Endometriosis

What is the incidence of endometriosis in women, and does the condition affect certain patient populations more often than others?

Dr. Taylor: Endometriosis occurs in about 5% to 10% of reproductive-aged women, and it is underdiagnosed. Many women have subtle endometriosis or asymptomatic endometriosis that may be missed or may take a long time to diagnose, and the incidence may be somewhat higher. It is much more common in women with pelvic pain, as these women have a greater than 50% incidence of endometriosis, and those with infertility similarly have roughly a 50% incidence of endometriosis. Endometriosis is a very common disease, most common in the reproductive age range, particularly more common in the most fertile years. The typical course of the disease is that it begins in teenagers or in the early 20s, progresses through the 20s and 30s, but starts to wane in the 40s, and goes away at the time of menopause in the early 50s. Those particularly susceptible to the disease are those with early menarche or frequent or heavy periods. Recurrent periods lead to more retrograde menstruation, which is menstrual flow through the fallopian tubes. It then starts to implant in the abdomen, specifically in the peritoneal cavity.

What are some of the reasons for missed or delayed diagnosis?

Dr. Taylor: There are many reasons why diagnosis may be missed or delayed. One of the most common reasons for delayed diagnosis is that the patient does not know that painful periods are not normal and may not report them to her clinician. Dysmenorrhea, or menstrual pain, is the only pain that we consider normal. It is the only experience we go through that is expected to hurt. It is also a very subjective issue. How do you know if your menstrual cramps are worse than someone else’s? Often, the first thing that happens when someone complains about severe dysmenorrhea is that their friends or family members will say to them, “We all get menstrual cramps. Just toughen up and bear with it.” But, of course, sometimes these menstrual cramps, or dysmenorrhea, get so bad that they become disabling. When people miss school or work, or they cannot participate in normal social or athletic activities, that is when they first get attention. Often, the disease has been bothering someone for a long time before it is diagnosed.

Another reason that diagnosis may be delayed is because of the social stigma surrounding discussing these types of issues. It is difficult sometimes, especially for a teenager, to talk about issues such as painful periods, pain with bowel movements or urination, or pain with intercourse. A generation ago, people did not talk about such topics so openly and publicly. Thankfully, it is becoming easier, and I think this generation is more open to talking about these issues, but it is still difficult for some who are hesitant to discuss it. Parents can also have a difficult time discussing these issues with their children, and they may dismiss it. Even physicians who are not familiar with this issue may not be comfortable discussing these matters.

Other times, it is truly asymptomatic. Someone can have significant endometriosis that does not show up until it is found on ultrasonography or until someone tries to get pregnant but experiences infertility, and then it is recognized. Typically, people with endometriosis do present with painful menses. If we are more attuned to listening for those symptoms and open to talking about these symptoms, I think we can catch this disease much earlier.

Another barrier to diagnosis is that for too long the gold standard has been surgery, a laparoscopy, to look for endometriosis. If that is a clinician’s method of determining if somebody has endometriosis, it creates quite a barrier to diagnosis. In the near future, I believe we will have noninvasive tests that will help us determine if somebody has endometriosis without surgery. Even now a clinical history can be very helpful in deciding who has endometriosis. I am also of the opinion that people are becoming much more confident about making a clinical diagnosis of endometriosis.

Diagnosing endometriosis relies on identifying flags in the patient’s history and through physical exams. How can clinicians better their chances for having the flags converge for successful diagnosis?

Dr. Taylor: I think it is important to keep the focus on some of the main symptoms of endometriosis. Most women with endometriosis start by having dysmenorrhea, which progresses over time. Some women with painful periods from menarche may not have endometriosis. Their primary dysmenorrhea may be due to other etiologies. If someone has relatively normal menses initially and then goes on to have progressively increasing dysmenorrhea, most often that is endometriosis. Eventually, the pain can spread to other times in the cycle, beyond just dysmenorrhea. Pain can start in the pelvis, but, as endometriosis causes side effects outside of the reproductive organs, it can start to affect other organs and start to cause pain outside of the pelvis. Endometriosis can also inflame the pelvis and affect the bowel, the bladder, and many other surrounding organs. If somebody has bowel symptoms or bladder symptoms that are cyclic and accompanied by dysmenorrhea or cyclic pelvic pain, endometriosis should be thought of first, rather than a primary bowel or bladder problem. Too often medical professionals can be misled by these other false clues. I have seen many patients who come to me after a very thorough workup for a gastrointestinal issue, including a colonoscopy, or a bladder issue, including a cystoscopy, when the underlying problem really was endometriosis. It is important not to be misled by these “red herrings,” and to focus on progressive cyclic pelvic pain.  Endometriosis is always at least initially cyclic in character.

We also know that endometriosis can have effects far beyond the pelvis. Conditions such as anxiety and depression are more common in patients with endometriosis. Women with endometriosis tend to be thinner. There are many other manifestations of this disease. Although it is complex, and can affect almost any organ system, we need to focus on the primary problem, which is cyclic pelvic pain that is progressive in nature. A woman who has dysmenorrhea that may progress to cyclic pain that gets worse over time, more than likely has endometriosis. We can rule out other etiologies, such as masses, fibroids, and cysts, with a simple physical exam and/or an ultrasound. In general, from a good history focusing on the cyclic progressive pelvic pain and a good physical exam to rule out other etiologies for that pain, we can rapidly narrow in on the diagnosis of endometriosis. We can make the diagnosis very straightforward. Cyclic progressive pelvic pain is essentially synonymous with endometriosis.

With a current medical lens focused on addressing racial disparities and inequities in medicine, do you feel that there are gaps in endometriosis study enrollment, diagnosis, and management that need to be addressed?

Dr. Taylor: Traditionally, there have been disparities in diagnosing endometriosis. There was a time when it was presumed that White women had endometriosis and Black women were more likely to have an infectious etiology for their pelvic pain—which is not true. The incidence is slightly higher in Asian and White women compared with Black women, but this is very likely because of bias and access to care. When examining women who have been diagnosed and are being evaluated and treated for infertility, those racial differences disappear. When access to care is available, when patients are seen by a physician, when they are under medical care for another reason, the racial disparities are not seen in endometriosis; it occurs equally. I think there clearly are disparities in access and bias in how we diagnose endometriosis; we should be cognizant of that and realize that endometriosis is very similar in its frequency in all ethnic groups.

What is the incidence of endometriosis in women, and does the condition affect certain patient populations more often than others?

Dr. Taylor: Endometriosis occurs in about 5% to 10% of reproductive-aged women, and it is underdiagnosed. Many women have subtle endometriosis or asymptomatic endometriosis that may be missed or may take a long time to diagnose, and the incidence may be somewhat higher. It is much more common in women with pelvic pain, as these women have a greater than 50% incidence of endometriosis, and those with infertility similarly have roughly a 50% incidence of endometriosis. Endometriosis is a very common disease, most common in the reproductive age range, particularly more common in the most fertile years. The typical course of the disease is that it begins in teenagers or in the early 20s, progresses through the 20s and 30s, but starts to wane in the 40s, and goes away at the time of menopause in the early 50s. Those particularly susceptible to the disease are those with early menarche or frequent or heavy periods. Recurrent periods lead to more retrograde menstruation, which is menstrual flow through the fallopian tubes. It then starts to implant in the abdomen, specifically in the peritoneal cavity.

What are some of the reasons for missed or delayed diagnosis?

Dr. Taylor: There are many reasons why diagnosis may be missed or delayed. One of the most common reasons for delayed diagnosis is that the patient does not know that painful periods are not normal and may not report them to her clinician. Dysmenorrhea, or menstrual pain, is the only pain that we consider normal. It is the only experience we go through that is expected to hurt. It is also a very subjective issue. How do you know if your menstrual cramps are worse than someone else’s? Often, the first thing that happens when someone complains about severe dysmenorrhea is that their friends or family members will say to them, “We all get menstrual cramps. Just toughen up and bear with it.” But, of course, sometimes these menstrual cramps, or dysmenorrhea, get so bad that they become disabling. When people miss school or work, or they cannot participate in normal social or athletic activities, that is when they first get attention. Often, the disease has been bothering someone for a long time before it is diagnosed.

Another reason that diagnosis may be delayed is because of the social stigma surrounding discussing these types of issues. It is difficult sometimes, especially for a teenager, to talk about issues such as painful periods, pain with bowel movements or urination, or pain with intercourse. A generation ago, people did not talk about such topics so openly and publicly. Thankfully, it is becoming easier, and I think this generation is more open to talking about these issues, but it is still difficult for some who are hesitant to discuss it. Parents can also have a difficult time discussing these issues with their children, and they may dismiss it. Even physicians who are not familiar with this issue may not be comfortable discussing these matters.

Other times, it is truly asymptomatic. Someone can have significant endometriosis that does not show up until it is found on ultrasonography or until someone tries to get pregnant but experiences infertility, and then it is recognized. Typically, people with endometriosis do present with painful menses. If we are more attuned to listening for those symptoms and open to talking about these symptoms, I think we can catch this disease much earlier.

Another barrier to diagnosis is that for too long the gold standard has been surgery, a laparoscopy, to look for endometriosis. If that is a clinician’s method of determining if somebody has endometriosis, it creates quite a barrier to diagnosis. In the near future, I believe we will have noninvasive tests that will help us determine if somebody has endometriosis without surgery. Even now a clinical history can be very helpful in deciding who has endometriosis. I am also of the opinion that people are becoming much more confident about making a clinical diagnosis of endometriosis.

Diagnosing endometriosis relies on identifying flags in the patient’s history and through physical exams. How can clinicians better their chances for having the flags converge for successful diagnosis?

Dr. Taylor: I think it is important to keep the focus on some of the main symptoms of endometriosis. Most women with endometriosis start by having dysmenorrhea, which progresses over time. Some women with painful periods from menarche may not have endometriosis. Their primary dysmenorrhea may be due to other etiologies. If someone has relatively normal menses initially and then goes on to have progressively increasing dysmenorrhea, most often that is endometriosis. Eventually, the pain can spread to other times in the cycle, beyond just dysmenorrhea. Pain can start in the pelvis, but, as endometriosis causes side effects outside of the reproductive organs, it can start to affect other organs and start to cause pain outside of the pelvis. Endometriosis can also inflame the pelvis and affect the bowel, the bladder, and many other surrounding organs. If somebody has bowel symptoms or bladder symptoms that are cyclic and accompanied by dysmenorrhea or cyclic pelvic pain, endometriosis should be thought of first, rather than a primary bowel or bladder problem. Too often medical professionals can be misled by these other false clues. I have seen many patients who come to me after a very thorough workup for a gastrointestinal issue, including a colonoscopy, or a bladder issue, including a cystoscopy, when the underlying problem really was endometriosis. It is important not to be misled by these “red herrings,” and to focus on progressive cyclic pelvic pain.  Endometriosis is always at least initially cyclic in character.

We also know that endometriosis can have effects far beyond the pelvis. Conditions such as anxiety and depression are more common in patients with endometriosis. Women with endometriosis tend to be thinner. There are many other manifestations of this disease. Although it is complex, and can affect almost any organ system, we need to focus on the primary problem, which is cyclic pelvic pain that is progressive in nature. A woman who has dysmenorrhea that may progress to cyclic pain that gets worse over time, more than likely has endometriosis. We can rule out other etiologies, such as masses, fibroids, and cysts, with a simple physical exam and/or an ultrasound. In general, from a good history focusing on the cyclic progressive pelvic pain and a good physical exam to rule out other etiologies for that pain, we can rapidly narrow in on the diagnosis of endometriosis. We can make the diagnosis very straightforward. Cyclic progressive pelvic pain is essentially synonymous with endometriosis.

With a current medical lens focused on addressing racial disparities and inequities in medicine, do you feel that there are gaps in endometriosis study enrollment, diagnosis, and management that need to be addressed?

Dr. Taylor: Traditionally, there have been disparities in diagnosing endometriosis. There was a time when it was presumed that White women had endometriosis and Black women were more likely to have an infectious etiology for their pelvic pain—which is not true. The incidence is slightly higher in Asian and White women compared with Black women, but this is very likely because of bias and access to care. When examining women who have been diagnosed and are being evaluated and treated for infertility, those racial differences disappear. When access to care is available, when patients are seen by a physician, when they are under medical care for another reason, the racial disparities are not seen in endometriosis; it occurs equally. I think there clearly are disparities in access and bias in how we diagnose endometriosis; we should be cognizant of that and realize that endometriosis is very similar in its frequency in all ethnic groups.

What is the incidence of endometriosis in women, and does the condition affect certain patient populations more often than others?

Dr. Taylor: Endometriosis occurs in about 5% to 10% of reproductive-aged women, and it is underdiagnosed. Many women have subtle endometriosis or asymptomatic endometriosis that may be missed or may take a long time to diagnose, and the incidence may be somewhat higher. It is much more common in women with pelvic pain, as these women have a greater than 50% incidence of endometriosis, and those with infertility similarly have roughly a 50% incidence of endometriosis. Endometriosis is a very common disease, most common in the reproductive age range, particularly more common in the most fertile years. The typical course of the disease is that it begins in teenagers or in the early 20s, progresses through the 20s and 30s, but starts to wane in the 40s, and goes away at the time of menopause in the early 50s. Those particularly susceptible to the disease are those with early menarche or frequent or heavy periods. Recurrent periods lead to more retrograde menstruation, which is menstrual flow through the fallopian tubes. It then starts to implant in the abdomen, specifically in the peritoneal cavity.

What are some of the reasons for missed or delayed diagnosis?

Dr. Taylor: There are many reasons why diagnosis may be missed or delayed. One of the most common reasons for delayed diagnosis is that the patient does not know that painful periods are not normal and may not report them to her clinician. Dysmenorrhea, or menstrual pain, is the only pain that we consider normal. It is the only experience we go through that is expected to hurt. It is also a very subjective issue. How do you know if your menstrual cramps are worse than someone else’s? Often, the first thing that happens when someone complains about severe dysmenorrhea is that their friends or family members will say to them, “We all get menstrual cramps. Just toughen up and bear with it.” But, of course, sometimes these menstrual cramps, or dysmenorrhea, get so bad that they become disabling. When people miss school or work, or they cannot participate in normal social or athletic activities, that is when they first get attention. Often, the disease has been bothering someone for a long time before it is diagnosed.

Another reason that diagnosis may be delayed is because of the social stigma surrounding discussing these types of issues. It is difficult sometimes, especially for a teenager, to talk about issues such as painful periods, pain with bowel movements or urination, or pain with intercourse. A generation ago, people did not talk about such topics so openly and publicly. Thankfully, it is becoming easier, and I think this generation is more open to talking about these issues, but it is still difficult for some who are hesitant to discuss it. Parents can also have a difficult time discussing these issues with their children, and they may dismiss it. Even physicians who are not familiar with this issue may not be comfortable discussing these matters.

Other times, it is truly asymptomatic. Someone can have significant endometriosis that does not show up until it is found on ultrasonography or until someone tries to get pregnant but experiences infertility, and then it is recognized. Typically, people with endometriosis do present with painful menses. If we are more attuned to listening for those symptoms and open to talking about these symptoms, I think we can catch this disease much earlier.

Another barrier to diagnosis is that for too long the gold standard has been surgery, a laparoscopy, to look for endometriosis. If that is a clinician’s method of determining if somebody has endometriosis, it creates quite a barrier to diagnosis. In the near future, I believe we will have noninvasive tests that will help us determine if somebody has endometriosis without surgery. Even now a clinical history can be very helpful in deciding who has endometriosis. I am also of the opinion that people are becoming much more confident about making a clinical diagnosis of endometriosis.

Diagnosing endometriosis relies on identifying flags in the patient’s history and through physical exams. How can clinicians better their chances for having the flags converge for successful diagnosis?

Dr. Taylor: I think it is important to keep the focus on some of the main symptoms of endometriosis. Most women with endometriosis start by having dysmenorrhea, which progresses over time. Some women with painful periods from menarche may not have endometriosis. Their primary dysmenorrhea may be due to other etiologies. If someone has relatively normal menses initially and then goes on to have progressively increasing dysmenorrhea, most often that is endometriosis. Eventually, the pain can spread to other times in the cycle, beyond just dysmenorrhea. Pain can start in the pelvis, but, as endometriosis causes side effects outside of the reproductive organs, it can start to affect other organs and start to cause pain outside of the pelvis. Endometriosis can also inflame the pelvis and affect the bowel, the bladder, and many other surrounding organs. If somebody has bowel symptoms or bladder symptoms that are cyclic and accompanied by dysmenorrhea or cyclic pelvic pain, endometriosis should be thought of first, rather than a primary bowel or bladder problem. Too often medical professionals can be misled by these other false clues. I have seen many patients who come to me after a very thorough workup for a gastrointestinal issue, including a colonoscopy, or a bladder issue, including a cystoscopy, when the underlying problem really was endometriosis. It is important not to be misled by these “red herrings,” and to focus on progressive cyclic pelvic pain.  Endometriosis is always at least initially cyclic in character.

We also know that endometriosis can have effects far beyond the pelvis. Conditions such as anxiety and depression are more common in patients with endometriosis. Women with endometriosis tend to be thinner. There are many other manifestations of this disease. Although it is complex, and can affect almost any organ system, we need to focus on the primary problem, which is cyclic pelvic pain that is progressive in nature. A woman who has dysmenorrhea that may progress to cyclic pain that gets worse over time, more than likely has endometriosis. We can rule out other etiologies, such as masses, fibroids, and cysts, with a simple physical exam and/or an ultrasound. In general, from a good history focusing on the cyclic progressive pelvic pain and a good physical exam to rule out other etiologies for that pain, we can rapidly narrow in on the diagnosis of endometriosis. We can make the diagnosis very straightforward. Cyclic progressive pelvic pain is essentially synonymous with endometriosis.

With a current medical lens focused on addressing racial disparities and inequities in medicine, do you feel that there are gaps in endometriosis study enrollment, diagnosis, and management that need to be addressed?

Dr. Taylor: Traditionally, there have been disparities in diagnosing endometriosis. There was a time when it was presumed that White women had endometriosis and Black women were more likely to have an infectious etiology for their pelvic pain—which is not true. The incidence is slightly higher in Asian and White women compared with Black women, but this is very likely because of bias and access to care. When examining women who have been diagnosed and are being evaluated and treated for infertility, those racial differences disappear. When access to care is available, when patients are seen by a physician, when they are under medical care for another reason, the racial disparities are not seen in endometriosis; it occurs equally. I think there clearly are disparities in access and bias in how we diagnose endometriosis; we should be cognizant of that and realize that endometriosis is very similar in its frequency in all ethnic groups.

Endometriosis, which affects 1 in 10 women, is one of the most common conditions that gynecologists treat. It is known to cause pain, pelvic adhesive disease, endometriotic cyst formation, and infertility. However, even more sinister, it also increases a woman’s risk for the development of epithelial ovarian cancer (known as endometriosis-associated ovarian cancer or EAOC). A woman with endometriosis has a two- to threefold increased risk of developing epithelial ovarian cancer, compared with nonaffected women.¹ This risk appears to be concentrated in the premenopausal age group, particularly the fifth decade of life. After menopause their risk of developing cancer returns to a baseline level.

EAOC classically presents as clear cell or endometrioid adenocarcinomas, rather than high-grade serous carcinomas. However, low-grade serous carcinomas are also frequently observed in this cohort.^2,3 Unlike high-grade serous carcinoma, EAOC is more likely to be diagnosed at an early stage, with the majority at stage I or II, and prognosis is better. After matching for age and stage with cases of high-grade serous carcinoma, there is improved disease-free and overall survival observed among cases of EAOC of clear cell and endometrioid histologic cell types.⁴ The phenomenon of dual primaries (synchronous endometrial and ovarian cancer) occurs more frequently in EAOC than it does in patients with nonendometriosis-related high-grade serous cancer (25% vs. 4%).

The genomics of these endometriosis-associated cancers are quite distinct. Similar to benign endometriosis implants, EAOC is associated with genomic mutations in ARID1A, PIK3CA, and PTEN, as well as progesterone resistance.^1,2 Multiple studies have shown that the adjacent eutopic endometrium carries similar gene mutations as those found in both benign endometriotic implants and EAOC.² This may explain the higher incidence (twofold) of endometrial cancer in patients with endometriosis as well as the increased incidence of dual ovarian and endometrial cancer primaries.

