Endometriosis

LAS VEGAS – An estimated 15%-25% of women aged 18-50 years suffer from chronic pelvic pain, a condition that commonly leads to sick days, reduced activity, and higher medication use. Treatments like surgery and opioids may seem feasible, but an obstetrician-gynecologist who studies pain urged colleagues to think twice.

KatarzynaBialasiewicz/Thinkstock

In some cases, pelvic pain patients may suffer from centralized pain syndromes, conditions linked to the central nervous system that may not respond well to those common treatments, said Sawsan As-Sanie, MD, MPH, director of the University of Michigan Endometriosis Center, Ann Arbor.

“If we have laser vision on the pelvis, we may help some patients, but many of us will do harm,” said Dr. As-Sanie, who spoke at the Pelvic Anatomy and Gynecologic Surgery Symposium.

Endometriosis is frequently linked to pelvic pain. But, she said, the link between the two is fuzzier than has been assumed.

“It would make sense that endometriosis or pelvic adhesions would activate nociceptive pain, and [there are] a lot of data to support that this is, in part, how endometriosis causes pain,” she said. “But I would argue it really isn’t that simple because the relationship between endometriosis and pelvic pain is very complex and not explained entirely by the lesion.” For example, “we know that pain recurs after medical and surgical therapy, often without evidence of recurrent endometriosis.” And, there’s little relationship between pain symptoms and the location or extent of endometriosis.

What’s going on? Dr. As-Sanie suggested central pain syndromes can play a significant role in pelvic pain. These syndromes are 1.5-2 times more common in women than men, and are triggered or exacerbated by stressors.

She also emphasized the wide-ranging effects of these syndromes. “We focus on pain, but it’s clearly not a just a pain disorder,” noting that patients can report fatigue, poor sleep, greater sensitivity to light and sound, and memory difficulties that produce “fibromyalgia fog.”

Research suggests that patients with central pain syndromes experience changes in both brain structure and function, she said. As for pelvic pain specifically, studies have linked it to increased pain sensitivity and altered central nervous system structure and function regardless of whether endometriosis is present.

How should patients with pelvic pain be treated in light of this information? Dr. As-Sanie suggests first trying “gold standard” approaches to treat contributing factors whether they’re gynecologic, urologic, gastrointestinal, musculoskeletal or nerve related.

If those strategies don’t work, she said, “consider treating centralized pain” with a blend of approaches: behavioral (such as diet and cognitive-behavior therapy), medical (such as hormone modulation), and interventional (such as physical therapy and surgery).

Also consider pharmacologic therapies, said Dr. As-Sanie, who identified dual reuptake inhibitors (venlafaxine [Effexor] and duloxetine [Cymbalta] are a class of antidepressants that block the reuptake of both serotonin and norepinephrine) and anticonvulsants as drugs with strong evidence as treatments for central pain syndromes.

“Start at low doses and titrate up,” she advised, and “if at any point a given medication doesn’t work, we should try another.”

The Pelvic Anatomy and Gynecologic Surgery Symposium was jointly provided by Global Academy for Medical Education and the University of Cincinnati. Global Academy and this news organization are owned by the same company.

Dr. As-Sanie discloses she is a consultant for AbbVie and Myovant.

LAS VEGAS – An estimated 15%-25% of women aged 18-50 years suffer from chronic pelvic pain, a condition that commonly leads to sick days, reduced activity, and higher medication use. Treatments like surgery and opioids may seem feasible, but an obstetrician-gynecologist who studies pain urged colleagues to think twice.

KatarzynaBialasiewicz/Thinkstock

In some cases, pelvic pain patients may suffer from centralized pain syndromes, conditions linked to the central nervous system that may not respond well to those common treatments, said Sawsan As-Sanie, MD, MPH, director of the University of Michigan Endometriosis Center, Ann Arbor.

“If we have laser vision on the pelvis, we may help some patients, but many of us will do harm,” said Dr. As-Sanie, who spoke at the Pelvic Anatomy and Gynecologic Surgery Symposium.

Endometriosis is frequently linked to pelvic pain. But, she said, the link between the two is fuzzier than has been assumed.

“It would make sense that endometriosis or pelvic adhesions would activate nociceptive pain, and [there are] a lot of data to support that this is, in part, how endometriosis causes pain,” she said. “But I would argue it really isn’t that simple because the relationship between endometriosis and pelvic pain is very complex and not explained entirely by the lesion.” For example, “we know that pain recurs after medical and surgical therapy, often without evidence of recurrent endometriosis.” And, there’s little relationship between pain symptoms and the location or extent of endometriosis.

What’s going on? Dr. As-Sanie suggested central pain syndromes can play a significant role in pelvic pain. These syndromes are 1.5-2 times more common in women than men, and are triggered or exacerbated by stressors.

She also emphasized the wide-ranging effects of these syndromes. “We focus on pain, but it’s clearly not a just a pain disorder,” noting that patients can report fatigue, poor sleep, greater sensitivity to light and sound, and memory difficulties that produce “fibromyalgia fog.”

Research suggests that patients with central pain syndromes experience changes in both brain structure and function, she said. As for pelvic pain specifically, studies have linked it to increased pain sensitivity and altered central nervous system structure and function regardless of whether endometriosis is present.

How should patients with pelvic pain be treated in light of this information? Dr. As-Sanie suggests first trying “gold standard” approaches to treat contributing factors whether they’re gynecologic, urologic, gastrointestinal, musculoskeletal or nerve related.

If those strategies don’t work, she said, “consider treating centralized pain” with a blend of approaches: behavioral (such as diet and cognitive-behavior therapy), medical (such as hormone modulation), and interventional (such as physical therapy and surgery).

Also consider pharmacologic therapies, said Dr. As-Sanie, who identified dual reuptake inhibitors (venlafaxine [Effexor] and duloxetine [Cymbalta] are a class of antidepressants that block the reuptake of both serotonin and norepinephrine) and anticonvulsants as drugs with strong evidence as treatments for central pain syndromes.

