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New drug offers promising breakthrough for endometriosis patients

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New drug offers promising breakthrough for endometriosis patients

A clinical trial for a drug typically used to treat metabolic diseases in children is moving into its second phase

Dichloroacetate (DCA), a drug typically used to treat metabolic diseases in children, has been seen to be effective in breaking down the cells that cause endometriosis – a painful gynaecological disease where cells similar to those that line the uterus grow elsewhere in the body.

The condition affects one in ten women globally and causes debilitating symptoms – including severe pain, fatigue, gastrointestinal issues, painful periods, pain during sex, and infertility.

There’s currently no cure for endometriosis, which is estimated to cost the UK economy £8.2bn a year in treatment, loss of work, and healthcare costs.

Management options available – including hormonal contraception, laser surgery, and even hysterectomies – can cause further complications for sufferers, and often fail to get the progressive condition under control.

This spring, Andrew Horne, Professor of Gynaecology and Reproductive Sciences at the University of Edinburgh, is moving a clinical trial of DCA in endometriosis cases into its second phase – with hopes the drug could be prescribed as a treatment on the NHS within the next five years.

Women with endometriosis produce more lactate – a harmful human waste product of glucose metabolism – than those without the disease. Professor Horne and his team found that increased lactate created an environment that supported the growth and spread of endometriosis cells. Targeting the cells with DCA was subsequently found to reduce lactate production – which could halt the progression of the disease in its tracks.

At the end of the clinical trial’s first phase, women who were given DCA reported significant improvements in symptoms as well as a reduction in the amount of pain medication they needed during their menstrual cycle.

“We’re really excited about the next phase of the trial. There have been very few trials of non-hormonal treatments, and so we are largely the leaders in this field,” Prof Horne told The Telegraph.

“We hope the drugs will reduce the disease volume, and our studies so far have given us an indication that they don’t only affect the symptoms but the disease and prevent it from progressing,” he continued.

The trial is still in its preliminary stages, and Horne and his team of researchers hope the launch of the next phase, EpIC2, will give a more definitive answer on DCA’s efficacy.

Source: https://www.telegraph.co.uk/global-health/women-and-girls/endometriosis-treatment-dca-trial-breakthrough/

Long-term outcomes of relugolix combination therapy for severe endometriosis

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Long-term outcomes of relugolix combination therapy for severe endometriosis

A recent study unveiled the sustained safety and efficacy of relugolix combination therapy over 2 years.

 

Relugolix combination therapy (CT) provides long-term safety and efficacy in patients with severe endometriosis, according to a recent study published in Human Reproduction.

 

Takeaways

 

The study affirms that Relugolix CT, a non-peptide GnRH receptor antagonist, provides sustained safety and efficacy over a period of up to 2 years in managing severe endometriosis.

 

Endometriosis affects approximately 10% of women, causing menstrual and non-menstrual pain, infertility, and dyspareunia. Current treatment methods, including surgery and pharmacologic suppression, may result in persistent or recurrent symptoms.

 

The study highlights the need for an oral therapy that reduces pain and is safe for long-term use, as existing options, such as GnRH agonists and antagonists, are associated with decreased bone mineral density.

Relugolix CT consists of 40 mg relugolix, 1 mg estradiol, and 0.5 mg norethisterone acetate taken orally once daily. Short-term data indicates efficacy and safety in managing severe endometriosis.

 

The 104-week study involving 681 patients reveals high compliance, with 98.7% and 98.8% reporting drug compliance. Responder rates for dysmenorrhea and non-menstrual pelvic pain were consistently favorable at weeks 52 and 104. Long-term safety data did not reveal new trends, with a low incidence of serious adverse events and stable bone mineral density over the study period.

 

Approximately 10% of women are impacted by endometriosis, which presents as menstrual and non-menstrual pain, infertility, and dyspareunia. Surgical removal and pharmacologic suppression of lesions is often utilized to treat patients with endometriosis, but these methods sometimes lead to persistent or recurrent symptoms.

 

Pain management is often accomplished with oral contraceptives, progestines, and sometimes androgens. GnRH agonists and antagonists may also be utilized, but these therapies are associated with decreased bone mineral density (BMD). This indicates a need for an oral therapy that reduces pain and is safe for long-term use.

 

Relugolix is a non-peptide GnRH receptor antagonist that prevents binding of endogenous GnRH through the production of varianoestradiol and progesterone. Relugolix CT includes 40 mg relugolix, 1 mg oestradiol, and 0.5 mg norethisterone acetate, and is taken orally once per day. Data has indicated short term efficacy and safety for managing severe endometriosis.

 

To determine the safety and efficacy of relugolix for up to 2 years, investigators conducted a multinational, open-label, single-arm, long-term efficacy, and safety extension study. Participants included women aged 18 to 50 years with moderate to severe dysmenorrhea and non-menstrual pelvic pain (NMPP).

 

Dysmenorrhea and NMPP were determined using baseline Numerical Rating Scale (NRS) scores. Participants received the study drug on days 1 to 14 of the menstrual cycle, with administration occurring during a fasted state in the morning. The use of non-hormonal contraception was required, and patients had to report a negative pregnancy test at baseline.

 

Oral relugolix CT was provided for up to 80 weeks. The proportion of dysmenorrhea and NMPP responders at week 52 and 104 or end of treatment (EOT) were measured as the primary outcomes of the analysis.

 

Daily NRS scores were used to measure efficacy outcomes. Adverse events (AEs) and endometrial biopsies were the safety outcomes of the analysis, as well as mammograms in patients aged over 40 years.

 

There were 681 patients with 52 weeks of treatment and 501 with 104 weeks of treatment analyzed. Study drug compliance was reported in 98.7% and 98.8% of these patients, respectively. Of participants, 8.2% reported AEs leading to discontinuation and 2% discontinued because of a lack of efficacy.

 

Patients were aged a mean 34 years, and 92% were White, one-third received an endometriosis diagnosis 5 or more years before the study, and 84% had received previous surgical interventions for endometriosis.

