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Cell atlas of the endometrium in women with PCOS may lead to better treatment

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Women with polycystic ovary syndrome (PCOS) find it harder to get pregnant, have more frequent miscarriages and have a higher risk of developing endometrial cancer. Now, researchers have shown that the uterine lining of these women differs in terms of both the composition of individual cells and gene expression. The results open the door to new drug treatments.

PCOS is the most common hormonal disorder affecting 11 to 13 per cent of women of reproductive age. Women with the syndrome have difficulty getting pregnant and are at increased risk of miscarriage and uterine cancer, especially cancer of the endometrium. It is also common for affected women to be overweight and insulin resistant.

By studying endometrial tissue samples from five healthy women and 12 women with PCOS, the researchers created a cell map of individual cells.

 

The women were all of similar age, weight and BMI and the tissue samples were taken at the same phase of the menstrual cycle to eliminate factors that could influence the analyses. In the study, all women were overweight, but only the women with PCOS were insulin resistant and had elevated levels of male sex hormones.

In total, almost 250,000 cell nuclei from the women’s uterine linings were analysed. The researchers found a clear difference in the composition of cell types with a higher proportion of so-called epithelial cells and a lower proportion of stromal cells in the uteruses of women with PCOS.

“These results show that the growth of the cells is affected, which may explain why it can take longer for affected women to become pregnant and why they are more likely to miscarry, as well as contributing to the increased risk of endometrial cancer,” said Elisabet Stener-Victorin, professor of Reproductive Physiology at Karolinska Institutet and research leader of the current study.

In the detailed cell map, the researchers can show that many genes in specific cell types have a disturbed expression in women with PCOS. A large proportion of the affected genes are linked to difficulties for the early embryo to attach to the uterus, miscarriage and endometrial cancer with functions affecting cell-to-cell attachment and communication.

“Our analyses show that certain cell types in the endometrium have disrupted communication and interaction specific to PCOS,” said Gustaw Eriksson, one of the study’s first authors and a doctoral student in Elisabet Stener-Victorin’s research group.

The study also included a part where the women with PCOS underwent treatment with the diabetes drug metformin with or without lifestyle advice on diet and exercise. After 16 weeks of treatment, the researchers found that many gene expressions in specific cell types, especially in the epithelial and stromal cells, were normalised by metformin, but also by lifestyle changes, although not as pronounced.

“We can show that metformin seems to have many more functions in women with PCOS than lowering blood sugar. In the study, all the women were overweight, but it is likely that metformin has similar effects in affected women who are not overweight but insulin resistant if they have problems getting pregnant or have repeated miscarriages,” said Elisabet Stener-Victorin.

Another important finding was the correlation between gene expression in specific cell types and important clinical features of PCOS, such as elevated levels of male sex hormone and insulin resistance, highlighting the complex relationship between hormonal and metabolic factors and endometrial dysfunction.

“As we identified changes in gene expression in specific cell types, this study provides crucial guidance for developing more targeted treatments for PCOS-related endometrial dysfunction,” said Elisabet Stener-Victorin.

The study is a collaboration with Dr Congru Li as joint first author, and Associate Professor Qiaolin Deng and Associate Professor Sophie Petropoulos with joint senior and corresponding authorship.

The research was funded by the Swedish Research Council, the Novo Nordisk Foundation, the Diabetes Foundation and the Knut and Alice Wallenberg Foundation, among others. The researchers declare that there are no conflicts of interest.

Fertility

No clear evidence common embryo transfer techniques improve IVF success, review finds

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Common IVF preparation techniques used before embryo transfer have no proven effect on pregnancy rates, according to a review.

Researchers said evidence for the widely used practices remains uncertain because available studies are limited and generally of low quality.

Embryo transfer is the final and most vulnerable stage of IVF, when an embryo is placed into the womb. Only around one in three transfers results in pregnancy.

