Conditions such as autism are diagnosed more frequently in males than females, and the reasons for that imbalance remain unresolved, spanning biological, diagnostic, and social hypotheses. If sex differences in the earliest attentional orientation toward social stimuli are genuinely present from birth, they may constitute one thread in the developmental fabric that eventually produces sex-differentiated profiles of social behaviour and vulnerability. The authors explicitly note that findings of this kind may help explain why several psychiatric and neurodevelopmental conditions show sex differences in prevalence — a claim offered as a research direction rather than a conclusion, and one that will require longitudinal follow-up linking newborn gaze measures to later developmental outcomes.

For now, the study’s most durable contribution is conceptual. It demonstrates that the relative allocation of attention between social and non-social visual worlds differs on average between male and female humans at the very threshold of postnatal life, while showing that neither sex looks more overall. That pattern is subtle, and the authors resist triumphalism: the effect could reflect prenatal biology, maturational differences, stimulus properties, or some combination of all three. What the study removes from the table, however, is the comfortable assumption that attentional sex differences must be products of the social environment alone. At 33 hours old, most of the social environment has not yet begun. Whatever tips these newborn girls’ eyes toward faces a little more often, it appears to have been installed before the first feed — and scientists now have a sharper, better-powered window into when and perhaps how that installation happens.

Subject of Research: Sex differences in newborn face-looking preferences and their possible prenatal origins

Article Title: Sex differences in face looking preferences at birth

Article References: Sex differences in face looking preferences at birth. (n.d.). https://doi.org/10.1186/s13293-026-00976-9

Image Credits: AI Generated

DOI: 10.1186/s13293-026-00976-9

Keywords: sex differences, newborns, face preference, eye-tracking, attention, prenatal hormones, neonatal development, social cognition, neurodevelopment, autism, infancy, Biology of Sex Differences

The article, the product of a consensus workshop at an international meeting of the Organization for the Study of Sex Differences in May 2019 and a subsequent expert meeting in Ottawa sponsored by the Institute of Gender and Health of the Canadian Institutes of Health Research, brings together a strikingly interdisciplinary authorship. Neuroscientists, physiologists, historians of science, internists, nephrologists, nurses, social workers, epidemiologists, and implementation scientists, led by co-first authors Gillian Einstein of the University of Toronto and Louise Pilote of McGill University, along with senior author Cara Tannenbaum of the Université de Montréal, collectively propose a name and a vision for what they call Sex and Gender Science. They describe it as a transdisciplinary, integrative, bio-social-medical field that combines diverse methods to investigate how sex and gender dynamically interact to shape disease outcomes, illness experiences, and the very conduct of science itself.

The conceptual core of the proposal rests on the claim that sex and gender are interactional and deeply interwoven. Within sex, the authors situate hormonal, genetic, physiological, and morphological processes and characteristics, from chromosomal complements and gonadal steroid fluctuations to organ-level physiology and morphology. Within gender, they include roles, relations, norms, institutional imperatives, and identities, along with their downstream consequences for behavior, environment, access to resources, and exposure to stress. Crucially, the authors argue, these domains are not merely additive; they operate on each other. Gendered expectations influence hormonal and physiological responses, while biological traits shape how institutions and individuals respond to a person. In this framing, gender literally gets under the skin, while sex expresses itself inescapably through social worlds.

Concrete clinical examples illustrate the stakes. Acute coronary syndrome presents differently across patients in ways that reflect both vascular biology and gendered patterns of symptom recognition, care-seeking, and triage in emergency departments. In Alzheimer’s disease, two-thirds of affected individuals are women, and research discussed in the article points to interactions between reproductive histories, such as surgical menopause, stress physiology involving corticotropin-releasing factor, and gendered lifecourse exposures, rather than a single biological cause. In nephrology, sex differences in kidney physiology intersect with gendered differences in access to dialysis, transplantation, and medication adherence. Even occupational health reflects the interplay, as shown by analyses of personal protective equipment designed around male body norms during the COVID-19 pandemic, where ill-fitting gear compromised the safety of women in frontline roles. The authors also cite emerging concerns about automatic gender recognition technologies and gendered patterns of cannabis use disorder as domains where simplistic binary assumptions fail patients and obscure mechanisms.

Methodologically, Sex and Gender Science is defined by its refusal to choose between reductionist and constructionist approaches. The authors assume complexity, question established stereotypes and binaries, and support evolving methods that can capture interactional effects over time. That means experimental work in animal models attentive to sex as a biological variable can be paired with qualitative and quantitative human studies of gendered environments; intersectional epidemiology can be integrated with endocrine and genetic measurement; and implementation science can test whether sex- and gender-informed findings actually change clinical practice. The transdisciplinary ambition is deliberate: rather than creating another silo, the field aims to weave together the humanities, social sciences, and biomedical sciences, drawing on decades of feminist scholarship, gender studies, and basic biology that have until now developed along separate tracks.