 

The dysmenorrhea responder definition was reported in 83.8% of the relugolix CT group at 52 weeks and the NMPP responder definition in 73.6%. At week 104 or EOT, these rates were 84.8% and 75.8%, respectively.

 

Responder rates at week 104 or EOT for the placebo to relugolix CT group were 80.4% and 73.1%, respectively. Similar rates were also reported in the delayed relugolix CT group.

 

The mean dysmenorrhea NRS score in the relugolix CT group was 7.4 at baseline. This score decreased to 1.2 at week 52 and remained stable until week 104, indicating a reduction of 84%. For the mean NMPP NRS score, a reduction from 5.9 at baseline to 2.2 at week 52 and 1.8 at week 104 was observed.

 

Long-term safety data did not reveal new safety trends. An AE was reported in 93.1% of women across the 104-week study period, but only 10.8% of patients reported grade 3 or higher events and only 4% serious AEs.

 

The rates of serious or non-serious AEs did not disproportionately increase between week 24 and week 104. Additionally, the small mean decrease in bone mineral density observed at week 24 did not increase by week 104.

 

These results indicated safety and efficacy from relugolix CT in managing severe endometriosis. Investigators recommended further research about long-term medical control of endometriosis symptoms.

 

Reference

Christian M Becker, Neil P Johnson, Sawsan As-Sanie, et al. Two-year efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: SPIRIT open-label extension study. Human Reproduction. 2024. doi:10.1093/humrep/dead263

 

https://academic.oup.com/humrep/advance-article/doi/10.1093/humrep/dead263/7577817

 

 

Why does receiving a diagnosis for endometriosis take so long?

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Why does receiving a diagnosis for endometriosis take so long?

There are multiple factors that contribute to an average endometriosis diagnosis taking eight years.

 

Endometriosis is a chronic condition that can cause intense pain in several circumstances, including during menstruation and sexual intercourse.

 

I​t can be challenging for some people to receive a prompt diagnosis of endometriosis.

 

Recent research found that several factors can delay an endometriosis diagnosis by as much as 11 years due to personal and societal barriers and the actions and training of healthcare professionals.

 

A​ recent systematic review and qualitative synthesis examined why receiving a prompt diagnosis of endometriosis is difficult.

 

The researchers identified several factors, including the normalization of menstrual pain, the diversity of symptoms, and a lack of training and prompt referrals among healthcare professionals.

 

The review sheds light on areas for improvement in the prompt diagnosis and, thus, treatment of endometriosis.

 

The study is published in Obstetrics and Gynecology.

 

The impact of endometriosis

 

Endometriosis is a condition in which uterine-like tissue grows outside of the uterus. These lesions can be present in several areas, including the ovaries, fallopian tubes, or bladder.

 

Endometriosis is chronic, and treatment mainly focuses on managing symptoms. The main symptom is pain, often in the pelvic area. The pain may occur at specific times, such as during menstruation. There may also be other symptoms, such as difficulty getting pregnant and fatigue. The symptoms of endometriosis may sometimes improve after menopause.

 

Dr. Ann Peters, an obstetric and gynecology specialist at Mercy Medical Center, who was not involved in the study, offered further insight into endometriosis to Medical News Today:

 

“[Endometriosis] is also a[n] extremely debilitating chronic disease that presents most commonly with painful periods but also a number of other complaints such as pain with intercourse, pain with bowel movements, diarrhea, constipation, urinary symptoms such as urinary frequency and urgency, heavy periods, chest pains, and chronic fatigue.”

 

“[One] out of 10 women are estimated to have endometriosis, but it is sometimes difficult to make the diagnosis because there currently are no noninvasive diagnostic modalities such as ultrasound or blood work testing that will reliably diagnose endometriosis.”

— Dr. Ann Peters

 

Researchers of the current review note that many women experience a delay in receiving an accurate medical diagnosis. They wanted to understand more about why this delay occurs.

 

 

Barriers to an endometriosis diagnosis

T​his review included 13 articles that met strict eligibility criteria. All the studies included either women with endometriosis or healthcare professionals who had experience diagnosing endometriosis.

 

The review specifically focused on qualitative studies where participants shared their views on the journey of receiving an endometriosis diagnosis. Based on an analysis of these articles, the authors identified themes that fell into four categories contributing to delayed diagnosis:

 

Individual factors

Interpersonal influences

Health system factors

F​actors specific to endometriosis

 

A​t the individual level, they found that women struggled with understanding typical menstruation pain. For example, there was a common assumption among participants that the pain was typical and that they just had to deal with it. These ideas and the use of self-care measures to manage symptoms likely influenced the time of endometriosis diagnosis.

 

A​t the interpersonal level, researchers found that stigma surrounding discussing menstrual problems and society viewing menstrual pain as normal may have further contributed to delayed diagnosis.

 

Finally, healthcare and endometriosis factors influenced diagnosis timing. For example, participants reported general practitioners brushing aside concerns or appearing to lack knowledge about endometriosis. Similarly, healthcare professional participants also expressed inadequate training regarding endometriosis, and many noted they also lacked clear clinical guidelines for diagnosis.

 

There were further problems in communication. Healthcare professionals sometimes use oral contraceptives to aid in diagnosing and treating endometriosis. Participants did not always receive clear explanations of ruling out other diagnoses or the strategy behind oral contraceptive use.

 

Lack of tests for endometriosis

Healthcare professionals further noted that symptoms of endometriosis can overlap with symptoms of other conditions, making delays in diagnosis possible. Endometriosis is also challenging to diagnose because there aren’t noninvasive tests that can give an accurate diagnosis. There were delays in referrals.

 

One reason for this was the misconception that laparoscopic surgery is the only means of diagnosis. Healthcare professionals also had doubts about the usefulness of an endometriosis diagnosis.