“Start at low doses and titrate up,” she advised, and “if at any point a given medication doesn’t work, we should try another.”

The Pelvic Anatomy and Gynecologic Surgery Symposium was jointly provided by Global Academy for Medical Education and the University of Cincinnati. Global Academy and this news organization are owned by the same company.

Dr. As-Sanie discloses she is a consultant for AbbVie and Myovant.

LAS VEGAS – An estimated 15%-25% of women aged 18-50 years suffer from chronic pelvic pain, a condition that commonly leads to sick days, reduced activity, and higher medication use. Treatments like surgery and opioids may seem feasible, but an obstetrician-gynecologist who studies pain urged colleagues to think twice.

KatarzynaBialasiewicz/Thinkstock

In some cases, pelvic pain patients may suffer from centralized pain syndromes, conditions linked to the central nervous system that may not respond well to those common treatments, said Sawsan As-Sanie, MD, MPH, director of the University of Michigan Endometriosis Center, Ann Arbor.

“If we have laser vision on the pelvis, we may help some patients, but many of us will do harm,” said Dr. As-Sanie, who spoke at the Pelvic Anatomy and Gynecologic Surgery Symposium.

Endometriosis is frequently linked to pelvic pain. But, she said, the link between the two is fuzzier than has been assumed.

“It would make sense that endometriosis or pelvic adhesions would activate nociceptive pain, and [there are] a lot of data to support that this is, in part, how endometriosis causes pain,” she said. “But I would argue it really isn’t that simple because the relationship between endometriosis and pelvic pain is very complex and not explained entirely by the lesion.” For example, “we know that pain recurs after medical and surgical therapy, often without evidence of recurrent endometriosis.” And, there’s little relationship between pain symptoms and the location or extent of endometriosis.

What’s going on? Dr. As-Sanie suggested central pain syndromes can play a significant role in pelvic pain. These syndromes are 1.5-2 times more common in women than men, and are triggered or exacerbated by stressors.

She also emphasized the wide-ranging effects of these syndromes. “We focus on pain, but it’s clearly not a just a pain disorder,” noting that patients can report fatigue, poor sleep, greater sensitivity to light and sound, and memory difficulties that produce “fibromyalgia fog.”

Research suggests that patients with central pain syndromes experience changes in both brain structure and function, she said. As for pelvic pain specifically, studies have linked it to increased pain sensitivity and altered central nervous system structure and function regardless of whether endometriosis is present.

How should patients with pelvic pain be treated in light of this information? Dr. As-Sanie suggests first trying “gold standard” approaches to treat contributing factors whether they’re gynecologic, urologic, gastrointestinal, musculoskeletal or nerve related.

If those strategies don’t work, she said, “consider treating centralized pain” with a blend of approaches: behavioral (such as diet and cognitive-behavior therapy), medical (such as hormone modulation), and interventional (such as physical therapy and surgery).

Also consider pharmacologic therapies, said Dr. As-Sanie, who identified dual reuptake inhibitors (venlafaxine [Effexor] and duloxetine [Cymbalta] are a class of antidepressants that block the reuptake of both serotonin and norepinephrine) and anticonvulsants as drugs with strong evidence as treatments for central pain syndromes.

“Start at low doses and titrate up,” she advised, and “if at any point a given medication doesn’t work, we should try another.”

The Pelvic Anatomy and Gynecologic Surgery Symposium was jointly provided by Global Academy for Medical Education and the University of Cincinnati. Global Academy and this news organization are owned by the same company.

Dr. As-Sanie discloses she is a consultant for AbbVie and Myovant.

LAS VEGAS – Laparoscopic endometriosis excision improves quality of life for at least 7 years, even when women have conservative, fertility-sparing surgery, according to a survey study from the University of Pittsburgh.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The work was likely the first to assess long-term outcomes after laparoscopic endometriosis excision with a disease-specific questionnaire, the Endometriosis Health Profile-30 (EHP-30). The findings should reassure both surgeons and patients. “I really feel these results can help us as endometriosis providers” to counsel women, said lead investigator Nicole M. Donnellan, MD, a gynecologic surgeon at the University of Pittsburgh.

Surgery “offers lasting improvement in all quality of life domains ... measured by the EHP-30”: pain; control/powerlessness; emotional well-being; social support; and self-image, with supplemental questions about work, sexual function, and other matters. Because “definitive surgery was not associated with improved outcomes when compared with fertility-sparing surgery ... fertility preservation should continue to be offered as first-line surgery for treatment of symptomatic disease,” Dr. Donnellan and her team concluded at a meeting sponsored by AAGL.

Surgery is the gold standard for endometriosis, but there just hasn’t been much data on long-term outcomes until now, especially with a potent questionnaire like the EHP-30. The gap left surgeons in the lurch on what to tell women how they’ll do, especially because results from previous, shorter, and less-rigorous studies have been mixed. The Pittsburgh results mean that competent surgeons can breathe easier and be confident in telling women what to expect.

The team administered EHP-30 to 61 women before surgery and at 4 weeks postoperatively; 45 patients (74%) had fertility-sparing excisions, 7 (11%) had hysterectomy with adnexa preservation, and 9 (15%) had hysterectomy with bilateral salpingo-oophorectomy. The women were contacted again in 2017 to fill out the survey anywhere from 3 to 7 years after their operation; 45 women agreed, a response rate of 74%.

There was a definitive, statistically significant reduction in scores across all five domains of the survey, both at 4 weeks and out to 7 years, and the improvements did not vary by endometriosis stage or the type of surgery women had.

The overall score – a combination of the five domains – fell from a preoperative median of 50 points out of a possible 100, with 100 being the worst possible score, to a median of about 20 points 4 weeks after surgery, and a median of about 10 points at long-term follow-up. Pain scores fell about the same amount; the greatest improvements were on questions that focused on sense of control and empowerment.

At long-term follow-up, overall scores improved a median of 43 points in women with American Society for Reproductive Medicine stage 1 endometriosis and 28 points among women with stage 4 disease (P = .705). Although the differences were not statistically significant, women with stage 1 disease generally reported the greatest improvements, except on the control and empowerment scale, where women reported the same improvement across all four stages, about 50 points out of 100.

