Endometriosis

Women who’ve had endometriosis carry an elevated risk of stroke with them for the rest of their lives, with the greatest risk found in women who’ve had a hysterectomy with an oophorectomy, according to a cohort study of the Nurses’ Health Study.

“This is yet additional evidence that those girls and women with endometriosis are having effects across their lives and in multiple aspects of their health and well-being,” senior study author Stacey A. Missmer, ScD, of the Michigan State University, East Lansing, said in an interview. “This is not, in quotes ‘just a gynecologic condition,’ ” Dr. Missmer added. “It is not strictly about the pelvic pain or infertility, but it really is about the whole health across the life course.”

The study included 112,056 women in the NHSII cohort study who were followed from 1989 to June 2017, documenting 893 incident cases of stroke among them – an incidence of less than 1%. Endometriosis was reported in 5,244 women, and 93% of the cohort were White.

Multivariate adjusted models showed that women who had laparoscopically confirmed endometriosis had a 34% greater risk of stroke than women without a history of endometriosis. Leslie V. Farland, ScD, of the University of Arizona, Tucson, was lead author of the study.

While previous studies have demonstrated an increased risk of cardiovascular disease, heart attack, angina, and atherosclerosis in women who’ve had endometriosis, this is the first study that has confirmed an additional increased risk of stroke, Dr. Missmer said.

Another novel finding, Dr. Missmer said, is that while the CVD risks for these women “seem to peak at an earlier age,” the study found no age differences for stroke risk. “That also reinforces that these stroke events are often happening in an age range typical for stroke, which is further removed from when women are thinking about their gynecologic health specifically.”

These findings don’t translate into a significantly greater risk for stroke overall in women who’ve had endometriosis, Dr. Missmer said. She characterized the risk as “not negligible, but it’s not a huge increased risk.” The absolute risk is still fairly low, she said.

“We don’t want to give the impression that all women with endometriosis need to be panicked or fearful about stroke, she said. “Rather, the messaging is that this yet another bit of evidence that whole health care for those with endometriosis is important.”

Women who’ve had endometriosis and their primary care providers need to be attuned to stroke risk, she said. “This is a critical condition that primary care physicians need to engage around, and perhaps if symptoms related to cardiovascular and cerebrovascular disease emerge in their patients, they need to be engaging cardiology and similar types of support. This is not just about the gynecologists.”

The study also explored other factors that may contribute to stroke risk, with the most significant being hysterectomy with bilateral oophorectomy, Dr. Missmer said.

This study was unique because it used laparoscopically confirmed rather than self-reported endometriosis, said Louise D. McCullough, MD, neurology chair at the University of Texas Health Science Center, Houston. Another strength of the study she noted was its longitudinal design, although the cohort study design yielded a low number of stroke patients.

“Regardless, I do think it was a very important study because we have a growing recognition about how women’s health and factors such as pregnancy, infertility, parity, complications, and gonadal hormones such as estrogen can influence a woman’s stroke risk much later in life,” Dr. McCullough said in an interview.

Future studies into the relationship between endometriosis and CVD and stroke risk should focus on the mechanism behind the inflammation that occurs in endometriosis, Dr. McCullough said. “Part of it is probably the loss of hormones if a patient has to have an oophorectomy, but part of it is just what do these diseases do for a woman’s later risk – and for primary care physicians, ob.gyns., and stroke neurologists to recognize that these are questions we should ask: Have you ever  had eclampsia or preeclampsia? Did you have endometriosis? Have you had miscarriages?”

The study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute for Neurological Disorders and Stroke. Dr. Missmer disclosed relationships with Shanghai Huilun Biotechnology, Roche, and AbbVie. Dr. McCullough has no relevant disclosures.


 

Women who’ve had endometriosis carry an elevated risk of stroke with them for the rest of their lives, with the greatest risk found in women who’ve had a hysterectomy with an oophorectomy, according to a cohort study of the Nurses’ Health Study.

“This is yet additional evidence that those girls and women with endometriosis are having effects across their lives and in multiple aspects of their health and well-being,” senior study author Stacey A. Missmer, ScD, of the Michigan State University, East Lansing, said in an interview. “This is not, in quotes ‘just a gynecologic condition,’ ” Dr. Missmer added. “It is not strictly about the pelvic pain or infertility, but it really is about the whole health across the life course.”

The study included 112,056 women in the NHSII cohort study who were followed from 1989 to June 2017, documenting 893 incident cases of stroke among them – an incidence of less than 1%. Endometriosis was reported in 5,244 women, and 93% of the cohort were White.

Multivariate adjusted models showed that women who had laparoscopically confirmed endometriosis had a 34% greater risk of stroke than women without a history of endometriosis. Leslie V. Farland, ScD, of the University of Arizona, Tucson, was lead author of the study.

While previous studies have demonstrated an increased risk of cardiovascular disease, heart attack, angina, and atherosclerosis in women who’ve had endometriosis, this is the first study that has confirmed an additional increased risk of stroke, Dr. Missmer said.

Another novel finding, Dr. Missmer said, is that while the CVD risks for these women “seem to peak at an earlier age,” the study found no age differences for stroke risk. “That also reinforces that these stroke events are often happening in an age range typical for stroke, which is further removed from when women are thinking about their gynecologic health specifically.”

These findings don’t translate into a significantly greater risk for stroke overall in women who’ve had endometriosis, Dr. Missmer said. She characterized the risk as “not negligible, but it’s not a huge increased risk.” The absolute risk is still fairly low, she said.

“We don’t want to give the impression that all women with endometriosis need to be panicked or fearful about stroke, she said. “Rather, the messaging is that this yet another bit of evidence that whole health care for those with endometriosis is important.”

Women who’ve had endometriosis and their primary care providers need to be attuned to stroke risk, she said. “This is a critical condition that primary care physicians need to engage around, and perhaps if symptoms related to cardiovascular and cerebrovascular disease emerge in their patients, they need to be engaging cardiology and similar types of support. This is not just about the gynecologists.”

The study also explored other factors that may contribute to stroke risk, with the most significant being hysterectomy with bilateral oophorectomy, Dr. Missmer said.

This study was unique because it used laparoscopically confirmed rather than self-reported endometriosis, said Louise D. McCullough, MD, neurology chair at the University of Texas Health Science Center, Houston. Another strength of the study she noted was its longitudinal design, although the cohort study design yielded a low number of stroke patients.

“Regardless, I do think it was a very important study because we have a growing recognition about how women’s health and factors such as pregnancy, infertility, parity, complications, and gonadal hormones such as estrogen can influence a woman’s stroke risk much later in life,” Dr. McCullough said in an interview.

Future studies into the relationship between endometriosis and CVD and stroke risk should focus on the mechanism behind the inflammation that occurs in endometriosis, Dr. McCullough said. “Part of it is probably the loss of hormones if a patient has to have an oophorectomy, but part of it is just what do these diseases do for a woman’s later risk – and for primary care physicians, ob.gyns., and stroke neurologists to recognize that these are questions we should ask: Have you ever  had eclampsia or preeclampsia? Did you have endometriosis? Have you had miscarriages?”

The study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute for Neurological Disorders and Stroke. Dr. Missmer disclosed relationships with Shanghai Huilun Biotechnology, Roche, and AbbVie. Dr. McCullough has no relevant disclosures.


 

Women who’ve had endometriosis carry an elevated risk of stroke with them for the rest of their lives, with the greatest risk found in women who’ve had a hysterectomy with an oophorectomy, according to a cohort study of the Nurses’ Health Study.

“This is yet additional evidence that those girls and women with endometriosis are having effects across their lives and in multiple aspects of their health and well-being,” senior study author Stacey A. Missmer, ScD, of the Michigan State University, East Lansing, said in an interview. “This is not, in quotes ‘just a gynecologic condition,’ ” Dr. Missmer added. “It is not strictly about the pelvic pain or infertility, but it really is about the whole health across the life course.”

The study included 112,056 women in the NHSII cohort study who were followed from 1989 to June 2017, documenting 893 incident cases of stroke among them – an incidence of less than 1%. Endometriosis was reported in 5,244 women, and 93% of the cohort were White.

Multivariate adjusted models showed that women who had laparoscopically confirmed endometriosis had a 34% greater risk of stroke than women without a history of endometriosis. Leslie V. Farland, ScD, of the University of Arizona, Tucson, was lead author of the study.

While previous studies have demonstrated an increased risk of cardiovascular disease, heart attack, angina, and atherosclerosis in women who’ve had endometriosis, this is the first study that has confirmed an additional increased risk of stroke, Dr. Missmer said.

Another novel finding, Dr. Missmer said, is that while the CVD risks for these women “seem to peak at an earlier age,” the study found no age differences for stroke risk. “That also reinforces that these stroke events are often happening in an age range typical for stroke, which is further removed from when women are thinking about their gynecologic health specifically.”

These findings don’t translate into a significantly greater risk for stroke overall in women who’ve had endometriosis, Dr. Missmer said. She characterized the risk as “not negligible, but it’s not a huge increased risk.” The absolute risk is still fairly low, she said.

“We don’t want to give the impression that all women with endometriosis need to be panicked or fearful about stroke, she said. “Rather, the messaging is that this yet another bit of evidence that whole health care for those with endometriosis is important.”

Women who’ve had endometriosis and their primary care providers need to be attuned to stroke risk, she said. “This is a critical condition that primary care physicians need to engage around, and perhaps if symptoms related to cardiovascular and cerebrovascular disease emerge in their patients, they need to be engaging cardiology and similar types of support. This is not just about the gynecologists.”

The study also explored other factors that may contribute to stroke risk, with the most significant being hysterectomy with bilateral oophorectomy, Dr. Missmer said.

This study was unique because it used laparoscopically confirmed rather than self-reported endometriosis, said Louise D. McCullough, MD, neurology chair at the University of Texas Health Science Center, Houston. Another strength of the study she noted was its longitudinal design, although the cohort study design yielded a low number of stroke patients.

“Regardless, I do think it was a very important study because we have a growing recognition about how women’s health and factors such as pregnancy, infertility, parity, complications, and gonadal hormones such as estrogen can influence a woman’s stroke risk much later in life,” Dr. McCullough said in an interview.

Future studies into the relationship between endometriosis and CVD and stroke risk should focus on the mechanism behind the inflammation that occurs in endometriosis, Dr. McCullough said. “Part of it is probably the loss of hormones if a patient has to have an oophorectomy, but part of it is just what do these diseases do for a woman’s later risk – and for primary care physicians, ob.gyns., and stroke neurologists to recognize that these are questions we should ask: Have you ever  had eclampsia or preeclampsia? Did you have endometriosis? Have you had miscarriages?”

The study received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute for Neurological Disorders and Stroke. Dr. Missmer disclosed relationships with Shanghai Huilun Biotechnology, Roche, and AbbVie. Dr. McCullough has no relevant disclosures.


 

A new imaging study hopes to make diagnosing endometriosis quicker, more accurate and reduce the need for invasive surgery.

In October 2020 the All Party Parliamentary Group on Endometriosis published a report that included within its recommendations “a commitment to drive down diagnosis times” for women with the condition. On average, it takes around 8 years for a woman to get a diagnosis of endometriosis, a figure, said the authors of the report, that had “not improved in the last decade.”

Indeed, in its report the APPG said that it was seeking a commitment from Governments in all four nations to reduce average diagnosis times with “targets of 4 years or less by 2025, and a year or less by 2030.”
 

Surgery often needed for endometriosis diagnosis

Endometriosis affects 1 in 10 women between puberty and menopause – 1.5 million in the United Kingdom – often results in multiple general practitioner and accident and emergency department visits, multiple scans, and often laparoscopic surgery to confirm the diagnosis, as there is currently no simple diagnostic test for the condition. One of the main reasons for the delay in diagnosis is the lack of noninvasive tests capable of detecting all endometriosis subtypes – ovarian, superficial, and deep disease.

Now, experts at the Endometriosis CaRe Centre and Nuffield Department of Women’s and Reproductive Health, University of Oxford (England), in collaboration with British life sciences company Serac Healthcare, hope to establish a faster process for diagnosing endometriosis.

Christian Becker, codirector of the Endometriosis CaRe Centre in Oxford, and a study lead, said: “There is an urgent unmet clinical need for a noninvasive marker to identify or rule out endometriosis as it is such a very common disease affecting more than 190 million women worldwide.”

In the study, researchers will investigate whether a 20-minute imaging scan can detect the most common types of endometriosis, which currently require surgery to diagnose. In turn, they hope that earlier diagnosis of the condition will allow women to seek appropriate treatment sooner. They will use an experimental imaging marker – ^99mTc-maraciclatide – that binds to areas of inflammation and that can be used in endometriosis to visualize the disease on a scan. The imaging marker has already been used for detecting inflammation in conditions such as rheumatoid arthritis.

Between 2 and 7 days before planned surgery for suspected endometriosis, participants will be invited for an imaging scan, and the team will compare the suspected locations of disease detected on the scan with those seen during surgery to confirm whether this imaging test could be an effective noninvasive method of detecting all endometriosis subtypes.
 

Doctor visits and repeated investigations reduced

The researchers commented that the potential strengths of the scan lie in the way the imaging marker binds to areas of inflammation, which may allow doctors to distinguish between new and old lesions and detect endometriosis in areas not easily seen during surgery, such as the lung.

They added that the development of a 20-minute imaging test would reduce the need for repeated visits to doctors, for repeated investigations, and for invasive surgery to obtain a diagnosis. This would ultimately “reduce the time taken to confirm or exclude endometriosis,” they pointed out.

Following the publication of the APPG report in October 2020 the group’s then chair, the late Sir David Amess, said: “Without investment in research, a reduction in diagnosis time, and appropriate NHS pathways, those with endometriosis will continue to face huge barriers in accessing the appropriate support at the right time.”

Krina Zondervan, head of department at the Nuffield Department of Women’s and Reproductive Health, University of Oxford, and a study lead, said: “This study highlights that close collaborations between academics, clinicians and industry are important to combine and accelerate discovery and innovation in addressing high-priority areas in women’s health such as endometriosis.”

David Hail, CEO of Serac Healthcare, said: “We are excited about the potential of ^99mTc-maraciclatide to diagnose endometriosis noninvasively and delighted to be working with the internationally renowned team at Oxford on this important first study.”

A version of this article first appeared on Medscape UK.

A new imaging study hopes to make diagnosing endometriosis quicker, more accurate and reduce the need for invasive surgery.

In October 2020 the All Party Parliamentary Group on Endometriosis published a report that included within its recommendations “a commitment to drive down diagnosis times” for women with the condition. On average, it takes around 8 years for a woman to get a diagnosis of endometriosis, a figure, said the authors of the report, that had “not improved in the last decade.”

Indeed, in its report the APPG said that it was seeking a commitment from Governments in all four nations to reduce average diagnosis times with “targets of 4 years or less by 2025, and a year or less by 2030.”
 

Surgery often needed for endometriosis diagnosis

Endometriosis affects 1 in 10 women between puberty and menopause – 1.5 million in the United Kingdom – often results in multiple general practitioner and accident and emergency department visits, multiple scans, and often laparoscopic surgery to confirm the diagnosis, as there is currently no simple diagnostic test for the condition. One of the main reasons for the delay in diagnosis is the lack of noninvasive tests capable of detecting all endometriosis subtypes – ovarian, superficial, and deep disease.