 

Study author Dr. Sophie Davenport, a doctor in England who conducted this research as part of a dissertation in Public Health (MPH), explained how the approach to overcoming these barriers will need to happen on many levels:

 

“The key highlights of the data are that delays to diagnosis exist throughout the journey. We need to target these at different levels – from society recognising what ‘normal’ menstruation is and being open to discussing menstrual problems, to clinicians being well-educated and up to date on the presentation and diagnosis and listening to patients when they say their periods aren’t normal.”

— Dr. Sophie Davenport, study author

 

Investigating the experience of endometriosis diagnosis

This research did have limitations that indicate the need for further research.

 

The studies included in the review were all conducted in high-income countries, and most of these countries had universal healthcare. Thus, it may not be possible to generalize the results, and this review doesn’t address financial barriers that may influence diagnosis.

 

Among studies that reported demographics, most participants were white women, indicating the need for more diversity in further research.

 

Among participants with endometriosis, the samples may be skewed toward those with more severe endometriosis.

 

In the studies that looked at the views of healthcare professionals, participants were doctors and mainly general practitioners. Further research could include other providers and specialists in the analysis. Finally, one reviewer conducted the review, introducing more risk for bias or method errors.

 

D​r. Davenport noted the following focus of continued research:

 

“A key area of research will be to investigate how [a] patient’s experiences of receiving a diagnosis of endometriosis change now that the clinical guidelines recommend treating empirically based on signs and symptoms, rather than a laparoscopic surgery being first-line. It was suggested in the papers that this deterred clinicians from referring women to specialist services and delayed women receiving a diagnosis and subsequent treatment.”

— D​r. Sophie Davenport

 

Speaking out about endometriosis symptoms is important

 

For those who think they may have endometriosis, seeking medical help is critical. This may include talking with a general practitioner. Dr. Davenport hoped their research would help encourage people and healthcare professionals to strive for prompt diagnosis.

 

“We would hope that the paper encourages patients to seek help if they feel that their periods are abnormal or causing them significant pain or distress, and [that it] encourages clinicians to take their concerns seriously and refer to specialist services early,” she said.

 

D​r. Peters further noted that women with endometriosis can support others and continue to raise awareness of the condition.

 

https://journals.lww.com/greenjournal/Abstract/9900/Barriers_to_a_Timely_Diagnosis_of_Endometriosis__A.821.aspx

 

Source: https://www.medicalnewstoday.com/articles/why-does-receiving-diagnosis-endometriosis-take-so-long

 

Endometriosis linked to reduction in live births before diagnosis of the disease

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Endometriosis linked to reduction in live births before diagnosis of the disease

Endometriosis is linked to a reduction in fertility in the years preceding a definitive surgical diagnosis of the condition, according to new research published in Human Reproduction, one of the world’s leading reproductive medicine journals.

In the first study to look at birth rates in a large group of women who eventually received a surgical verification of endometriosis, researchers in Finland found that the number of first live births in the period before diagnosis was half that of women without the painful condition. This was the case regardless of what form of endometriosis the women had: ovarian, peritoneal, deep endometriosis or other types.

In addition, the researchers found evidence that the number of babies women had before endometriosis was diagnosed was significantly reduced, compared to women who did not have endometriosis.

Professor Oskari Heikinheimo, of Helsinki University Hospital (Finland), who led the study, said: “Our findings suggest that doctors who see women suffering from painful menstruation and chronic pelvic pain, should keep in mind the possibility of endometriosis and treat them effectively. Doctors should discuss with these women the possible effects on their fertility, in addition to the effects of their age, and the impairment of fertility should be minimised by offering relevant treatment for endometriosis without delay.”

Endometriosis is a chronic inflammatory condition that affects up to about 10% of women of child-bearing age. Tissue from the lining of the womb grows in other places, such as the ovarian and fallopian tubes. Typical symptoms include painful menstruation, pain in the pelvic area, difficult or painful sexual intercourse, and difficulty getting pregnant. Correct diagnosis is often delayed by around seven years. Surgery has traditionally been the ‘gold standard’ for diagnosing the condition and classifying the type of endometriosis, although diagnosis by ultrasonographic findings or the symptoms alone is currently accepted.

Until now, there has been little information about the live birth rate among women with endometriosis, and little is known about the possible effects of different types of endometriosis on fertility, especially in the years before a diagnosis.

“Given the chronic nature and typical long delay in diagnosis of endometriosis, we wanted to find out if there were differences in first birth rates before diagnosis in a large group of women in the population,” said Prof. Heikinheimo.

He and his colleagues looked at 18,324 women in Finland, aged between 15 and 49 years, who had surgical verification of endometriosis between 1998 and 2012. They matched them with 35,793 women of similar age who did not have an endometriosis diagnosis. The follow-up period started at the age of 15 years, and continued until the first live birth, sterilization, removal of the ovaries or womb, or until the surgical diagnosis of endometriosis, whichever came first. The group of women with endometriosis were also divided into four groups according to the type of endometriosis.

The average (mean) time of follow-up before surgical diagnosis was 15.2 years. The average (median) age at the time of diagnosis of endometriosis was 35 years.

A total of 7,363 women (40%) with endometriosis and 23,718 women (66%) without endometriosis delivered a live born baby during the follow-up period. The incidence rate of first live births among women with endometriosis was half that of women without the condition (0.51%).

When analysed according to women’s birth decade from 1940s to 1970s, the birth rate decreased in both groups of women. Importantly, over the decades, an increasingly lower first live birth rate was seen in women with endometriosis, compared to women without. In those women born in 1940-1949, the difference in live birth rates between the two groups was 28% before surgically diagnosed endometriosis, but this difference increased steadily to 87% by 1970-1979.

“We assume that this is associated with the older age of women when they have their first baby, earlier surgical diagnosis of endometriosis and accumulating adverse effects of endometriosis in women affected by the condition,” said Prof. Heikinheimo.

The number of children that women had before their diagnosis of endometriosis was 1.93 and 2.16 for women without endometriosis.

“The possible effect of endometriosis on the desired number of children highlights the importance of early diagnosis and treatment of the disease,” he said.

