Fertility
Unlocking new potential in stem cell-based embryo models
Researchers have identified Nr1h2, a critical transcription factor essential for early embryo development. The findings enhance our understanding of gene regulation during blastoid formation and hold promise for regenerative medicine, fertility treatments, and developmental biology research.
At the earliest stages of life, the blastocyst—a highly organised structure critical for implantation—begins to form. Its development is tightly controlled by genetic and epigenetic programmes.
Stem cell-based embryo models, such as blastoids, serve as models of the blastocyst and are invaluable tools for studying embryogenesis and early human development. However, the variability in blastoid induction has limited their utility, due to a limited understanding of the genetic drivers of blastoid formation.
The researhers addressed this gap by uncovering the role of Nr1h2 in regulating stem cell fate and driving high-quality blastoid formation.
Using a loss-of-function screen, the researchers pinpointed Nr1h2 as a key transcription factor conserved across mammalian species. Nr1h2 activation was sufficient to enhance the functional and genetic fidelity of stem cell-derived embryo models.
To test Nr1h2’s potential, the team treated embryonic stem cells with the small-molecule agonist T0901317. The treated cells, termed NrESCs, exhibited expanded pluripotency, expressing canonical markers and generating both embryonic and extra-embryonic lineages.
Transcriptomic and epigenetic analyses showed that NrESC-derived blastoids closely resembled natural blastocysts, surpassing current EPSC-derived models in genetic and physiological fidelity.
“Nr1h2 activation rewires embryonic stem cells into an expanded pluripotent state, creating a robust platform to study early developmental processes and identify therapeutic targets,” said Dr Jonathan Yuin-Han Loh of the A*STAR Institute of Molecular and Cell Biology (IMCB).
Therapeutic potential
The discovery also has profound implications for reproductive health. Trophectoderm cells, essential for implantation, were more physiologically faithful in NrESC-derived blastoids.
When transferred into mice, these blastoids achieved significantly higher implantation rates compared to EPSC-derived counterparts. Nr1h2 activation also enhanced blastocyst generation in both mice and pigs, suggesting a highly conserved mechanism across species.
Nr1h2’s identification as a master regulator of early embryogenesis opens new avenues for developmental biology. By refining stem cell-based embryo models, this discovery supports the design of targeted therapies, advances regenerative medicine, and improves our ability to explore the earliest stages of life.
The team’s work sets the stage for future research into transcriptional networks and their role in lineage determination.
“Stem cell-based embryo models are revolutionising drug discovery and reproductive biology,” Dr Loh said.
“Our findings demonstrate that activating Nr1h2 enhances the fidelity of these models, providing an innovative approach to tackle developmental disorders, infertility, and beyond.”
Women with primary infertility may face a higher risk of early menopause and reach it about a year earlier, a study suggests.
The findings suggest women with primary infertility may be more likely to enter menopause before the age of 45.
The increased risk appeared most notable among women with unexplained infertility or a history of endometriosis.
Dr Stephanie Faubion, medical director for The Menopause Society, said: “This study shows that women with primary infertility, specifically those with unexplained infertility or a history of endometriosis, were at risk for early menopause.
“Given that early menopause is linked to adverse long-term health consequences, these women may benefit from counselling that they are at risk of early menopause.
“This will allow them to monitor for early menopause and to seek treatment with hormone therapy, if indicated.”
Early menopause is usually defined as menopause before age 45, while premature menopause is menopause before age 40.
Women who experience menopause earlier may face symptoms for longer and have a higher risk of long-term health problems.
These can include cardiovascular disease, osteoporosis and neurocognitive disorders. Osteoporosis weakens bones, while neurocognitive disorders affect memory, thinking or brain function.
The study, highlighted by The Menopause Society, involved nearly 700 people, roughly half of whom had been diagnosed with primary infertility.
It found that women with a history of primary infertility underwent natural menopause about one year earlier than those without such a history.
Researchers found no association between infertility and premature menopause.
Infertility affects around one in six people globally and can have consequences beyond family planning.
Previous research has linked infertility with higher rates of cancer and cardiovascular disease, although causes vary and may involve genetic, hormonal, in-utero or lifestyle factors.
In-utero factors are influences that occur while a baby is developing in the womb.
Earlier studies looking at links between infertility and early or premature menopause have produced mixed results, with some not accounting for different types of infertility.
The new study suggested that women with unexplained infertility or a history of endometriosis may have an increased risk of early menopause.