Now, experts at the Endometriosis CaRe Centre and Nuffield Department of Women’s and Reproductive Health, University of Oxford (England), in collaboration with British life sciences company Serac Healthcare, hope to establish a faster process for diagnosing endometriosis.

Christian Becker, codirector of the Endometriosis CaRe Centre in Oxford, and a study lead, said: “There is an urgent unmet clinical need for a noninvasive marker to identify or rule out endometriosis as it is such a very common disease affecting more than 190 million women worldwide.”

In the study, researchers will investigate whether a 20-minute imaging scan can detect the most common types of endometriosis, which currently require surgery to diagnose. In turn, they hope that earlier diagnosis of the condition will allow women to seek appropriate treatment sooner. They will use an experimental imaging marker – ^99mTc-maraciclatide – that binds to areas of inflammation and that can be used in endometriosis to visualize the disease on a scan. The imaging marker has already been used for detecting inflammation in conditions such as rheumatoid arthritis.

Between 2 and 7 days before planned surgery for suspected endometriosis, participants will be invited for an imaging scan, and the team will compare the suspected locations of disease detected on the scan with those seen during surgery to confirm whether this imaging test could be an effective noninvasive method of detecting all endometriosis subtypes.
 

Doctor visits and repeated investigations reduced

The researchers commented that the potential strengths of the scan lie in the way the imaging marker binds to areas of inflammation, which may allow doctors to distinguish between new and old lesions and detect endometriosis in areas not easily seen during surgery, such as the lung.

They added that the development of a 20-minute imaging test would reduce the need for repeated visits to doctors, for repeated investigations, and for invasive surgery to obtain a diagnosis. This would ultimately “reduce the time taken to confirm or exclude endometriosis,” they pointed out.

Following the publication of the APPG report in October 2020 the group’s then chair, the late Sir David Amess, said: “Without investment in research, a reduction in diagnosis time, and appropriate NHS pathways, those with endometriosis will continue to face huge barriers in accessing the appropriate support at the right time.”

Krina Zondervan, head of department at the Nuffield Department of Women’s and Reproductive Health, University of Oxford, and a study lead, said: “This study highlights that close collaborations between academics, clinicians and industry are important to combine and accelerate discovery and innovation in addressing high-priority areas in women’s health such as endometriosis.”

David Hail, CEO of Serac Healthcare, said: “We are excited about the potential of ^99mTc-maraciclatide to diagnose endometriosis noninvasively and delighted to be working with the internationally renowned team at Oxford on this important first study.”

A version of this article first appeared on Medscape UK.

A new imaging study hopes to make diagnosing endometriosis quicker, more accurate and reduce the need for invasive surgery.

In October 2020 the All Party Parliamentary Group on Endometriosis published a report that included within its recommendations “a commitment to drive down diagnosis times” for women with the condition. On average, it takes around 8 years for a woman to get a diagnosis of endometriosis, a figure, said the authors of the report, that had “not improved in the last decade.”

Indeed, in its report the APPG said that it was seeking a commitment from Governments in all four nations to reduce average diagnosis times with “targets of 4 years or less by 2025, and a year or less by 2030.”
 

Surgery often needed for endometriosis diagnosis

Endometriosis affects 1 in 10 women between puberty and menopause – 1.5 million in the United Kingdom – often results in multiple general practitioner and accident and emergency department visits, multiple scans, and often laparoscopic surgery to confirm the diagnosis, as there is currently no simple diagnostic test for the condition. One of the main reasons for the delay in diagnosis is the lack of noninvasive tests capable of detecting all endometriosis subtypes – ovarian, superficial, and deep disease.

Now, experts at the Endometriosis CaRe Centre and Nuffield Department of Women’s and Reproductive Health, University of Oxford (England), in collaboration with British life sciences company Serac Healthcare, hope to establish a faster process for diagnosing endometriosis.

Christian Becker, codirector of the Endometriosis CaRe Centre in Oxford, and a study lead, said: “There is an urgent unmet clinical need for a noninvasive marker to identify or rule out endometriosis as it is such a very common disease affecting more than 190 million women worldwide.”

In the study, researchers will investigate whether a 20-minute imaging scan can detect the most common types of endometriosis, which currently require surgery to diagnose. In turn, they hope that earlier diagnosis of the condition will allow women to seek appropriate treatment sooner. They will use an experimental imaging marker – ^99mTc-maraciclatide – that binds to areas of inflammation and that can be used in endometriosis to visualize the disease on a scan. The imaging marker has already been used for detecting inflammation in conditions such as rheumatoid arthritis.

Between 2 and 7 days before planned surgery for suspected endometriosis, participants will be invited for an imaging scan, and the team will compare the suspected locations of disease detected on the scan with those seen during surgery to confirm whether this imaging test could be an effective noninvasive method of detecting all endometriosis subtypes.
 

Doctor visits and repeated investigations reduced

The researchers commented that the potential strengths of the scan lie in the way the imaging marker binds to areas of inflammation, which may allow doctors to distinguish between new and old lesions and detect endometriosis in areas not easily seen during surgery, such as the lung.

They added that the development of a 20-minute imaging test would reduce the need for repeated visits to doctors, for repeated investigations, and for invasive surgery to obtain a diagnosis. This would ultimately “reduce the time taken to confirm or exclude endometriosis,” they pointed out.

Following the publication of the APPG report in October 2020 the group’s then chair, the late Sir David Amess, said: “Without investment in research, a reduction in diagnosis time, and appropriate NHS pathways, those with endometriosis will continue to face huge barriers in accessing the appropriate support at the right time.”

Krina Zondervan, head of department at the Nuffield Department of Women’s and Reproductive Health, University of Oxford, and a study lead, said: “This study highlights that close collaborations between academics, clinicians and industry are important to combine and accelerate discovery and innovation in addressing high-priority areas in women’s health such as endometriosis.”

David Hail, CEO of Serac Healthcare, said: “We are excited about the potential of ^99mTc-maraciclatide to diagnose endometriosis noninvasively and delighted to be working with the internationally renowned team at Oxford on this important first study.”

A version of this article first appeared on Medscape UK.

A French research team has developed a microRNA (miRNA) signature for diagnosing endometriosis through a simple saliva test. Its validation in a larger cohort could soon allow doctors to have a cheap, noninvasive, and accurate tool to use in diagnosing a disease that, for the time being, is difficult to identify with any certainty. The researchers suggest that their methodology could be used as a blueprint to investigate other pathologies, both benign and malignant.

ENDO-miRNA study

miRNAs regulate as much as 60% of gene expression at the posttranscriptional level. In the setting of endometriosis, several authors have evaluated the relevance of a blood-based miRNA signature, but the results are discordant because of methodological and control group issues. Other researchers have also sought to develop a miRNA saliva test. A French team wanted to determine whether it was possible to define a saliva-based diagnostic miRNome signature that would allow patients with and without endometriosis to be differentiated and, from there, develop the first specific diagnostic test for the disease.

The prospective ENDO-miRNA study included saliva samples obtained from women with chronic pelvic pain suggestive of endometriosis. Exploratory procedures were performed to look for lesions. All the patients underwent either a laparoscopic procedure (therapeutic or diagnostic laparoscopy) and/or MRI imaging. For the patients who underwent laparoscopy, diagnosis was confirmed by histology. For the patients diagnosed with endometriosis without laparoscopic evaluation, all had MRI imaging with features of deep endometriosis.

One part of the study involved the identification of a biomarker based on genomewide miRNA expression profiling by small RNA sequencing using next-generation sequencing. The second part involved the development of a saliva-based miRNA diagnostic signature according to expression and accuracy profiling using a random forest algorithm.
 

High sensitivity, specificity

Among the 200 patients (mean age, 31 years) enrolled in the study, 76.5% (n = 153) were diagnosed with endometriosis. On average, their pain was statistically more severe than that of the women in the control group. The Visual Analogue Scale (VAS) scores were, respectively: dysmenorrhea 6 versus 5.0 (P < .001), dyspareunia 5.28 versus 4.95 (P < .001), and urinary pain during menstruation 4.35 versus 2.84 (P < .001).

Next-generation sequencing identified an average of 2,561 expressed miRNAs in the saliva samples. The feature selection method generated a subset of 109 miRNAs composing the endometriosis diagnostic signature. Among those miRNAs, 29 were associated with the main signaling pathways of endometriosis: PI3K/AKT, PTEN, Wnt/beta-catenin, HIF1-alpha/NF kappa B, and YAP/TAZ/EGFR.

The accuracy and reproducibility of the signature were tested on several data sets randomly composed of the same proportion of controls and patients with endometriosis. The respective sensitivity, specificity, and area under the curve for the diagnostic miRNA signature were 96.7%, 100%, and 98.3%, respectively.

The study’s results support the use of a saliva-based miRNA signature for diagnosing whether a patient is discordant/complex (chronic pelvic pain suggestive of endometriosis and both negative clinical examination and imaging findings) or has early-stage or advanced-stage endometriosis.

A version of this article first appeared on Medscape.com.

A French research team has developed a microRNA (miRNA) signature for diagnosing endometriosis through a simple saliva test. Its validation in a larger cohort could soon allow doctors to have a cheap, noninvasive, and accurate tool to use in diagnosing a disease that, for the time being, is difficult to identify with any certainty. The researchers suggest that their methodology could be used as a blueprint to investigate other pathologies, both benign and malignant.

ENDO-miRNA study

miRNAs regulate as much as 60% of gene expression at the posttranscriptional level. In the setting of endometriosis, several authors have evaluated the relevance of a blood-based miRNA signature, but the results are discordant because of methodological and control group issues. Other researchers have also sought to develop a miRNA saliva test. A French team wanted to determine whether it was possible to define a saliva-based diagnostic miRNome signature that would allow patients with and without endometriosis to be differentiated and, from there, develop the first specific diagnostic test for the disease.

The prospective ENDO-miRNA study included saliva samples obtained from women with chronic pelvic pain suggestive of endometriosis. Exploratory procedures were performed to look for lesions. All the patients underwent either a laparoscopic procedure (therapeutic or diagnostic laparoscopy) and/or MRI imaging. For the patients who underwent laparoscopy, diagnosis was confirmed by histology. For the patients diagnosed with endometriosis without laparoscopic evaluation, all had MRI imaging with features of deep endometriosis.

One part of the study involved the identification of a biomarker based on genomewide miRNA expression profiling by small RNA sequencing using next-generation sequencing. The second part involved the development of a saliva-based miRNA diagnostic signature according to expression and accuracy profiling using a random forest algorithm.
 

High sensitivity, specificity

Among the 200 patients (mean age, 31 years) enrolled in the study, 76.5% (n = 153) were diagnosed with endometriosis. On average, their pain was statistically more severe than that of the women in the control group. The Visual Analogue Scale (VAS) scores were, respectively: dysmenorrhea 6 versus 5.0 (P < .001), dyspareunia 5.28 versus 4.95 (P < .001), and urinary pain during menstruation 4.35 versus 2.84 (P < .001).

Next-generation sequencing identified an average of 2,561 expressed miRNAs in the saliva samples. The feature selection method generated a subset of 109 miRNAs composing the endometriosis diagnostic signature. Among those miRNAs, 29 were associated with the main signaling pathways of endometriosis: PI3K/AKT, PTEN, Wnt/beta-catenin, HIF1-alpha/NF kappa B, and YAP/TAZ/EGFR.

The accuracy and reproducibility of the signature were tested on several data sets randomly composed of the same proportion of controls and patients with endometriosis. The respective sensitivity, specificity, and area under the curve for the diagnostic miRNA signature were 96.7%, 100%, and 98.3%, respectively.

The study’s results support the use of a saliva-based miRNA signature for diagnosing whether a patient is discordant/complex (chronic pelvic pain suggestive of endometriosis and both negative clinical examination and imaging findings) or has early-stage or advanced-stage endometriosis.

A version of this article first appeared on Medscape.com.

A French research team has developed a microRNA (miRNA) signature for diagnosing endometriosis through a simple saliva test. Its validation in a larger cohort could soon allow doctors to have a cheap, noninvasive, and accurate tool to use in diagnosing a disease that, for the time being, is difficult to identify with any certainty. The researchers suggest that their methodology could be used as a blueprint to investigate other pathologies, both benign and malignant.

ENDO-miRNA study

miRNAs regulate as much as 60% of gene expression at the posttranscriptional level. In the setting of endometriosis, several authors have evaluated the relevance of a blood-based miRNA signature, but the results are discordant because of methodological and control group issues. Other researchers have also sought to develop a miRNA saliva test. A French team wanted to determine whether it was possible to define a saliva-based diagnostic miRNome signature that would allow patients with and without endometriosis to be differentiated and, from there, develop the first specific diagnostic test for the disease.

The prospective ENDO-miRNA study included saliva samples obtained from women with chronic pelvic pain suggestive of endometriosis. Exploratory procedures were performed to look for lesions. All the patients underwent either a laparoscopic procedure (therapeutic or diagnostic laparoscopy) and/or MRI imaging. For the patients who underwent laparoscopy, diagnosis was confirmed by histology. For the patients diagnosed with endometriosis without laparoscopic evaluation, all had MRI imaging with features of deep endometriosis.

One part of the study involved the identification of a biomarker based on genomewide miRNA expression profiling by small RNA sequencing using next-generation sequencing. The second part involved the development of a saliva-based miRNA diagnostic signature according to expression and accuracy profiling using a random forest algorithm.
 

High sensitivity, specificity

Among the 200 patients (mean age, 31 years) enrolled in the study, 76.5% (n = 153) were diagnosed with endometriosis. On average, their pain was statistically more severe than that of the women in the control group. The Visual Analogue Scale (VAS) scores were, respectively: dysmenorrhea 6 versus 5.0 (P < .001), dyspareunia 5.28 versus 4.95 (P < .001), and urinary pain during menstruation 4.35 versus 2.84 (P < .001).

Next-generation sequencing identified an average of 2,561 expressed miRNAs in the saliva samples. The feature selection method generated a subset of 109 miRNAs composing the endometriosis diagnostic signature. Among those miRNAs, 29 were associated with the main signaling pathways of endometriosis: PI3K/AKT, PTEN, Wnt/beta-catenin, HIF1-alpha/NF kappa B, and YAP/TAZ/EGFR.

The accuracy and reproducibility of the signature were tested on several data sets randomly composed of the same proportion of controls and patients with endometriosis. The respective sensitivity, specificity, and area under the curve for the diagnostic miRNA signature were 96.7%, 100%, and 98.3%, respectively.

The study’s results support the use of a saliva-based miRNA signature for diagnosing whether a patient is discordant/complex (chronic pelvic pain suggestive of endometriosis and both negative clinical examination and imaging findings) or has early-stage or advanced-stage endometriosis.

A version of this article first appeared on Medscape.com.

Researchers evaluating whether endometriosis is linked with preterm birth found no such association in a multicenter cohort study of more than 1300 women.

These new findings, which were published online in JAMA Network Open, suggest that changing monitoring strategies to prevent preterm birth for women with the disease may not be necessary.

The research team, led by Louis Marcellin, MD, PhD, with the department of obstetrics and gynecology at Université de Paris, also found that disease phenotype or whether the preterm birth was induced or spontaneous did not appear to alter the result.

