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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

Immunotherapy may temporarily restore fertility in premature menopause

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Immunotherapy may temporarily restore fertility in women with autoimmune premature ovarian insufficiency, a pilot study suggests.

Three of the 10 women who received treatment later gave birth to healthy babies.

Premature ovarian insufficiency, or POI, affects just over three per cent of women worldwide and occurs when the ovaries stop functioning before the age of 40.

The condition significantly reduces fertility and can have several causes, including autoimmune processes and genetics.

Researchers at Karolinska Institutet examined whether immunotherapy could make the ovaries temporarily responsive to hormonal stimulation in women with POI caused by autoimmunity.

The study included 12 women aged between 18 and 35 with autoimmune POI.

Two withdrew before treatment began. The remaining 10 underwent ovarian hormone stimulation before receiving rituximab and again four to six months after treatment.

Rituximab is an approved and well-established medicine used to treat several autoimmune conditions and cancers.

None of the women responded to ovarian stimulation before receiving the drug.

After treatment, six developed follicles that made it possible to retrieve eggs in response to ovarian stimulation.

Follicles are small sacs within the ovaries where eggs develop.

Professor Angelica Lindén Hirschberg, the study’s first author and a professor at Karolinska Institutet’s Department of Women’s and Children’s Health, said: “The results show that in some women there remains an egg reserve that can be activated when the autoimmune process is suppressed.”

In five women, mature eggs could be frozen or fertilised.

Three later had embryos transferred and all three gave birth to healthy babies.

For safety reasons, the embryo transfers took place no earlier than one year after treatment.

One serious side effect was reported and was linked to the hormone stimulation rather than the immunotherapy.

Women with autoimmune POI commonly have other autoimmune diseases.

All six women who responded to the treatment also had autoimmune Addison’s disease, a condition in which the immune system destroys the adrenal glands.

The study was a proof-of-concept investigation without a control group and involved a small number of participants, meaning the findings must be interpreted cautiously.

A proof-of-concept study is an early investigation designed to assess whether an approach could work before it is tested more widely.

Professor Lindén Hirschberg said: “This is a first step. To determine whether the method is effective and safe, larger, randomised studies are required.”

The research team has launched a larger randomised study.

The work was carried out by researchers at Karolinska Institutet, Karolinska University Hospital and the University of Bergen.

It was funded by organisations including the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Novo Nordisk Foundation and Region Stockholm.

The researchers reported no conflicts of interest.

POI is also linked to long-term health risks caused by oestrogen deficiency, including osteoporosis, an increased risk of cardiovascular disease, cognitive decline and poorer mental and sexual wellbeing.

Hormone replacement therapy can relieve menopausal symptoms and reduce many of these risks, but no treatment has been reliably shown to restore fertility in women with POI.

Egg donation was previously the only option for women with the condition who wanted to become pregnant.

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Most IVF add-ons not backed by reliable evidence, research finds

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Most IVF add-ons lack reliable evidence, with benefits either absent or inconclusive, the largest review of its kind has found.

More than 70 per cent of IVF patients in the UK, Australia and New Zealand reportedly pay for one or more additional treatments.

However, researchers found that most of the procedures, medicines and techniques had no effect on fertility or were backed by limited or low-quality evidence.

Unproven add-ons can also lead to false hope, greater financial strain and unnecessary medical procedures at an already difficult time for patients.

Dr Sarah Lensen, of the University of Melbourne, said: “In many countries, infertility care is largely provided by private clinics where IVF is highly commercialised, and some add-ons are extremely expensive.

“Our review finds a lack of evidence that most of the IVF add-ons we assessed provide any benefit to patients. Unproven add-ons can lead to false hope, greater financial strain and unnecessary medical procedures at what already can be a very difficult time for patients.”

Researchers said concerns have grown in recent years about potentially untrustworthy randomised controlled trials in reproductive medicine, including studies of IVF add-ons.

The team set out to review the effectiveness and safety of 10 commonly offered add-ons using trustworthy studies.

Researchers initially identified 157 potentially eligible randomised controlled trials but excluded 72 because of concerns about their reliability.

Randomised controlled trials compare treatments by assigning participants to different groups, helping researchers assess whether an intervention causes a particular outcome.

The team combined data from the remaining 85 trials in a meta-analysis, which brings together findings from several studies.

The review found no effect on fertility or inconclusive evidence for seven of the 10 add-ons examined.

These included acupuncture, which involves inserting thin needles into points on the body, and corticosteroids, medicines that reduce inflammation and suppress immune activity.

Endometrial receptivity testing was also not backed by reliable evidence. The procedure involves taking a sample from the lining of the womb to examine patterns of gene activity.

Another add-on was intralipid infusion, which delivers a fat-containing liquid into the bloodstream.

Researchers separately examined injections of platelet-rich plasma into the ovaries and infusions of platelet-rich plasma into the womb.