Endometriosis is a condition where tissue similar to the lining of the womb grows elsewhere in the body. It can cause pain, heavy periods and fertility problems.
Known risk factors for early or premature menopause include tobacco use, low body mass index, not having given birth and starting periods at a younger age.
Women who have had more childbirths and those with a history of oral contraceptive use have previously been linked to later menopause.
The researchers said women with primary infertility may benefit from additional counselling because of the systemic and long-term health effects of early menopause.
They also said women should be encouraged to seek evaluation and treatment if they experience a new loss of menstrual cycles.
Even when standard clinical tests show normal hormone levels, men and women may have hidden problems in how their reproductive hormones are timed and coordinated, potentially affecting fertility, new research suggests.
The findings suggest reproductive health may depend not only on hormone levels in the bloodstream but also on the rhythm, timing and synchronisation of hormone changes across hours, days and the menstrual cycle.
Researchers said a wearable skin sensor patch, combined with artificial intelligence, could help detect endocrine dysfunction earlier and support more personalised fertility care.
Unexplained infertility affects about 15 to 30 per cent of couples and is diagnosed when standard investigations reveal no clear cause.
In men, current tests for infertility or hypogonadism, defined clinically as low testosterone, often include a single morning serum testosterone measurement.
In women, fertility assessment typically examines menstrual cycle characteristics and reproductive hormones such as luteinising hormone, follicle-stimulating hormone, oestradiol and progesterone.
However, reproductive hormones are not static markers. They are dynamic biological signals that rise and fall in regulated patterns throughout the day and across the menstrual cycle.
Testosterone, for example, follows a diurnal rhythm, meaning it changes across the day, while female reproductive hormones act through coordinated feedback loops involving the hypothalamic, pituitary and ovarian systems.
A single blood test may therefore miss clinically important disruption in hormonal timing.
In one study, Dr Tinatin Kutchukhidze, from the University of Oxford, examined 102 men in Georgia and the UK.
The participants were aged 22 to 38 and had normal morning total testosterone levels, measured at 12 to 35 nanomoles per litre, with or without infertility or symptoms of hypogonadism.
Hypogonadism is a condition in which the body produces too little testosterone or other sex hormones.
Kutchukhidze and colleagues used wearable AI-enabled skin sensor patches to measure testosterone levels every 15 minutes across four days.
The team found that men with symptoms had significantly disrupted testosterone rhythms, despite standard laboratory tests showing normal testosterone levels.
These previously undetected rhythm abnormalities were also associated with reduced sperm concentration and symptoms of androgen deficiency.
Androgens are hormones, including testosterone, that play an important role in reproductive health.
Kutchukhidze said: “For the first time, we have been able to track androgen patterns in real time across several days with a novel, non-invasive, continuous, AI-driven testosterone monitoring patch, compatible with Android and iPhone mobile devices.
“Previous research suggests that a normal morning testosterone level is sufficient to exclude clinically significant androgen deficiency. However, our findings challenge that assumption by demonstrating that men with normal serum testosterone may still exhibit marked disturbances in hormonal rhythmicity associated with reproductive dysfunction.”
According to the abstract, the study compared 54 men with infertility or hypogonadal symptoms with 48 age-matched healthy controls.
Mean morning serum testosterone did not differ significantly between symptomatic men and controls, at 22.4 ± 3.1 compared with 23.1 ± 3.5 nanomoles per litre.
Continuous AI-assisted monitoring, however, revealed significant differences in androgen dynamics.
Men with symptoms had lower diurnal amplitude than controls, at 5.2 ± 1.1 compared with 8.7 ± 1.4 nanomoles per litre.
The AI-derived rhythm indices predicted subclinical dysfunction with an area under the curve of 0.87, compared with 0.61 for static serum testosterone testing.
In diagnostic research, the area under the curve is used to assess how well a test distinguishes between groups, with higher values indicating stronger discrimination.
A second study by Kutchukhidze’s team examined female reproductive hormone rhythms.
The researchers developed an AI-driven metric called Endocrine Rhythm Integrity to assess whether reproductive hormones were changing in the correct pattern, at the correct time and in the correct relationship to one another across the menstrual cycle.
Endocrine refers to the hormone system, while endocrine dysfunction means hormones are not being produced or regulated in a typical way.
The team analysed data from 312 women aged 18 to 22 who had self-reported regular menstrual cycles.
Participants included fertile controls and women with unexplained infertility.
The researchers assessed key reproductive hormones during the luteal phase, including luteinising hormone, follicle-stimulating hormone, oestradiol and progesterone.