Just as there are multiple theories regarding the mechanism of benign endometriosis, we have theories rather than conclusions regarding the origins of EAOC. One such theory is that it develops from malignant transformation in an existing endometriotic cyst.⁵ Endometriotic cysts provide an iron-rich environment which promotes reactive oxygen species that promote carcinogenesis by inducing gene mutations and epigenetic alterations. However, if prolonged exposure to oxidative stress within endometriotic cysts were to be the cause for EAOC, we would expect to see a progressively increasing incidence of ovarian cancer over time in patients with expectantly managed cysts. However, in cases of expectant management, an initial, early, increased risk for cancer within the first 5 years is followed by a subsequent decreasing incidence over time.⁶ This early incidence spike suggests that some endometriotic cysts may have been misclassified as benign, then rapidly declare themselves as malignant during the observation period rather than a transformation into malignancy from a benign endometrioma over time.

An alternative, and favored, theory for the origins of EAOC are that endometrial cells with carcinogenic genomic alterations reflux through the fallopian tubes during menstruation and settle onto the ovarian epithelium which itself is damaged from recent ovulation thus providing an environment that is highly suitable for oncogenesis.² Genomic analyses of both the eutopic endometrium and malignant cells in patients with EAOC have shown that both tissues contain the same genomic alterations.¹ Given that menstruation, including retrograde menstruation, ends after menopause, this mechanism supports the observation that EAOC is predominantly a malignancy of premenopausal women. Additionally, salpingectomy and hysterectomy confers a protective effect on the development of EAOC, theoretically by preventing the retrograde transfer of these mutant progenitor endometrial cells. Furthermore, the factors that increase the number of menstrual cycles (such as an early age of menarche and delayed or nonchildbearing states) increases the risk for EAOC and factors that inhibit menstruation, such as oral contraceptive pill use, appear to decrease its risk.

EAOC most commonly arises in the ovary, and not in the deep endometriosis implants of adjacent pelvic structures (such as the anterior and posterior cul de sac and pelvic peritoneum). It is suggested that the ovary itself provides a uniquely favorable environment for carcinogenesis. As stated above, it is hypothesized that refluxed endometrial cells, carrying important progenitor mutations, may become trapped in the tissues of traumatized ovarian epithelium, ripe with inflammatory changes, post ovulation.² This microenvironment may promote the development of malignancy.

Given these theories and their supporting evidence, how can we attempt to reduce the incidence of this cancer for our patients with endometriosis? Despite their increased risk for ovarian and endometrial cancers, current recommendations do not support routine cancer screening in women with endometriosis.⁷ However, risk-mitigation strategies can still be pursued. Hormonal contraceptives to decrease ovulation and menstrual cycling are protective against ovarian cancer and are also helpful in mitigating the symptoms of endometriosis. While removal of endometriotic cysts may not, in and of itself, be a strategy to prevent EAOC, it is still generally recommended because these cysts are commonly a source of pain and infertility. While they do not appear to undergo malignant transformation, it can be difficult to definitively rule out an early ovarian cancer in these complex ovarian cysts, particularly as they are often associated with tumor marker abnormalities such as elevations in CA 125. Therefore, if surgical excision of an endometriotic cyst is not performed, it should be closely followed for at least 5 years to ensure it is a benign structure. If surgery is pursued and ovarian preservation is desired, removal of the fallopian tubes and uterus can help mitigate the risk for EAOC.⁸

Endometriosis is a morbid condition for many young women. In addition to causing pain and infertility it increases a woman’s risk for ovarian and endometrial cancer, particularly ovarian clear cell, endometrioid, and low-grade serous cancers and synchronous endometrial and ovarian cancers. Endometriotic cysts should be removed or closely monitored, and clinicians should discuss treatment options that minimize frequency of ovulation and menstruation events as a preventative strategy.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Endocrinology. 2019;160(3):626-38.

2. Cancers. 2020;12(6):1676.

3. Lancet Oncol. 2012;13:385-94.

4. Gynecol Oncol. 2014;132(3):760-6.

5. Redox Rep. 2016;21:119-26.

6. Int. J Clin Oncol. 2020;25:51-8.

7. Hum Reprod. 2013;28:1552-68.

8. J Natl Cancer Inst. 2019;111:1097-103.

Endometriosis, which affects 1 in 10 women, is one of the most common conditions that gynecologists treat. It is known to cause pain, pelvic adhesive disease, endometriotic cyst formation, and infertility. However, even more sinister, it also increases a woman’s risk for the development of epithelial ovarian cancer (known as endometriosis-associated ovarian cancer or EAOC). A woman with endometriosis has a two- to threefold increased risk of developing epithelial ovarian cancer, compared with nonaffected women.¹ This risk appears to be concentrated in the premenopausal age group, particularly the fifth decade of life. After menopause their risk of developing cancer returns to a baseline level.

EAOC classically presents as clear cell or endometrioid adenocarcinomas, rather than high-grade serous carcinomas. However, low-grade serous carcinomas are also frequently observed in this cohort.^2,3 Unlike high-grade serous carcinoma, EAOC is more likely to be diagnosed at an early stage, with the majority at stage I or II, and prognosis is better. After matching for age and stage with cases of high-grade serous carcinoma, there is improved disease-free and overall survival observed among cases of EAOC of clear cell and endometrioid histologic cell types.⁴ The phenomenon of dual primaries (synchronous endometrial and ovarian cancer) occurs more frequently in EAOC than it does in patients with nonendometriosis-related high-grade serous cancer (25% vs. 4%).

The genomics of these endometriosis-associated cancers are quite distinct. Similar to benign endometriosis implants, EAOC is associated with genomic mutations in ARID1A, PIK3CA, and PTEN, as well as progesterone resistance.^1,2 Multiple studies have shown that the adjacent eutopic endometrium carries similar gene mutations as those found in both benign endometriotic implants and EAOC.² This may explain the higher incidence (twofold) of endometrial cancer in patients with endometriosis as well as the increased incidence of dual ovarian and endometrial cancer primaries.

Just as there are multiple theories regarding the mechanism of benign endometriosis, we have theories rather than conclusions regarding the origins of EAOC. One such theory is that it develops from malignant transformation in an existing endometriotic cyst.⁵ Endometriotic cysts provide an iron-rich environment which promotes reactive oxygen species that promote carcinogenesis by inducing gene mutations and epigenetic alterations. However, if prolonged exposure to oxidative stress within endometriotic cysts were to be the cause for EAOC, we would expect to see a progressively increasing incidence of ovarian cancer over time in patients with expectantly managed cysts. However, in cases of expectant management, an initial, early, increased risk for cancer within the first 5 years is followed by a subsequent decreasing incidence over time.⁶ This early incidence spike suggests that some endometriotic cysts may have been misclassified as benign, then rapidly declare themselves as malignant during the observation period rather than a transformation into malignancy from a benign endometrioma over time.

An alternative, and favored, theory for the origins of EAOC are that endometrial cells with carcinogenic genomic alterations reflux through the fallopian tubes during menstruation and settle onto the ovarian epithelium which itself is damaged from recent ovulation thus providing an environment that is highly suitable for oncogenesis.² Genomic analyses of both the eutopic endometrium and malignant cells in patients with EAOC have shown that both tissues contain the same genomic alterations.¹ Given that menstruation, including retrograde menstruation, ends after menopause, this mechanism supports the observation that EAOC is predominantly a malignancy of premenopausal women. Additionally, salpingectomy and hysterectomy confers a protective effect on the development of EAOC, theoretically by preventing the retrograde transfer of these mutant progenitor endometrial cells. Furthermore, the factors that increase the number of menstrual cycles (such as an early age of menarche and delayed or nonchildbearing states) increases the risk for EAOC and factors that inhibit menstruation, such as oral contraceptive pill use, appear to decrease its risk.

EAOC most commonly arises in the ovary, and not in the deep endometriosis implants of adjacent pelvic structures (such as the anterior and posterior cul de sac and pelvic peritoneum). It is suggested that the ovary itself provides a uniquely favorable environment for carcinogenesis. As stated above, it is hypothesized that refluxed endometrial cells, carrying important progenitor mutations, may become trapped in the tissues of traumatized ovarian epithelium, ripe with inflammatory changes, post ovulation.² This microenvironment may promote the development of malignancy.

Given these theories and their supporting evidence, how can we attempt to reduce the incidence of this cancer for our patients with endometriosis? Despite their increased risk for ovarian and endometrial cancers, current recommendations do not support routine cancer screening in women with endometriosis.⁷ However, risk-mitigation strategies can still be pursued. Hormonal contraceptives to decrease ovulation and menstrual cycling are protective against ovarian cancer and are also helpful in mitigating the symptoms of endometriosis. While removal of endometriotic cysts may not, in and of itself, be a strategy to prevent EAOC, it is still generally recommended because these cysts are commonly a source of pain and infertility. While they do not appear to undergo malignant transformation, it can be difficult to definitively rule out an early ovarian cancer in these complex ovarian cysts, particularly as they are often associated with tumor marker abnormalities such as elevations in CA 125. Therefore, if surgical excision of an endometriotic cyst is not performed, it should be closely followed for at least 5 years to ensure it is a benign structure. If surgery is pursued and ovarian preservation is desired, removal of the fallopian tubes and uterus can help mitigate the risk for EAOC.⁸

Endometriosis is a morbid condition for many young women. In addition to causing pain and infertility it increases a woman’s risk for ovarian and endometrial cancer, particularly ovarian clear cell, endometrioid, and low-grade serous cancers and synchronous endometrial and ovarian cancers. Endometriotic cysts should be removed or closely monitored, and clinicians should discuss treatment options that minimize frequency of ovulation and menstruation events as a preventative strategy.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Endocrinology. 2019;160(3):626-38.

2. Cancers. 2020;12(6):1676.

3. Lancet Oncol. 2012;13:385-94.

4. Gynecol Oncol. 2014;132(3):760-6.

5. Redox Rep. 2016;21:119-26.

6. Int. J Clin Oncol. 2020;25:51-8.

7. Hum Reprod. 2013;28:1552-68.

8. J Natl Cancer Inst. 2019;111:1097-103.

Endometriosis, which affects 1 in 10 women, is one of the most common conditions that gynecologists treat. It is known to cause pain, pelvic adhesive disease, endometriotic cyst formation, and infertility. However, even more sinister, it also increases a woman’s risk for the development of epithelial ovarian cancer (known as endometriosis-associated ovarian cancer or EAOC). A woman with endometriosis has a two- to threefold increased risk of developing epithelial ovarian cancer, compared with nonaffected women.¹ This risk appears to be concentrated in the premenopausal age group, particularly the fifth decade of life. After menopause their risk of developing cancer returns to a baseline level.

EAOC classically presents as clear cell or endometrioid adenocarcinomas, rather than high-grade serous carcinomas. However, low-grade serous carcinomas are also frequently observed in this cohort.^2,3 Unlike high-grade serous carcinoma, EAOC is more likely to be diagnosed at an early stage, with the majority at stage I or II, and prognosis is better. After matching for age and stage with cases of high-grade serous carcinoma, there is improved disease-free and overall survival observed among cases of EAOC of clear cell and endometrioid histologic cell types.⁴ The phenomenon of dual primaries (synchronous endometrial and ovarian cancer) occurs more frequently in EAOC than it does in patients with nonendometriosis-related high-grade serous cancer (25% vs. 4%).

The genomics of these endometriosis-associated cancers are quite distinct. Similar to benign endometriosis implants, EAOC is associated with genomic mutations in ARID1A, PIK3CA, and PTEN, as well as progesterone resistance.^1,2 Multiple studies have shown that the adjacent eutopic endometrium carries similar gene mutations as those found in both benign endometriotic implants and EAOC.² This may explain the higher incidence (twofold) of endometrial cancer in patients with endometriosis as well as the increased incidence of dual ovarian and endometrial cancer primaries.

Just as there are multiple theories regarding the mechanism of benign endometriosis, we have theories rather than conclusions regarding the origins of EAOC. One such theory is that it develops from malignant transformation in an existing endometriotic cyst.⁵ Endometriotic cysts provide an iron-rich environment which promotes reactive oxygen species that promote carcinogenesis by inducing gene mutations and epigenetic alterations. However, if prolonged exposure to oxidative stress within endometriotic cysts were to be the cause for EAOC, we would expect to see a progressively increasing incidence of ovarian cancer over time in patients with expectantly managed cysts. However, in cases of expectant management, an initial, early, increased risk for cancer within the first 5 years is followed by a subsequent decreasing incidence over time.⁶ This early incidence spike suggests that some endometriotic cysts may have been misclassified as benign, then rapidly declare themselves as malignant during the observation period rather than a transformation into malignancy from a benign endometrioma over time.

An alternative, and favored, theory for the origins of EAOC are that endometrial cells with carcinogenic genomic alterations reflux through the fallopian tubes during menstruation and settle onto the ovarian epithelium which itself is damaged from recent ovulation thus providing an environment that is highly suitable for oncogenesis.² Genomic analyses of both the eutopic endometrium and malignant cells in patients with EAOC have shown that both tissues contain the same genomic alterations.¹ Given that menstruation, including retrograde menstruation, ends after menopause, this mechanism supports the observation that EAOC is predominantly a malignancy of premenopausal women. Additionally, salpingectomy and hysterectomy confers a protective effect on the development of EAOC, theoretically by preventing the retrograde transfer of these mutant progenitor endometrial cells. Furthermore, the factors that increase the number of menstrual cycles (such as an early age of menarche and delayed or nonchildbearing states) increases the risk for EAOC and factors that inhibit menstruation, such as oral contraceptive pill use, appear to decrease its risk.

EAOC most commonly arises in the ovary, and not in the deep endometriosis implants of adjacent pelvic structures (such as the anterior and posterior cul de sac and pelvic peritoneum). It is suggested that the ovary itself provides a uniquely favorable environment for carcinogenesis. As stated above, it is hypothesized that refluxed endometrial cells, carrying important progenitor mutations, may become trapped in the tissues of traumatized ovarian epithelium, ripe with inflammatory changes, post ovulation.² This microenvironment may promote the development of malignancy.

Given these theories and their supporting evidence, how can we attempt to reduce the incidence of this cancer for our patients with endometriosis? Despite their increased risk for ovarian and endometrial cancers, current recommendations do not support routine cancer screening in women with endometriosis.⁷ However, risk-mitigation strategies can still be pursued. Hormonal contraceptives to decrease ovulation and menstrual cycling are protective against ovarian cancer and are also helpful in mitigating the symptoms of endometriosis. While removal of endometriotic cysts may not, in and of itself, be a strategy to prevent EAOC, it is still generally recommended because these cysts are commonly a source of pain and infertility. While they do not appear to undergo malignant transformation, it can be difficult to definitively rule out an early ovarian cancer in these complex ovarian cysts, particularly as they are often associated with tumor marker abnormalities such as elevations in CA 125. Therefore, if surgical excision of an endometriotic cyst is not performed, it should be closely followed for at least 5 years to ensure it is a benign structure. If surgery is pursued and ovarian preservation is desired, removal of the fallopian tubes and uterus can help mitigate the risk for EAOC.⁸

Endometriosis is a morbid condition for many young women. In addition to causing pain and infertility it increases a woman’s risk for ovarian and endometrial cancer, particularly ovarian clear cell, endometrioid, and low-grade serous cancers and synchronous endometrial and ovarian cancers. Endometriotic cysts should be removed or closely monitored, and clinicians should discuss treatment options that minimize frequency of ovulation and menstruation events as a preventative strategy.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill.

References

1. Endocrinology. 2019;160(3):626-38.

2. Cancers. 2020;12(6):1676.

3. Lancet Oncol. 2012;13:385-94.

4. Gynecol Oncol. 2014;132(3):760-6.

5. Redox Rep. 2016;21:119-26.

6. Int. J Clin Oncol. 2020;25:51-8.

7. Hum Reprod. 2013;28:1552-68.

8. J Natl Cancer Inst. 2019;111:1097-103.

Uterine leiomyomata (fibroids) are the most common pelvic tumor diagnosed in women.¹ Women with symptomatic fibroids often report abnormal uterine bleeding (AUB) and pelvic cramping, fullness, or pain. Fibroids also may cause frequency of urination and contribute to fertility and pregnancy problems. Treatment options for the AUB caused by fibroids include, but are not limited to, hysterectomy, myomectomy, uterine artery embolization, endometrial ablation, insertion of a levonorgestrel intrauterine device, focused ultrasound surgery, radiofrequency ablation, leuprolide acetate, and elagolix plus low-dose hormone add-back (Oriahnn; AbbVie, North Chicago, Illinois).¹ Oriahnn is the most recent addition to our treatment armamentarium for fibroids and represents the first US Food and Drug Administration (FDA)-approved long-term hormonal option for AUB caused by fibroids.

Gene dysregulation contributes to fibroid development

Most uterine fibroids are clonal tumors, which develop following a somatic mutation in a precursor uterine myocyte. The somatic mutation causes gene dysregulation that stimulates cell growth resulting in a benign tumor mass. The majority of fibroids contain a mutation in one of the following 6 genes: mediator complex subunit 12 (MED12), high mobility group AT-hook (HMGA2 or HMGA1), RAD51B, fumarate hydratase (FH), collagen type IV, alpha 5 chain (COL4A5), or collagen type IV alpha 6 chain (COL4A6).²

Gene dysregulation in fibroids may arise following chromothripsis of the uterine myocyte genome

Chromothripsis is a catastrophic intracellular genetic event in which one or more chromosomes are broken and reassemble in a new nucleic acid sequence, producing a derivative chromosome that contains complex genetic rearrangements.³ Chromothripsis is believed to occur frequently in uterine myocytes. It is unknown why uterine myocytes are susceptible to chromothripsis,³ or why a catastrophic intracellular event such as chromothripsis results in preferential mutations in the 6 genes that are associated with myoma formation.

Estrogen and progesterone influence fibroid size and cell activity

Although uterine fibroids are clonal tumors containing broken genes, they are also exquisitely responsive to estradiol and progesterone. Estradiol and progesterone play an important role in regulating fibroid size and function.⁴ Estrogen stimulates uterine fibroids to increase in size. In a hypoestrogenic state, uterine fibroids decrease in size. In addition, a hypoestrogenic state results in an atrophic endometrium and thereby reduces AUB. For women with uterine fibroids and AUB, a reversible hypoestrogenic state can be induced either with a parenteral GnRH-agonist analogue (leuprolide) or an oral GnRH-antagonist (elagolix). Both leuprolide and elagolix are approved for the treatment of uterine fibroids (see below).

Surprisingly, progesterone stimulates cell division in normal uterine myocytes and fibroid cells.⁵ In the luteal phase of the menstrual cycle, uterine myocyte mitoses are more frequent than in the follicular phase. In addition, synthetic progestins appear to maintain fibroid size in a hypoestrogenic environment. In one randomized trial, women with uterine fibroids treated with leuprolide acetate plus a placebo pill for 24 weeks had a 51% reduction in uterine volume as measured by ultrasound.⁶ Women with uterine fibroids treated with leuprolide acetate plus the synthetic progestin, oral medroxyprogesterone acetate 20 mg daily, had only a 15% reduction in uterine volume.⁶ This finding suggests that synthetic progestins partially block the decrease in uterine volume that occurs in a hypoestrogenic state.

Further evidence that progesterone plays a role in fibroid biology is the observation that treatment of women with uterine fibroids with the antiprogestin ulipristal decreases fibroid size and reduces AUB.^7-9 Ulipristal was approved for the treatment of fibroids in many countries but not the United States. Reports of severe, life-threatening liver injury—some necessitating liver transplantation—among women using ulipristal prompted the European Medicines Agency (EMA) in 2020 to recommend that women stop taking ulipristal. In addition, the EMA recommended that no woman should initiate ulipristal treatment at this time.¹⁰

Continue to: Leuprolide acetate...

Leuprolide acetate

Leuprolide acetate is a peptide GnRH-agonist analogue. Initiation of leuprolide treatment stimulates gonadotropin release, but with chronic administration pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) decreases, resulting in reduced ovarian follicular activity, anovulation, and low serum concentration of estradiol and progesterone. Leuprolide treatment concomitant with iron therapy is approved by the FDA for improving red blood cell volume prior to surgery in women with fibroids, AUB, and anemia.¹¹ Among women with fibroids, AUB, and anemia, after 12 weeks of treatment, the hemoglobin concentration was ≥12 g/dL in 79% treated with leuprolide plus iron and 56% treated with iron alone.¹¹ The FDA recommends limiting preoperative leuprolide treatment to no more than 3 months. The approved leuprolide regimens are a maximum of 3 monthly injections of leuprolide 3.75 mg or a single injection of leuprolide 11.25 mg. Leuprolide treatment prior to hysterectomy surgery for uterine fibroids usually will result in a decrease in uterine size and may facilitate vaginal hysterectomy.