Practice varies between clinics, with some routinely using preparation techniques such as adjusting bladder fullness while others do not consider them necessary.

Dr Ryosuke Akino, practising obstetrician-gynaecologist from Kato Ladies Clinic, said: “To an extent, this is a case of tradition driving practice rather than the evidence.

“Current practices in this area often reflect local protocols, clinician preference, and historical convention rather than strong, high-quality evidence.”

The Cochrane review analysed 11 studies involving 2,524 women undergoing embryo transfer.

Researchers looked at three preparation techniques used by fertility clinics: having women arrive with a full bladder to straighten the angle between the uterus and cervix, removing cervical mucus and using a technique called afterloading.

Afterloading is a technique used to guide the embryo through the cervix.

The review found no reliable evidence that any of the three approaches improved pregnancy rates compared with standard care.

Researchers rated the evidence as low or very low certainty because the trials were small and had methodological weaknesses. They found no grounds to recommend any of the techniques over standard care.

There was also limited information about possible side effects.

The review team, which included methodologists and practising obstetrician-gynaecologists, said full bladder preparation and cervical mucus removal were generally considered safe, with no clear evidence of harm or major complications.

Dr James Brown, obstetrician-gynaecologist from Women’s Health and Research Institute Australia, said: “While these techniques are generally considered safe, it’s still important to test their effectiveness.”

Akino and Brown added: “A full bladder can be uncomfortable, although it may ease catheter insertion in certain uterine positions and reduce procedural difficulty.

“Mucus removal is usually quick, but if done roughly and causes bleeding, it may affect the woman’s experience.

“Overall, the risks are minor and relate mostly to discomfort and procedural factors rather than clinical harm.”

The authors said embryo transfer has changed relatively little despite major advances elsewhere in IVF.

Research has instead focused more heavily on embryo quality and genetic factors, which have a greater bearing on treatment success than transfer technique.

Embryo transfer also depends heavily on the person carrying out the procedure and can be difficult to standardise, making large, rigorous clinical trials harder to design.

Researchers said women may also be reluctant to risk valuable embryos by taking part in randomised studies comparing different transfer techniques.

Dr Noyuri Yamaji from Showa Medical University in Japan said: “Sixteen years of research still haven’t answered a basic IVF technique question.

“This is a critical step in the IVF process and these small changes and techniques have the possibility to make a massive difference, but we won’t know more until more robust, better-quality trials are conducted.”

All the studies assessed were carried out in high-income countries, meaning the findings may not necessarily apply to other healthcare settings and populations.

The authors said further research could be particularly valuable in resource-limited settings, where these procedures are inexpensive and simple to change and basic procedural standardisation could matter more than advanced technical modifications.

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Insight

Natural Cycles receives sixth FDA clearance for fertility algorithm

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Natural Cycles has received its sixth FDA clearance for an updated fertility algorithm designed to personalise digital contraception.

The regulator cleared the company’s next-generation NC° Fertility Algorithm, which combines statistical modelling with machine learning to predict fertile and non-fertile days.

Natural Cycles said the algorithm was trained on tens of millions of real-world fertility data points and adapts to individual cycle patterns.

“People don’t just want effective birth control; they want a method that fits naturally into their lives,” said Dr Elina Berglund Scherwitzl, chief executive and co-founder of Natural Cycles.

“One of the unique advantages of a software-based contraceptive is that it can continue to evolve.

“As our scientific understanding of fertility grows and we continue to learn from more than a decade of real-world data, we can responsibly refine the technology through rigorous research, clinical validation, and FDA review.

“This latest clearance is the result of that work, helping us give many users more flexibility while maintaining the effectiveness they rely on.”

Evidence supporting the FDA clearance showed that the updated system maintained the app’s established safety and effectiveness while giving many users more Green Days.

Green Days are those on which the app confirms that pregnancy protection is not needed.

The birth control app remains 98 per cent effective when used as intended and 93 per cent effective with typical use, according to the company.