Long-term score improvements were pretty much identical among women who had fertility-sparing surgery and those who had hysterectomies, with, for instance, both groups reporting about a 33-point improvement in pain scores. The two groups separated out only on emotional well-being scores, a 38-point improvement in the hysterectomy group versus 21 points, but the difference was not statistically significant (P = .525).

The long-term results remained the same when eight women who had subsequent gynecologic surgery were excluded.

In the end, the take home is that “all of these women improved,” Dr. Donnellan said.

The investigators didn’t report any disclosures.

[email protected]

SOURCE: Donnellan NM et al. 2018 AAGL Global Congress, Abstract 82.

LAS VEGAS – Laparoscopic endometriosis excision improves quality of life for at least 7 years, even when women have conservative, fertility-sparing surgery, according to a survey study from the University of Pittsburgh.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The work was likely the first to assess long-term outcomes after laparoscopic endometriosis excision with a disease-specific questionnaire, the Endometriosis Health Profile-30 (EHP-30). The findings should reassure both surgeons and patients. “I really feel these results can help us as endometriosis providers” to counsel women, said lead investigator Nicole M. Donnellan, MD, a gynecologic surgeon at the University of Pittsburgh.

Surgery “offers lasting improvement in all quality of life domains ... measured by the EHP-30”: pain; control/powerlessness; emotional well-being; social support; and self-image, with supplemental questions about work, sexual function, and other matters. Because “definitive surgery was not associated with improved outcomes when compared with fertility-sparing surgery ... fertility preservation should continue to be offered as first-line surgery for treatment of symptomatic disease,” Dr. Donnellan and her team concluded at a meeting sponsored by AAGL.

Surgery is the gold standard for endometriosis, but there just hasn’t been much data on long-term outcomes until now, especially with a potent questionnaire like the EHP-30. The gap left surgeons in the lurch on what to tell women how they’ll do, especially because results from previous, shorter, and less-rigorous studies have been mixed. The Pittsburgh results mean that competent surgeons can breathe easier and be confident in telling women what to expect.

The team administered EHP-30 to 61 women before surgery and at 4 weeks postoperatively; 45 patients (74%) had fertility-sparing excisions, 7 (11%) had hysterectomy with adnexa preservation, and 9 (15%) had hysterectomy with bilateral salpingo-oophorectomy. The women were contacted again in 2017 to fill out the survey anywhere from 3 to 7 years after their operation; 45 women agreed, a response rate of 74%.

There was a definitive, statistically significant reduction in scores across all five domains of the survey, both at 4 weeks and out to 7 years, and the improvements did not vary by endometriosis stage or the type of surgery women had.

The overall score – a combination of the five domains – fell from a preoperative median of 50 points out of a possible 100, with 100 being the worst possible score, to a median of about 20 points 4 weeks after surgery, and a median of about 10 points at long-term follow-up. Pain scores fell about the same amount; the greatest improvements were on questions that focused on sense of control and empowerment.

At long-term follow-up, overall scores improved a median of 43 points in women with American Society for Reproductive Medicine stage 1 endometriosis and 28 points among women with stage 4 disease (P = .705). Although the differences were not statistically significant, women with stage 1 disease generally reported the greatest improvements, except on the control and empowerment scale, where women reported the same improvement across all four stages, about 50 points out of 100.

Long-term score improvements were pretty much identical among women who had fertility-sparing surgery and those who had hysterectomies, with, for instance, both groups reporting about a 33-point improvement in pain scores. The two groups separated out only on emotional well-being scores, a 38-point improvement in the hysterectomy group versus 21 points, but the difference was not statistically significant (P = .525).

The long-term results remained the same when eight women who had subsequent gynecologic surgery were excluded.

In the end, the take home is that “all of these women improved,” Dr. Donnellan said.

The investigators didn’t report any disclosures.

[email protected]

SOURCE: Donnellan NM et al. 2018 AAGL Global Congress, Abstract 82.

LAS VEGAS – Laparoscopic endometriosis excision improves quality of life for at least 7 years, even when women have conservative, fertility-sparing surgery, according to a survey study from the University of Pittsburgh.

U.S. Air Force photo by Staff Sgt. Ciara Gosier

The work was likely the first to assess long-term outcomes after laparoscopic endometriosis excision with a disease-specific questionnaire, the Endometriosis Health Profile-30 (EHP-30). The findings should reassure both surgeons and patients. “I really feel these results can help us as endometriosis providers” to counsel women, said lead investigator Nicole M. Donnellan, MD, a gynecologic surgeon at the University of Pittsburgh.

Surgery “offers lasting improvement in all quality of life domains ... measured by the EHP-30”: pain; control/powerlessness; emotional well-being; social support; and self-image, with supplemental questions about work, sexual function, and other matters. Because “definitive surgery was not associated with improved outcomes when compared with fertility-sparing surgery ... fertility preservation should continue to be offered as first-line surgery for treatment of symptomatic disease,” Dr. Donnellan and her team concluded at a meeting sponsored by AAGL.

Surgery is the gold standard for endometriosis, but there just hasn’t been much data on long-term outcomes until now, especially with a potent questionnaire like the EHP-30. The gap left surgeons in the lurch on what to tell women how they’ll do, especially because results from previous, shorter, and less-rigorous studies have been mixed. The Pittsburgh results mean that competent surgeons can breathe easier and be confident in telling women what to expect.

The team administered EHP-30 to 61 women before surgery and at 4 weeks postoperatively; 45 patients (74%) had fertility-sparing excisions, 7 (11%) had hysterectomy with adnexa preservation, and 9 (15%) had hysterectomy with bilateral salpingo-oophorectomy. The women were contacted again in 2017 to fill out the survey anywhere from 3 to 7 years after their operation; 45 women agreed, a response rate of 74%.