Elagolix plus estradiol plus norethindrone acetate (Oriahnn)

GnRH analogues cause a hypoestrogenic state resulting in adverse effects, including moderate to severe hot flashes and a reduction in bone mineral density. One approach to reducing the unwanted effects of hot flashes and decreased bone density is to combine a GnRH analogue with low-dose steroid hormone add-back therapy. Combining a GnRH analogue with low-dose steroid hormone add-back permits long-term treatment of AUB caused by fibroids, with few hot flashes and a minimal decrease in bone mineral density. The FDA recently has approved the combination of elagolix plus low-dose estradiol and norethindrone acetate (Oriahnn) for the long-term treatment of AUB caused by fibroids.

Elagolix is a nonpeptide oral GnRH antagonist that reduces pituitary secretion of LH and FSH, resulting in a decrease in ovarian follicular activity, anovulation, and low serum concentration of estradiol and progesterone. Unlike leuprolide, which causes an initial increase in LH and FSH secretion, the initiation of elagolix treatment causes an immediate and sustained reduction in LH and FSH secretion. Combining elagolix with a low dose of estradiol and norethindrone acetate reduces the side effects of hot flashes and decreased bone density. Clinical trials have reported that the combination of elagolix (300 mg) twice daily plus estradiol (1 mg) and norethindrone acetate (0.5 mg) once daily is an effective long-term treatment of AUB caused by uterine fibroids.

To study the efficacy of elagolix (alone or with estrogen-progestin add-back therapy) for the treatment of AUB caused by uterine fibroids, two identical trials were performed,¹² in which 790 women participated. The participants had a mean age of 42 years and were documented to have heavy menstrual bleeding (>80 mL blood loss per cycle) and ultrasound-diagnosed uterine fibroids. The participants were randomized to one of 3 groups:

• elagolix (300 mg twice daily) plus low-dose steroid add-back (1 mg estradiol and 0.5 mg norethindrone acetate once daily),
• elagolix 300 mg twice daily with no steroid add-back (elagolix alone), or
• placebo for 6 months.¹²

Menstrual blood loss was quantified using the alkaline hematin method on collected sanitary products. The primary endpoint was menstrual blood loss <80 mL per cycle as well as a ≥50% reduction in quantified blood loss from baseline during the final month of treatment. At 6 months, the percentage of women achieving the primary endpoint in the first trial was 84% (elagolix alone), 69% (elagolix plus add-back), and 9% (placebo). Mean changes from baseline in lumbar spine bone density were −2.95% (elagolix alone), −0.76% (elagolix plus add-back), and −0.21% (placebo). The percentage of women reporting hot flashes was 64% in the elagolix group, 20% in the elagolix plus low-dose steroid add-back group, and 9% in the placebo group. Results were similar in the second trial.¹²

The initial trials were extended to 12 months with two groups: elagolix 300 mg twice daily plus low-dose hormone add-back with 1 mg estradiol and 0.5 mg norethindrone acetate once daily (n = 218) or elagolix 300 mg twice daily (elagolix alone) (n = 98).¹³ Following 12 months of treatment, heavy menstrual bleeding was controlled in 88% and 89% of women treated with elagolix plus add-back and elagolix alone, respectively. Amenorrhea was reported by 65% of the women in the elagolix plus add-back group. Compared with baseline bone density, at the end of 12 months of treatment, bone mineral density in the lumbar spine was reduced by -1.5% and -4.8% in the women treated with elagolix plus add-back and elagolix alone, respectively. Compared with baseline bone density, at 1 year following completion of treatment, bone mineral density in the lumbar spine was reduced by -0.6% and -2.0% in the women treated with elagolix plus add-back and elagolix alone, respectively. Similar trends were observed in total hip and femoral neck bone density. During treatment with elagolix plus add-back, adverse effects were modest, including hot flushes (6%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). Two women developed liver transaminase levels >3 times the upper limit of normal, resulting in one woman discontinuing treatment.¹³

Continue to: Contraindications to Oriahnn include known allergies...

Contraindications to Oriahnn include known allergies to the components of the medication (including the yellow dye tartrazine); high risk of arterial, venous thrombotic or thromboembolic disorders; pregnancy; known osteoporosis; current breast cancer or other hormonally-sensitive malignancies; known liver disease; and concurrent use of organic anion transporting polypeptide 1B1 inhibitors, which includes many HIV antiviral medications.¹⁴ Undiagnosed AUB is a contraindication, and all women prescribed Oriahnn should have endometrial sampling before initiating treatment. Oriahnn should not be used for more than 24 months due to the risk of irreversible bone loss.¹⁴ Systemic estrogen and progestin combinations, a component of Oriahnn, increases the risk for pulmonary embolism, deep vein thrombosis, stroke, and myocardial infarction, especially in women at increased risk for these events (such as women >35 years who smoke cigarettes and women with uncontrolled hypertension).¹⁴ In two studies there was a higher incidence of depression, depressed mood, and/or tearfulness in women taking Oriahnn (3%) compared with those taking a placebo (1%).¹⁴ The FDA recommends promptly evaluating women with depressive symptoms to determine the risks of initiating and continuing Oriahnn therapy. In two studies there was a higher risk of reported alopecia among women taking Oriahnn (3.5%) compared with placebo (1%).¹⁴

It should be noted that elagolix is approved for the treatment of pelvic pain caused by endometriosis at a dose of 150 mg daily for 24 months or 200 mg twice daily for 6 months. The elagolix dose for the treatment of AUB caused by fibroids is 300 mg twice daily for up to 24 months, necessitating the addition of low-dose estradiol-norethindrone add-back to reduce the frequency and severity of hot flashes and minimize the loss of bone density. Norethindrone acetate also protects the endometrium from the stimulatory effect of estradiol, reducing the risk of developing endometrial hyperplasia and cancer. Oriahnn is formulated as two different capsules. A yellow and white capsule contains elagolix 300 mg plus estradiol 1 mg and norethindrone acetate 0.5 mg to be taken in the morning, and a blue and white capsule contains elagolix 300 mg to be taken in the evening.

AUB caused by fibroids is a common problem in gyn practice

There are many procedural interventions that are effective in reducing AUB caused by fibroids. However, prior to the approval of Oriahnn there were no hormonal medications that were FDA approved for the long-term treatment of AUB caused by fibroids. Hence, Oriahnn represents an important advance in the hormonal treatment of AUB caused by fibroids and expands the treatment options available to our patients. ●

Uterine leiomyomata (fibroids) are the most common pelvic tumor diagnosed in women.¹ Women with symptomatic fibroids often report abnormal uterine bleeding (AUB) and pelvic cramping, fullness, or pain. Fibroids also may cause frequency of urination and contribute to fertility and pregnancy problems. Treatment options for the AUB caused by fibroids include, but are not limited to, hysterectomy, myomectomy, uterine artery embolization, endometrial ablation, insertion of a levonorgestrel intrauterine device, focused ultrasound surgery, radiofrequency ablation, leuprolide acetate, and elagolix plus low-dose hormone add-back (Oriahnn; AbbVie, North Chicago, Illinois).¹ Oriahnn is the most recent addition to our treatment armamentarium for fibroids and represents the first US Food and Drug Administration (FDA)-approved long-term hormonal option for AUB caused by fibroids.

Gene dysregulation contributes to fibroid development

Most uterine fibroids are clonal tumors, which develop following a somatic mutation in a precursor uterine myocyte. The somatic mutation causes gene dysregulation that stimulates cell growth resulting in a benign tumor mass. The majority of fibroids contain a mutation in one of the following 6 genes: mediator complex subunit 12 (MED12), high mobility group AT-hook (HMGA2 or HMGA1), RAD51B, fumarate hydratase (FH), collagen type IV, alpha 5 chain (COL4A5), or collagen type IV alpha 6 chain (COL4A6).²

Gene dysregulation in fibroids may arise following chromothripsis of the uterine myocyte genome

Chromothripsis is a catastrophic intracellular genetic event in which one or more chromosomes are broken and reassemble in a new nucleic acid sequence, producing a derivative chromosome that contains complex genetic rearrangements.³ Chromothripsis is believed to occur frequently in uterine myocytes. It is unknown why uterine myocytes are susceptible to chromothripsis,³ or why a catastrophic intracellular event such as chromothripsis results in preferential mutations in the 6 genes that are associated with myoma formation.

Estrogen and progesterone influence fibroid size and cell activity

Although uterine fibroids are clonal tumors containing broken genes, they are also exquisitely responsive to estradiol and progesterone. Estradiol and progesterone play an important role in regulating fibroid size and function.⁴ Estrogen stimulates uterine fibroids to increase in size. In a hypoestrogenic state, uterine fibroids decrease in size. In addition, a hypoestrogenic state results in an atrophic endometrium and thereby reduces AUB. For women with uterine fibroids and AUB, a reversible hypoestrogenic state can be induced either with a parenteral GnRH-agonist analogue (leuprolide) or an oral GnRH-antagonist (elagolix). Both leuprolide and elagolix are approved for the treatment of uterine fibroids (see below).

Surprisingly, progesterone stimulates cell division in normal uterine myocytes and fibroid cells.⁵ In the luteal phase of the menstrual cycle, uterine myocyte mitoses are more frequent than in the follicular phase. In addition, synthetic progestins appear to maintain fibroid size in a hypoestrogenic environment. In one randomized trial, women with uterine fibroids treated with leuprolide acetate plus a placebo pill for 24 weeks had a 51% reduction in uterine volume as measured by ultrasound.⁶ Women with uterine fibroids treated with leuprolide acetate plus the synthetic progestin, oral medroxyprogesterone acetate 20 mg daily, had only a 15% reduction in uterine volume.⁶ This finding suggests that synthetic progestins partially block the decrease in uterine volume that occurs in a hypoestrogenic state.

Further evidence that progesterone plays a role in fibroid biology is the observation that treatment of women with uterine fibroids with the antiprogestin ulipristal decreases fibroid size and reduces AUB.^7-9 Ulipristal was approved for the treatment of fibroids in many countries but not the United States. Reports of severe, life-threatening liver injury—some necessitating liver transplantation—among women using ulipristal prompted the European Medicines Agency (EMA) in 2020 to recommend that women stop taking ulipristal. In addition, the EMA recommended that no woman should initiate ulipristal treatment at this time.¹⁰

Continue to: Leuprolide acetate...

Leuprolide acetate

Leuprolide acetate is a peptide GnRH-agonist analogue. Initiation of leuprolide treatment stimulates gonadotropin release, but with chronic administration pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) decreases, resulting in reduced ovarian follicular activity, anovulation, and low serum concentration of estradiol and progesterone. Leuprolide treatment concomitant with iron therapy is approved by the FDA for improving red blood cell volume prior to surgery in women with fibroids, AUB, and anemia.¹¹ Among women with fibroids, AUB, and anemia, after 12 weeks of treatment, the hemoglobin concentration was ≥12 g/dL in 79% treated with leuprolide plus iron and 56% treated with iron alone.¹¹ The FDA recommends limiting preoperative leuprolide treatment to no more than 3 months. The approved leuprolide regimens are a maximum of 3 monthly injections of leuprolide 3.75 mg or a single injection of leuprolide 11.25 mg. Leuprolide treatment prior to hysterectomy surgery for uterine fibroids usually will result in a decrease in uterine size and may facilitate vaginal hysterectomy.

Elagolix plus estradiol plus norethindrone acetate (Oriahnn)

GnRH analogues cause a hypoestrogenic state resulting in adverse effects, including moderate to severe hot flashes and a reduction in bone mineral density. One approach to reducing the unwanted effects of hot flashes and decreased bone density is to combine a GnRH analogue with low-dose steroid hormone add-back therapy. Combining a GnRH analogue with low-dose steroid hormone add-back permits long-term treatment of AUB caused by fibroids, with few hot flashes and a minimal decrease in bone mineral density. The FDA recently has approved the combination of elagolix plus low-dose estradiol and norethindrone acetate (Oriahnn) for the long-term treatment of AUB caused by fibroids.

Elagolix is a nonpeptide oral GnRH antagonist that reduces pituitary secretion of LH and FSH, resulting in a decrease in ovarian follicular activity, anovulation, and low serum concentration of estradiol and progesterone. Unlike leuprolide, which causes an initial increase in LH and FSH secretion, the initiation of elagolix treatment causes an immediate and sustained reduction in LH and FSH secretion. Combining elagolix with a low dose of estradiol and norethindrone acetate reduces the side effects of hot flashes and decreased bone density. Clinical trials have reported that the combination of elagolix (300 mg) twice daily plus estradiol (1 mg) and norethindrone acetate (0.5 mg) once daily is an effective long-term treatment of AUB caused by uterine fibroids.

To study the efficacy of elagolix (alone or with estrogen-progestin add-back therapy) for the treatment of AUB caused by uterine fibroids, two identical trials were performed,¹² in which 790 women participated. The participants had a mean age of 42 years and were documented to have heavy menstrual bleeding (>80 mL blood loss per cycle) and ultrasound-diagnosed uterine fibroids. The participants were randomized to one of 3 groups:

• elagolix (300 mg twice daily) plus low-dose steroid add-back (1 mg estradiol and 0.5 mg norethindrone acetate once daily),
• elagolix 300 mg twice daily with no steroid add-back (elagolix alone), or
• placebo for 6 months.¹²

Menstrual blood loss was quantified using the alkaline hematin method on collected sanitary products. The primary endpoint was menstrual blood loss <80 mL per cycle as well as a ≥50% reduction in quantified blood loss from baseline during the final month of treatment. At 6 months, the percentage of women achieving the primary endpoint in the first trial was 84% (elagolix alone), 69% (elagolix plus add-back), and 9% (placebo). Mean changes from baseline in lumbar spine bone density were −2.95% (elagolix alone), −0.76% (elagolix plus add-back), and −0.21% (placebo). The percentage of women reporting hot flashes was 64% in the elagolix group, 20% in the elagolix plus low-dose steroid add-back group, and 9% in the placebo group. Results were similar in the second trial.¹²

The initial trials were extended to 12 months with two groups: elagolix 300 mg twice daily plus low-dose hormone add-back with 1 mg estradiol and 0.5 mg norethindrone acetate once daily (n = 218) or elagolix 300 mg twice daily (elagolix alone) (n = 98).¹³ Following 12 months of treatment, heavy menstrual bleeding was controlled in 88% and 89% of women treated with elagolix plus add-back and elagolix alone, respectively. Amenorrhea was reported by 65% of the women in the elagolix plus add-back group. Compared with baseline bone density, at the end of 12 months of treatment, bone mineral density in the lumbar spine was reduced by -1.5% and -4.8% in the women treated with elagolix plus add-back and elagolix alone, respectively. Compared with baseline bone density, at 1 year following completion of treatment, bone mineral density in the lumbar spine was reduced by -0.6% and -2.0% in the women treated with elagolix plus add-back and elagolix alone, respectively. Similar trends were observed in total hip and femoral neck bone density. During treatment with elagolix plus add-back, adverse effects were modest, including hot flushes (6%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). Two women developed liver transaminase levels >3 times the upper limit of normal, resulting in one woman discontinuing treatment.¹³

Continue to: Contraindications to Oriahnn include known allergies...

Contraindications to Oriahnn include known allergies to the components of the medication (including the yellow dye tartrazine); high risk of arterial, venous thrombotic or thromboembolic disorders; pregnancy; known osteoporosis; current breast cancer or other hormonally-sensitive malignancies; known liver disease; and concurrent use of organic anion transporting polypeptide 1B1 inhibitors, which includes many HIV antiviral medications.¹⁴ Undiagnosed AUB is a contraindication, and all women prescribed Oriahnn should have endometrial sampling before initiating treatment. Oriahnn should not be used for more than 24 months due to the risk of irreversible bone loss.¹⁴ Systemic estrogen and progestin combinations, a component of Oriahnn, increases the risk for pulmonary embolism, deep vein thrombosis, stroke, and myocardial infarction, especially in women at increased risk for these events (such as women >35 years who smoke cigarettes and women with uncontrolled hypertension).¹⁴ In two studies there was a higher incidence of depression, depressed mood, and/or tearfulness in women taking Oriahnn (3%) compared with those taking a placebo (1%).¹⁴ The FDA recommends promptly evaluating women with depressive symptoms to determine the risks of initiating and continuing Oriahnn therapy. In two studies there was a higher risk of reported alopecia among women taking Oriahnn (3.5%) compared with placebo (1%).¹⁴

It should be noted that elagolix is approved for the treatment of pelvic pain caused by endometriosis at a dose of 150 mg daily for 24 months or 200 mg twice daily for 6 months. The elagolix dose for the treatment of AUB caused by fibroids is 300 mg twice daily for up to 24 months, necessitating the addition of low-dose estradiol-norethindrone add-back to reduce the frequency and severity of hot flashes and minimize the loss of bone density. Norethindrone acetate also protects the endometrium from the stimulatory effect of estradiol, reducing the risk of developing endometrial hyperplasia and cancer. Oriahnn is formulated as two different capsules. A yellow and white capsule contains elagolix 300 mg plus estradiol 1 mg and norethindrone acetate 0.5 mg to be taken in the morning, and a blue and white capsule contains elagolix 300 mg to be taken in the evening.

AUB caused by fibroids is a common problem in gyn practice

There are many procedural interventions that are effective in reducing AUB caused by fibroids. However, prior to the approval of Oriahnn there were no hormonal medications that were FDA approved for the long-term treatment of AUB caused by fibroids. Hence, Oriahnn represents an important advance in the hormonal treatment of AUB caused by fibroids and expands the treatment options available to our patients. ●

Uterine leiomyomata (fibroids) are the most common pelvic tumor diagnosed in women.¹ Women with symptomatic fibroids often report abnormal uterine bleeding (AUB) and pelvic cramping, fullness, or pain. Fibroids also may cause frequency of urination and contribute to fertility and pregnancy problems. Treatment options for the AUB caused by fibroids include, but are not limited to, hysterectomy, myomectomy, uterine artery embolization, endometrial ablation, insertion of a levonorgestrel intrauterine device, focused ultrasound surgery, radiofrequency ablation, leuprolide acetate, and elagolix plus low-dose hormone add-back (Oriahnn; AbbVie, North Chicago, Illinois).¹ Oriahnn is the most recent addition to our treatment armamentarium for fibroids and represents the first US Food and Drug Administration (FDA)-approved long-term hormonal option for AUB caused by fibroids.

Gene dysregulation contributes to fibroid development

Most uterine fibroids are clonal tumors, which develop following a somatic mutation in a precursor uterine myocyte. The somatic mutation causes gene dysregulation that stimulates cell growth resulting in a benign tumor mass. The majority of fibroids contain a mutation in one of the following 6 genes: mediator complex subunit 12 (MED12), high mobility group AT-hook (HMGA2 or HMGA1), RAD51B, fumarate hydratase (FH), collagen type IV, alpha 5 chain (COL4A5), or collagen type IV alpha 6 chain (COL4A6).²

Gene dysregulation in fibroids may arise following chromothripsis of the uterine myocyte genome

Chromothripsis is a catastrophic intracellular genetic event in which one or more chromosomes are broken and reassemble in a new nucleic acid sequence, producing a derivative chromosome that contains complex genetic rearrangements.³ Chromothripsis is believed to occur frequently in uterine myocytes. It is unknown why uterine myocytes are susceptible to chromothripsis,³ or why a catastrophic intracellular event such as chromothripsis results in preferential mutations in the 6 genes that are associated with myoma formation.

Estrogen and progesterone influence fibroid size and cell activity

Although uterine fibroids are clonal tumors containing broken genes, they are also exquisitely responsive to estradiol and progesterone. Estradiol and progesterone play an important role in regulating fibroid size and function.⁴ Estrogen stimulates uterine fibroids to increase in size. In a hypoestrogenic state, uterine fibroids decrease in size. In addition, a hypoestrogenic state results in an atrophic endometrium and thereby reduces AUB. For women with uterine fibroids and AUB, a reversible hypoestrogenic state can be induced either with a parenteral GnRH-agonist analogue (leuprolide) or an oral GnRH-antagonist (elagolix). Both leuprolide and elagolix are approved for the treatment of uterine fibroids (see below).