He continued: “It is important to note that this study reports on live births before a definitive diagnosis of endometriosis. Next, we will be reporting on the fertility rates after the surgical diagnosis and treatment of endometriosis. We hope that the fertility of women with endometriosis catches up with that of the women without the condition after surgical management.”

The strength of the study is its large size, and that it includes information about women nationwide in Finland contained in the high-quality Finish national health care registers. There are some limitations. These include its focus on only surgically-confirmed endometriosis, which may have ruled out women with milder symptoms who were treated for the condition. There were no data available on whether or not women wanted to become pregnant. The researchers could not rule out the possible effect of fertility treatments or the effect of adenomyosis, which is known to occur often with endometriosis, and which also affects fertility and pregnancy outcomes. Differences in socioeconomic and educational backgrounds between the two groups of women might have affected the findings.
Read more: https://academic.oup.com/humrep/advance-article/doi/10.1093/humrep/dead120/7218807

Why some antibiotics may help reduce endometriosis symptoms

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Why some antibiotics may help reduce endometriosis symptoms

Researchers found that nearly two-thirds of patients with endometriosis have elevated levels of certain bacterium around their uterus, compared to less than 10 percent of people without the condition.

 

After giving antibiotics to mice with endometriosis, the researchers saw that both the levels of the bacteria and the formation of endometriosis-related lesions were reduced. However, further studies are needed to see whether the findings apply to humans.

 

Endometriosis is a condition in which cells similar to those found in uterine lining grow outside the uterus. This can lead to the formation of scar tissue and inflammation in the pelvic region as well as various organs, alongside symptoms including pain and nausea.

 

Worldwide, around 10% of women of reproductive age live with endometriosis. While there are some treatments that can help manage the condition, there is currently no cure. There is also no way to prevent the condition.

 

Further research into endometriosis could improve the health and quality of life for millions of people worldwide.

 

Recently, researchers found that targeting a specific bacterium may reduce lesions linked to endometriosis in mice.

 

The study was published in Science Translational Medicine.

 

Dr. Marc Winter, medical director of Minimally Invasive Surgical Gynecology at Hoag, who was not involved in the study, told Medical News Today:

 

“This study from Japan is extremely interesting as it implicates Fusobacterium — a type of bacteria — as a possible agent stimulating the formation of inflammatory cells that lead to inflammation, scar tissue, and pain associated with endometriosis. This discovery could lead to adding specific antibiotics as a critical part of endometriosis treatment.”

 

Fusobacterium in endometriosis

 

To begin, the researchers conducted a genetic analysis of fibroblasts from four patients with endometriosis and four patients without. Fibroblasts are cells that form connective tissues and are involved in wound healing.

 

They found that a gene called transgelin (TAGLN) was substantially upregulated in people with endometriosis. The protein it codes for, also called transgelin, is involved in processes such as cell replication, which play a key role in the condition’s development.

 

Inflammation can upregulate TAGLN expression which may arise from a bacterial infection. Previous research suggests that certain bacterial genera are significantly increased in patients with endometriosis compared to healthy individuals.

 

To see how the presence of these bacteria in the uterine influences endometriosis, the researchers next assessed the frequency of a bacterium known as Fusobacterium inside and outside of the uteruses of 79 individuals with and 76 without endometriosis.

 

Among patients with endometriosis, 64.3% had significantly higher levels of Fusobacterium in their uterine endometrial tissue, and 52.4% had higher levels in endometrial tissue that had formed outside the uterus. Higher levels of the bacterium were found in the uterus of just 7.1% of those without the condition.

 

Next, the researchers investigated whether Fusobacterium promoted endometriosis in nine mouse models of the condition. They found that mice with Fusobacterium developed more lesions in the uterus than controls.

 

Comparatively, mice without Fusobacterium did not develop as many lesions in their uteri. This difference remained even after they were stimulated by estrogen, which doctors think could cause uterine-lining-like tissue to form outside the uterus.

 

Antibiotic treatment reduced symptoms

 

Lastly, the researchers sought to see whether antibiotics could eradicate Fusobacterium in mice, thus reducing symptoms of endometriosis.

 

To do so, they administered two different antibiotics — metronidazole and chloramphenicol — to mouse models of endometriosis for 5 days. After a week, they found that Fusobacterium was no longer present in the mice and that transgelin expression decreased around the uterus.

 

They further noted that antibiotic-treated mice developed fewer and smaller endometriosis lesions than untreated mice.

 

The researchers wrote that their findings suggest that both antibiotics may be able to treat endometriosis. They noted, however, that the reason why Fusobacterium infects some individuals is unknown.

 

Unknowns about bacteria in endometriosis

 

MNT spoke with Dr. Karnika Kapoor, a family physician with Medical Offices of Manhattan, who was not involved in the study, about its limitations.

 

“The mouse model used in this research has some limitations in itself as mice lack a menstrual cycle and do not develop spontaneous endometriosis,” she said.

 

She added that the study lacks evidence to support the hypothesis that Fusobacterium around the uterus promotes endometriosis following retrograde menstruation (when the period flows upward through the fallopian tubes) which some researchers consider to be a likely cause for the condition.

 

MNT also spoke with Dr. Steven Vasilev, a board-certified integrative gynecologic oncologist and medical director of Integrative Gynecologic Oncology at Providence Saint John’s Health Center and Professor at Saint John’s Cancer Institute in Santa Monica, CA, who was also not involved in the study.

 

“While not a limitation per se, this is relatively early laboratory and mouse model data. This means, as usual, [that] the extrapolation of these findings and proposed molecular mechanisms to humans can’t readily be made yet,” he noted.

 

“However, this helps form a solid base of understanding toward unraveling how the microbiome and dysbiosis might lead to the formation and growth of endometriotic lesions,” he added.

 

Future treatments for endometriosis

 

Dr. Kapoor described current treatment options for endometriosis and their limitations.

 

“Treatment options for endometriosis are currently based on hormonal therapy but this means women cannot get pregnant during the treatment. Surgical treatment is an option for patients with recurrent pelvic pain but there is a high recurrence rate which is why removal of endometrial lesions is a concern,” she explained.