There was a definitive, statistically significant reduction in scores across all five domains of the survey, both at 4 weeks and out to 7 years, and the improvements did not vary by endometriosis stage or the type of surgery women had.

The overall score – a combination of the five domains – fell from a preoperative median of 50 points out of a possible 100, with 100 being the worst possible score, to a median of about 20 points 4 weeks after surgery, and a median of about 10 points at long-term follow-up. Pain scores fell about the same amount; the greatest improvements were on questions that focused on sense of control and empowerment.

At long-term follow-up, overall scores improved a median of 43 points in women with American Society for Reproductive Medicine stage 1 endometriosis and 28 points among women with stage 4 disease (P = .705). Although the differences were not statistically significant, women with stage 1 disease generally reported the greatest improvements, except on the control and empowerment scale, where women reported the same improvement across all four stages, about 50 points out of 100.

Long-term score improvements were pretty much identical among women who had fertility-sparing surgery and those who had hysterectomies, with, for instance, both groups reporting about a 33-point improvement in pain scores. The two groups separated out only on emotional well-being scores, a 38-point improvement in the hysterectomy group versus 21 points, but the difference was not statistically significant (P = .525).

The long-term results remained the same when eight women who had subsequent gynecologic surgery were excluded.

In the end, the take home is that “all of these women improved,” Dr. Donnellan said.

The investigators didn’t report any disclosures.

[email protected]

SOURCE: Donnellan NM et al. 2018 AAGL Global Congress, Abstract 82.

Medical science’s broad knowledge of endometriosis notwithstanding, “many questions remain unanswered” about the management of a condition that is often refractory to established therapies, observed Sawsan As-Sanie, MD, MPH, at the 2018 Pelvic Anatomy and Gynecologic Surgery Symposium meeting in Las Vegas, Nevada. Dr. As-Sanie is Associate Professor and Director, Minimally Invasive Gynecologic Surgery Fellowship, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor. How, then, should clinicians approach the challenge of caring for women with this enigmatic disease in the larger context of chronic pelvic pain, in which, as Dr. As-Sanie said, “one size never fits all”?

Complex correlation between endometriosis and CPP

Despite high prevalence and negative impact on the health and quality of life of women who suffer from endometriosis, Dr. As-Sanie emphasized, it remains unclear why only some women with endometriosis develop chronic pelvic pain (CPP) and why there is little, if any, correlation between disease severity and the intensity of pain.

The clinical approach to endometriosis and CPP can be frustrating for several reasons: there is minimal relationship between extent or location of disease with pain symptoms; there is no consistent relationship among inflammatory markers, nerve-fiber density, and pain symptoms; and pain can recur after medical and surgical therapy—often without evidence of recurrent endometriosis. Furthermore, the differential diagnosis of CPP is broad, and also includes adenomyosis, adhesions, chronic pelvic inflammatory disease, uterine fibroids, pelvic congestion, ovarian remnant, and residual ovarian syndrome. Chronic overlapping pain conditions are prevalent, too, including interstitial cystitis, irritable bowel syndrome, and vulvodynia, to name a few.¹

_

CPP is not just a pain disorder

Dr. As-Sanie said that understanding of CPP must extend to include fatigue, memory difficulties, poor sleep, and heightened sensitivity to multiple sensory stimuli (e.g., sound and light).² So what, she asked, do we know about endometriosis, chronic pelvic pain, and the brain? We know that CPP, with and without endometriosis, is associated with increased pain sensitivity and altered central nervous system structure and function.^3-5 Central amplification of pain can lead to chronic pain independent of nociceptive signals, including multifocal, widespread pain; higher lifetime history of pain throughout the body; and pain triggered or exacerbated by stressors. And CPP brings with it other, potentially debilitating problems, including elevated distress, decreased activity, isolation, poor sleep, and maladaptive illness behaviors.

Finding, then addressing, the culprit

Identifying the underlying cause(s) of CPP in the individual woman should guide clinical care. This includes the decision to proceed with, or avoid, surgery. Remember: Patients with centralized pain respond differently to therapy; surgery is less likely to help relieve the pain.

Dr. As-Sanie offered several fundamental guidelines for managing CPP:

• Treat early, to prevent transition from acute to chronic pain; treatment delay increases connectivity between pain regulatory regions.
• Hysterectomy is not definitive therapy for all women with endometriosis or CPP.⁶
• Take a multisystem approach, comprising medical, behavioral, and interventional strategies.
• If an organ- or disease-based diagnostic and treatment approach does not work, reconsider the diagnosis; re-evaluate comorbid psychosocial variables; and consider treating centralized pain.
• Choice of treatment should include consideration of cost and adverse-effect profile.
• If one modality is ineffective, try another.

Continue to: What are the levels of evidence for centralized pain treatment?

Available pharmacotherapeutic agents have modest benefit, possibly because the population of pain patients is heterogeneous, with various underlying mechanisms of pain. And, Dr. As-Sanie pointed out, clinical tools do not currently exist to pre-emptively select the right medicine for individual patients.

Evidence is strong, Dr. As-Sanie noted, for dual reuptake-inhibitor antidepressants, such as tricyclic compounds (amitriptyline, cyclobenzaprine) and serotonin–norepinephrine reuptake inhibitors, and for anticonvulsants with analgesic properties (pregabalin, gabapentin). Evidence is “modest,” Dr. As-Sanie said, for tramadol, gamma hydroxybutyrate, and low-dose naltrexone, and “weak” for cannabinoids, human growth hormone, 5-hydroxytryptamine, tropisetron, and S-adenosyl-L-methionine. There is no evidence for using opioids, corticosteroids, nonsteroidal anti-inflammatory drugs, benzodiazepine and non–benzodiazepine hypnotics, or guaifenesin.⁷

When surgery or pharmacotherapy alone fail to yield the necessary outcome, consider adjunctive nonpharmacotherapy.⁸ For example, there is strong evidence for patient education, aerobic exercise, and cognitive behavior therapy; modest evidence for acupressure, acupuncture, strength training, hypnotherapy, biofeedback, trigger-point injection, and neuromodulation; but only weak evidence for chiropractic, manual and massage therapy, electrotherapy, and ultrasound. ⁷

_

With CPP, “one size never fits all”

Dr. As-Sanie concluded with a reminder that CPP can be the product of any of a range of underlying contributory causes. Pathology might stand foremost as you search for the source of pain and an effective treatment, but keep in mind that genetics, environment, co-existing pain conditions, the patient’s ability to cope, and her resilience and social support might play a role.