Surprisingly, progesterone stimulates cell division in normal uterine myocytes and fibroid cells.⁵ In the luteal phase of the menstrual cycle, uterine myocyte mitoses are more frequent than in the follicular phase. In addition, synthetic progestins appear to maintain fibroid size in a hypoestrogenic environment. In one randomized trial, women with uterine fibroids treated with leuprolide acetate plus a placebo pill for 24 weeks had a 51% reduction in uterine volume as measured by ultrasound.⁶ Women with uterine fibroids treated with leuprolide acetate plus the synthetic progestin, oral medroxyprogesterone acetate 20 mg daily, had only a 15% reduction in uterine volume.⁶ This finding suggests that synthetic progestins partially block the decrease in uterine volume that occurs in a hypoestrogenic state.

Further evidence that progesterone plays a role in fibroid biology is the observation that treatment of women with uterine fibroids with the antiprogestin ulipristal decreases fibroid size and reduces AUB.^7-9 Ulipristal was approved for the treatment of fibroids in many countries but not the United States. Reports of severe, life-threatening liver injury—some necessitating liver transplantation—among women using ulipristal prompted the European Medicines Agency (EMA) in 2020 to recommend that women stop taking ulipristal. In addition, the EMA recommended that no woman should initiate ulipristal treatment at this time.¹⁰

Continue to: Leuprolide acetate...

Leuprolide acetate

Leuprolide acetate is a peptide GnRH-agonist analogue. Initiation of leuprolide treatment stimulates gonadotropin release, but with chronic administration pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) decreases, resulting in reduced ovarian follicular activity, anovulation, and low serum concentration of estradiol and progesterone. Leuprolide treatment concomitant with iron therapy is approved by the FDA for improving red blood cell volume prior to surgery in women with fibroids, AUB, and anemia.¹¹ Among women with fibroids, AUB, and anemia, after 12 weeks of treatment, the hemoglobin concentration was ≥12 g/dL in 79% treated with leuprolide plus iron and 56% treated with iron alone.¹¹ The FDA recommends limiting preoperative leuprolide treatment to no more than 3 months. The approved leuprolide regimens are a maximum of 3 monthly injections of leuprolide 3.75 mg or a single injection of leuprolide 11.25 mg. Leuprolide treatment prior to hysterectomy surgery for uterine fibroids usually will result in a decrease in uterine size and may facilitate vaginal hysterectomy.

Elagolix plus estradiol plus norethindrone acetate (Oriahnn)

GnRH analogues cause a hypoestrogenic state resulting in adverse effects, including moderate to severe hot flashes and a reduction in bone mineral density. One approach to reducing the unwanted effects of hot flashes and decreased bone density is to combine a GnRH analogue with low-dose steroid hormone add-back therapy. Combining a GnRH analogue with low-dose steroid hormone add-back permits long-term treatment of AUB caused by fibroids, with few hot flashes and a minimal decrease in bone mineral density. The FDA recently has approved the combination of elagolix plus low-dose estradiol and norethindrone acetate (Oriahnn) for the long-term treatment of AUB caused by fibroids.

Elagolix is a nonpeptide oral GnRH antagonist that reduces pituitary secretion of LH and FSH, resulting in a decrease in ovarian follicular activity, anovulation, and low serum concentration of estradiol and progesterone. Unlike leuprolide, which causes an initial increase in LH and FSH secretion, the initiation of elagolix treatment causes an immediate and sustained reduction in LH and FSH secretion. Combining elagolix with a low dose of estradiol and norethindrone acetate reduces the side effects of hot flashes and decreased bone density. Clinical trials have reported that the combination of elagolix (300 mg) twice daily plus estradiol (1 mg) and norethindrone acetate (0.5 mg) once daily is an effective long-term treatment of AUB caused by uterine fibroids.

To study the efficacy of elagolix (alone or with estrogen-progestin add-back therapy) for the treatment of AUB caused by uterine fibroids, two identical trials were performed,¹² in which 790 women participated. The participants had a mean age of 42 years and were documented to have heavy menstrual bleeding (>80 mL blood loss per cycle) and ultrasound-diagnosed uterine fibroids. The participants were randomized to one of 3 groups:

• elagolix (300 mg twice daily) plus low-dose steroid add-back (1 mg estradiol and 0.5 mg norethindrone acetate once daily),
• elagolix 300 mg twice daily with no steroid add-back (elagolix alone), or
• placebo for 6 months.¹²

Menstrual blood loss was quantified using the alkaline hematin method on collected sanitary products. The primary endpoint was menstrual blood loss <80 mL per cycle as well as a ≥50% reduction in quantified blood loss from baseline during the final month of treatment. At 6 months, the percentage of women achieving the primary endpoint in the first trial was 84% (elagolix alone), 69% (elagolix plus add-back), and 9% (placebo). Mean changes from baseline in lumbar spine bone density were −2.95% (elagolix alone), −0.76% (elagolix plus add-back), and −0.21% (placebo). The percentage of women reporting hot flashes was 64% in the elagolix group, 20% in the elagolix plus low-dose steroid add-back group, and 9% in the placebo group. Results were similar in the second trial.¹²

The initial trials were extended to 12 months with two groups: elagolix 300 mg twice daily plus low-dose hormone add-back with 1 mg estradiol and 0.5 mg norethindrone acetate once daily (n = 218) or elagolix 300 mg twice daily (elagolix alone) (n = 98).¹³ Following 12 months of treatment, heavy menstrual bleeding was controlled in 88% and 89% of women treated with elagolix plus add-back and elagolix alone, respectively. Amenorrhea was reported by 65% of the women in the elagolix plus add-back group. Compared with baseline bone density, at the end of 12 months of treatment, bone mineral density in the lumbar spine was reduced by -1.5% and -4.8% in the women treated with elagolix plus add-back and elagolix alone, respectively. Compared with baseline bone density, at 1 year following completion of treatment, bone mineral density in the lumbar spine was reduced by -0.6% and -2.0% in the women treated with elagolix plus add-back and elagolix alone, respectively. Similar trends were observed in total hip and femoral neck bone density. During treatment with elagolix plus add-back, adverse effects were modest, including hot flushes (6%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). Two women developed liver transaminase levels >3 times the upper limit of normal, resulting in one woman discontinuing treatment.¹³

Continue to: Contraindications to Oriahnn include known allergies...

Contraindications to Oriahnn include known allergies to the components of the medication (including the yellow dye tartrazine); high risk of arterial, venous thrombotic or thromboembolic disorders; pregnancy; known osteoporosis; current breast cancer or other hormonally-sensitive malignancies; known liver disease; and concurrent use of organic anion transporting polypeptide 1B1 inhibitors, which includes many HIV antiviral medications.¹⁴ Undiagnosed AUB is a contraindication, and all women prescribed Oriahnn should have endometrial sampling before initiating treatment. Oriahnn should not be used for more than 24 months due to the risk of irreversible bone loss.¹⁴ Systemic estrogen and progestin combinations, a component of Oriahnn, increases the risk for pulmonary embolism, deep vein thrombosis, stroke, and myocardial infarction, especially in women at increased risk for these events (such as women >35 years who smoke cigarettes and women with uncontrolled hypertension).¹⁴ In two studies there was a higher incidence of depression, depressed mood, and/or tearfulness in women taking Oriahnn (3%) compared with those taking a placebo (1%).¹⁴ The FDA recommends promptly evaluating women with depressive symptoms to determine the risks of initiating and continuing Oriahnn therapy. In two studies there was a higher risk of reported alopecia among women taking Oriahnn (3.5%) compared with placebo (1%).¹⁴

It should be noted that elagolix is approved for the treatment of pelvic pain caused by endometriosis at a dose of 150 mg daily for 24 months or 200 mg twice daily for 6 months. The elagolix dose for the treatment of AUB caused by fibroids is 300 mg twice daily for up to 24 months, necessitating the addition of low-dose estradiol-norethindrone add-back to reduce the frequency and severity of hot flashes and minimize the loss of bone density. Norethindrone acetate also protects the endometrium from the stimulatory effect of estradiol, reducing the risk of developing endometrial hyperplasia and cancer. Oriahnn is formulated as two different capsules. A yellow and white capsule contains elagolix 300 mg plus estradiol 1 mg and norethindrone acetate 0.5 mg to be taken in the morning, and a blue and white capsule contains elagolix 300 mg to be taken in the evening.

AUB caused by fibroids is a common problem in gyn practice

There are many procedural interventions that are effective in reducing AUB caused by fibroids. However, prior to the approval of Oriahnn there were no hormonal medications that were FDA approved for the long-term treatment of AUB caused by fibroids. Hence, Oriahnn represents an important advance in the hormonal treatment of AUB caused by fibroids and expands the treatment options available to our patients. ●

Among women who have a coincidental appendectomy during surgery for chronic pelvic pain or endometriosis, about 15% have appendiceal endometriosis confirmed by pathological examination, according to a study.

“In the women with appendiceal endometriosis, only 26% had an appendix that looked abnormal,” said Whitney T. Ross, MD, of the department of obstetrics and gynecology at Penn State Health, Hershey.

The results, presented at the virtual annual scientific meeting of the Society of Gynecologic Surgeons, indicate that “appendiceal endometriosis is common in women receiving surgery for chronic pelvic pain or endometriosis,” she said. “This study and multiple other studies have also demonstrated that coincidental appendectomy is safe.”

The long-term impact of coincidental appendectomy and its effect on quality of life are not known, however, which may make it difficult to weigh the costs and benefits of the procedure, Dr. Ross said. “It is important to talk to patients about this procedure and determine which approach is the right approach for your institution.”

The study of 609 coincidental appendectomies did not include patients with retrocecal appendices, which may confound the true rate of appendiceal endometriosis, commented Saifuddin T. Mama, MD, MPH, of Rowan University, Camden, N.J.

When the investigators started the study, they were not sure of the risks and benefits of the procedure in patients with retrocecal appendices. An anecdotal report from another research group suggests that outcomes with retrocecal appendices may not be significantly different. “But that is certainly an important question and one that we would like to address in a future prospective study,” Dr. Ross said.

Surgeons have debated the role of coincidental appendectomy during gynecologic surgery. Concerns about safety and questions about the prevalence of appendiceal pathology are reasons that coincidental appendectomy has not been more widely adopted. On the other hand, the procedure may benefit patients and aid diagnosis.

To evaluate the role of coincidental appendectomy in the surgical excision of endometriosis, Dr. Ross and colleagues analyzed data from consecutive coincidental appendectomies performed at one institution between 2013 and 2019. They identified cases in a prospectively maintained surgical database to assess safety and the prevalence of appendiceal pathology.

iStockphoto.com

The indication for surgery was chronic pelvic pain but no visualized endometriosis for 42 patients, stage I-II endometriosis for 388 patients, and stage III-IV endometriosis for 179 patients.

Surgeries included laparoscopic hysterectomy (77.5%), operative laparoscopy (19.9%), and laparoscopic trachelectomy (2.6%). Pathological analysis of the appendices identified endometriosis in 14.9%, malignancy in 0.7%, polyps in 0.5%, and appendicitis in 0.3%.

Among women with chronic pelvic pain but no visualized endometriosis, 2.4% had appendiceal endometriosis. Among those with stage I-II endometriosis, 7% had appendiceal endometriosis, and in patients with stage III-IV endometriosis, the rate of appendiceal endometriosis was 35.2%.

In about 6% of patients with appendiceal endometriosis, the appendix was the only site of pathologically confirmed endometriosis.

Compared with chronic pelvic pain, stage III-IV endometriosis was associated with a significantly increased risk of appendiceal endometriosis (odds ratio, 22.2). The likelihood of appendiceal endometriosis also increased when the appendix looked abnormal (odds ratio, 6.5).

The probability of diagnosing appendiceal endometriosis also increases with the number of other locations of confirmed endometriosis.

“Our surgical decision making is based off of intraoperative findings. However, the final gold-standard diagnosis can’t take place until the pathologic specimen is analyzed,” she said. “We also know that there is a significant discordance, as high as 50%, in early-stage endometriosis between visual inspection and pathology findings.”

There were no complications related to the performance of a coincidental appendectomy during surgery or in the 12 weeks after.

Dr. Ross outlined surgeons’ three main options for performing coincidental appendectomy in patients undergoing surgery for chronic pelvic pain or endometriosis: universal coincidental appendectomy, targeted appendectomy based on operative findings, and performing the procedure based on the appearance of the appendix.

Basing the decision on appearance “is going to miss a lot of appendiceal endometriosis,” Dr. Ross said. In the present study, 67 of the 91 cases, about 74%, would have been missed.

Dr. Ross and Dr. Mama had no relevant financial disclosures. The study coauthors disclosed ties to Titan Medical, Merck, and AbbVie.

jremaly@mdedge.com

SOURCE: Ross WT et al. SGS 2020, Abstract 14.

Among women who have a coincidental appendectomy during surgery for chronic pelvic pain or endometriosis, about 15% have appendiceal endometriosis confirmed by pathological examination, according to a study.

“In the women with appendiceal endometriosis, only 26% had an appendix that looked abnormal,” said Whitney T. Ross, MD, of the department of obstetrics and gynecology at Penn State Health, Hershey.

The results, presented at the virtual annual scientific meeting of the Society of Gynecologic Surgeons, indicate that “appendiceal endometriosis is common in women receiving surgery for chronic pelvic pain or endometriosis,” she said. “This study and multiple other studies have also demonstrated that coincidental appendectomy is safe.”

The long-term impact of coincidental appendectomy and its effect on quality of life are not known, however, which may make it difficult to weigh the costs and benefits of the procedure, Dr. Ross said. “It is important to talk to patients about this procedure and determine which approach is the right approach for your institution.”

The study of 609 coincidental appendectomies did not include patients with retrocecal appendices, which may confound the true rate of appendiceal endometriosis, commented Saifuddin T. Mama, MD, MPH, of Rowan University, Camden, N.J.

When the investigators started the study, they were not sure of the risks and benefits of the procedure in patients with retrocecal appendices. An anecdotal report from another research group suggests that outcomes with retrocecal appendices may not be significantly different. “But that is certainly an important question and one that we would like to address in a future prospective study,” Dr. Ross said.

Surgeons have debated the role of coincidental appendectomy during gynecologic surgery. Concerns about safety and questions about the prevalence of appendiceal pathology are reasons that coincidental appendectomy has not been more widely adopted. On the other hand, the procedure may benefit patients and aid diagnosis.

To evaluate the role of coincidental appendectomy in the surgical excision of endometriosis, Dr. Ross and colleagues analyzed data from consecutive coincidental appendectomies performed at one institution between 2013 and 2019. They identified cases in a prospectively maintained surgical database to assess safety and the prevalence of appendiceal pathology.

iStockphoto.com

The indication for surgery was chronic pelvic pain but no visualized endometriosis for 42 patients, stage I-II endometriosis for 388 patients, and stage III-IV endometriosis for 179 patients.

Surgeries included laparoscopic hysterectomy (77.5%), operative laparoscopy (19.9%), and laparoscopic trachelectomy (2.6%). Pathological analysis of the appendices identified endometriosis in 14.9%, malignancy in 0.7%, polyps in 0.5%, and appendicitis in 0.3%.

Among women with chronic pelvic pain but no visualized endometriosis, 2.4% had appendiceal endometriosis. Among those with stage I-II endometriosis, 7% had appendiceal endometriosis, and in patients with stage III-IV endometriosis, the rate of appendiceal endometriosis was 35.2%.

In about 6% of patients with appendiceal endometriosis, the appendix was the only site of pathologically confirmed endometriosis.

Compared with chronic pelvic pain, stage III-IV endometriosis was associated with a significantly increased risk of appendiceal endometriosis (odds ratio, 22.2). The likelihood of appendiceal endometriosis also increased when the appendix looked abnormal (odds ratio, 6.5).

The probability of diagnosing appendiceal endometriosis also increases with the number of other locations of confirmed endometriosis.

“Our surgical decision making is based off of intraoperative findings. However, the final gold-standard diagnosis can’t take place until the pathologic specimen is analyzed,” she said. “We also know that there is a significant discordance, as high as 50%, in early-stage endometriosis between visual inspection and pathology findings.”

There were no complications related to the performance of a coincidental appendectomy during surgery or in the 12 weeks after.

Dr. Ross outlined surgeons’ three main options for performing coincidental appendectomy in patients undergoing surgery for chronic pelvic pain or endometriosis: universal coincidental appendectomy, targeted appendectomy based on operative findings, and performing the procedure based on the appearance of the appendix.

Basing the decision on appearance “is going to miss a lot of appendiceal endometriosis,” Dr. Ross said. In the present study, 67 of the 91 cases, about 74%, would have been missed.

Dr. Ross and Dr. Mama had no relevant financial disclosures. The study coauthors disclosed ties to Titan Medical, Merck, and AbbVie.

jremaly@mdedge.com

SOURCE: Ross WT et al. SGS 2020, Abstract 14.

Among women who have a coincidental appendectomy during surgery for chronic pelvic pain or endometriosis, about 15% have appendiceal endometriosis confirmed by pathological examination, according to a study.

“In the women with appendiceal endometriosis, only 26% had an appendix that looked abnormal,” said Whitney T. Ross, MD, of the department of obstetrics and gynecology at Penn State Health, Hershey.

The results, presented at the virtual annual scientific meeting of the Society of Gynecologic Surgeons, indicate that “appendiceal endometriosis is common in women receiving surgery for chronic pelvic pain or endometriosis,” she said. “This study and multiple other studies have also demonstrated that coincidental appendectomy is safe.”

The long-term impact of coincidental appendectomy and its effect on quality of life are not known, however, which may make it difficult to weigh the costs and benefits of the procedure, Dr. Ross said. “It is important to talk to patients about this procedure and determine which approach is the right approach for your institution.”

The study of 609 coincidental appendectomies did not include patients with retrocecal appendices, which may confound the true rate of appendiceal endometriosis, commented Saifuddin T. Mama, MD, MPH, of Rowan University, Camden, N.J.

When the investigators started the study, they were not sure of the risks and benefits of the procedure in patients with retrocecal appendices. An anecdotal report from another research group suggests that outcomes with retrocecal appendices may not be significantly different. “But that is certainly an important question and one that we would like to address in a future prospective study,” Dr. Ross said.

Surgeons have debated the role of coincidental appendectomy during gynecologic surgery. Concerns about safety and questions about the prevalence of appendiceal pathology are reasons that coincidental appendectomy has not been more widely adopted. On the other hand, the procedure may benefit patients and aid diagnosis.

To evaluate the role of coincidental appendectomy in the surgical excision of endometriosis, Dr. Ross and colleagues analyzed data from consecutive coincidental appendectomies performed at one institution between 2013 and 2019. They identified cases in a prospectively maintained surgical database to assess safety and the prevalence of appendiceal pathology.

iStockphoto.com

The indication for surgery was chronic pelvic pain but no visualized endometriosis for 42 patients, stage I-II endometriosis for 388 patients, and stage III-IV endometriosis for 179 patients.

Surgeries included laparoscopic hysterectomy (77.5%), operative laparoscopy (19.9%), and laparoscopic trachelectomy (2.6%). Pathological analysis of the appendices identified endometriosis in 14.9%, malignancy in 0.7%, polyps in 0.5%, and appendicitis in 0.3%.

Among women with chronic pelvic pain but no visualized endometriosis, 2.4% had appendiceal endometriosis. Among those with stage I-II endometriosis, 7% had appendiceal endometriosis, and in patients with stage III-IV endometriosis, the rate of appendiceal endometriosis was 35.2%.

In about 6% of patients with appendiceal endometriosis, the appendix was the only site of pathologically confirmed endometriosis.

Compared with chronic pelvic pain, stage III-IV endometriosis was associated with a significantly increased risk of appendiceal endometriosis (odds ratio, 22.2). The likelihood of appendiceal endometriosis also increased when the appendix looked abnormal (odds ratio, 6.5).

The probability of diagnosing appendiceal endometriosis also increases with the number of other locations of confirmed endometriosis.

“Our surgical decision making is based off of intraoperative findings. However, the final gold-standard diagnosis can’t take place until the pathologic specimen is analyzed,” she said. “We also know that there is a significant discordance, as high as 50%, in early-stage endometriosis between visual inspection and pathology findings.”