Natural Cycles said these rates place it in the same effectiveness category as the combined oral contraceptive pill.

Typical use includes mistakes or inconsistent use, while intended use means following the method correctly.

Digital contraception uses technology and physiological data, such as body temperature, to provide personalised fertility predictions.

Natural Cycles said its updated algorithm can identify fertile and non-fertile days more precisely than traditional fertility awareness methods, which may classify larger parts of the cycle as potentially fertile.

The changes provide more Green Days while maintaining effectiveness, improve performance for people with irregular cycles and better handle lower-quality temperature or biomarker data, the company said.

A biomarker is a measurable biological signal, such as body temperature, that provides information about processes taking place in the body.

Natural Cycles also said the system can personalise its predictions more quickly as a user’s menstrual cycle changes over time.

“Years ago, the question was whether digital contraception could work. Today, Natural Cycles has demonstrated robust clinical and real-world evidence that it can,” said Dr Kerry Krauss, senior medical adviser at Natural Cycles.

“The next chapter for digital contraception is making it more personalised and easier to use while maintaining the same high standard of safety.

“This FDA clearance demonstrates how advances in AI and machine learning can improve the user experience while preserving the scientific rigour expected of a regulated medical device.”

Natural Cycles has filed a patent application covering key innovations in the updated algorithm.

The decision follows the FDA’s first De Novo clearance of the company’s birth control app in 2018.

Later clearances allowed the app to integrate with the Oura Ring in 2021 and Apple Watch in 2023.

In 2024, the FDA cleared a Predetermined Change Control Plan, creating a regulatory pathway for future hardware integrations.

Natural Cycles said the plan has since enabled the launch of its NC° Band and other hardware integrations, including a Garmin connection introduced in March 2026.

A further clearance in 2025 allowed the birth control app to be offered both over the counter and by prescription.

The company has also received regulatory authorisations in more than eight markets worldwide, including Europe, Canada, Brazil, Australia, South Korea and Singapore.

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Entrepreneur

Fertility startup American Baby Company secures US$4m

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A fertility startup has raised US$4m and will open its first lower-cost IVF clinic in West Palm Beach later this year.

It will offer a full IVF cycle, including medications, for US$8,995.

Around 12 per cent of American couples struggle with infertility, according to the company, but only 14 per cent of them receive IVF because of the cost.

A single IVF cycle costs an average of US$23,500, it said, with the cost nearly doubling if further cycles are needed.

Co-founder and chief executive Van Spina said: “We’re building ABC around a straightforward premise: IVF has become unnecessarily expensive, and many patients are priced out before they ever have a real chance to start a family.”

“This is personal for me. My fiancée and I went through IVF ourselves, including multiple failed cycles,” Spina continued, citing Jamie Rapp.

“That experience pushed me to build the kind of fertility company we wished had existed when we began treatment.”

The US$4m seed round was led by Wormhole Capital and Tower Research Ventures.

In a blog post, New York-based Tower Research described ABC as a new model for fertility care, praising its “evidence-based protocols, AI-assisted intake, and modern lab workflows.”

“When we met the team at The American Baby Company (ABC), we saw an opportunity to rethink how fertility care is delivered in the US from the ground up,” the post said.

Co-founder and chief medical officer Dr Paul Magarelli is a board-certified reproductive endocrinologist and one of the most prominent voices in the US on expanding access to fertility care, according to Tower.

Reproductive endocrinology is a branch of medicine concerned with hormones and fertility.

Magarelli developed the Clinical Fertility Physician certification programme, which trains generalist clinicians to deliver routine fertility procedures under specialist oversight.

Spina spent his early career as a technology investor at Warburg Pincus before founding an institutionally backed data business in private credit.

“We’re on a mission to become the place Americans go to start their families,” Spina said.

“Our 10-year goal is to help make 250,000 babies per year.”

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