Those results differ from previous research. Data on the phenotypes and their link with preterm birth have been scarce, but previous studies have shown the risk for preterm birth is more pronounced in women who have deep endometriosis than in women with ovarian endometriosis.

Dr. Marcellin said in an interview that “little is known about the impact of endometriosis on obstetric outcomes. In contrast to previous studies, we reported no differences in the risk for preterm delivery between women with endometriosis (34 of 470 [7.2%]) and those without endometriosis (53 of 881 [6.0%]), even when adjusted for multiple factors.”

The authors accounted for mother’s age, body mass index before pregnancy, birth country, number of times the woman had given birth, previous cesarean delivery, and history of preterm birth. After adjusting for potential confounders, endometriosis was not associated with preterm birth (adjusted odds ratio, 1.07; 95% confidence interval, 0.64-1.77).

The researchers found no differences among preterm births based on a mother’s endometriosis phenotype. Those phenotypes include Isolated superficial peritoneal endometriosis, ovarian endometrioma, and deep endometriosis.

“Monitoring pregnancy beyond the normal protocols or changing management strategies may not be warranted in cases of endometriosis,” Dr. Marcellin said.

More research on endometriosis’ potential link to birth outcomes is needed.

An expert not involved with the study said the new paper highlights important new avenues of research but should not be seen as the final word on the connection between endometriosis and preterm birth.

Of the 1,351 study participants (mean age, 32.9 years) who had a singleton delivery after 22 weeks’ gestation, 470 were assigned to the endometriosis group, and 881 were assigned to the control group.

The authors concluded that “pregnant women with endometriosis should not be considered to have an exceptionally high risk for preterm birth. However, further studies are needed to examine the potential for other adverse perinatal outcomes or specific but rare complications.”

Daniela Carusi, MD, said the difficulty with the study’s design is that “premature birth is not one problem or one disease.”

Many very different problems can all end with premature birth. Sometimes it’s an infection or inflammation or bleeding in the uterus or hypertension in the mother, for example, and all those things can lead to a preterm birth, she explained.

“This study inherently lumps all those things together,” said Dr. Carusi, who is director of surgical obstetrics and placental abnormalities in the department of obstetrics and gynecology at Brigham and Women’s Hospital, Boston. “It’s quite possible endometriosis can have a big impact in one of those areas and no impact in the other areas, but the study design wouldn’t be able to pick that up.”
 

Editorialists: Results challenge findings of previous studies

In an accompanying commentary, Liisu Saavalainen, MD, PhD, and Oskari Heikinheimo, MD, PhD, both with the department of obstetrics and gynecology, Helsinki University Hospital, wrote that several previous studies have suggested that women with endometriosis have a slightly higher risk for preterm birth.

Those studies were mostly retrospective and differed in the way they classified endometriosis and the way they selected patients, the editorialists write. Also, most women in these studies typically had subfertility, they added.

The study by Dr. Marcellin and colleagues differs from previous related research in that was prospective and assessed the risk for preterm delivery in women both with endometriosis and those without endometriosis from several maternity centers in France. The women with endometriosis were classified according to the severity of their disease.

The editorialists wrote: “The novel results by Marcellin et al. challenge the findings of most previous studies on this topic. These results are valuable and comforting. However, they are also likely to trigger new studies on the pregnancy risks associated with different types of endometriosis. That is good news.”

Dr. Carusi said the study was well done and included a notably large size. Further complimenting the research, she said it’s important to talk about this little-discussed pregnancy complication. There’s been much more focus for women with endometriosis and their physicians on getting pregnant and on talking about the length of their term.

The study leaves some things unanswered.

The study was funded by research grants from the French Ministry of Health and was sponsored by the Département de la Recherche Clinique et du Développement de l’Assistance Publique–Hôpitaux de Paris. Dr. Carusi reported no relevant financial relationships. One study coauthor reported receiving personal fees from Bioserinity and Ferring outside the submitted work. No other disclosures were reported.

A version of this article first appeared on Medscape.com.

Researchers evaluating whether endometriosis is linked with preterm birth found no such association in a multicenter cohort study of more than 1300 women.

These new findings, which were published online in JAMA Network Open, suggest that changing monitoring strategies to prevent preterm birth for women with the disease may not be necessary.

The research team, led by Louis Marcellin, MD, PhD, with the department of obstetrics and gynecology at Université de Paris, also found that disease phenotype or whether the preterm birth was induced or spontaneous did not appear to alter the result.

Those results differ from previous research. Data on the phenotypes and their link with preterm birth have been scarce, but previous studies have shown the risk for preterm birth is more pronounced in women who have deep endometriosis than in women with ovarian endometriosis.

Dr. Marcellin said in an interview that “little is known about the impact of endometriosis on obstetric outcomes. In contrast to previous studies, we reported no differences in the risk for preterm delivery between women with endometriosis (34 of 470 [7.2%]) and those without endometriosis (53 of 881 [6.0%]), even when adjusted for multiple factors.”

The authors accounted for mother’s age, body mass index before pregnancy, birth country, number of times the woman had given birth, previous cesarean delivery, and history of preterm birth. After adjusting for potential confounders, endometriosis was not associated with preterm birth (adjusted odds ratio, 1.07; 95% confidence interval, 0.64-1.77).

The researchers found no differences among preterm births based on a mother’s endometriosis phenotype. Those phenotypes include Isolated superficial peritoneal endometriosis, ovarian endometrioma, and deep endometriosis.

“Monitoring pregnancy beyond the normal protocols or changing management strategies may not be warranted in cases of endometriosis,” Dr. Marcellin said.

More research on endometriosis’ potential link to birth outcomes is needed.

An expert not involved with the study said the new paper highlights important new avenues of research but should not be seen as the final word on the connection between endometriosis and preterm birth.

Of the 1,351 study participants (mean age, 32.9 years) who had a singleton delivery after 22 weeks’ gestation, 470 were assigned to the endometriosis group, and 881 were assigned to the control group.

The authors concluded that “pregnant women with endometriosis should not be considered to have an exceptionally high risk for preterm birth. However, further studies are needed to examine the potential for other adverse perinatal outcomes or specific but rare complications.”

Daniela Carusi, MD, said the difficulty with the study’s design is that “premature birth is not one problem or one disease.”

Many very different problems can all end with premature birth. Sometimes it’s an infection or inflammation or bleeding in the uterus or hypertension in the mother, for example, and all those things can lead to a preterm birth, she explained.

“This study inherently lumps all those things together,” said Dr. Carusi, who is director of surgical obstetrics and placental abnormalities in the department of obstetrics and gynecology at Brigham and Women’s Hospital, Boston. “It’s quite possible endometriosis can have a big impact in one of those areas and no impact in the other areas, but the study design wouldn’t be able to pick that up.”
 

Editorialists: Results challenge findings of previous studies

In an accompanying commentary, Liisu Saavalainen, MD, PhD, and Oskari Heikinheimo, MD, PhD, both with the department of obstetrics and gynecology, Helsinki University Hospital, wrote that several previous studies have suggested that women with endometriosis have a slightly higher risk for preterm birth.

Those studies were mostly retrospective and differed in the way they classified endometriosis and the way they selected patients, the editorialists write. Also, most women in these studies typically had subfertility, they added.

The study by Dr. Marcellin and colleagues differs from previous related research in that was prospective and assessed the risk for preterm delivery in women both with endometriosis and those without endometriosis from several maternity centers in France. The women with endometriosis were classified according to the severity of their disease.

The editorialists wrote: “The novel results by Marcellin et al. challenge the findings of most previous studies on this topic. These results are valuable and comforting. However, they are also likely to trigger new studies on the pregnancy risks associated with different types of endometriosis. That is good news.”

Dr. Carusi said the study was well done and included a notably large size. Further complimenting the research, she said it’s important to talk about this little-discussed pregnancy complication. There’s been much more focus for women with endometriosis and their physicians on getting pregnant and on talking about the length of their term.

The study leaves some things unanswered.

The study was funded by research grants from the French Ministry of Health and was sponsored by the Département de la Recherche Clinique et du Développement de l’Assistance Publique–Hôpitaux de Paris. Dr. Carusi reported no relevant financial relationships. One study coauthor reported receiving personal fees from Bioserinity and Ferring outside the submitted work. No other disclosures were reported.

A version of this article first appeared on Medscape.com.

Researchers evaluating whether endometriosis is linked with preterm birth found no such association in a multicenter cohort study of more than 1300 women.

These new findings, which were published online in JAMA Network Open, suggest that changing monitoring strategies to prevent preterm birth for women with the disease may not be necessary.

The research team, led by Louis Marcellin, MD, PhD, with the department of obstetrics and gynecology at Université de Paris, also found that disease phenotype or whether the preterm birth was induced or spontaneous did not appear to alter the result.

Those results differ from previous research. Data on the phenotypes and their link with preterm birth have been scarce, but previous studies have shown the risk for preterm birth is more pronounced in women who have deep endometriosis than in women with ovarian endometriosis.

Dr. Marcellin said in an interview that “little is known about the impact of endometriosis on obstetric outcomes. In contrast to previous studies, we reported no differences in the risk for preterm delivery between women with endometriosis (34 of 470 [7.2%]) and those without endometriosis (53 of 881 [6.0%]), even when adjusted for multiple factors.”

The authors accounted for mother’s age, body mass index before pregnancy, birth country, number of times the woman had given birth, previous cesarean delivery, and history of preterm birth. After adjusting for potential confounders, endometriosis was not associated with preterm birth (adjusted odds ratio, 1.07; 95% confidence interval, 0.64-1.77).

The researchers found no differences among preterm births based on a mother’s endometriosis phenotype. Those phenotypes include Isolated superficial peritoneal endometriosis, ovarian endometrioma, and deep endometriosis.

“Monitoring pregnancy beyond the normal protocols or changing management strategies may not be warranted in cases of endometriosis,” Dr. Marcellin said.

More research on endometriosis’ potential link to birth outcomes is needed.

An expert not involved with the study said the new paper highlights important new avenues of research but should not be seen as the final word on the connection between endometriosis and preterm birth.

Of the 1,351 study participants (mean age, 32.9 years) who had a singleton delivery after 22 weeks’ gestation, 470 were assigned to the endometriosis group, and 881 were assigned to the control group.

The authors concluded that “pregnant women with endometriosis should not be considered to have an exceptionally high risk for preterm birth. However, further studies are needed to examine the potential for other adverse perinatal outcomes or specific but rare complications.”

Daniela Carusi, MD, said the difficulty with the study’s design is that “premature birth is not one problem or one disease.”

Many very different problems can all end with premature birth. Sometimes it’s an infection or inflammation or bleeding in the uterus or hypertension in the mother, for example, and all those things can lead to a preterm birth, she explained.

“This study inherently lumps all those things together,” said Dr. Carusi, who is director of surgical obstetrics and placental abnormalities in the department of obstetrics and gynecology at Brigham and Women’s Hospital, Boston. “It’s quite possible endometriosis can have a big impact in one of those areas and no impact in the other areas, but the study design wouldn’t be able to pick that up.”
 

Editorialists: Results challenge findings of previous studies

In an accompanying commentary, Liisu Saavalainen, MD, PhD, and Oskari Heikinheimo, MD, PhD, both with the department of obstetrics and gynecology, Helsinki University Hospital, wrote that several previous studies have suggested that women with endometriosis have a slightly higher risk for preterm birth.

Those studies were mostly retrospective and differed in the way they classified endometriosis and the way they selected patients, the editorialists write. Also, most women in these studies typically had subfertility, they added.

The study by Dr. Marcellin and colleagues differs from previous related research in that was prospective and assessed the risk for preterm delivery in women both with endometriosis and those without endometriosis from several maternity centers in France. The women with endometriosis were classified according to the severity of their disease.

The editorialists wrote: “The novel results by Marcellin et al. challenge the findings of most previous studies on this topic. These results are valuable and comforting. However, they are also likely to trigger new studies on the pregnancy risks associated with different types of endometriosis. That is good news.”

Dr. Carusi said the study was well done and included a notably large size. Further complimenting the research, she said it’s important to talk about this little-discussed pregnancy complication. There’s been much more focus for women with endometriosis and their physicians on getting pregnant and on talking about the length of their term.

The study leaves some things unanswered.

The study was funded by research grants from the French Ministry of Health and was sponsored by the Département de la Recherche Clinique et du Développement de l’Assistance Publique–Hôpitaux de Paris. Dr. Carusi reported no relevant financial relationships. One study coauthor reported receiving personal fees from Bioserinity and Ferring outside the submitted work. No other disclosures were reported.

A version of this article first appeared on Medscape.com.

Updated guidelines for the management and treatment of endometriosis reflect changes in clinical practice to guide clinician and patient decision-making, according to a statement from the European Society of Human Reproduction and Embryology, which issued the guidelines in February 2022.

Although the exact prevalence of endometriosis remains unclear, estimates suggest that approximately 190 million women and adolescent girls are affected by endometriosis during their reproductive years, and women continue to suffer beyond menopause, according to the authors. Endometriosis has a significant impact on society through both direct and indirect health care costs comparable to those of type 2 diabetes, rheumatoid arthritis, and Crohn’s disease, they noted.

The guidelines are the first update on the topic of endometriosis since 2014, and include more than 100 recommendations, according to the European Society of Human Reproduction and Embryology (ESHRE). The target audience, according to the authors, is secondary and tertiary health care providers who treat women with endometriosis. The recommendations were based on research papers published up to Dec. 1, 2020.

Although most of the recent studies confirm previous ESHRE recommendations, several topics reflect significant changes in clinical practice.

Notably, laparoscopy is no longer recommended as the diagnostic gold standard, and should be used only in patients with negative imaging for whom empirical treatment was unsuccessful.

For pain management, studies support the use of GnRH antagonists as a second-line treatment, while laparoscopic uterosacral nerve ablation and presacral neurectomy are no longer included in the recommendations.

The guidelines include new information on pregnancy and fertility preservation for women with endometriosis. The Endometriosis Fertility Index (EFI) was added to support joint decision-making for women seeking pregnancy after surgery. However, the extended use of GnRH antagonist prior to assisted reproductive technology treatments to improve live birth rate is not recommended.

Endometriosis in adolescent patients is included in the guidelines for the first time, and strong recommendations include taking a careful history and using ultrasound if appropriate, but the use of serum biomarkers is not recommended for diagnosis. Strong recommendations for treatment strategies for adolescents include hormonal contraceptives or progestins as a first-line therapy.

Recommendations for managing endometriosis in menopause are more extensive than in previous guidelines and the strongest update is against the use of estrogen-only treatment in these patients. However, the guidelines continue to recommend treating women with a history of endometriosis after surgical menopause with combined estrogen-progestogen therapy “at least up to the age of natural menopause.”

Expanded recommendations related to endometriosis and cancer begin with a strong recommendation for clinicians to advise women that endometriosis is not associated with a significantly higher risk of cancer overall. “Although endometriosis is associated with a higher risk of ovarian, breast, and thyroid cancers in particular, the increase in absolute risk compared with women in the general population is low,” the authors wrote. Other strong recommendations include reassuring women with endometriosis of the low risk of malignancy associated with hormonal contraceptive use, and performing cancer screening according to the existing population-based guidelines without additional screening. Epidemiologic data show that complete excision of visible endometriosis may reduce the risk of ovarian cancer, but the potential benefits must be weighed against the risks of surgery, including morbidity, pain, and ovarian reserve, the authors said.