There were no complications related to the performance of a coincidental appendectomy during surgery or in the 12 weeks after.

Dr. Ross outlined surgeons’ three main options for performing coincidental appendectomy in patients undergoing surgery for chronic pelvic pain or endometriosis: universal coincidental appendectomy, targeted appendectomy based on operative findings, and performing the procedure based on the appearance of the appendix.

Basing the decision on appearance “is going to miss a lot of appendiceal endometriosis,” Dr. Ross said. In the present study, 67 of the 91 cases, about 74%, would have been missed.

Dr. Ross and Dr. Mama had no relevant financial disclosures. The study coauthors disclosed ties to Titan Medical, Merck, and AbbVie.

jremaly@mdedge.com

SOURCE: Ross WT et al. SGS 2020, Abstract 14.

Simon JA, Al-Hendy A, Archer DF, et al. Elagolix treatment for up to 12 months in women with heavy menstrual bleeding and uterine leiomyomas. Obstet Gynecol. 2020;135:1313-1326.

Expert Commentary

Uterine fibroids are common (occurring in up to 80% of reproductive-age women),^1,2 and often associated with heavy menstrual bleeding (HMB). There are surgical and medical options, but typically medical options are used for short periods of time. Elagolix with hormonal add-back therapy was recently approved (May 29, 2020) by the US Food and Drug Administration (FDA) for treatment of HMB in women with uterine fibroids for up to 24 months.

Elagolix is an oral, nonpeptide gonadotropin-releasing hormone antagonist that results in a dose-dependent reduction of gonadotropins and ovarian sex hormones. There are now 2 approved products containing elagolix, with different indications:

• Orilissa. Elagolix was approved in 2018 by the FDA for moderate to severe pain associated with endometriosis. For that indication there are 2 dose options of elagolix (150 mg for up to 2 years and 200 mg for up to 6 months) and there is no hormonal add-back therapy.
• Oriahnn. Elagolix and hormonal add-back therapy was approved in 2020 for HMB associated with uterine fibroids for up to 24 months. The total daily dose of elagolix is 600 mg (elagolix 300 mg in the morning with estradiol 1 mg/norethindrone acetate 0.5 mg and then in the evening elagolix 300 mg and no hormonal add-back).

This new class of drug, GnRH antagonist, is an important one for women’s health, and emerging science will continue to expand its potential uses, such as in reproductive health, as well as long-term efficacy and safety. The difference in daily dose of elagolix for endometriosis (150 mg for 24 months) compared with HMB associated with fibroids (600 mg for 24 months) is why the hormonal add-back therapy is important and allows for protection of bone density.

This is an important manuscript because it highlights a medical option for women with HMB associated with fibroids, which can be used for a long period of time. Further, the improvement in bleeding is both impressive and maintained in the extension study. Approximately 90% of women show improvement in their menstrual bleeding associated with fibroids.

The question of what to do after 24 months of therapy with elagolix and hormonal add-back therapy is an important one, but providers should recognize that the limiting factor with this elagolix and hormonal add-back therapy is bone mineral density (BMD). We will only learn more and more moving forward if this is a clinically meaningful reason for stopping treatment at 24 months. The FDA takes a strict view of safety, and providers must weigh this with the benefit of therapy.

One other highlight between the 2 approved medications is that Orilissa does not have a black box warning, given that there is no hormonal add-back therapy. Oriahnn does have a warning, regarding thromboembolic disorders and vascular events:

• Estrogen and progestin combinations, including Oriahnn, increase the risk of thrombotic or thromboembolic disorders, especially in women at increased risk for these events.
• Oriahnn is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women over 35 years of age who smoke or women with uncontrolled hypertension.

Continue to: Details about the study...

Details about the study

The study by Simon et al is an extension study (UF-EXTEND), in that women could participate if they had completed 1 of the 2 pivotal studies on elagolix. The pivotal studies (Elaris UF1 and UF2) were both randomized, double-blinded, placebo-controlled studies with up to 6 months of therapy; for UF-EXTEND, however, participants were randomly assigned to either combined elagolix and hormone replacement therapy or elagolix alone for an additional 6 months of therapy. Although it was known that all participants would receive elagolix in UF-EXTEND, those who received hormonal add-back therapy were blinded. All women were then followed up for an additional 12 months after treatment ended.

The efficacy of elagolix was measured by the objective alkaline hematin method for menstrual blood loss with the a priori coprimary endpoints. The elagolix and hormonal add-back therapy group showed objective improvement in menstrual blood loss at 12 months in 87.9% of women in the extension study (89.4% in the elagolix alone group). This compares with 72.2% improvement at 6 months of treatment in the UF1 and UF2 studies for those taking elagolix and hormonal add-back therapy. These findings illustrate maintenance of the efficacy seen within the 6-month pivotal studies using elagolix over an extended amount of time.

The safety of elagolix also was demonstrated in UF-EXTEND. The 3 most common adverse events were similar to those found in Elaris UF1 and UF2 and included hot flushes, headache, and nausea. In the elagolix and hormonal add-back therapy group during the extension study, the percentage with hot flushes was 7%, headache 6%, and nausea 4%. These are small percentages, which is encouraging for providers and women with HMB associated with fibroids.

Effects on bone density

Bone density was evaluated at baseline in the UF1 and UF2 studies, through treatment, and then 12 months after the extended treatment was stopped. The hormonal add-back therapy of estradiol 1 mg/norethindrone acetate 0.5 mg significantly protected bone density. Some women did not have a decrease in bone density, but for those who did the average was less than 5% for the lumbar spine. The lumbar spine is considered the most reactive, so this illustrates the safety that combined therapy offers women with HMB and fibroids.

The lumbar spine is considered the most reactive, so this site is often used as the main focus with BMD studies. As Simon et al show, the lumbar spine mean BMD percent change from baseline for the elagolix with add-back therapy was -1.5% (95% confidence interval [CI], -1.9 to -1.0) in women who received up to 12 months of treatment at month 6 in the extension study. After stopping elagolix with add-back therapy, at 6 months the elagolix with add-back therapy had a Z-score of -0.6% (95% CI, -1.1 to -0.1). This shows a trend toward baseline, or a recovery within a short time from stopping medication.

Continue to: Study strengths and limitations...

Study strengths and limitations

Strengths of this study include its overall design; efficacy endpoints, which were all established a priori; the fact that measurement of menstrual blood loss was done with the objective alkaline hematin method; and the statistical analysis, which is thorough and well presented. This extension study allowed further evaluation of efficacy and safety for elagolix. Although the authors point out that there may be some selection bias in an extension study, the fact that so many women elected to continue into the extended study is a positive reflection of the treatment.

As providers learn of new therapies for management of HMB associated with fibroids, it is important to consider who will benefit the most. In my opinion, any woman with heavy periods associated with fibroids could be a candidate for elagolix with add-back therapy. This treatment is highly effective, well tolerated, and safe. My approach to management includes educating a woman on all potential therapies and this new option of elagolix and add-back therapy is an important one. The decision for an individual woman on how to manage heavy periods associated with fibroids should consider her contraceptive needs, medical issues, and the risk and benefit of individual therapies. ●

Simon JA, Al-Hendy A, Archer DF, et al. Elagolix treatment for up to 12 months in women with heavy menstrual bleeding and uterine leiomyomas. Obstet Gynecol. 2020;135:1313-1326.

Expert Commentary

Uterine fibroids are common (occurring in up to 80% of reproductive-age women),^1,2 and often associated with heavy menstrual bleeding (HMB). There are surgical and medical options, but typically medical options are used for short periods of time. Elagolix with hormonal add-back therapy was recently approved (May 29, 2020) by the US Food and Drug Administration (FDA) for treatment of HMB in women with uterine fibroids for up to 24 months.

Elagolix is an oral, nonpeptide gonadotropin-releasing hormone antagonist that results in a dose-dependent reduction of gonadotropins and ovarian sex hormones. There are now 2 approved products containing elagolix, with different indications:

• Orilissa. Elagolix was approved in 2018 by the FDA for moderate to severe pain associated with endometriosis. For that indication there are 2 dose options of elagolix (150 mg for up to 2 years and 200 mg for up to 6 months) and there is no hormonal add-back therapy.
• Oriahnn. Elagolix and hormonal add-back therapy was approved in 2020 for HMB associated with uterine fibroids for up to 24 months. The total daily dose of elagolix is 600 mg (elagolix 300 mg in the morning with estradiol 1 mg/norethindrone acetate 0.5 mg and then in the evening elagolix 300 mg and no hormonal add-back).

This new class of drug, GnRH antagonist, is an important one for women’s health, and emerging science will continue to expand its potential uses, such as in reproductive health, as well as long-term efficacy and safety. The difference in daily dose of elagolix for endometriosis (150 mg for 24 months) compared with HMB associated with fibroids (600 mg for 24 months) is why the hormonal add-back therapy is important and allows for protection of bone density.

This is an important manuscript because it highlights a medical option for women with HMB associated with fibroids, which can be used for a long period of time. Further, the improvement in bleeding is both impressive and maintained in the extension study. Approximately 90% of women show improvement in their menstrual bleeding associated with fibroids.

The question of what to do after 24 months of therapy with elagolix and hormonal add-back therapy is an important one, but providers should recognize that the limiting factor with this elagolix and hormonal add-back therapy is bone mineral density (BMD). We will only learn more and more moving forward if this is a clinically meaningful reason for stopping treatment at 24 months. The FDA takes a strict view of safety, and providers must weigh this with the benefit of therapy.

One other highlight between the 2 approved medications is that Orilissa does not have a black box warning, given that there is no hormonal add-back therapy. Oriahnn does have a warning, regarding thromboembolic disorders and vascular events:

• Estrogen and progestin combinations, including Oriahnn, increase the risk of thrombotic or thromboembolic disorders, especially in women at increased risk for these events.
• Oriahnn is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women over 35 years of age who smoke or women with uncontrolled hypertension.

Continue to: Details about the study...

Details about the study

The study by Simon et al is an extension study (UF-EXTEND), in that women could participate if they had completed 1 of the 2 pivotal studies on elagolix. The pivotal studies (Elaris UF1 and UF2) were both randomized, double-blinded, placebo-controlled studies with up to 6 months of therapy; for UF-EXTEND, however, participants were randomly assigned to either combined elagolix and hormone replacement therapy or elagolix alone for an additional 6 months of therapy. Although it was known that all participants would receive elagolix in UF-EXTEND, those who received hormonal add-back therapy were blinded. All women were then followed up for an additional 12 months after treatment ended.

The efficacy of elagolix was measured by the objective alkaline hematin method for menstrual blood loss with the a priori coprimary endpoints. The elagolix and hormonal add-back therapy group showed objective improvement in menstrual blood loss at 12 months in 87.9% of women in the extension study (89.4% in the elagolix alone group). This compares with 72.2% improvement at 6 months of treatment in the UF1 and UF2 studies for those taking elagolix and hormonal add-back therapy. These findings illustrate maintenance of the efficacy seen within the 6-month pivotal studies using elagolix over an extended amount of time.

The safety of elagolix also was demonstrated in UF-EXTEND. The 3 most common adverse events were similar to those found in Elaris UF1 and UF2 and included hot flushes, headache, and nausea. In the elagolix and hormonal add-back therapy group during the extension study, the percentage with hot flushes was 7%, headache 6%, and nausea 4%. These are small percentages, which is encouraging for providers and women with HMB associated with fibroids.

Effects on bone density

Bone density was evaluated at baseline in the UF1 and UF2 studies, through treatment, and then 12 months after the extended treatment was stopped. The hormonal add-back therapy of estradiol 1 mg/norethindrone acetate 0.5 mg significantly protected bone density. Some women did not have a decrease in bone density, but for those who did the average was less than 5% for the lumbar spine. The lumbar spine is considered the most reactive, so this illustrates the safety that combined therapy offers women with HMB and fibroids.

The lumbar spine is considered the most reactive, so this site is often used as the main focus with BMD studies. As Simon et al show, the lumbar spine mean BMD percent change from baseline for the elagolix with add-back therapy was -1.5% (95% confidence interval [CI], -1.9 to -1.0) in women who received up to 12 months of treatment at month 6 in the extension study. After stopping elagolix with add-back therapy, at 6 months the elagolix with add-back therapy had a Z-score of -0.6% (95% CI, -1.1 to -0.1). This shows a trend toward baseline, or a recovery within a short time from stopping medication.

Continue to: Study strengths and limitations...

Study strengths and limitations

Strengths of this study include its overall design; efficacy endpoints, which were all established a priori; the fact that measurement of menstrual blood loss was done with the objective alkaline hematin method; and the statistical analysis, which is thorough and well presented. This extension study allowed further evaluation of efficacy and safety for elagolix. Although the authors point out that there may be some selection bias in an extension study, the fact that so many women elected to continue into the extended study is a positive reflection of the treatment.

As providers learn of new therapies for management of HMB associated with fibroids, it is important to consider who will benefit the most. In my opinion, any woman with heavy periods associated with fibroids could be a candidate for elagolix with add-back therapy. This treatment is highly effective, well tolerated, and safe. My approach to management includes educating a woman on all potential therapies and this new option of elagolix and add-back therapy is an important one. The decision for an individual woman on how to manage heavy periods associated with fibroids should consider her contraceptive needs, medical issues, and the risk and benefit of individual therapies. ●

Simon JA, Al-Hendy A, Archer DF, et al. Elagolix treatment for up to 12 months in women with heavy menstrual bleeding and uterine leiomyomas. Obstet Gynecol. 2020;135:1313-1326.

Expert Commentary

Uterine fibroids are common (occurring in up to 80% of reproductive-age women),^1,2 and often associated with heavy menstrual bleeding (HMB). There are surgical and medical options, but typically medical options are used for short periods of time. Elagolix with hormonal add-back therapy was recently approved (May 29, 2020) by the US Food and Drug Administration (FDA) for treatment of HMB in women with uterine fibroids for up to 24 months.

Elagolix is an oral, nonpeptide gonadotropin-releasing hormone antagonist that results in a dose-dependent reduction of gonadotropins and ovarian sex hormones. There are now 2 approved products containing elagolix, with different indications:

• Orilissa. Elagolix was approved in 2018 by the FDA for moderate to severe pain associated with endometriosis. For that indication there are 2 dose options of elagolix (150 mg for up to 2 years and 200 mg for up to 6 months) and there is no hormonal add-back therapy.
• Oriahnn. Elagolix and hormonal add-back therapy was approved in 2020 for HMB associated with uterine fibroids for up to 24 months. The total daily dose of elagolix is 600 mg (elagolix 300 mg in the morning with estradiol 1 mg/norethindrone acetate 0.5 mg and then in the evening elagolix 300 mg and no hormonal add-back).

This new class of drug, GnRH antagonist, is an important one for women’s health, and emerging science will continue to expand its potential uses, such as in reproductive health, as well as long-term efficacy and safety. The difference in daily dose of elagolix for endometriosis (150 mg for 24 months) compared with HMB associated with fibroids (600 mg for 24 months) is why the hormonal add-back therapy is important and allows for protection of bone density.

This is an important manuscript because it highlights a medical option for women with HMB associated with fibroids, which can be used for a long period of time. Further, the improvement in bleeding is both impressive and maintained in the extension study. Approximately 90% of women show improvement in their menstrual bleeding associated with fibroids.

The question of what to do after 24 months of therapy with elagolix and hormonal add-back therapy is an important one, but providers should recognize that the limiting factor with this elagolix and hormonal add-back therapy is bone mineral density (BMD). We will only learn more and more moving forward if this is a clinically meaningful reason for stopping treatment at 24 months. The FDA takes a strict view of safety, and providers must weigh this with the benefit of therapy.

One other highlight between the 2 approved medications is that Orilissa does not have a black box warning, given that there is no hormonal add-back therapy. Oriahnn does have a warning, regarding thromboembolic disorders and vascular events:

• Estrogen and progestin combinations, including Oriahnn, increase the risk of thrombotic or thromboembolic disorders, especially in women at increased risk for these events.
• Oriahnn is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women over 35 years of age who smoke or women with uncontrolled hypertension.

Continue to: Details about the study...

Details about the study

The study by Simon et al is an extension study (UF-EXTEND), in that women could participate if they had completed 1 of the 2 pivotal studies on elagolix. The pivotal studies (Elaris UF1 and UF2) were both randomized, double-blinded, placebo-controlled studies with up to 6 months of therapy; for UF-EXTEND, however, participants were randomly assigned to either combined elagolix and hormone replacement therapy or elagolix alone for an additional 6 months of therapy. Although it was known that all participants would receive elagolix in UF-EXTEND, those who received hormonal add-back therapy were blinded. All women were then followed up for an additional 12 months after treatment ended.

The efficacy of elagolix was measured by the objective alkaline hematin method for menstrual blood loss with the a priori coprimary endpoints. The elagolix and hormonal add-back therapy group showed objective improvement in menstrual blood loss at 12 months in 87.9% of women in the extension study (89.4% in the elagolix alone group). This compares with 72.2% improvement at 6 months of treatment in the UF1 and UF2 studies for those taking elagolix and hormonal add-back therapy. These findings illustrate maintenance of the efficacy seen within the 6-month pivotal studies using elagolix over an extended amount of time.

The safety of elagolix also was demonstrated in UF-EXTEND. The 3 most common adverse events were similar to those found in Elaris UF1 and UF2 and included hot flushes, headache, and nausea. In the elagolix and hormonal add-back therapy group during the extension study, the percentage with hot flushes was 7%, headache 6%, and nausea 4%. These are small percentages, which is encouraging for providers and women with HMB associated with fibroids.

Effects on bone density

Bone density was evaluated at baseline in the UF1 and UF2 studies, through treatment, and then 12 months after the extended treatment was stopped. The hormonal add-back therapy of estradiol 1 mg/norethindrone acetate 0.5 mg significantly protected bone density. Some women did not have a decrease in bone density, but for those who did the average was less than 5% for the lumbar spine. The lumbar spine is considered the most reactive, so this illustrates the safety that combined therapy offers women with HMB and fibroids.

The lumbar spine is considered the most reactive, so this site is often used as the main focus with BMD studies. As Simon et al show, the lumbar spine mean BMD percent change from baseline for the elagolix with add-back therapy was -1.5% (95% confidence interval [CI], -1.9 to -1.0) in women who received up to 12 months of treatment at month 6 in the extension study. After stopping elagolix with add-back therapy, at 6 months the elagolix with add-back therapy had a Z-score of -0.6% (95% CI, -1.1 to -0.1). This shows a trend toward baseline, or a recovery within a short time from stopping medication.

Continue to: Study strengths and limitations...

Study strengths and limitations

Strengths of this study include its overall design; efficacy endpoints, which were all established a priori; the fact that measurement of menstrual blood loss was done with the objective alkaline hematin method; and the statistical analysis, which is thorough and well presented. This extension study allowed further evaluation of efficacy and safety for elagolix. Although the authors point out that there may be some selection bias in an extension study, the fact that so many women elected to continue into the extended study is a positive reflection of the treatment.

As providers learn of new therapies for management of HMB associated with fibroids, it is important to consider who will benefit the most. In my opinion, any woman with heavy periods associated with fibroids could be a candidate for elagolix with add-back therapy. This treatment is highly effective, well tolerated, and safe. My approach to management includes educating a woman on all potential therapies and this new option of elagolix and add-back therapy is an important one. The decision for an individual woman on how to manage heavy periods associated with fibroids should consider her contraceptive needs, medical issues, and the risk and benefit of individual therapies. ●

NATIONAL HARBOR, MD. – Botulinum toxin injection into the vagina appears to relieve pain associated with endometriosis by relaxing the pelvic floor muscles, new research suggests.

In a randomized study, women with surgically diagnosed endometriosis who had chronic pelvic pain despite optimal surgical and hormonal treatment had less pain after injection vs their counterparts who received placebo.

This result suggests pelvic floor spasm may be an important factor in endometriosis-associated pelvic pain, the investigators note.

“Botulinum toxin injection offers an alternative approach for women with pelvic pain,” lead author Barbara Illowsky Karp, MD, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md., told Medscape Medical News.

“We focused on endometriosis, but there are reasons to think it may be effective for pelvic pain from other causes if there is spasm of the muscle,” said Karp, a neurologist who has used botulinum toxin therapeutically since it was first developed in the 1980s.

She noted that it is unknown whether the toxin will work in women who do not have actual spasm, “but the effect on spasm is not the sole effect of toxin,” as demonstrated by its use in other pain conditions.