The historical context for this synthesis is instructive. Biomedical research long treated male bodies as the default experimental subject, from clinical trials to preclinical animal studies, on the grounds that hormonal cycles made female subjects inconveniently variable. Landmark policy changes in the United States, Canada, and Europe over the past three decades required the inclusion of women in clinical research and the accounting for sex as a biological variable in grant applications. Simultaneously, scholars in gender and health demonstrated that social positions assigned by gender produce measurable health inequities, from differential exposure to violence and occupational hazards to differences in healthcare access and treatment. What was missing, the authors argue, was a systematic framework linking these two streams, so that researchers could ask not simply whether men and women differ, but how biological and social variables interact to produce particular outcomes in particular individuals.

The consensus process behind the article gives its claims unusual weight. By convening basic scientists who study sexually dimorphic neural circuits and stress pathways alongside clinicians, historians, and social scientists, the meeting produced a shared vocabulary and a shared commitment. The resulting highlights, as stated by the authors, include forging new ways of knowing about wellness, health, and disease; assuming complexity and questioning binaries; providing a more comprehensive picture of human health when sex and gender are studied together; and starting from the particularity of individuals with the ultimate goal of improving the well-being of all. That final point is significant politically as well as scientifically: the field explicitly encompasses transgender and gender-diverse populations, recognizing that gender identity itself interacts with biology in ways that mainstream medicine has historically ignored or pathologized.

For clinical practice, the implications are immediate. Diagnostic criteria, drug dosing, device design, and screening schedules built on averages derived from unrepresentative populations can be reexamined through the interactional lens that Sex and Gender Science provides. A patient is never just a sex and never just a gender; each person embodies a unique configuration of hormonal milieu, genetic background, organ physiology, gendered labor and caregiving burdens, institutional exposure, and identity. Precision medicine that ignores either domain is, on this argument, not precise at all. The authors point to the growth of national organizations, such as the Canadian Organization for Sex and Gender, and to curriculum reform in medical schools as evidence that institutional infrastructure is beginning to catch up with the science.

The article also acknowledges open questions and future directions. Measuring gender as rigorously as sex is measured remains an active methodological challenge, with validated instruments still evolving. Distinguishing interaction effects from confounding in observational data requires statistical sophistication and large, diverse cohorts. And the field must navigate political controversies surrounding sex and gender discourse without retreating from empirical evidence. The authors frame these challenges as generative rather than paralyzing, arguing that the very friction of integrating methods across disciplines produces better science, sharper questions, and more honest uncertainty. They call for funding structures, training programs, and publication venues that reward transdisciplinary work rather than penalizing it in favor of narrow, single-domain studies.

If Sex and Gender Science succeeds on its own terms, the payoff could be a medicine that finally matches the complexity of the patients it serves: one in which a heart attack, a dementia diagnosis, a kidney transplant, or a workplace injury is understood through the full entanglement of chromosomes, hormones, organs, identities, relationships, and institutions that shaped it. The article’s message to researchers is blunt in its simplicity. It is not either sex or gender; it is both, together. After decades of separation, the biological and the social are being brought back into a single scientific frame, and the authors argue that the health of everyone stands to gain from what this emerging field discovers next.

Subject of Research: Sex and Gender Science, an emerging transdisciplinary field integrating biological sex and social gender in health research

Article Title: Sex & Gender Science: integrating the social with the biological

Article References: Einstein, G., Pilote, L., De Vries, G., Richardson, S., Forger, N., Perović, M., Ahmed, S., Bauer, G., Graham, I. D., Greaves, L., Klinge, I., Logie, C. H., McKay, D., McMurtry, M. S., Oliffe, J. L., & Tannenbaum, C. (2026). Sex & Gender Science: integrating the social with the biological. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00977-8

Image Credits: AI Generated

DOI: 10.1186/s13293-026-00977-8

Keywords: sex and gender science, biological sex, gender and health, transdisciplinary research, Biology of Sex Differences, health inequities, sex differences, gender identity, precision medicine, Alzheimer's disease, cardiovascular disease, Canadian Institutes of Health Research

Imprinted genes are a peculiar subset of the genome. Most genes are expressed from both the maternal and paternal copies, but imprinted genes carry chemical tags laid down in the egg or sperm that silence one copy entirely, leaving only the maternal or paternal version active. In the placenta, these parent-of-origin effects are thought to reflect evolutionary conflict: paternal genes tend to push for greater extraction of maternal resources, while maternal genes restrain fetal demands to preserve the mother’s ability to sustain current and future pregnancies. Phlda2, formally known as Pleckstrin Homology-Like Domain Family A Member 2, is one of the maternal army’s foot soldiers, normally expressed only from the chromosome inherited from the mother.

Researchers at Cardiff University, led by R. M. John together with colleagues including A. R. Isles, had previously shown that elevated Phlda2 expression, a state mimicking loss of imprinting in which the gene’s dosage is effectively doubled, produces placentas that secrete fewer hormones, fetuses that grow poorly, and mothers that neglect their pups after birth. Their earlier work on the paternally expressed gene Peg3 had already demonstrated that imprinted genes can act as master regulators of placental endocrine lineages and that disrupting them can produce sexually dimorphic outcomes, with males suffering more. The natural question was whether a maternally expressed gene would show the same pattern, or whether the sexes would flip.