The guidelines include recommendations related to asymptomatic endometriosis, extrapelvic endometriosis, and primary prevention of endometriosis, but without major changes to the 2014 guidelines.
 

Guidelines expand strategies, but research gaps remain

In 2021, an international working group of the American Association of Gynecologic Laparoscopists, the European Society for Gynecologic Endoscopy, ESHRE, and the World Endometriosis Society defined endometriosis as “a disease characterized by the presence of endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually with an associated inflammatory process,” Mark P. Trolice, MD, director of The IVF Center, Orlando, Fla., and professor of obstetrics and gynecology at the University of Central Florida, said in an interview.

Although the current guidelines represent the second update since 2005, many unanswered questions remain, Dr. Trolice said. “There is a large diagnostic void between the onset of symptoms and the time to a reliable diagnosis averaging between 8 and 12 years,” he emphasized.

Dr. Trolice noted the change of the addition of an oral GnRH antagonist, “now FDA approved for the treatment of pain associated with endometriosis,” he said. However, “Extended GnRH agonist prior to ART is not recommended due to the lack of any clear benefit,” he noted.

Dr. Trolice noted the inclusion of the Endometriosis Fertility Index (EFI), published in 2010, “as a useful scoring system to predict postoperative non-IVF pregnancy rates (both by natural means and IUI [intrauterine insemination]) based on patient characteristics, revised ASRM staging, and ‘least function score of the adnexa.’ ” He agreed with the need for expanded information on the topics of endometriosis and adolescence and endometriosis and cancer.

The most important changes for clinical practice include reducing unnecessary laparoscopy and procedures without benefit, such as laparoscopic uterosacral nerve ablation and presacral neurectomy, and GnRH suppression using an oral antagonist, said Dr. Trolice. Other especially practical guidance includes the recommendation to discontinue advising patients that pregnancy will reduce symptoms of endometriosis, and to avoid prescribing estrogen-only treatment in menopause given the risk of malignant transformation of endometriosis, he said.

Another clinically useful recommendation, though not a significant update, is the need to identify extrapelvic endometriosis symptoms, such as cyclical shoulder pain, cyclical spontaneous pneumothorax, cyclical cough, or nodules that enlarge during menses, Dr. Trolice added.

Barriers to implementing the updated guidelines include lack of education of clinicians, including primary care providers, and the lack of definitive evidence for many areas, he noted.

As for additional research, more data are needed to explore the genetic, mutational, and epigenetic profile of endometriosis, and to identify biomarkers to noninvasively detect and provide a prognosis for endometriosis, and optimal methods for prevention and management, said Dr. Trolice. Other research gaps include “definitive medical and surgical treatment of endometriosis for improvement of fertility, quality of life, and reduction of pain,” he noted. From a fertility standpoint, more studies are needed on “the use of ovarian tissue or oocytes cryopreservation in adolescents and adults who undergo ovarian surgery for endometriomas, and the role of the EFI as a presurgical triage tool and to predict IUI outcomes,” said Dr. Trolice.

Overall, society recommendations such as these from ESHRE “serve as guides for physicians by providing evidence-based medicine and dispelling prior unproven practices so patients may receive the most effective care of endometriosis, throughout a woman’s life,” Dr. Trolice emphasized.

The current guideline will be considered for revision in 2025, and the full version is available on the ESHRE website.

Members of the ESHRE guideline development group received no payment for participating in the development process, although they were reimbursed for travel expenses related to guideline meetings.

Dr. Trolice had no financial conflicts to disclose and serves on the editorial advisory board of Ob.Gyn News.

Updated guidelines for the management and treatment of endometriosis reflect changes in clinical practice to guide clinician and patient decision-making, according to a statement from the European Society of Human Reproduction and Embryology, which issued the guidelines in February 2022.

Although the exact prevalence of endometriosis remains unclear, estimates suggest that approximately 190 million women and adolescent girls are affected by endometriosis during their reproductive years, and women continue to suffer beyond menopause, according to the authors. Endometriosis has a significant impact on society through both direct and indirect health care costs comparable to those of type 2 diabetes, rheumatoid arthritis, and Crohn’s disease, they noted.

The guidelines are the first update on the topic of endometriosis since 2014, and include more than 100 recommendations, according to the European Society of Human Reproduction and Embryology (ESHRE). The target audience, according to the authors, is secondary and tertiary health care providers who treat women with endometriosis. The recommendations were based on research papers published up to Dec. 1, 2020.

Although most of the recent studies confirm previous ESHRE recommendations, several topics reflect significant changes in clinical practice.

Notably, laparoscopy is no longer recommended as the diagnostic gold standard, and should be used only in patients with negative imaging for whom empirical treatment was unsuccessful.

For pain management, studies support the use of GnRH antagonists as a second-line treatment, while laparoscopic uterosacral nerve ablation and presacral neurectomy are no longer included in the recommendations.

The guidelines include new information on pregnancy and fertility preservation for women with endometriosis. The Endometriosis Fertility Index (EFI) was added to support joint decision-making for women seeking pregnancy after surgery. However, the extended use of GnRH antagonist prior to assisted reproductive technology treatments to improve live birth rate is not recommended.

Endometriosis in adolescent patients is included in the guidelines for the first time, and strong recommendations include taking a careful history and using ultrasound if appropriate, but the use of serum biomarkers is not recommended for diagnosis. Strong recommendations for treatment strategies for adolescents include hormonal contraceptives or progestins as a first-line therapy.

Recommendations for managing endometriosis in menopause are more extensive than in previous guidelines and the strongest update is against the use of estrogen-only treatment in these patients. However, the guidelines continue to recommend treating women with a history of endometriosis after surgical menopause with combined estrogen-progestogen therapy “at least up to the age of natural menopause.”

Expanded recommendations related to endometriosis and cancer begin with a strong recommendation for clinicians to advise women that endometriosis is not associated with a significantly higher risk of cancer overall. “Although endometriosis is associated with a higher risk of ovarian, breast, and thyroid cancers in particular, the increase in absolute risk compared with women in the general population is low,” the authors wrote. Other strong recommendations include reassuring women with endometriosis of the low risk of malignancy associated with hormonal contraceptive use, and performing cancer screening according to the existing population-based guidelines without additional screening. Epidemiologic data show that complete excision of visible endometriosis may reduce the risk of ovarian cancer, but the potential benefits must be weighed against the risks of surgery, including morbidity, pain, and ovarian reserve, the authors said.

The guidelines include recommendations related to asymptomatic endometriosis, extrapelvic endometriosis, and primary prevention of endometriosis, but without major changes to the 2014 guidelines.
 

Guidelines expand strategies, but research gaps remain

In 2021, an international working group of the American Association of Gynecologic Laparoscopists, the European Society for Gynecologic Endoscopy, ESHRE, and the World Endometriosis Society defined endometriosis as “a disease characterized by the presence of endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually with an associated inflammatory process,” Mark P. Trolice, MD, director of The IVF Center, Orlando, Fla., and professor of obstetrics and gynecology at the University of Central Florida, said in an interview.

Although the current guidelines represent the second update since 2005, many unanswered questions remain, Dr. Trolice said. “There is a large diagnostic void between the onset of symptoms and the time to a reliable diagnosis averaging between 8 and 12 years,” he emphasized.

Dr. Trolice noted the change of the addition of an oral GnRH antagonist, “now FDA approved for the treatment of pain associated with endometriosis,” he said. However, “Extended GnRH agonist prior to ART is not recommended due to the lack of any clear benefit,” he noted.

Dr. Trolice noted the inclusion of the Endometriosis Fertility Index (EFI), published in 2010, “as a useful scoring system to predict postoperative non-IVF pregnancy rates (both by natural means and IUI [intrauterine insemination]) based on patient characteristics, revised ASRM staging, and ‘least function score of the adnexa.’ ” He agreed with the need for expanded information on the topics of endometriosis and adolescence and endometriosis and cancer.

The most important changes for clinical practice include reducing unnecessary laparoscopy and procedures without benefit, such as laparoscopic uterosacral nerve ablation and presacral neurectomy, and GnRH suppression using an oral antagonist, said Dr. Trolice. Other especially practical guidance includes the recommendation to discontinue advising patients that pregnancy will reduce symptoms of endometriosis, and to avoid prescribing estrogen-only treatment in menopause given the risk of malignant transformation of endometriosis, he said.

Another clinically useful recommendation, though not a significant update, is the need to identify extrapelvic endometriosis symptoms, such as cyclical shoulder pain, cyclical spontaneous pneumothorax, cyclical cough, or nodules that enlarge during menses, Dr. Trolice added.

Barriers to implementing the updated guidelines include lack of education of clinicians, including primary care providers, and the lack of definitive evidence for many areas, he noted.

As for additional research, more data are needed to explore the genetic, mutational, and epigenetic profile of endometriosis, and to identify biomarkers to noninvasively detect and provide a prognosis for endometriosis, and optimal methods for prevention and management, said Dr. Trolice. Other research gaps include “definitive medical and surgical treatment of endometriosis for improvement of fertility, quality of life, and reduction of pain,” he noted. From a fertility standpoint, more studies are needed on “the use of ovarian tissue or oocytes cryopreservation in adolescents and adults who undergo ovarian surgery for endometriomas, and the role of the EFI as a presurgical triage tool and to predict IUI outcomes,” said Dr. Trolice.

Overall, society recommendations such as these from ESHRE “serve as guides for physicians by providing evidence-based medicine and dispelling prior unproven practices so patients may receive the most effective care of endometriosis, throughout a woman’s life,” Dr. Trolice emphasized.

The current guideline will be considered for revision in 2025, and the full version is available on the ESHRE website.

Members of the ESHRE guideline development group received no payment for participating in the development process, although they were reimbursed for travel expenses related to guideline meetings.

Dr. Trolice had no financial conflicts to disclose and serves on the editorial advisory board of Ob.Gyn News.

Updated guidelines for the management and treatment of endometriosis reflect changes in clinical practice to guide clinician and patient decision-making, according to a statement from the European Society of Human Reproduction and Embryology, which issued the guidelines in February 2022.

Although the exact prevalence of endometriosis remains unclear, estimates suggest that approximately 190 million women and adolescent girls are affected by endometriosis during their reproductive years, and women continue to suffer beyond menopause, according to the authors. Endometriosis has a significant impact on society through both direct and indirect health care costs comparable to those of type 2 diabetes, rheumatoid arthritis, and Crohn’s disease, they noted.

The guidelines are the first update on the topic of endometriosis since 2014, and include more than 100 recommendations, according to the European Society of Human Reproduction and Embryology (ESHRE). The target audience, according to the authors, is secondary and tertiary health care providers who treat women with endometriosis. The recommendations were based on research papers published up to Dec. 1, 2020.

Although most of the recent studies confirm previous ESHRE recommendations, several topics reflect significant changes in clinical practice.

Notably, laparoscopy is no longer recommended as the diagnostic gold standard, and should be used only in patients with negative imaging for whom empirical treatment was unsuccessful.

For pain management, studies support the use of GnRH antagonists as a second-line treatment, while laparoscopic uterosacral nerve ablation and presacral neurectomy are no longer included in the recommendations.

The guidelines include new information on pregnancy and fertility preservation for women with endometriosis. The Endometriosis Fertility Index (EFI) was added to support joint decision-making for women seeking pregnancy after surgery. However, the extended use of GnRH antagonist prior to assisted reproductive technology treatments to improve live birth rate is not recommended.

Endometriosis in adolescent patients is included in the guidelines for the first time, and strong recommendations include taking a careful history and using ultrasound if appropriate, but the use of serum biomarkers is not recommended for diagnosis. Strong recommendations for treatment strategies for adolescents include hormonal contraceptives or progestins as a first-line therapy.

Recommendations for managing endometriosis in menopause are more extensive than in previous guidelines and the strongest update is against the use of estrogen-only treatment in these patients. However, the guidelines continue to recommend treating women with a history of endometriosis after surgical menopause with combined estrogen-progestogen therapy “at least up to the age of natural menopause.”

Expanded recommendations related to endometriosis and cancer begin with a strong recommendation for clinicians to advise women that endometriosis is not associated with a significantly higher risk of cancer overall. “Although endometriosis is associated with a higher risk of ovarian, breast, and thyroid cancers in particular, the increase in absolute risk compared with women in the general population is low,” the authors wrote. Other strong recommendations include reassuring women with endometriosis of the low risk of malignancy associated with hormonal contraceptive use, and performing cancer screening according to the existing population-based guidelines without additional screening. Epidemiologic data show that complete excision of visible endometriosis may reduce the risk of ovarian cancer, but the potential benefits must be weighed against the risks of surgery, including morbidity, pain, and ovarian reserve, the authors said.

The guidelines include recommendations related to asymptomatic endometriosis, extrapelvic endometriosis, and primary prevention of endometriosis, but without major changes to the 2014 guidelines.
 

Guidelines expand strategies, but research gaps remain

In 2021, an international working group of the American Association of Gynecologic Laparoscopists, the European Society for Gynecologic Endoscopy, ESHRE, and the World Endometriosis Society defined endometriosis as “a disease characterized by the presence of endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually with an associated inflammatory process,” Mark P. Trolice, MD, director of The IVF Center, Orlando, Fla., and professor of obstetrics and gynecology at the University of Central Florida, said in an interview.

Although the current guidelines represent the second update since 2005, many unanswered questions remain, Dr. Trolice said. “There is a large diagnostic void between the onset of symptoms and the time to a reliable diagnosis averaging between 8 and 12 years,” he emphasized.

Dr. Trolice noted the change of the addition of an oral GnRH antagonist, “now FDA approved for the treatment of pain associated with endometriosis,” he said. However, “Extended GnRH agonist prior to ART is not recommended due to the lack of any clear benefit,” he noted.

Dr. Trolice noted the inclusion of the Endometriosis Fertility Index (EFI), published in 2010, “as a useful scoring system to predict postoperative non-IVF pregnancy rates (both by natural means and IUI [intrauterine insemination]) based on patient characteristics, revised ASRM staging, and ‘least function score of the adnexa.’ ” He agreed with the need for expanded information on the topics of endometriosis and adolescence and endometriosis and cancer.

The most important changes for clinical practice include reducing unnecessary laparoscopy and procedures without benefit, such as laparoscopic uterosacral nerve ablation and presacral neurectomy, and GnRH suppression using an oral antagonist, said Dr. Trolice. Other especially practical guidance includes the recommendation to discontinue advising patients that pregnancy will reduce symptoms of endometriosis, and to avoid prescribing estrogen-only treatment in menopause given the risk of malignant transformation of endometriosis, he said.

Another clinically useful recommendation, though not a significant update, is the need to identify extrapelvic endometriosis symptoms, such as cyclical shoulder pain, cyclical spontaneous pneumothorax, cyclical cough, or nodules that enlarge during menses, Dr. Trolice added.

Barriers to implementing the updated guidelines include lack of education of clinicians, including primary care providers, and the lack of definitive evidence for many areas, he noted.