“It seems to have a direct effect on the pain pathways in the nervous system as well,” Karp added.

The study findings were presented here at the American Academy of Pain Medicine (AAPM) 2020 Annual Meeting.
 

Less pain

The investigators randomly assigned 29 women between the ages of 18 and 50 years to receive injections with 100 U onabotulinumtoxinA (n = 15) or saline placebo (n = 14).

All of the women had endometriosis with chronic pelvic pain lasting at least 3 months (mean time, 6 years) and confirmed pelvic floor spasm as a main pain generator.

One month after treatment, participants were asked if they had improvement in their pain.

“Our primary outcome was just simply asking the women if they felt better or not, because we were blinded as to what treatment they received. One month is typically when the toxin reaches its maximal effect,” Karp said.

At 1 month, 11 women in the placebo group reported that they had no benefit, compared with only 4 women in the botulinum toxin group (P = .027).

The botulinum toxin group reported a greater degree of benefit compared with the placebo group (P = .030) and greater percent of improvement (P = .034).

Neither group reported substantial changes in pain rating on the visual analog scale. However, a definite pain score is often difficult to measure in women with chronic pelvic pain, coinvestigator Pamela Stratton, MD, a gynecologist in Bethesda, said.

“Some women report their pain as a 2, some as an 8. Also, women may have a lot of pain one day and not have that much pain another day, and how do you measure that? This is why we have not focused solely on the pain score but instead wanted the women to tell us if they were improved or not,” Stratton told Medscape Medical News.

Disability worsened considerably in the placebo group, but remained consistent in the botulinum toxin group. Five patients in the botulinum toxin group were able to reduce pain medication compared with one patient in the placebo group.
 

“Compelling” findings but early days

Commenting on the findings for Medscape Medical News, Ann E. Hansen, MD, Chronic Pain Wellness Center, Phoenix VA Health Care System, Arizona, noted that this “preliminary study” showed some benefit for a complex and challenging-to-treat syndrome.

“Injection of botulinum toxin prevents local muscle contraction, thus effectively relieving a variety of neuromuscular conditions such as torticollis; spasticity; pain syndromes such as headache and migraine; and some neurologic disorders, for instance, overactive bladder,” said Hansen, who was not involved with the research.

“Using botulinum toxin injection to target pelvic floor muscle spasm, a known pain generator in women suffering from chronic pelvic pain, makes sense. Future studies will be helpful in elucidating optimal treatment protocols for this debilitating condition,” she added.

Also commenting for Medscape Medical News, Kathryn T. Hall, PhD, MPH, Brigham & Women’s Hospital, Boston, Massachusetts, called the results “quite compelling” although, “it’s still early days.”

“It remains to be seen if the treatment effect will endure or if side effects will emerge. Hopefully all will go well,” Hall said.

The study was funded by an unrestricted grant from the National Institutes of Health. Allergan provided the botulinum toxin that was used in the study. Karp, Stratton, Hansen, and Hall have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

NATIONAL HARBOR, MD. – Botulinum toxin injection into the vagina appears to relieve pain associated with endometriosis by relaxing the pelvic floor muscles, new research suggests.

In a randomized study, women with surgically diagnosed endometriosis who had chronic pelvic pain despite optimal surgical and hormonal treatment had less pain after injection vs their counterparts who received placebo.

This result suggests pelvic floor spasm may be an important factor in endometriosis-associated pelvic pain, the investigators note.

“Botulinum toxin injection offers an alternative approach for women with pelvic pain,” lead author Barbara Illowsky Karp, MD, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md., told Medscape Medical News.

“We focused on endometriosis, but there are reasons to think it may be effective for pelvic pain from other causes if there is spasm of the muscle,” said Karp, a neurologist who has used botulinum toxin therapeutically since it was first developed in the 1980s.

She noted that it is unknown whether the toxin will work in women who do not have actual spasm, “but the effect on spasm is not the sole effect of toxin,” as demonstrated by its use in other pain conditions.

“It seems to have a direct effect on the pain pathways in the nervous system as well,” Karp added.

The study findings were presented here at the American Academy of Pain Medicine (AAPM) 2020 Annual Meeting.
 

Less pain

The investigators randomly assigned 29 women between the ages of 18 and 50 years to receive injections with 100 U onabotulinumtoxinA (n = 15) or saline placebo (n = 14).

All of the women had endometriosis with chronic pelvic pain lasting at least 3 months (mean time, 6 years) and confirmed pelvic floor spasm as a main pain generator.

One month after treatment, participants were asked if they had improvement in their pain.

“Our primary outcome was just simply asking the women if they felt better or not, because we were blinded as to what treatment they received. One month is typically when the toxin reaches its maximal effect,” Karp said.

At 1 month, 11 women in the placebo group reported that they had no benefit, compared with only 4 women in the botulinum toxin group (P = .027).

The botulinum toxin group reported a greater degree of benefit compared with the placebo group (P = .030) and greater percent of improvement (P = .034).

Neither group reported substantial changes in pain rating on the visual analog scale. However, a definite pain score is often difficult to measure in women with chronic pelvic pain, coinvestigator Pamela Stratton, MD, a gynecologist in Bethesda, said.

“Some women report their pain as a 2, some as an 8. Also, women may have a lot of pain one day and not have that much pain another day, and how do you measure that? This is why we have not focused solely on the pain score but instead wanted the women to tell us if they were improved or not,” Stratton told Medscape Medical News.

Disability worsened considerably in the placebo group, but remained consistent in the botulinum toxin group. Five patients in the botulinum toxin group were able to reduce pain medication compared with one patient in the placebo group.
 

“Compelling” findings but early days

Commenting on the findings for Medscape Medical News, Ann E. Hansen, MD, Chronic Pain Wellness Center, Phoenix VA Health Care System, Arizona, noted that this “preliminary study” showed some benefit for a complex and challenging-to-treat syndrome.

“Injection of botulinum toxin prevents local muscle contraction, thus effectively relieving a variety of neuromuscular conditions such as torticollis; spasticity; pain syndromes such as headache and migraine; and some neurologic disorders, for instance, overactive bladder,” said Hansen, who was not involved with the research.

“Using botulinum toxin injection to target pelvic floor muscle spasm, a known pain generator in women suffering from chronic pelvic pain, makes sense. Future studies will be helpful in elucidating optimal treatment protocols for this debilitating condition,” she added.

Also commenting for Medscape Medical News, Kathryn T. Hall, PhD, MPH, Brigham & Women’s Hospital, Boston, Massachusetts, called the results “quite compelling” although, “it’s still early days.”

“It remains to be seen if the treatment effect will endure or if side effects will emerge. Hopefully all will go well,” Hall said.

The study was funded by an unrestricted grant from the National Institutes of Health. Allergan provided the botulinum toxin that was used in the study. Karp, Stratton, Hansen, and Hall have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

NATIONAL HARBOR, MD. – Botulinum toxin injection into the vagina appears to relieve pain associated with endometriosis by relaxing the pelvic floor muscles, new research suggests.

In a randomized study, women with surgically diagnosed endometriosis who had chronic pelvic pain despite optimal surgical and hormonal treatment had less pain after injection vs their counterparts who received placebo.

This result suggests pelvic floor spasm may be an important factor in endometriosis-associated pelvic pain, the investigators note.

“Botulinum toxin injection offers an alternative approach for women with pelvic pain,” lead author Barbara Illowsky Karp, MD, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md., told Medscape Medical News.

“We focused on endometriosis, but there are reasons to think it may be effective for pelvic pain from other causes if there is spasm of the muscle,” said Karp, a neurologist who has used botulinum toxin therapeutically since it was first developed in the 1980s.

She noted that it is unknown whether the toxin will work in women who do not have actual spasm, “but the effect on spasm is not the sole effect of toxin,” as demonstrated by its use in other pain conditions.

“It seems to have a direct effect on the pain pathways in the nervous system as well,” Karp added.

The study findings were presented here at the American Academy of Pain Medicine (AAPM) 2020 Annual Meeting.
 

Less pain

The investigators randomly assigned 29 women between the ages of 18 and 50 years to receive injections with 100 U onabotulinumtoxinA (n = 15) or saline placebo (n = 14).

All of the women had endometriosis with chronic pelvic pain lasting at least 3 months (mean time, 6 years) and confirmed pelvic floor spasm as a main pain generator.

One month after treatment, participants were asked if they had improvement in their pain.

“Our primary outcome was just simply asking the women if they felt better or not, because we were blinded as to what treatment they received. One month is typically when the toxin reaches its maximal effect,” Karp said.

At 1 month, 11 women in the placebo group reported that they had no benefit, compared with only 4 women in the botulinum toxin group (P = .027).

The botulinum toxin group reported a greater degree of benefit compared with the placebo group (P = .030) and greater percent of improvement (P = .034).

Neither group reported substantial changes in pain rating on the visual analog scale. However, a definite pain score is often difficult to measure in women with chronic pelvic pain, coinvestigator Pamela Stratton, MD, a gynecologist in Bethesda, said.

“Some women report their pain as a 2, some as an 8. Also, women may have a lot of pain one day and not have that much pain another day, and how do you measure that? This is why we have not focused solely on the pain score but instead wanted the women to tell us if they were improved or not,” Stratton told Medscape Medical News.

Disability worsened considerably in the placebo group, but remained consistent in the botulinum toxin group. Five patients in the botulinum toxin group were able to reduce pain medication compared with one patient in the placebo group.
 

“Compelling” findings but early days

Commenting on the findings for Medscape Medical News, Ann E. Hansen, MD, Chronic Pain Wellness Center, Phoenix VA Health Care System, Arizona, noted that this “preliminary study” showed some benefit for a complex and challenging-to-treat syndrome.

“Injection of botulinum toxin prevents local muscle contraction, thus effectively relieving a variety of neuromuscular conditions such as torticollis; spasticity; pain syndromes such as headache and migraine; and some neurologic disorders, for instance, overactive bladder,” said Hansen, who was not involved with the research.

“Using botulinum toxin injection to target pelvic floor muscle spasm, a known pain generator in women suffering from chronic pelvic pain, makes sense. Future studies will be helpful in elucidating optimal treatment protocols for this debilitating condition,” she added.

Also commenting for Medscape Medical News, Kathryn T. Hall, PhD, MPH, Brigham & Women’s Hospital, Boston, Massachusetts, called the results “quite compelling” although, “it’s still early days.”

“It remains to be seen if the treatment effect will endure or if side effects will emerge. Hopefully all will go well,” Hall said.

The study was funded by an unrestricted grant from the National Institutes of Health. Allergan provided the botulinum toxin that was used in the study. Karp, Stratton, Hansen, and Hall have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Whether or not women experience symptoms from uterine fibroid(s) can be dependent on a fibroid’s size and location. Heavy menstrual bleeding (HMB) is the most common symptom resulting from fibroids, and it occurs in up to one-third of women with fibroids. For fibroids that are large (>10 cm), “bulk” symptoms may occur, including pelvic pressure, urinary urgency or frequency, incontinence, constipation, abdominal protrusion, etc.¹

Elagolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, was US Food and Drug Administration–approved in 2018 to treat moderate to severe pain caused by endometriosis. ² Elagolix is being evaluated in 2 phase 3 randomized, double-blind trials for the additional treatment of HMB associated with uterine fibroids. The results of these studies were presented at the 2019 AAGL meeting on November 12, in Vancouver, Canada.
 

Phase 3 study details

Premenopausal women aged 18 to 51 years were included in the Elaris UF-1 and UF-2 studies if they had HMB (defined using the alkaline hematin methodology as menstrual blood loss [MBL] >80 mL/cycle) and uterine fibroids as confirmed through ultrasound. Because elagolix suppresses estrogen and progesterone, treatment results in dose- and duration-dependent decreases in bone mineral density (BMD),² and add-back therapy can lessen these adverse effects. Subsequently, participants were randomly assigned 1:1:2 to placebo, elagolix 300 mg twice daily, or elagolix 300 mg twice daily with add-back therapy (1 mg estradiol/0.5 mg norethidrone acetate [E2/NETA]) once daily. Uterine volume and size and location of uterine fibroid(s) were assessed by ultrasound. Subgroups were defined by baseline FIGO categories, grouped FIGO 0-3, FIGO 4, or FIGO 5-8.³

Over the 6-month studies, 72.2% (95% confidence interval [CI], 67.65–76.73) of the 395 women who received elagolix plus E2/NETA achieved < 80 mL MBL during the final month and ≥ 50% MBL reduction from baseline to the final month. When stratified by FIGO classification, the results were similar for all subgroups: FIGO 0-3, 77.7% (95% CI, 67.21–80.85). Similar results were seen in women with a primary fibroid volume of either greater or less than 36.2 cm³ (median).³



The most frequently reported adverse events among women taking elagolix plus E2/NETA were hot flushes, night sweats, nausea, and headache. Changes in BMD among these women were not significant compared with women taking placebo.³

The Elaris UF-1 and UF-2 studies are funded by AbbVie Inc.

Whether or not women experience symptoms from uterine fibroid(s) can be dependent on a fibroid’s size and location. Heavy menstrual bleeding (HMB) is the most common symptom resulting from fibroids, and it occurs in up to one-third of women with fibroids. For fibroids that are large (>10 cm), “bulk” symptoms may occur, including pelvic pressure, urinary urgency or frequency, incontinence, constipation, abdominal protrusion, etc.¹

Elagolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, was US Food and Drug Administration–approved in 2018 to treat moderate to severe pain caused by endometriosis. ² Elagolix is being evaluated in 2 phase 3 randomized, double-blind trials for the additional treatment of HMB associated with uterine fibroids. The results of these studies were presented at the 2019 AAGL meeting on November 12, in Vancouver, Canada.
 

Phase 3 study details

Premenopausal women aged 18 to 51 years were included in the Elaris UF-1 and UF-2 studies if they had HMB (defined using the alkaline hematin methodology as menstrual blood loss [MBL] >80 mL/cycle) and uterine fibroids as confirmed through ultrasound. Because elagolix suppresses estrogen and progesterone, treatment results in dose- and duration-dependent decreases in bone mineral density (BMD),² and add-back therapy can lessen these adverse effects. Subsequently, participants were randomly assigned 1:1:2 to placebo, elagolix 300 mg twice daily, or elagolix 300 mg twice daily with add-back therapy (1 mg estradiol/0.5 mg norethidrone acetate [E2/NETA]) once daily. Uterine volume and size and location of uterine fibroid(s) were assessed by ultrasound. Subgroups were defined by baseline FIGO categories, grouped FIGO 0-3, FIGO 4, or FIGO 5-8.³

Over the 6-month studies, 72.2% (95% confidence interval [CI], 67.65–76.73) of the 395 women who received elagolix plus E2/NETA achieved < 80 mL MBL during the final month and ≥ 50% MBL reduction from baseline to the final month. When stratified by FIGO classification, the results were similar for all subgroups: FIGO 0-3, 77.7% (95% CI, 67.21–80.85). Similar results were seen in women with a primary fibroid volume of either greater or less than 36.2 cm³ (median).³



The most frequently reported adverse events among women taking elagolix plus E2/NETA were hot flushes, night sweats, nausea, and headache. Changes in BMD among these women were not significant compared with women taking placebo.³

The Elaris UF-1 and UF-2 studies are funded by AbbVie Inc.

Whether or not women experience symptoms from uterine fibroid(s) can be dependent on a fibroid’s size and location. Heavy menstrual bleeding (HMB) is the most common symptom resulting from fibroids, and it occurs in up to one-third of women with fibroids. For fibroids that are large (>10 cm), “bulk” symptoms may occur, including pelvic pressure, urinary urgency or frequency, incontinence, constipation, abdominal protrusion, etc.¹

Elagolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, was US Food and Drug Administration–approved in 2018 to treat moderate to severe pain caused by endometriosis. ² Elagolix is being evaluated in 2 phase 3 randomized, double-blind trials for the additional treatment of HMB associated with uterine fibroids. The results of these studies were presented at the 2019 AAGL meeting on November 12, in Vancouver, Canada.
 

Phase 3 study details

Premenopausal women aged 18 to 51 years were included in the Elaris UF-1 and UF-2 studies if they had HMB (defined using the alkaline hematin methodology as menstrual blood loss [MBL] >80 mL/cycle) and uterine fibroids as confirmed through ultrasound. Because elagolix suppresses estrogen and progesterone, treatment results in dose- and duration-dependent decreases in bone mineral density (BMD),² and add-back therapy can lessen these adverse effects. Subsequently, participants were randomly assigned 1:1:2 to placebo, elagolix 300 mg twice daily, or elagolix 300 mg twice daily with add-back therapy (1 mg estradiol/0.5 mg norethidrone acetate [E2/NETA]) once daily. Uterine volume and size and location of uterine fibroid(s) were assessed by ultrasound. Subgroups were defined by baseline FIGO categories, grouped FIGO 0-3, FIGO 4, or FIGO 5-8.³

Over the 6-month studies, 72.2% (95% confidence interval [CI], 67.65–76.73) of the 395 women who received elagolix plus E2/NETA achieved < 80 mL MBL during the final month and ≥ 50% MBL reduction from baseline to the final month. When stratified by FIGO classification, the results were similar for all subgroups: FIGO 0-3, 77.7% (95% CI, 67.21–80.85). Similar results were seen in women with a primary fibroid volume of either greater or less than 36.2 cm³ (median).³



The most frequently reported adverse events among women taking elagolix plus E2/NETA were hot flushes, night sweats, nausea, and headache. Changes in BMD among these women were not significant compared with women taking placebo.³

The Elaris UF-1 and UF-2 studies are funded by AbbVie Inc.

VANCOUVER – Presurgical ultrasound does a good job predicting advanced versus early American Society of Reproductive Medicine endometriosis stage, and that can help ensure that a patient gets to the right surgeon.

Researchers retrospectively collected data from ultrasounds, using it to create an ASRM stage, and compared the results with the stage seen at surgery. “We’re very good at telling people what they should expect at surgery,” said Mathew Leonardi, MD, who is a gynecologist at the University of Sydney’s Nepean Hospital.

The researchers conducted the study because of perceived mistrust among surgeons when it comes to presurgical imaging. “There is still a lot of cynicism and a lot of hesitancy to adopt this,” Dr. Leonardi said at the meeting sponsored by AAGL. He was unapologetic about the activist nature of the research. “We thought, what better way [to convince surgeons] than to produce an ultrasound-based ASRM scoring system to then match to the surgical findings, because if we can predict the ASRM score preoperatively, there may be more buy-in by the surgeons for the value of imaging.”

He noted that surgeons differ in their training, so getting the patient to the right surgeon is critical. “If you go to a gynecologist who is not minimally invasive trained, you may [end up with] an abandoned surgery, or an incomplete surgical excision leading to residual disease. So being able to predict the severity of the disease preoperatively, you can allow the patient to get to the right surgeon with the right team members.”

The analysis included 204 procedures performed between January 2016 and April 2018. Participants underwent deep endometriosis transvaginal ultrasound at one of two tertiary referral service centers, and laparoscopy by surgeons in the Sydney metropolitan area. Each case was received as a ASRM score of 0-4 at both ultrasound and surgery, and scores of 0-2 and 3-4 were grouped together for analysis.

“We grouped patients that have ASRM 3-4 into one group and those who have less than that [into another group], because clinically that seems to be where the most practical divide is,” said Dr. Leonardi.

It was difficult to differentiate individual ASRM stages from one another using ultrasound, but the technique performed much better in the combined analysis. In assigning a patient to the ASRM stage 0-2 endometriosis group, it had 94.9% sensitivity and 93.8% specificity, and for assigning to ASRM stage 3-4, it had values of 93.8% and 94.9%, respectively.

The success is encouraging, but there is more work to be done. “We are going to have to differentiate those with early-stage endometriosis or stage 1-2, and those that are negative. We are working on being able to identify superficial endometriosis noninvasively, but for now, as a triaging tool ultrasound can get the patient to the right surgeon,” Dr. Leonardi said.

Dr. Leonardi reported no relevant financial disclosures

VANCOUVER – Presurgical ultrasound does a good job predicting advanced versus early American Society of Reproductive Medicine endometriosis stage, and that can help ensure that a patient gets to the right surgeon.

Researchers retrospectively collected data from ultrasounds, using it to create an ASRM stage, and compared the results with the stage seen at surgery. “We’re very good at telling people what they should expect at surgery,” said Mathew Leonardi, MD, who is a gynecologist at the University of Sydney’s Nepean Hospital.