The luteal phase is the part of the menstrual cycle after ovulation. Ovulation is the release of an egg from the ovary.
They also incorporated physiological data such as basal body temperature, heart rate and sleep patterns.
Basal body temperature is the body’s resting temperature and can shift slightly around ovulation.
The study found that women with unexplained infertility had lower Endocrine Rhythm Integrity scores even when conventional hormone levels appeared normal.
Lower scores predicted infertility and were also associated with a higher incidence of implantation failure, when an embryo does not successfully attach to the womb lining.
Kutchukhidze said: “Our study reveals that a woman may have a seemingly healthy menstrual cycle and normal hormone levels but still experience hidden endocrine dysfunction that affects her ability to conceive.
“Rather than analysing hormone levels as isolated values, Endocrine Rhythm Integrity evaluates whether reproductive hormones are changing in the correct pattern, at the correct time and in the correct relationship to one another across the menstrual cycle.”
In the female study, mean cycle length did not differ significantly between fertile and infertile groups, at 28.9 ± 2.3 compared with 28.9 ± 2.5 days.
Endocrine Rhythm Integrity scores, however, were lower in the infertility group, at 0.61 ± 0.12 compared with 0.78 ± 0.10.
Disrupted endocrine rhythm integrity was observed in 64 per cent of infertile participants despite hormonally normal mid-luteal progesterone levels.
The metric independently predicted infertility status after adjustment for age, body mass index and anti-Müllerian hormone.
Anti-Müllerian hormone is made by reproductive tissues and is best known as a marker of ovarian reserve, meaning an estimate of the number of eggs remaining in the ovaries.
Receiver operating characteristic analysis indicated that Endocrine Rhythm Integrity identified infertility more effectively than cycle length or single-time-point progesterone assessment.
Lower Endocrine Rhythm Integrity scores were also associated with a higher incidence of implantation failure.
Kutchukhidze said: “Our AI-driven rhythm analyses were significantly better at identifying subclinical reproductive dysfunction than conventional testing, suggesting that both female and male endocrine disorders may not simply be disorders of hormone quantity, but rather disorders of hormonal timing, synchronisation and biological rhythm.”
The team will next assess whether the tool can reliably predict fertility outcomes across different reproductive conditions in larger and more diverse populations.
Gum disease may impair female fertility by triggering inflammation that affects the ovaries and egg quality, a study in mice suggests.
The findings point to a possible biological link between oral health and unexplained infertility.
Researchers said chronic oral inflammation was linked to oxidative damage, disrupted follicle development and reduced live birth rates in mice.
The study was led by prof Michael Klutstein at the Hebrew University of Jerusalem and prof Asaf Wilensky at the Hebrew University-Hadassah Medical Center, with students Dr Paz Kles and Stephen Ameho.
Scientists examined inflammation linked to dental implants in a mouse model, a common clinical scenario, meaning the research was carried out in animals rather than people.
They tracked how immune signals moved through the body and found the inflammation did not appear to stay confined to the mouth.
Instead, it triggered a systemic immune response, meaning an immune reaction across the body, that reached the ovaries.
The animals had increased levels of inflammatory cytokines in the ovaries. Cytokines are proteins used by immune cells to send signals during inflammation.
Researchers also found changes in immune cell populations, oxidative damage to ovarian tissue, impaired follicle development and reduced oocyte quality.
Oxidative damage happens when harmful molecules damage cells. Oocytes are immature egg cells, while follicles are small structures in the ovaries that contain developing eggs.
These biological changes were linked to reduced live birth rates under inflammatory conditions.
The study also found that oocytes showed DNA damage and epigenetic alterations similar to those seen in reproductive ageing.
Epigenetic changes affect how genes behave without changing the underlying DNA code.
Prof Klutstein said: “Inflammation is often thought of as a localised response, but our findings show that it can have systemic consequences that extend as far as the reproductive system.
“This work suggests that chronic oral inflammation may be an underrecognised factor in female infertility, potentially contributing to cases that currently have no clear explanation.”
The researchers said the findings add to growing evidence linking oral health with overall health.
Chronic oral inflammatory conditions, such as periodontitis, are widespread and have previously been associated with systemic diseases.
Periodontitis is a severe form of gum disease that can damage the tissue and bone supporting the teeth.
The authors said further research in clinical settings would be needed to understand whether the findings translate to patient care.
If confirmed in humans, they said the work could support new approaches to diagnosis and treatment, including anti-inflammatory or antioxidant strategies aimed at improving fertility outcomes.
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