As for additional research, more data are needed to explore the genetic, mutational, and epigenetic profile of endometriosis, and to identify biomarkers to noninvasively detect and provide a prognosis for endometriosis, and optimal methods for prevention and management, said Dr. Trolice. Other research gaps include “definitive medical and surgical treatment of endometriosis for improvement of fertility, quality of life, and reduction of pain,” he noted. From a fertility standpoint, more studies are needed on “the use of ovarian tissue or oocytes cryopreservation in adolescents and adults who undergo ovarian surgery for endometriomas, and the role of the EFI as a presurgical triage tool and to predict IUI outcomes,” said Dr. Trolice.

Overall, society recommendations such as these from ESHRE “serve as guides for physicians by providing evidence-based medicine and dispelling prior unproven practices so patients may receive the most effective care of endometriosis, throughout a woman’s life,” Dr. Trolice emphasized.

The current guideline will be considered for revision in 2025, and the full version is available on the ESHRE website.

Members of the ESHRE guideline development group received no payment for participating in the development process, although they were reimbursed for travel expenses related to guideline meetings.

Dr. Trolice had no financial conflicts to disclose and serves on the editorial advisory board of Ob.Gyn News.

Can you talk about your research thus far and what your overall lab work has shown regarding endometriosis as a chronic systemic disease?

Dr. Flores: Endometriosis has traditionally been characterized by its pelvic manifestation however, it is important to understand that it is profoundly more than a pelvic disease—it is a chronic, systemic disease with multifactorial effects throughout the body.

We and other groups have found increased expression of several inflammatory cytokines in women with endometriosis. Our lab has found that compared to women without endometriosis, women with endometriosis not only have certain inflammatory cytokines elevated but also have altered expression of microRNAs. MicroRNAs are small noncoding RNAs that bind to and modulate translation of mRNA. To help determine whether these miRNAs were involved in mediating increased expression of inflammatory cytokines in women with endometriosis, we then transfected these miRNAs into a macrophage cell line, and again found altered inflammatory cytokine expression. We and others have also found a role for stem cells (from bone marrow and other sources) in the pathogenesis of endometriosis. In addition, we have found that in endometriosis, women have a low body-mass index and altered metabolism, which is related to induction of induction of hepatic (anorexigenic) gene expression and microRNA-mediated changes in adipocyte (metabolic) gene expression. Furthermore, we have found altered gene expression in regions of the brain associated with anxiety and depression and altered pain sensitization. Taken together, this work helps provide support for the systemic nature of endometriosis.

How can your findings in this space help us in diagnosing clinically and ultimately avoid diagnostic delay?

Dr. Flores: It’s about understanding that endometriosis is not just a pelvic disease and understanding that endometriosis is leading to inflammation and altered expression of miRNAs which allows endometriosis to have long-range effects. For example, women with endometriosis commonly have anxiety and depression and low BMI. As mentioned earlier, we have found that in a murine model of endometriosis, there is altered gene expression in regions of the brain associated with anxiety and depression and altered metabolism in a murine model of endometriosis. Other groups have also found changes in brain volume in these same areas in women with endometriosis, and we have seen low BMI in women with endometriosis.  In fact, a common misconception was that being thin was a risk factor for endometriosis, however we have found that the endometriosis itself, is causing women alteration in genes associated with metabolism.

With respect to the endometrium, in addition to being a pelvic pain disorder, we also see that women with endometriosis have a higher likelihood of having infertility. And we think that's in part because one, just like the lesions can be resistant to progesterone, the endometrium of these women can also be resistant to progesterone. Progesterone is necessary for decidualization/implantation. We have also seen that stem cells can be recruited and ultimately incorrectly incorporated into the endometrium, which may also contribute to infertility in women with endometriosis.

If we can understand this multifactorial nature of endometriosis, I think this will help us not only shift toward diagnosing endometriosis clinically, but also avoid diagnostic delay. If we can understand that endometriosis is not just a pelvic disorder, but that It can also involve altered mood, bowel/bladder symptoms, inflammation, altered metabolism and/or cause infertility, I think that will ultimately help us to diagnosing earlier.

In addition, we can also utilize pelvic pain symptomatology to help with diagnosis as well. We can ask about cyclic pelvic pain that's been getting progressively worse over the years, not responding to non-steroidal anti-inflammatory medications. Also, in understanding that endometriosis can affect other organs, asking about cyclic pain/symptoms in other areas, such as cyclical bowel or bladder symptoms.

Thinking about the fact that if you do have a patient like that, you're seeing that they have altered mood symptoms, or alterations in inflammatory markers. Maybe that will help us shift from a disease that was typically only considered to be diagnosed by surgery, by switching to a clinical diagnosis for endometriosis. Doing that will hopefully help avoid diagnostic delay.

If we understand that while we typically describe endometriosis as causing cyclic pain symptoms, sometimes because of the existing diagnostic delay, ultimately women can present with chronic pelvic pain. Thus, it's also important to ask patients presenting with chronic pelvic pain what the symptoms were like beforehand (i.e., was the pain cyclic and progressively worsening over the years/before it became chronic) doing so will also help in terms of diagnosing sooner.

Lastly, circulating miRNAs have been considered promising biomarker candidates because they are stable in circulation and have highly specific expression profiles. We have found that the combination of several miRNAs reliably distinguished endometriosis patients from controls, and a prospective, blinded study showed that the combination of several miRNAs could be used to accurately identify patients with endometriosis, with an area under the receiver operating characteristic curve of 0.93.

Roughly 11%, or more than 6.5 million, women in the United States between the ages of 15–44 years, may have endometriosis. Is this disease more common in any particular age range or ethnicity?

Dr. Flores: We’re actually actively investigating that right now. And I think what makes it challenging, especially with respect to the age range, is now we're -- I think in part because of so much more awareness and more research is being done looking at this disease as a chronic systemic disease-- we're now starting to see/diagnose adolescents with endometriosis.

I think as we start gathering more information about these individuals, we'll be able to better say if there is a particular age range. Right now, we usually say it's in the reproductive years, however for some women it may be later if they were not diagnosed earlier. Conversely, some who are hopefully reading this, and also who conduct research on endometriosis, may be able to diagnose someone earlier that may have been missed until they were in their 30s or 40s, for example.

With respect to ethnicity, I'm the task force leader for diversity, equity, and inclusion in research and recruitment. This is something that I'm actively starting to work on, as are other groups. I don't have the answer for that yet, but as we continue to collect more data, we will have more information on this.

What are some of the existing hormonal therapies you rely upon as well as the biomarkers in predicting response to treatment, and are there any new research or treatments on the horizon?

Dr. Flores: I'll first start by telling you a bit about our existing treatment regimens, and then how I decide who would benefit from a given one. First line has always been progestin-based therapy, either in the form of a combined oral contraceptive pill or as progesterone only pills. However, up to 1/3 of women fail progestin-based therapy—this is termed progesterone resistance.

When progestin-based therapies fail, we then rely on other agents that are focused more on estrogen deprivation because, while we don't know the complete etiology of endometriosis, we do know that it is estrogen-dependent. There are two classes— gonadotropin releasing hormone (GnRH) agonists and GnRH antagonists. The agonist binds to the GnRH receptors, and initially can cause a flare effect due to its agonist properties, initially stimulate release of estradiol,  and ultimately the GnRH receptor becomes downregulated and estradiol is decreased to the menopausal range. As a result we routinely provided add-back therapy with norethindrone to help prevent hot flashes and ensure bone protection.

Within the past three years, there has been a new oral GnRH receptor antagonist approved for treating endometriosis. The medication is available as a once a day or twice a day dosing regimen. As this is a GnRH antagonist, upon binding to the GnRH receptor, it blocks receptor activity, thus avoiding the flare affect; essentially, within 24 hours, there is a decrease in estradiol production.

As two doses are available, you can tailor how much you dial down estrogen for a given patient. The low dose lowers estradiol to a range of 40 picograms while the high (twice a day) dosing lowers your estrogen to about 6 picograms. Also, although it was not studied originally in terms of giving add-back therapy for the higher dose, given the safety  (and effectiveness) of add-back therapy with GnRH agonists we are using the same norethindrone add-back therapy for women who are taking the GnRH receptor antagonist.

The next question is, how do we decide which medication a given patient receives? To answer that, I will tell you a bit about my precision-based medicine research. As mentioned before, while progestin-based therapy is first-line, failure rates are high, and unfortunately, we previously have not been able to identify who will or will not respond to first-line therapy.  As such, I decided to assess progesterone receptor expression in endometriotic lesions from women who had undergone surgery for endometriosis, and determine whether progesterone receptor expression levels in lesions could be used to predict response to progestin-based therapy. I found that in women that had high levels of the progesterone receptor, they responded completely to progestin-based therapy-- there was a 100% response rate to progestin-based therapy. This is in sharp contrast to women who had low PR expression, where there was only a 6% response rate to progestin-based therapy.

While this is great with respect to being able to predict who will or will not respond to first line therapy, the one limitation is that would mean that women have to undergo surgery in order to determine progesterone receptor status/response to progestin-based therapy. However, given that within two to five years following surgery, up to 50% of women will have recurrence of pain symptoms, where I see my test coming into play is postoperatively.  This is because many times , women who had pain, or who were failing a given agent, are placed back on that same medical therapy they were failing after surgery. Usually that was a progestin. Therefore, instead of putting them on that same therapy that they were failing, we can use my test to place them on an alternative therapy (such as a GnRH analogue) that more specifically targets estradiol production.

In terms of future directions with respect to treatment, there is a microRNA that has been found to be low in women with endometriosis—miRNALet-7b. In a murine model of endometriosis, we have found that if we supplement with Let-7, there is decreased inflammation and decreased lesion size of endometriosis.  We have also found that supplementing miRNA Let-7b in human endometriotic lesions results in decreased inflammation in cell culture.

That would be future directions in terms of focusing on microRNAs and seeing how we can manipulate those to essentially block inflammation and lesion growth. Furthermore, such treatment would be non-hormonal, which would be a novel therapeutic approach.

Can you talk about your research thus far and what your overall lab work has shown regarding endometriosis as a chronic systemic disease?

Dr. Flores: Endometriosis has traditionally been characterized by its pelvic manifestation however, it is important to understand that it is profoundly more than a pelvic disease—it is a chronic, systemic disease with multifactorial effects throughout the body.

We and other groups have found increased expression of several inflammatory cytokines in women with endometriosis. Our lab has found that compared to women without endometriosis, women with endometriosis not only have certain inflammatory cytokines elevated but also have altered expression of microRNAs. MicroRNAs are small noncoding RNAs that bind to and modulate translation of mRNA. To help determine whether these miRNAs were involved in mediating increased expression of inflammatory cytokines in women with endometriosis, we then transfected these miRNAs into a macrophage cell line, and again found altered inflammatory cytokine expression. We and others have also found a role for stem cells (from bone marrow and other sources) in the pathogenesis of endometriosis. In addition, we have found that in endometriosis, women have a low body-mass index and altered metabolism, which is related to induction of induction of hepatic (anorexigenic) gene expression and microRNA-mediated changes in adipocyte (metabolic) gene expression. Furthermore, we have found altered gene expression in regions of the brain associated with anxiety and depression and altered pain sensitization. Taken together, this work helps provide support for the systemic nature of endometriosis.

How can your findings in this space help us in diagnosing clinically and ultimately avoid diagnostic delay?

Dr. Flores: It’s about understanding that endometriosis is not just a pelvic disease and understanding that endometriosis is leading to inflammation and altered expression of miRNAs which allows endometriosis to have long-range effects. For example, women with endometriosis commonly have anxiety and depression and low BMI. As mentioned earlier, we have found that in a murine model of endometriosis, there is altered gene expression in regions of the brain associated with anxiety and depression and altered metabolism in a murine model of endometriosis. Other groups have also found changes in brain volume in these same areas in women with endometriosis, and we have seen low BMI in women with endometriosis.  In fact, a common misconception was that being thin was a risk factor for endometriosis, however we have found that the endometriosis itself, is causing women alteration in genes associated with metabolism.

With respect to the endometrium, in addition to being a pelvic pain disorder, we also see that women with endometriosis have a higher likelihood of having infertility. And we think that's in part because one, just like the lesions can be resistant to progesterone, the endometrium of these women can also be resistant to progesterone. Progesterone is necessary for decidualization/implantation. We have also seen that stem cells can be recruited and ultimately incorrectly incorporated into the endometrium, which may also contribute to infertility in women with endometriosis.

If we can understand this multifactorial nature of endometriosis, I think this will help us not only shift toward diagnosing endometriosis clinically, but also avoid diagnostic delay. If we can understand that endometriosis is not just a pelvic disorder, but that It can also involve altered mood, bowel/bladder symptoms, inflammation, altered metabolism and/or cause infertility, I think that will ultimately help us to diagnosing earlier.

In addition, we can also utilize pelvic pain symptomatology to help with diagnosis as well. We can ask about cyclic pelvic pain that's been getting progressively worse over the years, not responding to non-steroidal anti-inflammatory medications. Also, in understanding that endometriosis can affect other organs, asking about cyclic pain/symptoms in other areas, such as cyclical bowel or bladder symptoms.

Thinking about the fact that if you do have a patient like that, you're seeing that they have altered mood symptoms, or alterations in inflammatory markers. Maybe that will help us shift from a disease that was typically only considered to be diagnosed by surgery, by switching to a clinical diagnosis for endometriosis. Doing that will hopefully help avoid diagnostic delay.

If we understand that while we typically describe endometriosis as causing cyclic pain symptoms, sometimes because of the existing diagnostic delay, ultimately women can present with chronic pelvic pain. Thus, it's also important to ask patients presenting with chronic pelvic pain what the symptoms were like beforehand (i.e., was the pain cyclic and progressively worsening over the years/before it became chronic) doing so will also help in terms of diagnosing sooner.

Lastly, circulating miRNAs have been considered promising biomarker candidates because they are stable in circulation and have highly specific expression profiles. We have found that the combination of several miRNAs reliably distinguished endometriosis patients from controls, and a prospective, blinded study showed that the combination of several miRNAs could be used to accurately identify patients with endometriosis, with an area under the receiver operating characteristic curve of 0.93.

Roughly 11%, or more than 6.5 million, women in the United States between the ages of 15–44 years, may have endometriosis. Is this disease more common in any particular age range or ethnicity?

Dr. Flores: We’re actually actively investigating that right now. And I think what makes it challenging, especially with respect to the age range, is now we're -- I think in part because of so much more awareness and more research is being done looking at this disease as a chronic systemic disease-- we're now starting to see/diagnose adolescents with endometriosis.

I think as we start gathering more information about these individuals, we'll be able to better say if there is a particular age range. Right now, we usually say it's in the reproductive years, however for some women it may be later if they were not diagnosed earlier. Conversely, some who are hopefully reading this, and also who conduct research on endometriosis, may be able to diagnose someone earlier that may have been missed until they were in their 30s or 40s, for example.

With respect to ethnicity, I'm the task force leader for diversity, equity, and inclusion in research and recruitment. This is something that I'm actively starting to work on, as are other groups. I don't have the answer for that yet, but as we continue to collect more data, we will have more information on this.

What are some of the existing hormonal therapies you rely upon as well as the biomarkers in predicting response to treatment, and are there any new research or treatments on the horizon?