 

“This research seems to show a potential mechanism of endometriosis involving Fusobacterium, and that eradication with antibiotics is a treatment option. We may be able to implement antibiotic treatments for endometriosis in our clinical practice if proven effective in future studies.”

 

Dr. Winter agreed that the findings may lead to new treatment options.

 

“The role of Fusobacterium in stimulating endometriosis may lead to an entirely different approach in its treatment. Further studies are needed to study the role of Fusobacterium with retrograde menstruation in the formation of endometriosis,” he said.

 

“The use of a commonly used antibiotic metronidazole may be a key in improving the effectiveness of endometriosis treatment,” he concluded.

Endometriosis gene regions shared with other inflammatory and chronic pain conditions

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Endometriosis gene regions shared with other inflammatory and chronic pain conditions

A large-scale genetic study of endometriosis has been carried out to better understand its link to other inflammatory and chronic conditions.

Published in Nature Genetics, the study analysed the genomes of 60,674 women with endometriosis and 701,926 healthy controls of European, American, Australian and Japanese ancestry to elucidate the mechanism behind known links between endometriosis and other inflammatory and chronic pain conditions.

‘Using different datasets of women with and without endometriosis, some of which had unprecedented detailed data on surgical findings and pain experience collected using standardised criteria, allowed us to generate a treasure trove of new information about genetically driven endometriosis subtypes and pain experience’ said Dr Nilufer Rahmioglu, first author of the study and senior researcher at the Wellcome Centre for Human Genetics, Oxford.

Endometriosis is characterised by the abnormal overgrowth of the lining of the uterus, the endometrium, in other parts of the body, such as the ovaries. Symptoms usually consist of severe pain, irregular periods, fatigue, nausea, and infertility. The exact cause of this condition is unknown, and available treatments are only used to manage symptoms. It affects five to ten percent of women around the world.

The scientists have identified 42 genetic loci linked to increased risk of endometriosis by conducting a genome-wide association study on participants of European ancestry.

Data used was largely from the UK BioBank or provided by online direct-to-consumer testing site 23andMe.com. These loci are the site of a range of genes that were differently expressed in the endometrium and therefore had a likely role in disease development. Using the large amount of genetic information gathered from this group, the researchers identified variants on these loci that are more frequently found in endometriosis patients.

Many of the genes present at the loci identified are linked to hormone maintenance as well as to 11 chronic pain conditions, such as migraine and chronic back pain. An association was also found between endometriosis and two inflammatory conditions – osteoarthritis and asthma.

This suggests a correlation between endometriosis, chronic inflammatory or pain conditions and possibly even perception of pain. The study also found that ovarian endometriosis has a distinct genetic profile, as opposed to other subtypes of the condition.

‘Endometriosis is now recognised as a major health issue affecting women’s lives’, said the co-author of the study Professor Krina Zondervan from the University of Oxford. ‘It has provided a wealth of new knowledge on the genetics underlying endometriosis, which will help the research community in their efforts to come up with new treatments and possibly new ways of diagnosing the disease benefiting millions of women worldwide.’

 

https://www.nature.com/articles/s41588-023-01323-z

 

Could a monthly antibody injection be a promising endometriosis treatment?

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Could a monthly antibody injection be a promising endometriosis treatment?

According to the World Health Organization (WHO), endometriosis affects around 10% of people who menstruate, some 190 million people globally.

 

Symptoms, including severe pain during menstruation, heavy menstrual bleeding, back and pelvic pain, pain during intercourse, and, in some people, problems with fertility, occur when tissue similar to the endometrium, or uterine lining, grows outside the uterus.

 

Inflammation leads to the formation of lesions and scar tissue, so the condition tends to worsen over time.

 

Currently, endometriosis is treated with pain relief medication, such as non-steroidal anti-inflammatory drugs (NSAIDs), hormonal treatments that stop the ovaries from producing estrogen, and surgery.

 

Although these treatments can alleviate the symptoms, the condition is currently regarded as incurable.

 

Now, a Japanese study has found that a monthly injection of an engineered antibody that targets interleukin-8 (IL-8), an inflammatory cytokine, can reduce lesions, scar tissue, and organ adhesions in monkeys with endometriosis.

 

The research, published in Science Translational Medicine, suggests that this might lead to the first disease-modifying therapy for people with endometriosis.

 

Why use a monkey model?

 

The researchers used cynomolgus macaques, which are physiologically, biologically, and genetically close to humans in their study.

 

Female macaques menstruate, just like human ones, with an average menstrual cycle of around 30 days. They also develop endometriosis, with similar pathology to that which occurs in people.

 

Dr. Steven Vasilev, a board-certified integrative gynecologic oncologist and medical director of Integrative Gynecologic Oncology at Providence Saint John’s Health Center, professor at Saint John’s Cancer Institute in Santa Monica, CA, not involved in this study, explained for Medical News Today:

 

“Endometriosis in monkeys closely simulates [the] behavior of human endometriosis, making this an excellent model.”

 

What happened in the study

 

In this study, the researchers used monkeys with spontaneous endometriosis and others with endometriosis induced by transplanting endometrial tissue into the peritoneum.

 

The researchers developed an antibody — AMY109 — that binds to IL-8. They further engineered it so that it could target IL-8 multiple times, meaning the antibody had to be administered only once a month.

 

They injected AMY109 into one group of monkeys with endometriosis every 4 weeks for 6 months. A control group was given similar injections that did not contain the engineered antibody.

 

Dr. Vasilev told MNT that there was supporting evidence that this approach could work.

 

“An immunologic basis for the genesis and progression of endometriosis is already theorized and IL-8 is one of the known key proinflammatory cytokines in this process, and fibrosis in general,” he noted.

 

Inflammation and lesions reduced

 

The AMY109 injections had no adverse effects on the menstrual cycles of the monkeys, and they experienced no other side effects. But there was an improvement in their endometriosis.