The researchers conducted the study because of perceived mistrust among surgeons when it comes to presurgical imaging. “There is still a lot of cynicism and a lot of hesitancy to adopt this,” Dr. Leonardi said at the meeting sponsored by AAGL. He was unapologetic about the activist nature of the research. “We thought, what better way [to convince surgeons] than to produce an ultrasound-based ASRM scoring system to then match to the surgical findings, because if we can predict the ASRM score preoperatively, there may be more buy-in by the surgeons for the value of imaging.”

He noted that surgeons differ in their training, so getting the patient to the right surgeon is critical. “If you go to a gynecologist who is not minimally invasive trained, you may [end up with] an abandoned surgery, or an incomplete surgical excision leading to residual disease. So being able to predict the severity of the disease preoperatively, you can allow the patient to get to the right surgeon with the right team members.”

The analysis included 204 procedures performed between January 2016 and April 2018. Participants underwent deep endometriosis transvaginal ultrasound at one of two tertiary referral service centers, and laparoscopy by surgeons in the Sydney metropolitan area. Each case was received as a ASRM score of 0-4 at both ultrasound and surgery, and scores of 0-2 and 3-4 were grouped together for analysis.

“We grouped patients that have ASRM 3-4 into one group and those who have less than that [into another group], because clinically that seems to be where the most practical divide is,” said Dr. Leonardi.

It was difficult to differentiate individual ASRM stages from one another using ultrasound, but the technique performed much better in the combined analysis. In assigning a patient to the ASRM stage 0-2 endometriosis group, it had 94.9% sensitivity and 93.8% specificity, and for assigning to ASRM stage 3-4, it had values of 93.8% and 94.9%, respectively.

The success is encouraging, but there is more work to be done. “We are going to have to differentiate those with early-stage endometriosis or stage 1-2, and those that are negative. We are working on being able to identify superficial endometriosis noninvasively, but for now, as a triaging tool ultrasound can get the patient to the right surgeon,” Dr. Leonardi said.

Dr. Leonardi reported no relevant financial disclosures

VANCOUVER – Presurgical ultrasound does a good job predicting advanced versus early American Society of Reproductive Medicine endometriosis stage, and that can help ensure that a patient gets to the right surgeon.

Researchers retrospectively collected data from ultrasounds, using it to create an ASRM stage, and compared the results with the stage seen at surgery. “We’re very good at telling people what they should expect at surgery,” said Mathew Leonardi, MD, who is a gynecologist at the University of Sydney’s Nepean Hospital.

The researchers conducted the study because of perceived mistrust among surgeons when it comes to presurgical imaging. “There is still a lot of cynicism and a lot of hesitancy to adopt this,” Dr. Leonardi said at the meeting sponsored by AAGL. He was unapologetic about the activist nature of the research. “We thought, what better way [to convince surgeons] than to produce an ultrasound-based ASRM scoring system to then match to the surgical findings, because if we can predict the ASRM score preoperatively, there may be more buy-in by the surgeons for the value of imaging.”

He noted that surgeons differ in their training, so getting the patient to the right surgeon is critical. “If you go to a gynecologist who is not minimally invasive trained, you may [end up with] an abandoned surgery, or an incomplete surgical excision leading to residual disease. So being able to predict the severity of the disease preoperatively, you can allow the patient to get to the right surgeon with the right team members.”

The analysis included 204 procedures performed between January 2016 and April 2018. Participants underwent deep endometriosis transvaginal ultrasound at one of two tertiary referral service centers, and laparoscopy by surgeons in the Sydney metropolitan area. Each case was received as a ASRM score of 0-4 at both ultrasound and surgery, and scores of 0-2 and 3-4 were grouped together for analysis.

“We grouped patients that have ASRM 3-4 into one group and those who have less than that [into another group], because clinically that seems to be where the most practical divide is,” said Dr. Leonardi.

It was difficult to differentiate individual ASRM stages from one another using ultrasound, but the technique performed much better in the combined analysis. In assigning a patient to the ASRM stage 0-2 endometriosis group, it had 94.9% sensitivity and 93.8% specificity, and for assigning to ASRM stage 3-4, it had values of 93.8% and 94.9%, respectively.

The success is encouraging, but there is more work to be done. “We are going to have to differentiate those with early-stage endometriosis or stage 1-2, and those that are negative. We are working on being able to identify superficial endometriosis noninvasively, but for now, as a triaging tool ultrasound can get the patient to the right surgeon,” Dr. Leonardi said.

Dr. Leonardi reported no relevant financial disclosures

Endometriosis is associated with an increased risk of adverse pregnancy outcomes such as ectopic pregnancy, gestational diabetes, and preterm birth, a large study has found.

designer491/Thinkstock

Leslie V. Farland, ScD, of the University of Arizona, Tucson, and coauthors reported their analysis of data from 196,722 pregnancies in 116,429 women aged 25-42 years enrolled in the Nurses Health Study II cohort in Obstetrics & Gynecology.

Among the women with eligible pregnancies, 4.5% had laparoscopically confirmed endometriosis. These women were found to have a 40% higher risk of spontaneous abortion than were women without endometriosis (19.3% vs. 12.3%) and a 46% higher risk of ectopic pregnancy (1.8% vs. 0.8%). The risk of ectopic pregnancy was even more pronounced in women without a history of infertility.

Researchers also saw a 16% higher risk of preterm birth in women with endometriosis (12% in women with endometriosis vs. 8.1% in women without endometriosis), and a 16% greater risk of low-birth-weight babies (5.6% in women with endometriosis vs. 3.6% in women without endometriosis).

There also was the suggestion of an increased risk of stillbirth, although the researchers said this finding should be interpreted with caution because of the small sample size.

Women with endometriosis also had a 35% greater risk of gestational diabetes than did women without endometriosis. This association was stronger in women younger than age 35 years, in women without a history of infertility, and in women undergoing their second or later pregnancy. Endometriosis also was associated with a 30% greater risk of hypertensive disorders of pregnancy, particularly in second or later pregnancies.

Dr. Farland and associates wrote that recent research on the relationship between endometriosis and pregnancy outcomes had yielded “mixed results.”

“For example, much of the research to date has been conducted among women attending infertility clinics, which may conflate the influence of advanced maternal age, fertility treatment, and infertility itself with endometriosis, given the known elevated risk of adverse pregnancy outcomes in this population,” they wrote.

They suggested that one possible mechanism for the association between endometriosis and adverse pregnancy outcomes was progesterone resistance, which was hypothesized to affect genes important for embryo implantation and therefore contribute to pregnancy loss. Another mechanism could be increased inflammation, which may increase the risk of preterm birth and abnormal placentation.

“Elucidating mechanisms of association and possible pathways for intervention or screening procedures will be critical to improve the health of women with endometriosis and their children,” they wrote.

Katrina Mark, MD, commented in an interview, “This study, which identifies an increased risk of adverse pregnancy outcomes in women with endometriosis, is an important step in improving reproductive success.

“Although some explanations for these findings were postulated by the researchers, the next step will be to study the underlying physiology that leads to these complications so that interventions can be offered to improve outcomes,” said Dr. Mark, who is an associate professor of obstetrics, gynecology & reproductive sciences at the University of Maryland School of Medicine. Dr. Mark, who is not a coauthor of the study, was asked to comment on the study’s merit.

The study was supported by grants from the National Institutes of Health. Daniela A. Carusi, MD, received funding from UpToDate; Andrew W. Horne, MB, ChB, PhD, declared European government grants funding and consultancies with the pharmaceutical sector unrelated to the present study; Jorge E. Chavarro, MD, and Stacey A. Missmer, ScD, declared institutional funding from the NIH, and Dr. Missmer also received institutional funding from other funding bodies, as well as consulting fees. Dr. Farland and the remaining coauthors had no relevant financial disclosures. Dr. Mark has no relevant financial disclosures.
 

SOURCE: Farland LV et al. Obstetr Gynecol. 2019. doi: 10.1097/AOG.0000000000003410.

Endometriosis is associated with an increased risk of adverse pregnancy outcomes such as ectopic pregnancy, gestational diabetes, and preterm birth, a large study has found.

designer491/Thinkstock

Leslie V. Farland, ScD, of the University of Arizona, Tucson, and coauthors reported their analysis of data from 196,722 pregnancies in 116,429 women aged 25-42 years enrolled in the Nurses Health Study II cohort in Obstetrics & Gynecology.

Among the women with eligible pregnancies, 4.5% had laparoscopically confirmed endometriosis. These women were found to have a 40% higher risk of spontaneous abortion than were women without endometriosis (19.3% vs. 12.3%) and a 46% higher risk of ectopic pregnancy (1.8% vs. 0.8%). The risk of ectopic pregnancy was even more pronounced in women without a history of infertility.

Researchers also saw a 16% higher risk of preterm birth in women with endometriosis (12% in women with endometriosis vs. 8.1% in women without endometriosis), and a 16% greater risk of low-birth-weight babies (5.6% in women with endometriosis vs. 3.6% in women without endometriosis).

There also was the suggestion of an increased risk of stillbirth, although the researchers said this finding should be interpreted with caution because of the small sample size.

Women with endometriosis also had a 35% greater risk of gestational diabetes than did women without endometriosis. This association was stronger in women younger than age 35 years, in women without a history of infertility, and in women undergoing their second or later pregnancy. Endometriosis also was associated with a 30% greater risk of hypertensive disorders of pregnancy, particularly in second or later pregnancies.

Dr. Farland and associates wrote that recent research on the relationship between endometriosis and pregnancy outcomes had yielded “mixed results.”

“For example, much of the research to date has been conducted among women attending infertility clinics, which may conflate the influence of advanced maternal age, fertility treatment, and infertility itself with endometriosis, given the known elevated risk of adverse pregnancy outcomes in this population,” they wrote.

They suggested that one possible mechanism for the association between endometriosis and adverse pregnancy outcomes was progesterone resistance, which was hypothesized to affect genes important for embryo implantation and therefore contribute to pregnancy loss. Another mechanism could be increased inflammation, which may increase the risk of preterm birth and abnormal placentation.

“Elucidating mechanisms of association and possible pathways for intervention or screening procedures will be critical to improve the health of women with endometriosis and their children,” they wrote.

Katrina Mark, MD, commented in an interview, “This study, which identifies an increased risk of adverse pregnancy outcomes in women with endometriosis, is an important step in improving reproductive success.

“Although some explanations for these findings were postulated by the researchers, the next step will be to study the underlying physiology that leads to these complications so that interventions can be offered to improve outcomes,” said Dr. Mark, who is an associate professor of obstetrics, gynecology & reproductive sciences at the University of Maryland School of Medicine. Dr. Mark, who is not a coauthor of the study, was asked to comment on the study’s merit.

The study was supported by grants from the National Institutes of Health. Daniela A. Carusi, MD, received funding from UpToDate; Andrew W. Horne, MB, ChB, PhD, declared European government grants funding and consultancies with the pharmaceutical sector unrelated to the present study; Jorge E. Chavarro, MD, and Stacey A. Missmer, ScD, declared institutional funding from the NIH, and Dr. Missmer also received institutional funding from other funding bodies, as well as consulting fees. Dr. Farland and the remaining coauthors had no relevant financial disclosures. Dr. Mark has no relevant financial disclosures.
 

SOURCE: Farland LV et al. Obstetr Gynecol. 2019. doi: 10.1097/AOG.0000000000003410.

Endometriosis is associated with an increased risk of adverse pregnancy outcomes such as ectopic pregnancy, gestational diabetes, and preterm birth, a large study has found.

designer491/Thinkstock

Leslie V. Farland, ScD, of the University of Arizona, Tucson, and coauthors reported their analysis of data from 196,722 pregnancies in 116,429 women aged 25-42 years enrolled in the Nurses Health Study II cohort in Obstetrics & Gynecology.

Among the women with eligible pregnancies, 4.5% had laparoscopically confirmed endometriosis. These women were found to have a 40% higher risk of spontaneous abortion than were women without endometriosis (19.3% vs. 12.3%) and a 46% higher risk of ectopic pregnancy (1.8% vs. 0.8%). The risk of ectopic pregnancy was even more pronounced in women without a history of infertility.

Researchers also saw a 16% higher risk of preterm birth in women with endometriosis (12% in women with endometriosis vs. 8.1% in women without endometriosis), and a 16% greater risk of low-birth-weight babies (5.6% in women with endometriosis vs. 3.6% in women without endometriosis).

There also was the suggestion of an increased risk of stillbirth, although the researchers said this finding should be interpreted with caution because of the small sample size.

Women with endometriosis also had a 35% greater risk of gestational diabetes than did women without endometriosis. This association was stronger in women younger than age 35 years, in women without a history of infertility, and in women undergoing their second or later pregnancy. Endometriosis also was associated with a 30% greater risk of hypertensive disorders of pregnancy, particularly in second or later pregnancies.

Dr. Farland and associates wrote that recent research on the relationship between endometriosis and pregnancy outcomes had yielded “mixed results.”

“For example, much of the research to date has been conducted among women attending infertility clinics, which may conflate the influence of advanced maternal age, fertility treatment, and infertility itself with endometriosis, given the known elevated risk of adverse pregnancy outcomes in this population,” they wrote.

They suggested that one possible mechanism for the association between endometriosis and adverse pregnancy outcomes was progesterone resistance, which was hypothesized to affect genes important for embryo implantation and therefore contribute to pregnancy loss. Another mechanism could be increased inflammation, which may increase the risk of preterm birth and abnormal placentation.

“Elucidating mechanisms of association and possible pathways for intervention or screening procedures will be critical to improve the health of women with endometriosis and their children,” they wrote.

Katrina Mark, MD, commented in an interview, “This study, which identifies an increased risk of adverse pregnancy outcomes in women with endometriosis, is an important step in improving reproductive success.

“Although some explanations for these findings were postulated by the researchers, the next step will be to study the underlying physiology that leads to these complications so that interventions can be offered to improve outcomes,” said Dr. Mark, who is an associate professor of obstetrics, gynecology & reproductive sciences at the University of Maryland School of Medicine. Dr. Mark, who is not a coauthor of the study, was asked to comment on the study’s merit.

The study was supported by grants from the National Institutes of Health. Daniela A. Carusi, MD, received funding from UpToDate; Andrew W. Horne, MB, ChB, PhD, declared European government grants funding and consultancies with the pharmaceutical sector unrelated to the present study; Jorge E. Chavarro, MD, and Stacey A. Missmer, ScD, declared institutional funding from the NIH, and Dr. Missmer also received institutional funding from other funding bodies, as well as consulting fees. Dr. Farland and the remaining coauthors had no relevant financial disclosures. Dr. Mark has no relevant financial disclosures.
 

SOURCE: Farland LV et al. Obstetr Gynecol. 2019. doi: 10.1097/AOG.0000000000003410.

Ovarian remnant syndrome (ORS) is an uncommon problem, but one that seems to be increasing in incidence and one that is important to diagnose and treat properly, as well as prevent. Retrospective cohort studies published in the past 15 years or so have improved our understanding of its presentation and the outcomes of surgical management – and recent literature has demonstrated that a minimally invasive surgical approach with either conventional laparoscopy or robot-assisted laparoscopy yields improved outcomes in a skilled surgeon’s hands.

Diagnosis is based on clinical history and should be further supported with imaging and laboratory evaluation. A definitive diagnosis of the disease comes through surgical intervention and pathological findings.

Patients with ovarian remnants tend to have a history of extensive adhesive disease and/or severe endometriosis including ovarian endometrioma. Surgery therefore is technically challenging, usually requiring complete ureterolysis, careful adhesiolysis (often enterolysis), and excision of much of the pelvic sidewall peritoneum with extirpation of the remnant and endometriosis. High ligation of the ovarian vasculature also often is required.

This complexity and the consequent risk of intraoperative injury to the bowel, bladder, and ureters requires careful preoperative preparation. When an ovarian remnant is suspected, it may be important to have other surgeons – such as gynecologic oncologists, urologists, colorectal surgeons, or general surgeons – either present or on standby during the surgical intervention. In expert hands, surgical intervention has been shown to resolve or improve pain in the majority of patients, with no recurrence of the syndrome.
 

Diagnosis of ORS

Vidyard Video

Courtesy Dr. Charles E. Miller and Dr. Kirsten J. Sasaki

Patients with ORS have had previous oophorectomies with incomplete removal of ovarian tissue. Pelvic pain, either cyclical or most commonly chronic, is a common symptom. Other symptoms can include dyspareunia, dysuria and other urinary symptoms, and bowel symptoms. Ovarian remnants may have an expanding cystic structure – oftentimes secondary to endometriosis – that causes mass-like effects leading to pain and inflammation and to symptoms such as low back pain, constipation, and even urinary retention.

It also is important to discuss the patient’s history of menopausal symptoms, because the absence of these symptoms after oophorectomy may be a sign that ovarian tissue has been left behind. Menopausal symptoms do not exclude the diagnosis, however. Endometriosis, extensive surgical history, and other diseases that lead to significant adhesion formation – and a higher risk of incomplete removal of ovarian tissue, theoretically – also should be explored during history-taking.

Laboratory assessment of serum follicle-stimulating hormone (FSH) and estradiol can be helpful. Values that are indicative of ovarian function – FSH less than 30 mIU/mL and estradiol greater than 35 pg/mL – point towards ORS, but the absence of such premenopausal values should not rule out the possibility of an ovarian remnant.

The literature shows that FSH and estradiol levels are variable in women with ORS. A retrospective review published in 2005 by Paul M. Magtibay, MD, and colleagues at the Mayo Clinic, Scottsdale, Ariz., and Rochester, Minn., involved 186 patients treated surgically from 1985 to 2003 with a mean follow-up, via questionnaire, of 1.2 years. This is the largest series published thus far of patients with pathologically confirmed ORS. It reported premenopausal levels of FSH and estradiol in 69% and 63% of patients, respectively, who had preoperative hormonal evaluations.¹

In another retrospective cohort study published in 2011 of 30 women – also with pathologically confirmed ovarian remnants – Deborah Arden, MD, and Ted Lee, MD, of the University of Pittsburgh Medical Center reported premenopausal levels of FSH and estradiol in 59% and 71%, respectively, of women whose concentrations were measured.²

ORS often involves a pelvic mass, and preoperative imaging is important in this regard. In Dr. Magtibay’s series, a pelvic mass was identified in 93%, 92%, and 78% of those who were imaged presurgically with ultrasonography, computed tomography, and magnetic resonance imaging, respectively.¹ As with laboratory testing, however, a negative result does not rule out the presence of an ovarian remnant.

Some authors have advocated the use of clomiphene citrate stimulation before preoperative imaging – or before repeat imaging – to identify remnant ovarian tissue. Typically, clomiphene citrate 100 mg is administered for 10 days prior to imaging to potentially induce ovulation in patients with suspected ORS. Alternatively, at the Advanced Gynecologic Surgery Institute in Naperville and Park Ridge, Ill., ovarian stimulation is performed using FSH 300 IUs for 5 days. A finding of cystic structures consistent with ovarian follicles will help narrow the diagnosis.

Use of gonadotropins is superior in that an intact pituitary-ovarian axis is not required. Moreover, monitoring can be in real time; increasing estradiol levels and increasing mass size on ultrasound can be monitored as gonadotropin treatment is rendered. Again, however, negative findings should not necessarily rule out ORS. Unfortunately, there have been no clinical studies looking at the use of controlled ovarian stimulation as a definitive test.

The differential diagnosis includes supernumerary ovary (a rare gynecologic congenital anomaly) and residual ovary syndrome (a condition in which an ovary is intentionally or unintentionally left in place during a hysterectomy, as well as often an intended bilateral oophorectomy, and later causes pain). The latter occurs when surgical anatomy is poor and the surgery is consequently very difficult.
 

 

 

Surgical principles and approach

Previously, laparotomy was believed to be the best approach for minimizing intraoperative complications and achieving the extensive dissections necessary for effective treatment of ORS. In recent years, conventional laparoscopy and robot-assisted laparoscopy have been shown in retrospective reviews such as that by Arden et al.² and a 2007 review by Rosanne M. Kho, MD,³ to be just as safe and effective provided that the same surgical principles – extensive retroperitoneal dissections and ureterolysis – are applied.

Good outcomes can be achieved with less blood loss, shorter operating room time, and less time in the hospital. The better visualization with greater magnification afforded by a minimally invasive approach offers a distinct advantage for such complex dissections.