Dr. Flores: I'll first start by telling you a bit about our existing treatment regimens, and then how I decide who would benefit from a given one. First line has always been progestin-based therapy, either in the form of a combined oral contraceptive pill or as progesterone only pills. However, up to 1/3 of women fail progestin-based therapy—this is termed progesterone resistance.

When progestin-based therapies fail, we then rely on other agents that are focused more on estrogen deprivation because, while we don't know the complete etiology of endometriosis, we do know that it is estrogen-dependent. There are two classes— gonadotropin releasing hormone (GnRH) agonists and GnRH antagonists. The agonist binds to the GnRH receptors, and initially can cause a flare effect due to its agonist properties, initially stimulate release of estradiol,  and ultimately the GnRH receptor becomes downregulated and estradiol is decreased to the menopausal range. As a result we routinely provided add-back therapy with norethindrone to help prevent hot flashes and ensure bone protection.

Within the past three years, there has been a new oral GnRH receptor antagonist approved for treating endometriosis. The medication is available as a once a day or twice a day dosing regimen. As this is a GnRH antagonist, upon binding to the GnRH receptor, it blocks receptor activity, thus avoiding the flare affect; essentially, within 24 hours, there is a decrease in estradiol production.

As two doses are available, you can tailor how much you dial down estrogen for a given patient. The low dose lowers estradiol to a range of 40 picograms while the high (twice a day) dosing lowers your estrogen to about 6 picograms. Also, although it was not studied originally in terms of giving add-back therapy for the higher dose, given the safety  (and effectiveness) of add-back therapy with GnRH agonists we are using the same norethindrone add-back therapy for women who are taking the GnRH receptor antagonist.

The next question is, how do we decide which medication a given patient receives? To answer that, I will tell you a bit about my precision-based medicine research. As mentioned before, while progestin-based therapy is first-line, failure rates are high, and unfortunately, we previously have not been able to identify who will or will not respond to first-line therapy.  As such, I decided to assess progesterone receptor expression in endometriotic lesions from women who had undergone surgery for endometriosis, and determine whether progesterone receptor expression levels in lesions could be used to predict response to progestin-based therapy. I found that in women that had high levels of the progesterone receptor, they responded completely to progestin-based therapy-- there was a 100% response rate to progestin-based therapy. This is in sharp contrast to women who had low PR expression, where there was only a 6% response rate to progestin-based therapy.

While this is great with respect to being able to predict who will or will not respond to first line therapy, the one limitation is that would mean that women have to undergo surgery in order to determine progesterone receptor status/response to progestin-based therapy. However, given that within two to five years following surgery, up to 50% of women will have recurrence of pain symptoms, where I see my test coming into play is postoperatively.  This is because many times , women who had pain, or who were failing a given agent, are placed back on that same medical therapy they were failing after surgery. Usually that was a progestin. Therefore, instead of putting them on that same therapy that they were failing, we can use my test to place them on an alternative therapy (such as a GnRH analogue) that more specifically targets estradiol production.

In terms of future directions with respect to treatment, there is a microRNA that has been found to be low in women with endometriosis—miRNALet-7b. In a murine model of endometriosis, we have found that if we supplement with Let-7, there is decreased inflammation and decreased lesion size of endometriosis.  We have also found that supplementing miRNA Let-7b in human endometriotic lesions results in decreased inflammation in cell culture.

That would be future directions in terms of focusing on microRNAs and seeing how we can manipulate those to essentially block inflammation and lesion growth. Furthermore, such treatment would be non-hormonal, which would be a novel therapeutic approach.

Can you talk about your research thus far and what your overall lab work has shown regarding endometriosis as a chronic systemic disease?

Dr. Flores: Endometriosis has traditionally been characterized by its pelvic manifestation however, it is important to understand that it is profoundly more than a pelvic disease—it is a chronic, systemic disease with multifactorial effects throughout the body.

We and other groups have found increased expression of several inflammatory cytokines in women with endometriosis. Our lab has found that compared to women without endometriosis, women with endometriosis not only have certain inflammatory cytokines elevated but also have altered expression of microRNAs. MicroRNAs are small noncoding RNAs that bind to and modulate translation of mRNA. To help determine whether these miRNAs were involved in mediating increased expression of inflammatory cytokines in women with endometriosis, we then transfected these miRNAs into a macrophage cell line, and again found altered inflammatory cytokine expression. We and others have also found a role for stem cells (from bone marrow and other sources) in the pathogenesis of endometriosis. In addition, we have found that in endometriosis, women have a low body-mass index and altered metabolism, which is related to induction of induction of hepatic (anorexigenic) gene expression and microRNA-mediated changes in adipocyte (metabolic) gene expression. Furthermore, we have found altered gene expression in regions of the brain associated with anxiety and depression and altered pain sensitization. Taken together, this work helps provide support for the systemic nature of endometriosis.

How can your findings in this space help us in diagnosing clinically and ultimately avoid diagnostic delay?

Dr. Flores: It’s about understanding that endometriosis is not just a pelvic disease and understanding that endometriosis is leading to inflammation and altered expression of miRNAs which allows endometriosis to have long-range effects. For example, women with endometriosis commonly have anxiety and depression and low BMI. As mentioned earlier, we have found that in a murine model of endometriosis, there is altered gene expression in regions of the brain associated with anxiety and depression and altered metabolism in a murine model of endometriosis. Other groups have also found changes in brain volume in these same areas in women with endometriosis, and we have seen low BMI in women with endometriosis.  In fact, a common misconception was that being thin was a risk factor for endometriosis, however we have found that the endometriosis itself, is causing women alteration in genes associated with metabolism.

With respect to the endometrium, in addition to being a pelvic pain disorder, we also see that women with endometriosis have a higher likelihood of having infertility. And we think that's in part because one, just like the lesions can be resistant to progesterone, the endometrium of these women can also be resistant to progesterone. Progesterone is necessary for decidualization/implantation. We have also seen that stem cells can be recruited and ultimately incorrectly incorporated into the endometrium, which may also contribute to infertility in women with endometriosis.

If we can understand this multifactorial nature of endometriosis, I think this will help us not only shift toward diagnosing endometriosis clinically, but also avoid diagnostic delay. If we can understand that endometriosis is not just a pelvic disorder, but that It can also involve altered mood, bowel/bladder symptoms, inflammation, altered metabolism and/or cause infertility, I think that will ultimately help us to diagnosing earlier.

In addition, we can also utilize pelvic pain symptomatology to help with diagnosis as well. We can ask about cyclic pelvic pain that's been getting progressively worse over the years, not responding to non-steroidal anti-inflammatory medications. Also, in understanding that endometriosis can affect other organs, asking about cyclic pain/symptoms in other areas, such as cyclical bowel or bladder symptoms.

Thinking about the fact that if you do have a patient like that, you're seeing that they have altered mood symptoms, or alterations in inflammatory markers. Maybe that will help us shift from a disease that was typically only considered to be diagnosed by surgery, by switching to a clinical diagnosis for endometriosis. Doing that will hopefully help avoid diagnostic delay.

If we understand that while we typically describe endometriosis as causing cyclic pain symptoms, sometimes because of the existing diagnostic delay, ultimately women can present with chronic pelvic pain. Thus, it's also important to ask patients presenting with chronic pelvic pain what the symptoms were like beforehand (i.e., was the pain cyclic and progressively worsening over the years/before it became chronic) doing so will also help in terms of diagnosing sooner.

Lastly, circulating miRNAs have been considered promising biomarker candidates because they are stable in circulation and have highly specific expression profiles. We have found that the combination of several miRNAs reliably distinguished endometriosis patients from controls, and a prospective, blinded study showed that the combination of several miRNAs could be used to accurately identify patients with endometriosis, with an area under the receiver operating characteristic curve of 0.93.

Roughly 11%, or more than 6.5 million, women in the United States between the ages of 15–44 years, may have endometriosis. Is this disease more common in any particular age range or ethnicity?

Dr. Flores: We’re actually actively investigating that right now. And I think what makes it challenging, especially with respect to the age range, is now we're -- I think in part because of so much more awareness and more research is being done looking at this disease as a chronic systemic disease-- we're now starting to see/diagnose adolescents with endometriosis.

I think as we start gathering more information about these individuals, we'll be able to better say if there is a particular age range. Right now, we usually say it's in the reproductive years, however for some women it may be later if they were not diagnosed earlier. Conversely, some who are hopefully reading this, and also who conduct research on endometriosis, may be able to diagnose someone earlier that may have been missed until they were in their 30s or 40s, for example.

With respect to ethnicity, I'm the task force leader for diversity, equity, and inclusion in research and recruitment. This is something that I'm actively starting to work on, as are other groups. I don't have the answer for that yet, but as we continue to collect more data, we will have more information on this.

What are some of the existing hormonal therapies you rely upon as well as the biomarkers in predicting response to treatment, and are there any new research or treatments on the horizon?

Dr. Flores: I'll first start by telling you a bit about our existing treatment regimens, and then how I decide who would benefit from a given one. First line has always been progestin-based therapy, either in the form of a combined oral contraceptive pill or as progesterone only pills. However, up to 1/3 of women fail progestin-based therapy—this is termed progesterone resistance.

When progestin-based therapies fail, we then rely on other agents that are focused more on estrogen deprivation because, while we don't know the complete etiology of endometriosis, we do know that it is estrogen-dependent. There are two classes— gonadotropin releasing hormone (GnRH) agonists and GnRH antagonists. The agonist binds to the GnRH receptors, and initially can cause a flare effect due to its agonist properties, initially stimulate release of estradiol,  and ultimately the GnRH receptor becomes downregulated and estradiol is decreased to the menopausal range. As a result we routinely provided add-back therapy with norethindrone to help prevent hot flashes and ensure bone protection.

Within the past three years, there has been a new oral GnRH receptor antagonist approved for treating endometriosis. The medication is available as a once a day or twice a day dosing regimen. As this is a GnRH antagonist, upon binding to the GnRH receptor, it blocks receptor activity, thus avoiding the flare affect; essentially, within 24 hours, there is a decrease in estradiol production.

As two doses are available, you can tailor how much you dial down estrogen for a given patient. The low dose lowers estradiol to a range of 40 picograms while the high (twice a day) dosing lowers your estrogen to about 6 picograms. Also, although it was not studied originally in terms of giving add-back therapy for the higher dose, given the safety  (and effectiveness) of add-back therapy with GnRH agonists we are using the same norethindrone add-back therapy for women who are taking the GnRH receptor antagonist.

The next question is, how do we decide which medication a given patient receives? To answer that, I will tell you a bit about my precision-based medicine research. As mentioned before, while progestin-based therapy is first-line, failure rates are high, and unfortunately, we previously have not been able to identify who will or will not respond to first-line therapy.  As such, I decided to assess progesterone receptor expression in endometriotic lesions from women who had undergone surgery for endometriosis, and determine whether progesterone receptor expression levels in lesions could be used to predict response to progestin-based therapy. I found that in women that had high levels of the progesterone receptor, they responded completely to progestin-based therapy-- there was a 100% response rate to progestin-based therapy. This is in sharp contrast to women who had low PR expression, where there was only a 6% response rate to progestin-based therapy.

While this is great with respect to being able to predict who will or will not respond to first line therapy, the one limitation is that would mean that women have to undergo surgery in order to determine progesterone receptor status/response to progestin-based therapy. However, given that within two to five years following surgery, up to 50% of women will have recurrence of pain symptoms, where I see my test coming into play is postoperatively.  This is because many times , women who had pain, or who were failing a given agent, are placed back on that same medical therapy they were failing after surgery. Usually that was a progestin. Therefore, instead of putting them on that same therapy that they were failing, we can use my test to place them on an alternative therapy (such as a GnRH analogue) that more specifically targets estradiol production.

In terms of future directions with respect to treatment, there is a microRNA that has been found to be low in women with endometriosis—miRNALet-7b. In a murine model of endometriosis, we have found that if we supplement with Let-7, there is decreased inflammation and decreased lesion size of endometriosis.  We have also found that supplementing miRNA Let-7b in human endometriotic lesions results in decreased inflammation in cell culture.

That would be future directions in terms of focusing on microRNAs and seeing how we can manipulate those to essentially block inflammation and lesion growth. Furthermore, such treatment would be non-hormonal, which would be a novel therapeutic approach.

Many women use cannabis to help manage gynecologic pain conditions.

Patients with chronic pelvic pain, vulvodynia, endometriosis, or gynecologic malignancy may use THC, CBD, or a combination of both in an effort to treat their pain, research shows.

When patients ask or tell clinicians about this treatment approach, however, few if any controlled trials exist to inform medical guidance.

A recent review of studies in this area presents a “thorough analysis of this very relevant topic,” said Erin A. Blake, MD, of Presbyterian Cancer Care, Rio Rancho, N.M..

The findings “are consistent with my anecdotal clinical findings as well as the results of my own research,” Dr. Blake said. “Cannabis products represent an underutilized but likely effective modality to relieve pain and other symptoms experienced by our patients.”
 

Mostly in the dark

Cannabis products “are unregulated and the data we have surrounding them is extremely limited due to outdated federal laws,” said Dr. Blake, who in 2019 described nonprescription cannabis use for symptom management by women with gynecologic malignancies. “Our ability to practice evidence-based medicine related to cannabis products will be limited until we are legally and financially able to design trials to evaluate them in a controlled fashion.”

For the new review, Jenell S. Coleman, MD, MPH, with Johns Hopkins University, Baltimore, and colleagues, identified 16 studies since 1990, including Dr. Blake’s, that examined the use of cannabinoids for managing pain from gynecologic conditions.

Dr. Coleman and her coauthors, Angela L. Liang and Erin L. Gingher, analyzed eight cross-sectional studies, six prospective studies, and two randomized controlled trials.

Patients who used cannabis tended to do so “multiple times per week, and they used a variety of delivery methods and a wide range of doses,” the authors said. “One of the most common reasons for cannabis use was pain management, and all the cross-sectional studies found that most women reported pain relief with cannabis use, especially among women who used a combination of CBD plus THC compared with either cannabinoid alone.”

Cross-sectional studies included patients with chronic pelvic pain (in two of the studies), vulvodynia (one), endometriosis (four), and gynecologic malignancy (two). These studies included between 36 and 3,426 participants and were conducted in the United States, Canada, Australia, and New Zealand.

In one Australian study, for example, Armour and colleagues asked 484 patients with endometriosis to rate the effectiveness of self-management strategies, including cannabis, heat, diet, and exercise, for reducing pelvic pain. Cannabis was used by 13% of the participants and had the highest average effectiveness rating: 7.6 on a 10-point scale.

In some cases, patients who use cannabis may decrease their use of other pain medications, the review found.

Cannabis side effects may include dry mouth, sleepiness, increased appetite, palpitations, and a “high” associated with THC.
 

Enhancing endogenous cannabinoids

The six prospective cohort studies and two randomized controlled trials examined the effectiveness of compounds – including palmitoylethanolamide (PEA) and a fatty acid amide hydrolase inhibitor – that can enhance endogenous cannabinoids.

Studies of PEA combined with antioxidants showed that these treatments significantly decreased pain from primary dysmenorrhea, pelvic pain, and interstitial cystitis. PEA-combination medications were well tolerated, with nausea and spotting as potential side effects.