 

The monthly subcutaneous injection of AMY109 reduced the volume of lesions and also diminished both fibrosis and adhesions.

 

“The authors developed a long-acting recycling antibody against IL-8 called AMY109 which objectively reduced inflammation and fibrosis associated with disease progression,” said Dr. Vasilev.

 

Unlike current hormone treatments, this anti–IL-8 antibody reduced fibrosis and adhesions in monkeys without affecting hormone secretion and menstruation.

 

However, the researchers were unable to confirm whether AMY109 also reduced the pain that the condition causes, or whether it improved fertility.

 

Clinical implications

 

Dr. G. Thomas Ruiz, OB/GYN lead at MemorialCare Orange Coast Medical Center in Fountain Valley, CA, not involved in this study, expressed some caution about the findings, but also a measure of hope: “It’s too soon to extrapolate to humans. But given the commonalities between primates and people, the data indicates it may be time to start human trials.”

 

And he stressed that it is very early days still: “We first need to establish safety and dosing for humans. Once that is completed, small trials will commence on volunteers.”

 

“Once stage 2 trials show safety and benefit, they can proceed to larger phase 3 trials to again analyze data across a large population,” he added. “Finally, the data will be reviewed by the FDA [Food and Drug Administration] for it to assess safety and efficacy.”

 

Possible future treatment

 

There is currently no cure for endometriosis, so treatments are targeted at managing symptoms, as Dr. Vasilev explained.

 

“There is a pressing need for disease-modifying drugs or biological agents to treat endometriosis,” he admitted. “Current pharmacological treatments, and newest clinical developments, are largely based on hormonal manipulation.”

 

“These are fraught with side effects and are limited to possibly providing pain relief but cannot cure the disease,” noted. Dr. Vasilev.

 

Surgery to remove lesions and adhesions is an option for those with severe endometriosis. It usually results in relief of pain, but at least one-third of those with the condition will need further surgery for continued problems.

 

This experimental antibody injection, might, according to Dr. Vasilev, help reduce the recurrence of endometriosis after surgery:

 

“Surgical excision is currently a cornerstone in [the] therapy of endometriosis. Surgery itself, in addition to the natural course of endometriosis, can produce fibrosis as part of the healing process. Reducing post-surgical fibrosis by modulating IL-8 may be an additional benefit in the multi-disciplinary medical and surgical management of endometriosis.”

 

So, if similar beneficial effects are seen in people, this finding could lead to the first disease-modifying treatment for endometriosis.

 

Although there is a long way to go before the antibody might be licensed for human use, this discovery should give hope to people with endometriosis.

 

Read more: https://www.science.org/doi/10.1126/scitranslmed.abq5858

 

Source: https://www.medicalnewstoday.com/articles/could-a-monthly-antibody-injection-be-a-promising-endometriosis-treatment

 

Gut microbiome may impact the progression of endometriosis

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Gut microbiome may impact the progression of endometriosis

A new study has found gut microbiota may play a pivotal role in the progression of endometriosis in an animal model.

Uterine microbiota, on the other hand, did not seem to affect the progression of endometriosis in mice.

Researchers found microbiota-derived metabolites—or products made by microbes—were significantly altered in the feces of mice with endometriosis.

The research suggests studying microbiota metabolites in human stool samples may serve as a diagnostic tool for endometriosis.

A poorly understood disease, endometriosis causes tissue similar to the lining of the uterus to grow outside the uterus, which can result in terrible pain, infertility, and a range of other symptoms.

About 10% of people who menstruate have endometriosis, according to the World Health Organization.

The gut microbiota, a collection of microbes present in the gastrointestinal tract, is considered a promising topic for scientific research.

Recently, researchers at Baylor College of Medicine looked at how altered gut microbiota may play a role in how endometriosis progresses.

 

Endometriosis and the gut

One widely accepted theory is that endometriosis may be caused by retrograde menstruation, where shed endometrial tissue moves through the fallopian tubes and enters the pelvic cavity, where it implants on surrounding tissue such as the intestine. However, up to 90% of women experience retrograde menstruation.

“So we thought there is in those women with endometriosis probably their peritoneal cavity, which is where the gut is [t]hat there’s something wrong,” Ramakrishna Kommagani, principal investigator and associate professor of immunology at Baylor College of Medicine in Houston, Texas, told Medical News Today.

The researchers also considered, according to Kommagani, how many people with endometriosis experience GI problems, such as irritable bowel syndrome.

Several other studies, including this one from 2021, have suggested a link between microbiota and the progression of endometriosis.

The researchers at Baylor College of Medicine set out to show whether gut microbiota directly influences the formation and growth of endometriosis lesions.

 

Gut microbiota’s causal role in endometriosis

In a 2019 study, Kommagani and other researchers found antibiotic therapy reduces endometriosis progression in mice. The researchers hypothesized that antibiotic therapy possibly reduced specific gut bacteria. However, they weren’t able to determine a causal role of gut microbiota in the progression of endometriosis.

For this study, researchers elected to study microbiota-depleted mice who have been raised normally and then given broad-spectrum antibiotics.

“So, this way we can study what happens in the mice which have normal microbiome and what happens in the mice where we removed the microbiome,” Kommagani explained.

Researchers then surgically induced endometriosis in both control and microbiota-depleted mice. Since surgery can also trigger an inflammatory response in mice, researchers also induced endometriosis using injections in both control and microbiota-depleted mice.

Researchers then gave control mice and microbiota-depleted mice feces from mice without endometriosis and feces from mice with endometriosis. They did this with both mice who had surgically-induced endometriosis and mice who had injection-induced endometriosis.

Additionally, researchers analyzed peritoneal fluid looking for immune cell populations in control and microbiota-depleted mice to determine if altered immune cell composition was associated with reduced lesion growth in microbiota-depleted mice.

Researchers also measured the relative metabolites, products made by microbes, in feces from mice with and without endometriosis. They then treated mice with endometriosis with quinic acid, a metabolite that was present at higher levels in mice with endometriosis.

The mice were given 5 mg/kg of quinic acid every 24 hours for 14 days.