Medical science’s broad knowledge of endometriosis notwithstanding, “many questions remain unanswered” about the management of a condition that is often refractory to established therapies, observed Sawsan As-Sanie, MD, MPH, at the 2018 Pelvic Anatomy and Gynecologic Surgery Symposium meeting in Las Vegas, Nevada. Dr. As-Sanie is Associate Professor and Director, Minimally Invasive Gynecologic Surgery Fellowship, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor. How, then, should clinicians approach the challenge of caring for women with this enigmatic disease in the larger context of chronic pelvic pain, in which, as Dr. As-Sanie said, “one size never fits all”?

Complex correlation between endometriosis and CPP

Despite high prevalence and negative impact on the health and quality of life of women who suffer from endometriosis, Dr. As-Sanie emphasized, it remains unclear why only some women with endometriosis develop chronic pelvic pain (CPP) and why there is little, if any, correlation between disease severity and the intensity of pain.

The clinical approach to endometriosis and CPP can be frustrating for several reasons: there is minimal relationship between extent or location of disease with pain symptoms; there is no consistent relationship among inflammatory markers, nerve-fiber density, and pain symptoms; and pain can recur after medical and surgical therapy—often without evidence of recurrent endometriosis. Furthermore, the differential diagnosis of CPP is broad, and also includes adenomyosis, adhesions, chronic pelvic inflammatory disease, uterine fibroids, pelvic congestion, ovarian remnant, and residual ovarian syndrome. Chronic overlapping pain conditions are prevalent, too, including interstitial cystitis, irritable bowel syndrome, and vulvodynia, to name a few.¹

_

CPP is not just a pain disorder

Dr. As-Sanie said that understanding of CPP must extend to include fatigue, memory difficulties, poor sleep, and heightened sensitivity to multiple sensory stimuli (e.g., sound and light).² So what, she asked, do we know about endometriosis, chronic pelvic pain, and the brain? We know that CPP, with and without endometriosis, is associated with increased pain sensitivity and altered central nervous system structure and function.^3-5 Central amplification of pain can lead to chronic pain independent of nociceptive signals, including multifocal, widespread pain; higher lifetime history of pain throughout the body; and pain triggered or exacerbated by stressors. And CPP brings with it other, potentially debilitating problems, including elevated distress, decreased activity, isolation, poor sleep, and maladaptive illness behaviors.

Finding, then addressing, the culprit

Identifying the underlying cause(s) of CPP in the individual woman should guide clinical care. This includes the decision to proceed with, or avoid, surgery. Remember: Patients with centralized pain respond differently to therapy; surgery is less likely to help relieve the pain.

Dr. As-Sanie offered several fundamental guidelines for managing CPP:

• Treat early, to prevent transition from acute to chronic pain; treatment delay increases connectivity between pain regulatory regions.
• Hysterectomy is not definitive therapy for all women with endometriosis or CPP.⁶
• Take a multisystem approach, comprising medical, behavioral, and interventional strategies.
• If an organ- or disease-based diagnostic and treatment approach does not work, reconsider the diagnosis; re-evaluate comorbid psychosocial variables; and consider treating centralized pain.
• Choice of treatment should include consideration of cost and adverse-effect profile.
• If one modality is ineffective, try another.

Continue to: What are the levels of evidence for centralized pain treatment?

Available pharmacotherapeutic agents have modest benefit, possibly because the population of pain patients is heterogeneous, with various underlying mechanisms of pain. And, Dr. As-Sanie pointed out, clinical tools do not currently exist to pre-emptively select the right medicine for individual patients.

Evidence is strong, Dr. As-Sanie noted, for dual reuptake-inhibitor antidepressants, such as tricyclic compounds (amitriptyline, cyclobenzaprine) and serotonin–norepinephrine reuptake inhibitors, and for anticonvulsants with analgesic properties (pregabalin, gabapentin). Evidence is “modest,” Dr. As-Sanie said, for tramadol, gamma hydroxybutyrate, and low-dose naltrexone, and “weak” for cannabinoids, human growth hormone, 5-hydroxytryptamine, tropisetron, and S-adenosyl-L-methionine. There is no evidence for using opioids, corticosteroids, nonsteroidal anti-inflammatory drugs, benzodiazepine and non–benzodiazepine hypnotics, or guaifenesin.⁷

When surgery or pharmacotherapy alone fail to yield the necessary outcome, consider adjunctive nonpharmacotherapy.⁸ For example, there is strong evidence for patient education, aerobic exercise, and cognitive behavior therapy; modest evidence for acupressure, acupuncture, strength training, hypnotherapy, biofeedback, trigger-point injection, and neuromodulation; but only weak evidence for chiropractic, manual and massage therapy, electrotherapy, and ultrasound. ⁷

_

With CPP, “one size never fits all”

Dr. As-Sanie concluded with a reminder that CPP can be the product of any of a range of underlying contributory causes. Pathology might stand foremost as you search for the source of pain and an effective treatment, but keep in mind that genetics, environment, co-existing pain conditions, the patient’s ability to cope, and her resilience and social support might play a role.

Medical science’s broad knowledge of endometriosis notwithstanding, “many questions remain unanswered” about the management of a condition that is often refractory to established therapies, observed Sawsan As-Sanie, MD, MPH, at the 2018 Pelvic Anatomy and Gynecologic Surgery Symposium meeting in Las Vegas, Nevada. Dr. As-Sanie is Associate Professor and Director, Minimally Invasive Gynecologic Surgery Fellowship, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor. How, then, should clinicians approach the challenge of caring for women with this enigmatic disease in the larger context of chronic pelvic pain, in which, as Dr. As-Sanie said, “one size never fits all”?