On the other hand, a study that assessed a fatty acid amide hydrolase inhibitor found that it did not decrease pain from interstitial cystitis.

Dr. Coleman began reviewing the endocannabinoid system and cannabis research after hearing from patients who were using cannabis for pelvic pain.

Seeing various preclinical data that suggest cannabis could be useful for pain conditions came as a surprise.

Still, the existing evidence base for clinical effectiveness is poor quality, Dr. Coleman said in an interview. Rigorous trials are needed.

“It is a whole field that is just waiting for the U.S. to do something in terms of legalization so that we can actually study to see, does this make sense?” Dr. Coleman said.
 

Cannabis should not be used while pregnant

In a recent meta-analysis based on data from nearly 60,000 individuals, women who used marijuana during pregnancy were at increased risk for adverse neonatal outcomes such as low birth weight and preterm birth. Study author Greg J. Marchand, MD, of the Marchand Institute for Minimally Invasive Surgery, Mesa, Ariz., noted that the results will force some difficult decisions for mothers who use marijuana to treat medical problems, and that there may not be good substitute treatments for some of these conditions, especially chronic pain and anxiety.

Dr. Coleman disclosed investments in a cannabis exchange-traded fund. Dr. Blake and Dr. Marchand had no relevant financial disclosures.

Many women use cannabis to help manage gynecologic pain conditions.

Patients with chronic pelvic pain, vulvodynia, endometriosis, or gynecologic malignancy may use THC, CBD, or a combination of both in an effort to treat their pain, research shows.

When patients ask or tell clinicians about this treatment approach, however, few if any controlled trials exist to inform medical guidance.

A recent review of studies in this area presents a “thorough analysis of this very relevant topic,” said Erin A. Blake, MD, of Presbyterian Cancer Care, Rio Rancho, N.M..

The findings “are consistent with my anecdotal clinical findings as well as the results of my own research,” Dr. Blake said. “Cannabis products represent an underutilized but likely effective modality to relieve pain and other symptoms experienced by our patients.”
 

Mostly in the dark

Cannabis products “are unregulated and the data we have surrounding them is extremely limited due to outdated federal laws,” said Dr. Blake, who in 2019 described nonprescription cannabis use for symptom management by women with gynecologic malignancies. “Our ability to practice evidence-based medicine related to cannabis products will be limited until we are legally and financially able to design trials to evaluate them in a controlled fashion.”

For the new review, Jenell S. Coleman, MD, MPH, with Johns Hopkins University, Baltimore, and colleagues, identified 16 studies since 1990, including Dr. Blake’s, that examined the use of cannabinoids for managing pain from gynecologic conditions.

Dr. Coleman and her coauthors, Angela L. Liang and Erin L. Gingher, analyzed eight cross-sectional studies, six prospective studies, and two randomized controlled trials.

Patients who used cannabis tended to do so “multiple times per week, and they used a variety of delivery methods and a wide range of doses,” the authors said. “One of the most common reasons for cannabis use was pain management, and all the cross-sectional studies found that most women reported pain relief with cannabis use, especially among women who used a combination of CBD plus THC compared with either cannabinoid alone.”

Cross-sectional studies included patients with chronic pelvic pain (in two of the studies), vulvodynia (one), endometriosis (four), and gynecologic malignancy (two). These studies included between 36 and 3,426 participants and were conducted in the United States, Canada, Australia, and New Zealand.

In one Australian study, for example, Armour and colleagues asked 484 patients with endometriosis to rate the effectiveness of self-management strategies, including cannabis, heat, diet, and exercise, for reducing pelvic pain. Cannabis was used by 13% of the participants and had the highest average effectiveness rating: 7.6 on a 10-point scale.

In some cases, patients who use cannabis may decrease their use of other pain medications, the review found.

Cannabis side effects may include dry mouth, sleepiness, increased appetite, palpitations, and a “high” associated with THC.
 

Enhancing endogenous cannabinoids

The six prospective cohort studies and two randomized controlled trials examined the effectiveness of compounds – including palmitoylethanolamide (PEA) and a fatty acid amide hydrolase inhibitor – that can enhance endogenous cannabinoids.

Studies of PEA combined with antioxidants showed that these treatments significantly decreased pain from primary dysmenorrhea, pelvic pain, and interstitial cystitis. PEA-combination medications were well tolerated, with nausea and spotting as potential side effects.

On the other hand, a study that assessed a fatty acid amide hydrolase inhibitor found that it did not decrease pain from interstitial cystitis.

Dr. Coleman began reviewing the endocannabinoid system and cannabis research after hearing from patients who were using cannabis for pelvic pain.

Seeing various preclinical data that suggest cannabis could be useful for pain conditions came as a surprise.

Still, the existing evidence base for clinical effectiveness is poor quality, Dr. Coleman said in an interview. Rigorous trials are needed.

“It is a whole field that is just waiting for the U.S. to do something in terms of legalization so that we can actually study to see, does this make sense?” Dr. Coleman said.
 

Cannabis should not be used while pregnant

In a recent meta-analysis based on data from nearly 60,000 individuals, women who used marijuana during pregnancy were at increased risk for adverse neonatal outcomes such as low birth weight and preterm birth. Study author Greg J. Marchand, MD, of the Marchand Institute for Minimally Invasive Surgery, Mesa, Ariz., noted that the results will force some difficult decisions for mothers who use marijuana to treat medical problems, and that there may not be good substitute treatments for some of these conditions, especially chronic pain and anxiety.

Dr. Coleman disclosed investments in a cannabis exchange-traded fund. Dr. Blake and Dr. Marchand had no relevant financial disclosures.

Many women use cannabis to help manage gynecologic pain conditions.

Patients with chronic pelvic pain, vulvodynia, endometriosis, or gynecologic malignancy may use THC, CBD, or a combination of both in an effort to treat their pain, research shows.

When patients ask or tell clinicians about this treatment approach, however, few if any controlled trials exist to inform medical guidance.

A recent review of studies in this area presents a “thorough analysis of this very relevant topic,” said Erin A. Blake, MD, of Presbyterian Cancer Care, Rio Rancho, N.M..

The findings “are consistent with my anecdotal clinical findings as well as the results of my own research,” Dr. Blake said. “Cannabis products represent an underutilized but likely effective modality to relieve pain and other symptoms experienced by our patients.”
 

Mostly in the dark

Cannabis products “are unregulated and the data we have surrounding them is extremely limited due to outdated federal laws,” said Dr. Blake, who in 2019 described nonprescription cannabis use for symptom management by women with gynecologic malignancies. “Our ability to practice evidence-based medicine related to cannabis products will be limited until we are legally and financially able to design trials to evaluate them in a controlled fashion.”

For the new review, Jenell S. Coleman, MD, MPH, with Johns Hopkins University, Baltimore, and colleagues, identified 16 studies since 1990, including Dr. Blake’s, that examined the use of cannabinoids for managing pain from gynecologic conditions.

Dr. Coleman and her coauthors, Angela L. Liang and Erin L. Gingher, analyzed eight cross-sectional studies, six prospective studies, and two randomized controlled trials.

Patients who used cannabis tended to do so “multiple times per week, and they used a variety of delivery methods and a wide range of doses,” the authors said. “One of the most common reasons for cannabis use was pain management, and all the cross-sectional studies found that most women reported pain relief with cannabis use, especially among women who used a combination of CBD plus THC compared with either cannabinoid alone.”

Cross-sectional studies included patients with chronic pelvic pain (in two of the studies), vulvodynia (one), endometriosis (four), and gynecologic malignancy (two). These studies included between 36 and 3,426 participants and were conducted in the United States, Canada, Australia, and New Zealand.

In one Australian study, for example, Armour and colleagues asked 484 patients with endometriosis to rate the effectiveness of self-management strategies, including cannabis, heat, diet, and exercise, for reducing pelvic pain. Cannabis was used by 13% of the participants and had the highest average effectiveness rating: 7.6 on a 10-point scale.

In some cases, patients who use cannabis may decrease their use of other pain medications, the review found.

Cannabis side effects may include dry mouth, sleepiness, increased appetite, palpitations, and a “high” associated with THC.
 

Enhancing endogenous cannabinoids

The six prospective cohort studies and two randomized controlled trials examined the effectiveness of compounds – including palmitoylethanolamide (PEA) and a fatty acid amide hydrolase inhibitor – that can enhance endogenous cannabinoids.

Studies of PEA combined with antioxidants showed that these treatments significantly decreased pain from primary dysmenorrhea, pelvic pain, and interstitial cystitis. PEA-combination medications were well tolerated, with nausea and spotting as potential side effects.

On the other hand, a study that assessed a fatty acid amide hydrolase inhibitor found that it did not decrease pain from interstitial cystitis.

Dr. Coleman began reviewing the endocannabinoid system and cannabis research after hearing from patients who were using cannabis for pelvic pain.

Seeing various preclinical data that suggest cannabis could be useful for pain conditions came as a surprise.

Still, the existing evidence base for clinical effectiveness is poor quality, Dr. Coleman said in an interview. Rigorous trials are needed.

“It is a whole field that is just waiting for the U.S. to do something in terms of legalization so that we can actually study to see, does this make sense?” Dr. Coleman said.
 

Cannabis should not be used while pregnant

In a recent meta-analysis based on data from nearly 60,000 individuals, women who used marijuana during pregnancy were at increased risk for adverse neonatal outcomes such as low birth weight and preterm birth. Study author Greg J. Marchand, MD, of the Marchand Institute for Minimally Invasive Surgery, Mesa, Ariz., noted that the results will force some difficult decisions for mothers who use marijuana to treat medical problems, and that there may not be good substitute treatments for some of these conditions, especially chronic pain and anxiety.

Dr. Coleman disclosed investments in a cannabis exchange-traded fund. Dr. Blake and Dr. Marchand had no relevant financial disclosures.

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) on December 17 recommended approval of linzagolix (Yselty, ObsEva), an oral gonadotropin-releasing hormone (GnRH) antagonist, for the management of moderate to severe symptoms of uterine fibroids (UF) in adult women of reproductive age.

If approved, linzagolix – which is taken once per day – would become the first GnRH receptor antagonist with a nonhormonal option to reach the market. The U.S. Food and Drug Administration in November accepted ObsEva’s new drug application for the medication, with a decision expected by September 2022.

“The positive CHMP opinion is an important milestone for millions of women in the EU living with UF to address the diverse medical needs of the women who suffer from this condition,” said Brian O’Callaghan, CEO of ObsEva, in a statement. “We will continue our productive, ongoing dialogue with [the] EMA toward potential marketing authorization in the EU and, in parallel, continue to work with the FDA to advance linzagolix through the U.S. regulatory process.”

The committee’s positive opinion was based on 52-week results from PRIMROSE 1 and PRIMROSE 2 phase 3 trials, involving more than 1,000 patients in the United States and Europe, as well as results from 76-week follow-up studies of patients in those trials. The two phase 3 trials assessed a 200-mg and 100-mg dose of linzagolix, with and without hormone add-back therapy (ABT; 1 mg estradiol and 0.5 mg norethisterone acetate).

According to ObsEVA, both trials met their primary endpoints, with all doses showing statistically significant and clinically relevant reductions in heavy menstrual bleeding (HMB) compared to placebo. The trials also achieved several secondary endpoints, including reduction in pain, rates of amenorrhea, time to reduced HMB, and amenorrhea and for the high dose without ABT, reductions in uterine and fibroid volume, the company said.

A version of this article first appeared on Medscape.com.

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) on December 17 recommended approval of linzagolix (Yselty, ObsEva), an oral gonadotropin-releasing hormone (GnRH) antagonist, for the management of moderate to severe symptoms of uterine fibroids (UF) in adult women of reproductive age.

If approved, linzagolix – which is taken once per day – would become the first GnRH receptor antagonist with a nonhormonal option to reach the market. The U.S. Food and Drug Administration in November accepted ObsEva’s new drug application for the medication, with a decision expected by September 2022.

“The positive CHMP opinion is an important milestone for millions of women in the EU living with UF to address the diverse medical needs of the women who suffer from this condition,” said Brian O’Callaghan, CEO of ObsEva, in a statement. “We will continue our productive, ongoing dialogue with [the] EMA toward potential marketing authorization in the EU and, in parallel, continue to work with the FDA to advance linzagolix through the U.S. regulatory process.”

The committee’s positive opinion was based on 52-week results from PRIMROSE 1 and PRIMROSE 2 phase 3 trials, involving more than 1,000 patients in the United States and Europe, as well as results from 76-week follow-up studies of patients in those trials. The two phase 3 trials assessed a 200-mg and 100-mg dose of linzagolix, with and without hormone add-back therapy (ABT; 1 mg estradiol and 0.5 mg norethisterone acetate).

According to ObsEVA, both trials met their primary endpoints, with all doses showing statistically significant and clinically relevant reductions in heavy menstrual bleeding (HMB) compared to placebo. The trials also achieved several secondary endpoints, including reduction in pain, rates of amenorrhea, time to reduced HMB, and amenorrhea and for the high dose without ABT, reductions in uterine and fibroid volume, the company said.

A version of this article first appeared on Medscape.com.

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) on December 17 recommended approval of linzagolix (Yselty, ObsEva), an oral gonadotropin-releasing hormone (GnRH) antagonist, for the management of moderate to severe symptoms of uterine fibroids (UF) in adult women of reproductive age.

If approved, linzagolix – which is taken once per day – would become the first GnRH receptor antagonist with a nonhormonal option to reach the market. The U.S. Food and Drug Administration in November accepted ObsEva’s new drug application for the medication, with a decision expected by September 2022.

“The positive CHMP opinion is an important milestone for millions of women in the EU living with UF to address the diverse medical needs of the women who suffer from this condition,” said Brian O’Callaghan, CEO of ObsEva, in a statement. “We will continue our productive, ongoing dialogue with [the] EMA toward potential marketing authorization in the EU and, in parallel, continue to work with the FDA to advance linzagolix through the U.S. regulatory process.”

The committee’s positive opinion was based on 52-week results from PRIMROSE 1 and PRIMROSE 2 phase 3 trials, involving more than 1,000 patients in the United States and Europe, as well as results from 76-week follow-up studies of patients in those trials. The two phase 3 trials assessed a 200-mg and 100-mg dose of linzagolix, with and without hormone add-back therapy (ABT; 1 mg estradiol and 0.5 mg norethisterone acetate).

According to ObsEVA, both trials met their primary endpoints, with all doses showing statistically significant and clinically relevant reductions in heavy menstrual bleeding (HMB) compared to placebo. The trials also achieved several secondary endpoints, including reduction in pain, rates of amenorrhea, time to reduced HMB, and amenorrhea and for the high dose without ABT, reductions in uterine and fibroid volume, the company said.

A version of this article first appeared on Medscape.com.

Patients with obesity and type 2 diabetes who underwent bariatric surgery and had 10-year durable diabetes remission had a 60% lower risk of incident cancer than patients who had usual obesity care.

And women who had bariatric surgery had a 42% lower risk of having cancer during a median 21-year follow-up, compared with women who had usual obesity care.

These findings from 701 patients in the Swedish Obese Subjects (SOS) study who had type 2 diabetes were recently published in Diabetes Care.