 

Microbiota and endometriosis lesion growth

When researchers surgically induced endometriosis in both control and microbiota-depleted mice, they found lesions in control mice to be significantly larger and “more obviously fluid—filled and vascularized” than lesions in microbiota-depleted mice.

With control and microbiota-depleted mice who were given injection-based endometriosis, lesions in control mice were significantly larger and greater in number than in microbiota-depleted mice.

Researchers administered fecal matter from mice with and without endometriosis to control mice and microbiota-depleted mice who had surgically induced endometriosis. Transplanting fecal matter from mice with endometriosis into microbiota-depleted mice resulted in typical endometriosis lesions.

Transplanting fecal matter from healthy mice into microbiota-depleted mice failed to restore lesions. Researchers performed similar studies in mice that had injection-induced endometriosis and experienced similar results.

The findings, the researchers write in their paper, suggest gut microbiota and microbiota-derived metabolites play a role in the progression of endometriosis.

Researchers also found that the mice with endometriosis who were given quinic acid for 14 days had enhanced cellular proliferation and developed larger endometriotic lesions than control mice. However, they did not observe changes in the lesion numbers.

The researchers also write in their paper that the results from the peritoneal fluid analysis suggest that “gut microbiota impacts endometriotic lesion growth, possibly through the modulation of peritoneal immune cell populations.”

Additionally, researchers performed several tests to illustrate that uterine microbiota is not responsible for the differences in lesion growth.

“Microbiota from the uterus has no impact on the cells when they grow outside of the uterus,” Kommagani told MNT.

The idea that depletion of gut microbiota would reduce endometriosis-associated inflammation makes sense to Dr. José D. Eugenio-Colón, who practices at The Center for Endometriosis Care in Atlanta, Georgia.

“[W]hen patients have endometriosis, any type of microbiome that would promote inflammation would actually make everything significantly worse because it would allow the endometriosis [t]o proliferate, so they can actually have deeper disease,” he told MNT.

 

Research in humans needed

A disadvantage of using mice for medical research is that there are anatomical and physiological differences between rats and humans.

“[O]bviously, animal studies have their limitations. Right?” asked Dr. Eugenio-Colón.

However, Kommagani and his team of researchers are already in the lab measuring metabolites in human stool to see if they see similar changes in the metabolites of women with endometriosis.

“[T]his all has to be transferred to human subjects,” Kommagani said.

 

More timely endometriosis diagnosis

 

Currently, it takes between four and eleven years for women to receive a diagnosis of endometriosis.

Being able to use human stool samples as a diagnostic tool could mean patients with endometriosis get diagnosed earlier.

“The goal of everything it’s basically to identify patients early, because when we identify them early, the teens, then we have significantly [fewer] possibilities of having them go through [i]infertility [o]r chronic pain, anxiety, and depression,” Dr. Eugenio-Colón told MNT.

Read more: https://www.nature.com/articles/s41420-023-01309-0#Sec2

 

Source:

https://www.medicalnewstoday.com/articles/gut-microbiome-may-impact-the-progression-of-endometriosis#More-timely-endometriosis-diagnosis

 

Endometriosis: Cellular mapping study could lead to new treatments

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Endometriosis: Cellular mapping study could lead to new treatments

Researchers have analyzed almost 400,000 cells in order to build a detailed profile of endometriosis.

 

Endometriosis affects roughly 10% of people who menstruate. In endometriosis, tissue similar to the uterine lining grows elsewhere in the body, causing painful, heavy periods, abdominal and pelvic pain, and a range of other symptoms.

 

More research is needed for this condition for which there is still no cure, diagnosis can take many years, and treatments are often ineffective.

 

New research analyzing almost 400,000 cells has revealed a detailed molecular profile of endometriosis, which may help improve diagnostic and therapeutic options for people with the condition.

 

Endometriosis is “a systemic disease that is often painful and chronic.” According to the World Health Organization (WHO), it affects around 190 million people — some 10% of people who menstruate worldwide.

 

People with the condition experience debilitating symptoms, due to the growth of tissue similar to the uterine lining, or endometrium, elsewhere in the body.

 

Symptoms may include:

  • heavy and painful periods
  • spotting between periods
  • pain during sexual intercourse or when emptying the bladder or bowels
  • abdominal, lower back, and pelvic pain

 

Currently, there is no cure for endometriosis, but symptoms can be treated with medications, such as nonsteroidal anti-inflammatories (NSAIDs), birth control pills, hormonal IUD, surgery, or a combination of these treatments.

 

Dr. Steven Vasilev, board-certified integrative gynecologic oncologist and medical director of integrative gynecologic oncology at Providence Saint John’s Health Center and Professor at Saint John’s Cancer Institute in Santa Monica, CA, explained the issues to Medical News Today:

 

“Endometriosis diagnosis and treatment today remains surgical, based on removing or destroying endometriotic lesions growing on the peritoneum (internal skin-like lining of the body) and ovaries, combined with various hormonal modulations. There has not been a major clinical advance in endometriosis diagnosis and treatment outside these relatively narrow parameters in decades.”

 

Now, a new study led by researchers from Cedars-Sinai Medical Center in Los Angeles, CA, published in Nature Genetics, has analyzed almost 400,000 cells to generate cellular and molecular profiles of endometrial cells.

 

Its findings may lead to easier diagnosis and more effective treatments for endometriosis.

 

Raising awareness

 

Although endometriosis affects 10% of people who menstruate, there is a lack of research into the condition. To date, there has been little cellular data about endometriosis.

 

This, says Dr. Kate Lawrenson, research scientist, co-senior and corresponding author of the study, and associate professor of obstetrics and gynecology and biomedical sciences at Cedars-Sinai, is why they undertook this research:

 

“Endometriosis has a devastating effect on so many people, and is remarkably common. Unfortunately, it is also one of the most underfunded diseases there is, and many basic questions remain unanswered — which is why this research provides a huge leap forward in understanding the biology of his disease.”