Platelet-rich plasma is made from a patient’s blood and contains a high concentration of platelets, which play a role in healing.

The seventh treatment was pre-implantation genetic testing for aneuploidy, which examines embryos to check whether they have the expected number of chromosomes.

The review found only weak evidence of a possible benefit from three other add-ons.

EmbryoGlue, an embryo transfer medium containing hyaluronic acid, may increase the probability of pregnancy and live birth. However, the evidence on live birth rates was not considered robust.

Endometrial scratching, a minor procedure that deliberately disturbs the lining of the womb, may also increase the probability of pregnancy and live birth.

Physiological intracytoplasmic sperm injection, known as PICSI, selects sperm based on their ability to bind to hyaluronic acid. Weak evidence suggested it may reduce the risk of miscarriage.

Lensen said: “There is widespread misinformation about IVF add-ons with private clinic websites and patient forums on social media – major information sources for patients – often overstating the benefits and omitting the costs and risks of add-ons.

“IVF clinics and clinicians should carefully consider whether it is appropriate to offer unproven add-ons, as their availability is often perceived by patients as implicit endorsement of benefit.”

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UK LGBTQ+ population faces barriers to fertility treatment, research finds

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LGBTQ+ people across the UK face discrimination, funding inequalities and gaps in fertility care, research has found.

Eligibility for NHS-funded treatment varies across the country, while many services are still structured around heterosexual couples.

People with diverse sexual orientations and gender identities can be left navigating complex systems, paying more for treatment and explaining their needs to healthcare professionals.

Co-author Dr Chloe He, of the UCL Institute of Epidemiology and Health Care, said: “Legal access is not the same as equitable access. LGBTQ+ patients are forced to navigate a Kafkaesque fertility care system alone – researching, self-advocating, and often educating the doctors and nurses treating them.

“In our study, we saw clinicians with no formal LGBTQ+ training, gay men pressured into being relentlessly cheerful to prove parent-worthiness to surrogacy services, and patients travelling hundreds of miles for care after experiencing transphobia at local clinics.”

The University of Stirling-led research involved 54 participants and 36 in-depth interviews with people who had used fertility services and professionals working in or alongside fertility care across the UK.

Researchers from Stirling, SKEMA Business School and University College London examined the extra work undertaken by LGBTIQA+ people seeking to have children.

They called this “reproductive labour”, which includes researching treatment, advocating for themselves, covering additional costs and educating clinicians.

The researchers said this work was used to manage “reproductive bioprecarity”, a term describing the uncertainty and vulnerability people can face while seeking reproductive healthcare.

The study, funded by a Santander Universities Research Grant, primarily reflected the experiences of cisgender lesbian participants.

One participant, Amanda, said she and her partner, Amy, spent a long time trying to find a GP willing to discuss fertility with them.

The couple eventually underwent fertility tests through the NHS, but their private clinic rejected the results because they had not been referred by a GP.

They had to repeat the tests and pay for them privately.

The researchers said lesbian couples are often required to self-fund multiple rounds of intrauterine insemination before becoming eligible for NHS support.

Intrauterine insemination, or IUI, involves placing sperm directly into the womb.

Gay men usually have to pursue surrogacy, which is not funded or supported by the NHS, while transgender people can face long waits to save eggs and sperm to allow them to have children.

Lead author Dr Carolyn Wilson-Nash, senior lecturer at the University of Stirling Business School, began investigating the issue after she and her wife made multiple attempts to conceive and faced challenges throughout the process.

The couple funded almost the entire process themselves and consulted a GP who had no experience of supporting same-sex couples seeking fertility care.

The researchers called for clearer treatment pathways, more inclusive services and better training for healthcare staff.

Dr Wilson-Nash, who is now the mother of a three-year-old boy, said: “The way the current system for fertility services is set up in the UK can lead to unequal pathways for the LGBTIQA+ population.

“For example, heterosexual couples can access NHS-funded in vitro fertilisation (IVF), whereas lesbian couples are often required to self-fund multiple rounds of intrauterine insemination (IUI) before becoming eligible for NHS support.

“Gay men usually have to pursue surrogacy, which is not funded by or supported by the NHS.

“And transgender individuals often face long waiting times to save eggs and sperm to allow them to have children. So legal access does not necessarily translate into equitable or inclusive care.

“Building a family should be neither exclusive nor this difficult. Fertility services should be available to all, regardless of their sexual orientation or gender identity.”

Laura-Rose Thorogood, founder of LGBT Mummies and part of the UK’s Fertility Justice Campaign, said: “Right now, intended LGBTQIA+ parents are being discriminated against because of who they are, and who they love.

“This is ultimately forcing them down alternative pathways which in turn put them at long-term risk physically, psychologically and socially.

“By providing access to treatment, our community can thrive and create the families they dream of by their chosen route.”

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