Complex correlation between endometriosis and CPP

Despite high prevalence and negative impact on the health and quality of life of women who suffer from endometriosis, Dr. As-Sanie emphasized, it remains unclear why only some women with endometriosis develop chronic pelvic pain (CPP) and why there is little, if any, correlation between disease severity and the intensity of pain.

The clinical approach to endometriosis and CPP can be frustrating for several reasons: there is minimal relationship between extent or location of disease with pain symptoms; there is no consistent relationship among inflammatory markers, nerve-fiber density, and pain symptoms; and pain can recur after medical and surgical therapy—often without evidence of recurrent endometriosis. Furthermore, the differential diagnosis of CPP is broad, and also includes adenomyosis, adhesions, chronic pelvic inflammatory disease, uterine fibroids, pelvic congestion, ovarian remnant, and residual ovarian syndrome. Chronic overlapping pain conditions are prevalent, too, including interstitial cystitis, irritable bowel syndrome, and vulvodynia, to name a few.¹

_

CPP is not just a pain disorder

Dr. As-Sanie said that understanding of CPP must extend to include fatigue, memory difficulties, poor sleep, and heightened sensitivity to multiple sensory stimuli (e.g., sound and light).² So what, she asked, do we know about endometriosis, chronic pelvic pain, and the brain? We know that CPP, with and without endometriosis, is associated with increased pain sensitivity and altered central nervous system structure and function.^3-5 Central amplification of pain can lead to chronic pain independent of nociceptive signals, including multifocal, widespread pain; higher lifetime history of pain throughout the body; and pain triggered or exacerbated by stressors. And CPP brings with it other, potentially debilitating problems, including elevated distress, decreased activity, isolation, poor sleep, and maladaptive illness behaviors.

Finding, then addressing, the culprit

Identifying the underlying cause(s) of CPP in the individual woman should guide clinical care. This includes the decision to proceed with, or avoid, surgery. Remember: Patients with centralized pain respond differently to therapy; surgery is less likely to help relieve the pain.

Dr. As-Sanie offered several fundamental guidelines for managing CPP:

• Treat early, to prevent transition from acute to chronic pain; treatment delay increases connectivity between pain regulatory regions.
• Hysterectomy is not definitive therapy for all women with endometriosis or CPP.⁶
• Take a multisystem approach, comprising medical, behavioral, and interventional strategies.
• If an organ- or disease-based diagnostic and treatment approach does not work, reconsider the diagnosis; re-evaluate comorbid psychosocial variables; and consider treating centralized pain.
• Choice of treatment should include consideration of cost and adverse-effect profile.
• If one modality is ineffective, try another.

Continue to: What are the levels of evidence for centralized pain treatment?

Available pharmacotherapeutic agents have modest benefit, possibly because the population of pain patients is heterogeneous, with various underlying mechanisms of pain. And, Dr. As-Sanie pointed out, clinical tools do not currently exist to pre-emptively select the right medicine for individual patients.

Evidence is strong, Dr. As-Sanie noted, for dual reuptake-inhibitor antidepressants, such as tricyclic compounds (amitriptyline, cyclobenzaprine) and serotonin–norepinephrine reuptake inhibitors, and for anticonvulsants with analgesic properties (pregabalin, gabapentin). Evidence is “modest,” Dr. As-Sanie said, for tramadol, gamma hydroxybutyrate, and low-dose naltrexone, and “weak” for cannabinoids, human growth hormone, 5-hydroxytryptamine, tropisetron, and S-adenosyl-L-methionine. There is no evidence for using opioids, corticosteroids, nonsteroidal anti-inflammatory drugs, benzodiazepine and non–benzodiazepine hypnotics, or guaifenesin.⁷

When surgery or pharmacotherapy alone fail to yield the necessary outcome, consider adjunctive nonpharmacotherapy.⁸ For example, there is strong evidence for patient education, aerobic exercise, and cognitive behavior therapy; modest evidence for acupressure, acupuncture, strength training, hypnotherapy, biofeedback, trigger-point injection, and neuromodulation; but only weak evidence for chiropractic, manual and massage therapy, electrotherapy, and ultrasound. ⁷

_

With CPP, “one size never fits all”

Dr. As-Sanie concluded with a reminder that CPP can be the product of any of a range of underlying contributory causes. Pathology might stand foremost as you search for the source of pain and an effective treatment, but keep in mind that genetics, environment, co-existing pain conditions, the patient’s ability to cope, and her resilience and social support might play a role.

Although it has been more than 100 years since endometriosis was first described in the literature, deciphering the mechanisms that cause pain in women with this enigmatic disease is an ongoing pursuit.

Pain is the most debilitating symptom of endometriosis.^1,2 In many cases, it has a profoundly negative impact on a patient’s quality of life, and contributes significantly to disease burden, as well as to personal and societal costs from lost productivity.^3,4 Women with endometriosis often experience chronic pelvic pain, deep dyspareunia, dysmenorrhea, and subfertility.⁵ The majority of women with the disease also have one or more comorbidities, including adenomyosis, adhesive disease, and other pelvic pain conditions such as interstitial cystitis, irritable bowel disease, inflammatory bowel disease, and pelvic floor myalgia.^6-8

Recent studies have yielded new insights into the development of endometriosis-associated pelvic pain. The role of peritoneal inflammation, de novo innervation of endometriosis implants, and changes in the central nervous system are becoming increasingly clear.^5,9,10 These discoveries have important treatment implications.

In this article, Andrea J. Rapkin, MD, Professor of Obstetrics and Gynecology at the University of California, Los Angeles, and Founder and Director of the UCLA Pelvic Pain Center, offers her expert opinion on the findings of key studies and their clinical implications, including the importance of a multidisciplinary treatment approach that focuses on the whole patient.

Q What mechanisms underlie the chronic pain that many women with endometriosis feel?