 

“I hope that work like ours can help bring conversations about endometriosis into the forefront, to improve awareness and also increase much-needed funding for endometriosis research,” she told MNT.

 

Cell research

 

In this new study, the researchers used state-of-the-art methods to analyze more than 370,000 cells from 21 participants, 17 of whom had endometriosis and four who did not.

 

They sampled different tissues — peritoneal endometriosis, ovarian endometriomas, eutopic endometrium samples, and uninvolved ovary tissues. Eutopic endometrium and uninvolved ovary tissues came from people with and without endometriosis.

 

“The methodology of the study is basic molecular biology. It has done something I have not seen in other endometriosis studies, which is [to] try and break down the various characteristics of endometriosis-type cells depending on [the] body location of the lesion. It is cataloging the cell type and surrounding microenvironment,” Dr. G. Thomas Ruiz, OB/GYN lead at MemorialCare Orange Coast Medical Center in Fountain Valley, CA, not involved in this study, explained for MNT.

 

The researchers analyzed the cells using droplet-based single-cell RNA sequencing. This method identifies which genes are transcribed to make RNA, determining which proteins the cell makes.

 

By identifying which genes are transcribed, researchers can see differences between the types of cells under investigation.

 

Using this method, the researchers identified molecular differences between the major subtypes of endometriosis, including peritoneal endometriosis and ovarian endometrioma.

 

Dr. Lawrenson explained their findings: “We saw a number of differences when we compared endometriosis cells to endometrium. The endometriosis cells are responding differently to hormones and communicate differently with the immune system.”

 

“The fact that they are behaving so differently is really exciting, as it potentially provides us with new opportunities for therapeutic targeting,” she added.

 

Pointers for diagnosis and treatment

 

“This atlas of molecular findings will help researchers move the ball forward towards achieving earlier diagnosis, differentiation between subtypes of endometriosis, a better understanding of the overlap with ovarian cancer in a small but significant percentage of endometriosis patients, and insights into eventual development of molecularly targeted therapy for endometriosis,” said Dr. Vasilev.

 

So could this research lead the way to new diagnosis and treatment methods? Dr. Lawrenson believes so, and is investigating potential diagnostics for the condition:

 

“We urgently need a blood test for endometriosis and this is now one of our top research priorities in the laboratory. We were encouraged to see that in endometriosis, multiple cell types overproduce the same genes, which should make it easier to detect those genes in the blood.”

 

The research discovered that endometriosis cells and normal cells respond differently to the immune system. New therapies that target the immune system might prove effective in treating the condition, as Dr. Lawrenson explained.

 

“Recent advances suggest that we might be able to treat endometriosis by correcting how the immune system responds to lesions. This is particularly exciting because there might be immune therapies used for other diseases that could be rapidly repurposed for the treatment of endometriosis,” she told MNT.

 

There is still a need for further research, and Dr. Ruiz suggested directions this research might take: “Endometrioma, superficial versus deep infiltrating had very specific cellular characteristics. The next step would be in vitro studies to see if various endometriosis cell types act differently to current hormone treatments.”

 

With the mapping of endometriosis, this research has highlighted potential diagnostic and treatment pathways for investigation — it can only be good news for the many people with this debilitating condition.

 

https://www.nature.com/articles/s41588-022-01254-1

 

Study seeks to look for a better treatment for endometriosis

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Study seeks to look for a better treatment for endometriosis

Up to 15% of women of reproductive age in the United States suffer from endometriosis, a condition characterized by pelvic pain, menstrual cramps and infertility. Endometriosis develops when tissue like the lining on the inside of the womb grows outside of the uterus. This growth may swell and bleed, leading to pain and other symptoms.

Endometriosis depends on estrogen, a hormone well known for regulating a woman’s reproductive functions. Estrogen also affects other organs such as the heart and blood vessels, bones, breasts, skin, hair, mucous membranes, pelvic muscles and the brain” said Dr. Sang Jun Han, corresponding author, associate professor of molecular and cellular biology and in the Center for Reproductive Medicine at Baylor College of Medicine.

Endometriosis’ dependence on estrogen and inflammation has guided treatments that are based on systematically removing estrogen and using anti-inflammatory drugs. “However, current endometriosis treatments have low efficacy, high recurrence rate and cause adverse effects in other tissues affected by estrogen,” said Han, who also is a member of Baylor’s Dan L Duncan Comprehensive Cancer Center. “Our goal in this study published in the Journal of Biomedical Science was to look for a better treatment for this condition.”

Since endometriosis is an estrogen-dependent disease, estrogen receptors (ERs) ER-alpha and ER-beta, which mediate the hormones’ effects on cells, play essential roles in the development and progression of the condition. Previous work by the Han lab and others has shown that ER-beta contributes significantly to the progression of endometriosis. “These findings suggest that selectively suppressing the activity of ER-beta could help treat the condition without side effects of current hormonal therapies targeting ER-alpha,” said first author Dr. Yuri Park, a postdoctoral associate in the Department of Molecular and Cellular Biology at Baylor.

Working with cells in the lab, Han and his colleagues screened a library of natural products searching for compounds that could be used to treat endometriosis as non-hormonal therapies.

The team found that oleuropein, a natural component found in olive leaves, selectively inhibits ER-beta activity, but not ER-alpha activity, and effectively suppresses the growth of mouse and human endometriosis lesions in mouse models.

“In addition, oleuropein treatment was neither toxic to the liver nor did it affect the ability of female mice to have offspring,” Han said. “In mice with endometriosis, oleuropein improved the pregnancy rate. We are excited by these promising findings as they support further exploration of the value of oleuropein as naturopathy for human endometriosis treatment. Oleuropein is less expensive than hormonal therapy, and our current findings suggest that it is safer than current treatments.”

Other contributors to this work include Yeon Jean Cho, Nuri Sung, Mi Jin Park, Xiaoming Guan, William E. Gibbons and Bert W. O’Malley. The authors are affiliated with Baylor College of Medicine.

This study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grant R01HD098059.

https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-022-00883-2

 

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