To find out, the team crossed wildtype C57BL/6 female mice with transgenic males carrying an extra bacterial artificial chromosome copy of Phlda2, generating embryos that overexpressed the gene and thus modelled loss of imprinting. They then dissected the placenta at embryonic day 14.5, a critical window when the placenta’s endocrine machinery is being established, and collected fetal and placental weights at embryonic day 18.5, near the end of gestation.

The team used RNAscope, a high-resolution in situ hybridization technique, combined with classical histology to map the placenta’s specialized cell populations. The mouse placenta is organized into two major compartments. The labyrinth zone handles nutrient and gas exchange, while the junctional zone is the endocrine heart of the organ, packed with hormone-producing cells including the spongiotrophoblast layer, glycogen cells, and parietal trophoblast giant cells. The spongiotrophoblast in particular churns out a vast repertoire of prolactin-related hormones and pregnancy-specific glycoproteins that remodel the mother’s physiology, directing blood flow, nutrient mobilization, and even priming her brain for maternal care.

What the researchers saw was unambiguous. In placentas carrying the Phlda2 overexpression, the junctional zone lost a significant number of spongiotrophoblast cells, and the depletion was substantially more severe in female placentas than in male ones. Glycogen cells and parietal trophoblast giant cells were also reduced in number, but those losses were even-handed between the sexes. The sexual dimorphism was confined specifically to the spongiotrophoblast compartment, the very cell population responsible for the placenta’s most powerful endocrine output.

Molecular measurements backed up the cellular picture. Using reverse-transcription quantitative PCR and bulk RNA sequencing, the team found that genes encoding placental hormones normally produced by the spongiotrophoblast were downregulated in the mutant placentas, and once again the reduction was biased toward females. Gene set enrichment analysis reinforced the conclusion: the female mutant placenta showed a more profound dampening of its hormone-producing program than the male, despite both sexes carrying the identical genetic modification.

The most consequential result, however, appeared in the growth curves. At embryonic day 18.5, late in gestation, female fetuses with elevated Phlda2 expression were significantly growth restricted compared with their wildtype female littermates. Male fetuses carrying the same transgene showed no comparable reduction in weight. In other words, the genetic perturbation narrowed the female placenta’s endocrine signalling capacity, and the female fetus paid the price by growing more slowly, while the male fetus maintained its growth trajectory despite the same molecular insult.

The authors interpret this asymmetry through the lens of evolutionary theory about parental resource allocation. Phlda2 is known to be responsive to maternal adversity: when the mother experiences nutritional deficiency or other forms of prenatal stress, placental Phlda2 expression rises, and the resulting restraint on hormone production lowers the fetus’s demands on her body. The new findings suggest that this demand-dampening system is not symmetrical. Female fetuses appear to reduce their claims on the mother when Phlda2 signalling rises, effectively shrinking their own growth to spare maternal reserves. Male fetuses, by contrast, hold their ground, continuing to extract resources even under adverse conditions. Such sex-specific strategies could reflect the different reproductive payoffs that sons and daughters offer under variable environmental conditions, with parent-of-origin imprinting serving as the molecular lever that mediates the negotiation.

The translational implications are hard to ignore. In human pregnancies, elevated placental PHLDA2 has repeatedly been associated with fetal growth restriction and low birthweight, yet these clinical studies have generally not accounted for the sex of the infant. If, as the mouse data suggest, the gene’s effects on growth are sex-specific, then pooling male and female pregnancies may have obscured important patterns and muddied the interpretation of biomarker studies. The Cardiff team argues that fetal sex deserves routine consideration in research on imprinted genes and pregnancy complications, from intrauterine growth restriction to the long-term metabolic and behavioural consequences of prenatal adversity. The work, funded by the Biotechnology and Biological Sciences Research Council, adds Phlda2 to a growing list of imprinted genes, alongside Peg3, whose disruption produces sex-dimorphic placental and offspring phenotypes, and it strengthens the broader hypothesis that the placenta is not merely a passive conduit for nutrients but an active, sexually differentiated endocrine organ that negotiates the terms of maternal investment on the fetus’s behalf.

Subject of Research: Sex-specific effects of loss-of-imprinting of the maternally expressed gene Phlda2 on placental endocrine development and fetal growth in mice

Article Title: Sex-specific consequences of loss-of-imprinting of the maternally expressed gene Pleckstrin Homology-Like Domain Family A Member 2 (Phlda2) on placental development and fetal growth

Article References: Chibnall, A., Harrison, D. J., Lysikova, E., Malinoshevska, M., Stoddart, A., Perry, I. A., Christofides, S., Isles, A. R., & John, R. M. (2026). Sex-specific consequences of loss-of-imprinting of the maternally expressed gene Pleckstrin Homology-Like Domain Family A Member 2 (Phlda2) on placental development and fetal growth. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00972-z

Image Credits: AI Generated

DOI: 10.1186/s13293-026-00972-z

Keywords: genomic imprinting, Phlda2, placenta, placental hormones, fetal growth restriction, sexual dimorphism, spongiotrophoblast, junctional zone, prenatal adversity, parent-of-origin effects, Biology of Sex Differences, Cardiff University