The results illustrate the “connection between glucose control and cancer prevention” and suggest that “among patients with type 2 diabetes, many cancer cases are preventable,” lead author Kajsa Sjöholm, PhD, associate professor of molecular medicine at Sahlgrenska Academy, University of Gothenburg (Sweden), said in a press release from the university.

“The global epidemic of both obesity and diabetes leads to an increased risk of cancer, as well as an increased risk of premature death,” added senior author Magdalena Taube, PhD, associate professor of molecular medicine in the same academy.

“It has been estimated that, over the next 10-15 years, obesity may cause more cancer cases than smoking in several countries,” she noted. Therefore, “strategies are needed to prevent this development, and our results can provide vital guidance for prevention of cancer in patients with obesity and type 2 diabetes.”
 

Durable diabetes remission seems key

Two-thirds of the patients in the bariatric surgery group had vertical banded gastroplasty (65%), and the rest had adjustable or nonadjustable gastric banding (18%) or gastric bypass (17%).

Each type of bariatric surgery was associated with higher diabetes remission rates, compared with usual care, in a previous study by these researchers, Dr. Taube said in an interview.

“In our present study,” she added, “we observed a nonsignificant trend, where patients with obesity and type 2 diabetes in the highest weight loss tertile (average weight loss, –44.8 kg) had somewhat lower risk of cancer compared to the lowest tertile [average weight loss, –14.9 kg].”

This might suggest, Dr. Taube continued, that with respect to cancer risk, surgery techniques resulting in greater weight loss (for example, Roux-en-Y gastric bypass and sleeve gastrectomy) should be recommended in patients with obesity and diabetes.

“However, it should also be noted that long-term diabetes remission seems imperative for cancer risk reduction,” she said, “and in a recent meta-analysis by McTigue et al., published in JAMA Surgery, it was shown that patients who had Roux-en-Y gastric bypass had greater weight loss, a slightly higher type 2 diabetes remission rate, less type 2 diabetes relapse, and better long-term glycemic control, compared with those who had sleeve gastrectomy.

“The observed cancer reduction in women with obesity and type 2 diabetes is in line with previous findings showing that cancer risk reduction following bariatric surgery in patients with obesity is more marked among women than men,” Dr. Taube noted. This may be because cancer rates are higher in women with diabetes than in men with diabetes, and common cancer types associated with obesity are female specific.

The main cancers in women were breast cancer, followed by endometrial and colorectal cancer. In men, the main cancers were colorectal, prostate, and urothelial/malignant skin cancer.
 

Study design and findings

It is well established that obesity is a risk factor for 13 types of cancer, and some of these cancers (liver, pancreatic, endometrial, colon and rectal, breast, and bladder) may be related to type 2 diabetes. And bariatric surgery has been shown to reduce cancer risk in patients with obesity.

However, it is not clear how bariatric surgery may affect cancer risk in patients with obesity and type 2 diabetes.

To study this, the researchers examined data from 393 patients who underwent bariatric surgery and 308 patients who received usual obesity treatment, who were part of the SOS study.

The SOS study enrolled men with a body mass index of at least 34 kg/m², and women with a BMI of at least 38 kg/m² who were aged 37-60 years between 1987 and 2001.

The current study outcome – cancer incidence in patients with obesity and type 2 diabetes – was not a prespecified outcome

The intervention groups were matched on 18 variables, including age, sex, serum insulin, alcohol, education, and smoking.

At baseline, the patients had a mean age of about 49 and 60% were women. They had a mean BMI of about 42 and a mean hemoglobin A1c of 7.8%.

On average, patients in the surgery group had lost 27.5 kg and 22.7 kg, and patients in the usual care group had lost 3.2 kg and 4.8 kg, at 2 years and 10 years, respectively.

During a median follow-up of 21 years, there were 74 incident cancers in the control group and 68 cancers in the bariatric surgery group.

The risk of cancer during follow-up was 37% lower in the surgery group than in the usual care group, after multivariable adjustment (adjusted hazard ratio, 0.63; 95% confidence interval, 0.44-0.89; P = .008).

A deeper dive showed that there were 86 incident cancers in women and 56 cancers in men. The risk of cancer was significantly lower in women who had bariatric surgery, compared with those who had usual care (aHR, 0.58; 95% CI 0.38-0.90, P = .016). However, the risk of cancer was not significantly lower in men who had bariatric surgery versus those who had usual care (aHR 0.79, 95% CI, 0.46-1.38; P = .413).

Diabetes remission at 10 years was associated with a 60% reduced cancer incidence (aHR, 0.40; 95% CI, 0.22-0.74, P = .003).

The study was funded by the Swedish state (under an agreement between the Swedish government and the county councils), the Swedish Research Council, the Novo Nordisk Foundation, the Swedish Heart-Lung Foundation, and the Swedish Diabetes Foundation. One author received consulting fees from Johnson & Johnson. The other authors had no relevant financial disclosures.

A version of this article first appeared on Medscape.com.

Patients with obesity and type 2 diabetes who underwent bariatric surgery and had 10-year durable diabetes remission had a 60% lower risk of incident cancer than patients who had usual obesity care.

And women who had bariatric surgery had a 42% lower risk of having cancer during a median 21-year follow-up, compared with women who had usual obesity care.

These findings from 701 patients in the Swedish Obese Subjects (SOS) study who had type 2 diabetes were recently published in Diabetes Care.

The results illustrate the “connection between glucose control and cancer prevention” and suggest that “among patients with type 2 diabetes, many cancer cases are preventable,” lead author Kajsa Sjöholm, PhD, associate professor of molecular medicine at Sahlgrenska Academy, University of Gothenburg (Sweden), said in a press release from the university.

“The global epidemic of both obesity and diabetes leads to an increased risk of cancer, as well as an increased risk of premature death,” added senior author Magdalena Taube, PhD, associate professor of molecular medicine in the same academy.

“It has been estimated that, over the next 10-15 years, obesity may cause more cancer cases than smoking in several countries,” she noted. Therefore, “strategies are needed to prevent this development, and our results can provide vital guidance for prevention of cancer in patients with obesity and type 2 diabetes.”
 

Durable diabetes remission seems key

Two-thirds of the patients in the bariatric surgery group had vertical banded gastroplasty (65%), and the rest had adjustable or nonadjustable gastric banding (18%) or gastric bypass (17%).

Each type of bariatric surgery was associated with higher diabetes remission rates, compared with usual care, in a previous study by these researchers, Dr. Taube said in an interview.

“In our present study,” she added, “we observed a nonsignificant trend, where patients with obesity and type 2 diabetes in the highest weight loss tertile (average weight loss, –44.8 kg) had somewhat lower risk of cancer compared to the lowest tertile [average weight loss, –14.9 kg].”

This might suggest, Dr. Taube continued, that with respect to cancer risk, surgery techniques resulting in greater weight loss (for example, Roux-en-Y gastric bypass and sleeve gastrectomy) should be recommended in patients with obesity and diabetes.

“However, it should also be noted that long-term diabetes remission seems imperative for cancer risk reduction,” she said, “and in a recent meta-analysis by McTigue et al., published in JAMA Surgery, it was shown that patients who had Roux-en-Y gastric bypass had greater weight loss, a slightly higher type 2 diabetes remission rate, less type 2 diabetes relapse, and better long-term glycemic control, compared with those who had sleeve gastrectomy.

“The observed cancer reduction in women with obesity and type 2 diabetes is in line with previous findings showing that cancer risk reduction following bariatric surgery in patients with obesity is more marked among women than men,” Dr. Taube noted. This may be because cancer rates are higher in women with diabetes than in men with diabetes, and common cancer types associated with obesity are female specific.

The main cancers in women were breast cancer, followed by endometrial and colorectal cancer. In men, the main cancers were colorectal, prostate, and urothelial/malignant skin cancer.
 

Study design and findings

It is well established that obesity is a risk factor for 13 types of cancer, and some of these cancers (liver, pancreatic, endometrial, colon and rectal, breast, and bladder) may be related to type 2 diabetes. And bariatric surgery has been shown to reduce cancer risk in patients with obesity.

However, it is not clear how bariatric surgery may affect cancer risk in patients with obesity and type 2 diabetes.

To study this, the researchers examined data from 393 patients who underwent bariatric surgery and 308 patients who received usual obesity treatment, who were part of the SOS study.

The SOS study enrolled men with a body mass index of at least 34 kg/m², and women with a BMI of at least 38 kg/m² who were aged 37-60 years between 1987 and 2001.

The current study outcome – cancer incidence in patients with obesity and type 2 diabetes – was not a prespecified outcome

The intervention groups were matched on 18 variables, including age, sex, serum insulin, alcohol, education, and smoking.

At baseline, the patients had a mean age of about 49 and 60% were women. They had a mean BMI of about 42 and a mean hemoglobin A1c of 7.8%.

On average, patients in the surgery group had lost 27.5 kg and 22.7 kg, and patients in the usual care group had lost 3.2 kg and 4.8 kg, at 2 years and 10 years, respectively.

During a median follow-up of 21 years, there were 74 incident cancers in the control group and 68 cancers in the bariatric surgery group.

The risk of cancer during follow-up was 37% lower in the surgery group than in the usual care group, after multivariable adjustment (adjusted hazard ratio, 0.63; 95% confidence interval, 0.44-0.89; P = .008).

A deeper dive showed that there were 86 incident cancers in women and 56 cancers in men. The risk of cancer was significantly lower in women who had bariatric surgery, compared with those who had usual care (aHR, 0.58; 95% CI 0.38-0.90, P = .016). However, the risk of cancer was not significantly lower in men who had bariatric surgery versus those who had usual care (aHR 0.79, 95% CI, 0.46-1.38; P = .413).

Diabetes remission at 10 years was associated with a 60% reduced cancer incidence (aHR, 0.40; 95% CI, 0.22-0.74, P = .003).

The study was funded by the Swedish state (under an agreement between the Swedish government and the county councils), the Swedish Research Council, the Novo Nordisk Foundation, the Swedish Heart-Lung Foundation, and the Swedish Diabetes Foundation. One author received consulting fees from Johnson & Johnson. The other authors had no relevant financial disclosures.

A version of this article first appeared on Medscape.com.

Patients with obesity and type 2 diabetes who underwent bariatric surgery and had 10-year durable diabetes remission had a 60% lower risk of incident cancer than patients who had usual obesity care.

And women who had bariatric surgery had a 42% lower risk of having cancer during a median 21-year follow-up, compared with women who had usual obesity care.

These findings from 701 patients in the Swedish Obese Subjects (SOS) study who had type 2 diabetes were recently published in Diabetes Care.

The results illustrate the “connection between glucose control and cancer prevention” and suggest that “among patients with type 2 diabetes, many cancer cases are preventable,” lead author Kajsa Sjöholm, PhD, associate professor of molecular medicine at Sahlgrenska Academy, University of Gothenburg (Sweden), said in a press release from the university.

“The global epidemic of both obesity and diabetes leads to an increased risk of cancer, as well as an increased risk of premature death,” added senior author Magdalena Taube, PhD, associate professor of molecular medicine in the same academy.

“It has been estimated that, over the next 10-15 years, obesity may cause more cancer cases than smoking in several countries,” she noted. Therefore, “strategies are needed to prevent this development, and our results can provide vital guidance for prevention of cancer in patients with obesity and type 2 diabetes.”
 

Durable diabetes remission seems key

Two-thirds of the patients in the bariatric surgery group had vertical banded gastroplasty (65%), and the rest had adjustable or nonadjustable gastric banding (18%) or gastric bypass (17%).

Each type of bariatric surgery was associated with higher diabetes remission rates, compared with usual care, in a previous study by these researchers, Dr. Taube said in an interview.

“In our present study,” she added, “we observed a nonsignificant trend, where patients with obesity and type 2 diabetes in the highest weight loss tertile (average weight loss, –44.8 kg) had somewhat lower risk of cancer compared to the lowest tertile [average weight loss, –14.9 kg].”

This might suggest, Dr. Taube continued, that with respect to cancer risk, surgery techniques resulting in greater weight loss (for example, Roux-en-Y gastric bypass and sleeve gastrectomy) should be recommended in patients with obesity and diabetes.

“However, it should also be noted that long-term diabetes remission seems imperative for cancer risk reduction,” she said, “and in a recent meta-analysis by McTigue et al., published in JAMA Surgery, it was shown that patients who had Roux-en-Y gastric bypass had greater weight loss, a slightly higher type 2 diabetes remission rate, less type 2 diabetes relapse, and better long-term glycemic control, compared with those who had sleeve gastrectomy.

“The observed cancer reduction in women with obesity and type 2 diabetes is in line with previous findings showing that cancer risk reduction following bariatric surgery in patients with obesity is more marked among women than men,” Dr. Taube noted. This may be because cancer rates are higher in women with diabetes than in men with diabetes, and common cancer types associated with obesity are female specific.

The main cancers in women were breast cancer, followed by endometrial and colorectal cancer. In men, the main cancers were colorectal, prostate, and urothelial/malignant skin cancer.
 

Study design and findings

It is well established that obesity is a risk factor for 13 types of cancer, and some of these cancers (liver, pancreatic, endometrial, colon and rectal, breast, and bladder) may be related to type 2 diabetes. And bariatric surgery has been shown to reduce cancer risk in patients with obesity.

However, it is not clear how bariatric surgery may affect cancer risk in patients with obesity and type 2 diabetes.

To study this, the researchers examined data from 393 patients who underwent bariatric surgery and 308 patients who received usual obesity treatment, who were part of the SOS study.

The SOS study enrolled men with a body mass index of at least 34 kg/m², and women with a BMI of at least 38 kg/m² who were aged 37-60 years between 1987 and 2001.

The current study outcome – cancer incidence in patients with obesity and type 2 diabetes – was not a prespecified outcome

The intervention groups were matched on 18 variables, including age, sex, serum insulin, alcohol, education, and smoking.

At baseline, the patients had a mean age of about 49 and 60% were women. They had a mean BMI of about 42 and a mean hemoglobin A1c of 7.8%.

On average, patients in the surgery group had lost 27.5 kg and 22.7 kg, and patients in the usual care group had lost 3.2 kg and 4.8 kg, at 2 years and 10 years, respectively.

During a median follow-up of 21 years, there were 74 incident cancers in the control group and 68 cancers in the bariatric surgery group.

The risk of cancer during follow-up was 37% lower in the surgery group than in the usual care group, after multivariable adjustment (adjusted hazard ratio, 0.63; 95% confidence interval, 0.44-0.89; P = .008).

A deeper dive showed that there were 86 incident cancers in women and 56 cancers in men. The risk of cancer was significantly lower in women who had bariatric surgery, compared with those who had usual care (aHR, 0.58; 95% CI 0.38-0.90, P = .016). However, the risk of cancer was not significantly lower in men who had bariatric surgery versus those who had usual care (aHR 0.79, 95% CI, 0.46-1.38; P = .413).

Diabetes remission at 10 years was associated with a 60% reduced cancer incidence (aHR, 0.40; 95% CI, 0.22-0.74, P = .003).

The study was funded by the Swedish state (under an agreement between the Swedish government and the county councils), the Swedish Research Council, the Novo Nordisk Foundation, the Swedish Heart-Lung Foundation, and the Swedish Diabetes Foundation. One author received consulting fees from Johnson & Johnson. The other authors had no relevant financial disclosures.

A version of this article first appeared on Medscape.com.