A remnant of ovarian tissue can be located anywhere along the pelvic sidewall, which makes the surgical protocol largely individualized and based on the suspected location of the remnant.

Still, there are certain standard components of any surgical approach to ORS: The retroperitoneum should be entered at the level of the pelvic brim and the ureter must be clearly identified; usually, a partial or complete ureterolysis is necessary. Then, a window into the broad ligament inferior to the infundibulopelvic (IP) ligament is created, or the peritoneum of the broad ligament is removed, in order to completely isolate both the IP ligament and the ureter.

Once the ovarian remnant is isolated, a wide excision at least 2 cm from all ovarian tissue is performed. This wide surgical clearance is critical to prevent recurrence.

These standard components form the crux of the most basic and straightforward surgery for ORS. In some cases, more extensive dissections such as a cystectomy or even a bowel resection might be necessary. Ligation of the IP ligament as high because its connection to the aortic bifurcation also may be necessary – depending, again, on the location of the ovarian remnant.

The risk of intraoperative injury to the bowel, bladder, and ureters is not insignificant, but with careful planning and the involvement of other surgeons in the most complex cases, these risks can be minimized.

For patients who have a significant surgical history and do not want more surgery, pharmacologic therapy, such as leuprolide (Lupron) or danazol, is an option for ORS. It’s important to note, however, that no studies have been done to demonstrate that medical therapy is a curative option. In addition, one must consider the small risk that remnants may harbor or develop malignancy.

Malignancy has been reported in ovarian remnant tissue. While the risk is believed to be very small, 2 of the 20 patients in Dr. Kho’s cohort had malignancy in remnant tissue,³ and it is generally recommended that surgeons send frozen sections of suspected ovarian tissue to pathology. Frozen-section diagnosis of ovarian tissue is about 95% accurate.
 

 

 

Preventing ovarian remnants

Oophorectomy is a common procedure performed by gynecologic surgeons. While routine, it is imperative that it be performed correctly to prevent ovarian remnants from occurring. When performing a laparoscopic or robot-assisted laparoscopic oophorectomy, it is important to optimize visualization of the ovary and the IP ligament, and to account for the significant magnification provided by laparoscopic cameras.

Surgeons must make sure all adhesions are completely cleared in order to optimally transect the IP ligament. Furthermore, wide excision around ovarian tissue is critical. Accessory ovarian tissue has been found up to 1.4 cm away from the ovary itself, which is why we recommend that surgeons excise at least 2-3 cm away from the IP in order to safely ensure complete removal of ovarian tissue.
 

Dr. Kooperman completed the American Association of Gynecologic Laparoscopists (AAGL) Fellowship Program in Minimally Invasive Gynecologic Surgery at Advocate Lutheran General Hospital, Park Ridge, Ill., and will be starting practice at the Highland Park (Ill.) North Shore Hospital System in August 2019. He reported no relevant disclosures.
 

References

1. Am J Obstet Gynecol. 2005;193(6):2062-6.

2. J Minim Invasive Gynecol. 2011;18(2):194-9.

3. Fertil Steril. 2007;87(5):1005-9.

Ovarian remnant syndrome (ORS) is an uncommon problem, but one that seems to be increasing in incidence and one that is important to diagnose and treat properly, as well as prevent. Retrospective cohort studies published in the past 15 years or so have improved our understanding of its presentation and the outcomes of surgical management – and recent literature has demonstrated that a minimally invasive surgical approach with either conventional laparoscopy or robot-assisted laparoscopy yields improved outcomes in a skilled surgeon’s hands.

Diagnosis is based on clinical history and should be further supported with imaging and laboratory evaluation. A definitive diagnosis of the disease comes through surgical intervention and pathological findings.

Patients with ovarian remnants tend to have a history of extensive adhesive disease and/or severe endometriosis including ovarian endometrioma. Surgery therefore is technically challenging, usually requiring complete ureterolysis, careful adhesiolysis (often enterolysis), and excision of much of the pelvic sidewall peritoneum with extirpation of the remnant and endometriosis. High ligation of the ovarian vasculature also often is required.

This complexity and the consequent risk of intraoperative injury to the bowel, bladder, and ureters requires careful preoperative preparation. When an ovarian remnant is suspected, it may be important to have other surgeons – such as gynecologic oncologists, urologists, colorectal surgeons, or general surgeons – either present or on standby during the surgical intervention. In expert hands, surgical intervention has been shown to resolve or improve pain in the majority of patients, with no recurrence of the syndrome.
 

Diagnosis of ORS

Vidyard Video

Courtesy Dr. Charles E. Miller and Dr. Kirsten J. Sasaki

Patients with ORS have had previous oophorectomies with incomplete removal of ovarian tissue. Pelvic pain, either cyclical or most commonly chronic, is a common symptom. Other symptoms can include dyspareunia, dysuria and other urinary symptoms, and bowel symptoms. Ovarian remnants may have an expanding cystic structure – oftentimes secondary to endometriosis – that causes mass-like effects leading to pain and inflammation and to symptoms such as low back pain, constipation, and even urinary retention.

It also is important to discuss the patient’s history of menopausal symptoms, because the absence of these symptoms after oophorectomy may be a sign that ovarian tissue has been left behind. Menopausal symptoms do not exclude the diagnosis, however. Endometriosis, extensive surgical history, and other diseases that lead to significant adhesion formation – and a higher risk of incomplete removal of ovarian tissue, theoretically – also should be explored during history-taking.

Laboratory assessment of serum follicle-stimulating hormone (FSH) and estradiol can be helpful. Values that are indicative of ovarian function – FSH less than 30 mIU/mL and estradiol greater than 35 pg/mL – point towards ORS, but the absence of such premenopausal values should not rule out the possibility of an ovarian remnant.

The literature shows that FSH and estradiol levels are variable in women with ORS. A retrospective review published in 2005 by Paul M. Magtibay, MD, and colleagues at the Mayo Clinic, Scottsdale, Ariz., and Rochester, Minn., involved 186 patients treated surgically from 1985 to 2003 with a mean follow-up, via questionnaire, of 1.2 years. This is the largest series published thus far of patients with pathologically confirmed ORS. It reported premenopausal levels of FSH and estradiol in 69% and 63% of patients, respectively, who had preoperative hormonal evaluations.¹

In another retrospective cohort study published in 2011 of 30 women – also with pathologically confirmed ovarian remnants – Deborah Arden, MD, and Ted Lee, MD, of the University of Pittsburgh Medical Center reported premenopausal levels of FSH and estradiol in 59% and 71%, respectively, of women whose concentrations were measured.²

ORS often involves a pelvic mass, and preoperative imaging is important in this regard. In Dr. Magtibay’s series, a pelvic mass was identified in 93%, 92%, and 78% of those who were imaged presurgically with ultrasonography, computed tomography, and magnetic resonance imaging, respectively.¹ As with laboratory testing, however, a negative result does not rule out the presence of an ovarian remnant.

Some authors have advocated the use of clomiphene citrate stimulation before preoperative imaging – or before repeat imaging – to identify remnant ovarian tissue. Typically, clomiphene citrate 100 mg is administered for 10 days prior to imaging to potentially induce ovulation in patients with suspected ORS. Alternatively, at the Advanced Gynecologic Surgery Institute in Naperville and Park Ridge, Ill., ovarian stimulation is performed using FSH 300 IUs for 5 days. A finding of cystic structures consistent with ovarian follicles will help narrow the diagnosis.

Use of gonadotropins is superior in that an intact pituitary-ovarian axis is not required. Moreover, monitoring can be in real time; increasing estradiol levels and increasing mass size on ultrasound can be monitored as gonadotropin treatment is rendered. Again, however, negative findings should not necessarily rule out ORS. Unfortunately, there have been no clinical studies looking at the use of controlled ovarian stimulation as a definitive test.

The differential diagnosis includes supernumerary ovary (a rare gynecologic congenital anomaly) and residual ovary syndrome (a condition in which an ovary is intentionally or unintentionally left in place during a hysterectomy, as well as often an intended bilateral oophorectomy, and later causes pain). The latter occurs when surgical anatomy is poor and the surgery is consequently very difficult.
 

 

 

Surgical principles and approach

Previously, laparotomy was believed to be the best approach for minimizing intraoperative complications and achieving the extensive dissections necessary for effective treatment of ORS. In recent years, conventional laparoscopy and robot-assisted laparoscopy have been shown in retrospective reviews such as that by Arden et al.² and a 2007 review by Rosanne M. Kho, MD,³ to be just as safe and effective provided that the same surgical principles – extensive retroperitoneal dissections and ureterolysis – are applied.

Good outcomes can be achieved with less blood loss, shorter operating room time, and less time in the hospital. The better visualization with greater magnification afforded by a minimally invasive approach offers a distinct advantage for such complex dissections.

A remnant of ovarian tissue can be located anywhere along the pelvic sidewall, which makes the surgical protocol largely individualized and based on the suspected location of the remnant.

Still, there are certain standard components of any surgical approach to ORS: The retroperitoneum should be entered at the level of the pelvic brim and the ureter must be clearly identified; usually, a partial or complete ureterolysis is necessary. Then, a window into the broad ligament inferior to the infundibulopelvic (IP) ligament is created, or the peritoneum of the broad ligament is removed, in order to completely isolate both the IP ligament and the ureter.

Once the ovarian remnant is isolated, a wide excision at least 2 cm from all ovarian tissue is performed. This wide surgical clearance is critical to prevent recurrence.

These standard components form the crux of the most basic and straightforward surgery for ORS. In some cases, more extensive dissections such as a cystectomy or even a bowel resection might be necessary. Ligation of the IP ligament as high because its connection to the aortic bifurcation also may be necessary – depending, again, on the location of the ovarian remnant.

The risk of intraoperative injury to the bowel, bladder, and ureters is not insignificant, but with careful planning and the involvement of other surgeons in the most complex cases, these risks can be minimized.

For patients who have a significant surgical history and do not want more surgery, pharmacologic therapy, such as leuprolide (Lupron) or danazol, is an option for ORS. It’s important to note, however, that no studies have been done to demonstrate that medical therapy is a curative option. In addition, one must consider the small risk that remnants may harbor or develop malignancy.

Malignancy has been reported in ovarian remnant tissue. While the risk is believed to be very small, 2 of the 20 patients in Dr. Kho’s cohort had malignancy in remnant tissue,³ and it is generally recommended that surgeons send frozen sections of suspected ovarian tissue to pathology. Frozen-section diagnosis of ovarian tissue is about 95% accurate.
 

 

 

Preventing ovarian remnants

Oophorectomy is a common procedure performed by gynecologic surgeons. While routine, it is imperative that it be performed correctly to prevent ovarian remnants from occurring. When performing a laparoscopic or robot-assisted laparoscopic oophorectomy, it is important to optimize visualization of the ovary and the IP ligament, and to account for the significant magnification provided by laparoscopic cameras.

Surgeons must make sure all adhesions are completely cleared in order to optimally transect the IP ligament. Furthermore, wide excision around ovarian tissue is critical. Accessory ovarian tissue has been found up to 1.4 cm away from the ovary itself, which is why we recommend that surgeons excise at least 2-3 cm away from the IP in order to safely ensure complete removal of ovarian tissue.
 

Dr. Kooperman completed the American Association of Gynecologic Laparoscopists (AAGL) Fellowship Program in Minimally Invasive Gynecologic Surgery at Advocate Lutheran General Hospital, Park Ridge, Ill., and will be starting practice at the Highland Park (Ill.) North Shore Hospital System in August 2019. He reported no relevant disclosures.
 

References

1. Am J Obstet Gynecol. 2005;193(6):2062-6.

2. J Minim Invasive Gynecol. 2011;18(2):194-9.

3. Fertil Steril. 2007;87(5):1005-9.

Ovarian remnant syndrome (ORS) is an uncommon problem, but one that seems to be increasing in incidence and one that is important to diagnose and treat properly, as well as prevent. Retrospective cohort studies published in the past 15 years or so have improved our understanding of its presentation and the outcomes of surgical management – and recent literature has demonstrated that a minimally invasive surgical approach with either conventional laparoscopy or robot-assisted laparoscopy yields improved outcomes in a skilled surgeon’s hands.

Diagnosis is based on clinical history and should be further supported with imaging and laboratory evaluation. A definitive diagnosis of the disease comes through surgical intervention and pathological findings.

Patients with ovarian remnants tend to have a history of extensive adhesive disease and/or severe endometriosis including ovarian endometrioma. Surgery therefore is technically challenging, usually requiring complete ureterolysis, careful adhesiolysis (often enterolysis), and excision of much of the pelvic sidewall peritoneum with extirpation of the remnant and endometriosis. High ligation of the ovarian vasculature also often is required.

This complexity and the consequent risk of intraoperative injury to the bowel, bladder, and ureters requires careful preoperative preparation. When an ovarian remnant is suspected, it may be important to have other surgeons – such as gynecologic oncologists, urologists, colorectal surgeons, or general surgeons – either present or on standby during the surgical intervention. In expert hands, surgical intervention has been shown to resolve or improve pain in the majority of patients, with no recurrence of the syndrome.
 

Diagnosis of ORS

Vidyard Video

Courtesy Dr. Charles E. Miller and Dr. Kirsten J. Sasaki

Patients with ORS have had previous oophorectomies with incomplete removal of ovarian tissue. Pelvic pain, either cyclical or most commonly chronic, is a common symptom. Other symptoms can include dyspareunia, dysuria and other urinary symptoms, and bowel symptoms. Ovarian remnants may have an expanding cystic structure – oftentimes secondary to endometriosis – that causes mass-like effects leading to pain and inflammation and to symptoms such as low back pain, constipation, and even urinary retention.

It also is important to discuss the patient’s history of menopausal symptoms, because the absence of these symptoms after oophorectomy may be a sign that ovarian tissue has been left behind. Menopausal symptoms do not exclude the diagnosis, however. Endometriosis, extensive surgical history, and other diseases that lead to significant adhesion formation – and a higher risk of incomplete removal of ovarian tissue, theoretically – also should be explored during history-taking.

Laboratory assessment of serum follicle-stimulating hormone (FSH) and estradiol can be helpful. Values that are indicative of ovarian function – FSH less than 30 mIU/mL and estradiol greater than 35 pg/mL – point towards ORS, but the absence of such premenopausal values should not rule out the possibility of an ovarian remnant.

The literature shows that FSH and estradiol levels are variable in women with ORS. A retrospective review published in 2005 by Paul M. Magtibay, MD, and colleagues at the Mayo Clinic, Scottsdale, Ariz., and Rochester, Minn., involved 186 patients treated surgically from 1985 to 2003 with a mean follow-up, via questionnaire, of 1.2 years. This is the largest series published thus far of patients with pathologically confirmed ORS. It reported premenopausal levels of FSH and estradiol in 69% and 63% of patients, respectively, who had preoperative hormonal evaluations.¹

In another retrospective cohort study published in 2011 of 30 women – also with pathologically confirmed ovarian remnants – Deborah Arden, MD, and Ted Lee, MD, of the University of Pittsburgh Medical Center reported premenopausal levels of FSH and estradiol in 59% and 71%, respectively, of women whose concentrations were measured.²

ORS often involves a pelvic mass, and preoperative imaging is important in this regard. In Dr. Magtibay’s series, a pelvic mass was identified in 93%, 92%, and 78% of those who were imaged presurgically with ultrasonography, computed tomography, and magnetic resonance imaging, respectively.¹ As with laboratory testing, however, a negative result does not rule out the presence of an ovarian remnant.

Some authors have advocated the use of clomiphene citrate stimulation before preoperative imaging – or before repeat imaging – to identify remnant ovarian tissue. Typically, clomiphene citrate 100 mg is administered for 10 days prior to imaging to potentially induce ovulation in patients with suspected ORS. Alternatively, at the Advanced Gynecologic Surgery Institute in Naperville and Park Ridge, Ill., ovarian stimulation is performed using FSH 300 IUs for 5 days. A finding of cystic structures consistent with ovarian follicles will help narrow the diagnosis.

Use of gonadotropins is superior in that an intact pituitary-ovarian axis is not required. Moreover, monitoring can be in real time; increasing estradiol levels and increasing mass size on ultrasound can be monitored as gonadotropin treatment is rendered. Again, however, negative findings should not necessarily rule out ORS. Unfortunately, there have been no clinical studies looking at the use of controlled ovarian stimulation as a definitive test.

The differential diagnosis includes supernumerary ovary (a rare gynecologic congenital anomaly) and residual ovary syndrome (a condition in which an ovary is intentionally or unintentionally left in place during a hysterectomy, as well as often an intended bilateral oophorectomy, and later causes pain). The latter occurs when surgical anatomy is poor and the surgery is consequently very difficult.
 

 

 

Surgical principles and approach

Previously, laparotomy was believed to be the best approach for minimizing intraoperative complications and achieving the extensive dissections necessary for effective treatment of ORS. In recent years, conventional laparoscopy and robot-assisted laparoscopy have been shown in retrospective reviews such as that by Arden et al.² and a 2007 review by Rosanne M. Kho, MD,³ to be just as safe and effective provided that the same surgical principles – extensive retroperitoneal dissections and ureterolysis – are applied.

Good outcomes can be achieved with less blood loss, shorter operating room time, and less time in the hospital. The better visualization with greater magnification afforded by a minimally invasive approach offers a distinct advantage for such complex dissections.

A remnant of ovarian tissue can be located anywhere along the pelvic sidewall, which makes the surgical protocol largely individualized and based on the suspected location of the remnant.

Still, there are certain standard components of any surgical approach to ORS: The retroperitoneum should be entered at the level of the pelvic brim and the ureter must be clearly identified; usually, a partial or complete ureterolysis is necessary. Then, a window into the broad ligament inferior to the infundibulopelvic (IP) ligament is created, or the peritoneum of the broad ligament is removed, in order to completely isolate both the IP ligament and the ureter.

Once the ovarian remnant is isolated, a wide excision at least 2 cm from all ovarian tissue is performed. This wide surgical clearance is critical to prevent recurrence.

These standard components form the crux of the most basic and straightforward surgery for ORS. In some cases, more extensive dissections such as a cystectomy or even a bowel resection might be necessary. Ligation of the IP ligament as high because its connection to the aortic bifurcation also may be necessary – depending, again, on the location of the ovarian remnant.

The risk of intraoperative injury to the bowel, bladder, and ureters is not insignificant, but with careful planning and the involvement of other surgeons in the most complex cases, these risks can be minimized.

For patients who have a significant surgical history and do not want more surgery, pharmacologic therapy, such as leuprolide (Lupron) or danazol, is an option for ORS. It’s important to note, however, that no studies have been done to demonstrate that medical therapy is a curative option. In addition, one must consider the small risk that remnants may harbor or develop malignancy.

Malignancy has been reported in ovarian remnant tissue. While the risk is believed to be very small, 2 of the 20 patients in Dr. Kho’s cohort had malignancy in remnant tissue,³ and it is generally recommended that surgeons send frozen sections of suspected ovarian tissue to pathology. Frozen-section diagnosis of ovarian tissue is about 95% accurate.
 

 

 

Preventing ovarian remnants

Oophorectomy is a common procedure performed by gynecologic surgeons. While routine, it is imperative that it be performed correctly to prevent ovarian remnants from occurring. When performing a laparoscopic or robot-assisted laparoscopic oophorectomy, it is important to optimize visualization of the ovary and the IP ligament, and to account for the significant magnification provided by laparoscopic cameras.

Surgeons must make sure all adhesions are completely cleared in order to optimally transect the IP ligament. Furthermore, wide excision around ovarian tissue is critical. Accessory ovarian tissue has been found up to 1.4 cm away from the ovary itself, which is why we recommend that surgeons excise at least 2-3 cm away from the IP in order to safely ensure complete removal of ovarian tissue.
 

Dr. Kooperman completed the American Association of Gynecologic Laparoscopists (AAGL) Fellowship Program in Minimally Invasive Gynecologic Surgery at Advocate Lutheran General Hospital, Park Ridge, Ill., and will be starting practice at the Highland Park (Ill.) North Shore Hospital System in August 2019. He reported no relevant disclosures.
 

References

1. Am J Obstet Gynecol. 2005;193(6):2062-6.

2. J Minim Invasive Gynecol. 2011;18(2):194-9.

3. Fertil Steril. 2007;87(5):1005-9.