Although pain is the primary symptom experienced by women with endometriosis, the disease burden and symptom severity do not often correlate.^11,12 “This was the first conundrum presented to clinicians,” noted Dr. Rapkin. “In fact, we do not know the true prevalence of endometriosis because women with endometriosis only come to diagnosis either based on pain or infertility. When infertility is the problem, very often we are surprised by how much disease is present in an individual with either no pain or minimal pain. Conversely, in other individuals with very severe pain, upon laparoscopic surgery, have minimal or mild endometriosis.”

Efforts to solve this clinical puzzle began decades ago. “Dr. Michael Vernon discovered that the small, red, endometriosis implants that looked like petechial hemorrhages produced more prostaglandin E2 (PGE2) in vitro than the older black-brown lesions. PGE2 is a pain-producing (algesic) chemical produced after cytokines stimulation,” said Dr. Rapkin. “This was the first evidence that, yes, there is a reason for pain in many individuals with lower-stage disease.”

“Prostaglandins are known to be a major cause of dysmenorrhea. Prostaglandins induce uterine cramping, sensitize nerve endings, and promote other inflammatory factors responsible for attracting monocytes that become macrophages, further contributing to inflammation,” Dr. Rapkin continued. “PGE2 also stimulates the enzyme aromatase, which allows androgens to be converted to estrogen, which promotes growth of endometriotic lesions. This is a self-feeding aspect of endometriosis.”

Continue to: These discoveries were followed by the realization that deeply infiltrating endometriosis...

Q What other chronic pain conditions might women with endometriosis experience?

Overlapping chronic pain conditions are common in women with endometriosis. “There is a very high co-occurrence of interstitial cystitis/painful bladder syndrome,” said Dr. Rapkin. “Irritable bowel syndrome is more common in women with endometriosis, as is vulvodynia. Fibromyalgia, migraine headache, temporo-mandibular joint pain (TMJ), anxiety, and depression also commonly co-occur in women with endometriosis.”

“Two concepts may be relevant to why these overlapping pain conditions develop,” Dr. Rapkin continued. “First, visceral sensitization: If one organ or tissue is inflamed and becomes hyperalgesic then other organs in the adjacent region with shared thoracolumbar and sacral innervation can become sensitized through shared cell bodies in the spinal cord, cross-sensitization in the cord, or at higher regions of the CNS. In addition, visceral somatic conversion occurs, whereby somatic tissues such as muscles and subcutaneous tissues with the same nerve supply as the affected organs become sensitized. This process may explain why abdominal wall and pelvic floor muscles become painful. The involvement of surrounding musculature is an important contributor to the pain in many women with endometriosis.”

“Finally, genetic studies of alterations in genes that encode for chemicals affecting the sensitivity and perception of pain are shedding light on the development of chronic pain. Ultimately these studies will advance our understanding of pain related to endometriosis.”

Continue to: Q How have new understandings about the pain mechanisms...

According to Dr. Rapkin, the increased understanding of the mechanisms involved in endometriosis-associated pain gained from these key studies led to a paradigm shift, with endometriosis being viewed not just as a condition with mechanical hypersensitivity due to altered anatomy and inflammation but also as a neurologic condition, or a nerve pain condition with peripheral and central sensitization. “This means there is upregulation or hyperactivity both in the periphery (in the pelvis) and centrally (in the spinal cord and brain),” said Dr. Rapkin.

“In the periphery, the endometriotic lesions develop an afferent sensory innervation and communicate with the brain. Stimulation of these nerves by the inflammatory milieu contributes to pain.” Dr. Rapkin noted research by Maria Adele Giamberardino, which demonstrated that women with endometriosis and pain have a lower threshold for feeling pain in the tissues overlying the pelvis (the abdominal wall and back).¹⁴ This also has been shown by Dr. Berkley in rodents given endometriosis.

“The muscles develop trigger points and tender hyperalgesic points as part of the sensitization process. In addition, distant sensitization develops—women with pelvic pain and endometriosis have a lower threshold for sensing experimental pain in areas outside the pelvis, for example the back, leg, or shoulder. These discoveries clearly reflect up regulation for pain processing in the central nervous system.”

Dr. Rapkin also pointed to research published in 2016 by Sawson As-Sanie, MD, MPH, that showed an association between endometriosis-associated pelvic pain and altered brain chemistry and function.¹⁶ “Dr. As-Sanie demonstrated a decrease in gray matter volume in key neural pain processing areas in the brain in women with pain with endometriosis. This was not found in women with endometriosis who did not have pain,” she said. “Altered connectivity in brain areas related to perception and inhibition of pain is important in maintaining pain. Dr. As-Sanie’s studies also found that these changes are correlated with anxiety, depression, and pain intensity in patients with endometriosis and chronic pain.”

Continue to: Q What are some newer treatment approaches to chronic pain with endometriosis?

Q What are some newer treatment approaches to chronic pain with endometriosis?

“Multidisciplinary approaches to endometriosis-related pain are important,” said Dr. Rapkin. “Although it is important to excise or cauterize endometriosis lesions, or debulk as much as can safely be removed during laparoscopic surgery, it is now standard of care that medical therapy, not surgery, is the first approach to treatment. Endometriosis is a chronic condition. Inflammatory factors will continue to proliferate in patients who menstruate and produce high levels of estrogen with ovulation. The goal of medical therapy is to decrease the levels of estrogen that contribute to maintenance and proliferation of the implants. We want to suppress estrogen in a way that is compatible with long-term quality of life for our patients. Wiping out estrogen and placing patients into a chemical or surgical menopause for most of their reproductive years is not desirable.”

Approaches to hormonally modulate endometriosis include combined hormonal contraceptives and progestin-only medications, such as the levonogestrol-containing IUD, progestin-containing contraceptive implants, injections, or tablets. Second-line medical therapy consists of gonadotropin-releasing hormone agonists and antagonists that can be used for 6 months to 2 years and allows for further lowering of estrogen levels. These may not provide sufficient pain relief for some patients. “There is some evidence from Dr. Giamberadino’s studies that after women with dysmenorrhea were treated with oral contraceptives, the abdominal wall hyperalgesia decreased,” said Dr. Rapkin. “The question is, why don’t we see this in all patients? We come to the realization that endometriosis has to be treated as a neurologically mediated disorder. We have to treat the peripheral and central sensitization in a multidisciplinary way.”

A holistic approach to endometriosis is a new and exciting area for the field, said Dr. Rapkin. “We have to treat ‘bottom-up’, and ‘top-down.’ Bottom-up means we are addressing the peripheral factors that contribute to pain: endometriotic lesions, other pelvic organ pain, myofascial pain, trigger points, the tender points, and the muscle dysfunction in the abdominal wall, the back, and the pelvic floor. Pelvic floor physical therapists help women with pain and endometriosis. Often, women with endometriosis have myofascial pain and pain related to the other comorbid pain conditions they may have developed. Peripheral nerve blocks and medications used for neuropathic pain that alter nerve firing can be helpful in many situations. Pain can be augmented by cognitions and beliefs about pain, and by anxiety and depression. So the top-down approach addresses the cognitions, depression, and anxiety. We do not consider endometriosis a psychosomatic condition, but we know that if you do not address the central upregulation, including anxiety and depression, we may not get anywhere.”

“Interestingly, neurotransmitters and brain regions governing mood contribute to nerve pain. Medications such as tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, anticonvulsants, and calcium channel blocking agents may prove fruitful. Cognitive behavioral therapy is another approach—to stimulate the prefrontal cortex, the area that is involved in pain inhibition, and other areas of the brain that may produce endogenous opioids to help with inhibiting pain. Bringing in complementary approaches is very important—for example, mindfulness-based meditation or yoga. There is growing evidence for acupuncture as well. Physical therapists, pain psychologists, anesthesiologists, or gynecologists who are facile with nerve blocks, to help tone down hyperalgesic tissues, in addition to medical and surgical therapy, have the possibility of really improving the lives of women with endometriosis.”

Q What key pearls would you like to share with readers?

“It is important to evaluate the entire individual,” she said. “Do not just viscerally focus on the uterus, the ovaries, fallopian tubes, and the peritoneum; investigate the adjacent organs and somatic tissues. Think about the abdominal wall, think about the pelvic floor. Learn how to evaluate these structures. There are simple evaluation techniques that gynecologists can learn and should include with every patient with pelvic pain, whether or not they are suspected of having endometriosis. You also want to get a complete history to determine if there are other co-occurring pain conditions. If there are, it is already a sign that there may be central sensitization.”

“Very often, it is necessary to bring in a pain psychologist—not because the disease is psychosomatic but because therapy can help the patient to learn how to use their brain to erase pain memory, and of course to address the concomitant anxiety, depression, and social isolation that happens with pain.”

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Although it has been more than 100 years since endometriosis was first described in the literature, deciphering the mechanisms that cause pain in women with this enigmatic disease is an ongoing pursuit.

Pain is the most debilitating symptom of endometriosis.^1,2 In many cases, it has a profoundly negative impact on a patient’s quality of life, and contributes significantly to disease burden, as well as to personal and societal costs from lost productivity.^3,4 Women with endometriosis often experience chronic pelvic pain, deep dyspareunia, dysmenorrhea, and subfertility.⁵ The majority of women with the disease also have one or more comorbidities, including adenomyosis, adhesive disease, and other pelvic pain conditions such as interstitial cystitis, irritable bowel disease, inflammatory bowel disease, and pelvic floor myalgia.^6-8

Recent studies have yielded new insights into the development of endometriosis-associated pelvic pain. The role of peritoneal inflammation, de novo innervation of endometriosis implants, and changes in the central nervous system are becoming increasingly clear.^5,9,10 These discoveries have important treatment implications.

In this article, Andrea J. Rapkin, MD, Professor of Obstetrics and Gynecology at the University of California, Los Angeles, and Founder and Director of the UCLA Pelvic Pain Center, offers her expert opinion on the findings of key studies and their clinical implications, including the importance of a multidisciplinary treatment approach that focuses on the whole patient.

Q What mechanisms underlie the chronic pain that many women with endometriosis feel?

Although pain is the primary symptom experienced by women with endometriosis, the disease burden and symptom severity do not often correlate.^11,12 “This was the first conundrum presented to clinicians,” noted Dr. Rapkin. “In fact, we do not know the true prevalence of endometriosis because women with endometriosis only come to diagnosis either based on pain or infertility. When infertility is the problem, very often we are surprised by how much disease is present in an individual with either no pain or minimal pain. Conversely, in other individuals with very severe pain, upon laparoscopic surgery, have minimal or mild endometriosis.”

Efforts to solve this clinical puzzle began decades ago. “Dr. Michael Vernon discovered that the small, red, endometriosis implants that looked like petechial hemorrhages produced more prostaglandin E2 (PGE2) in vitro than the older black-brown lesions. PGE2 is a pain-producing (algesic) chemical produced after cytokines stimulation,” said Dr. Rapkin. “This was the first evidence that, yes, there is a reason for pain in many individuals with lower-stage disease.”

“Prostaglandins are known to be a major cause of dysmenorrhea. Prostaglandins induce uterine cramping, sensitize nerve endings, and promote other inflammatory factors responsible for attracting monocytes that become macrophages, further contributing to inflammation,” Dr. Rapkin continued. “PGE2 also stimulates the enzyme aromatase, which allows androgens to be converted to estrogen, which promotes growth of endometriotic lesions. This is a self-feeding aspect of endometriosis.”

Continue to: These discoveries were followed by the realization that deeply infiltrating endometriosis...

Q What other chronic pain conditions might women with endometriosis experience?

Overlapping chronic pain conditions are common in women with endometriosis. “There is a very high co-occurrence of interstitial cystitis/painful bladder syndrome,” said Dr. Rapkin. “Irritable bowel syndrome is more common in women with endometriosis, as is vulvodynia. Fibromyalgia, migraine headache, temporo-mandibular joint pain (TMJ), anxiety, and depression also commonly co-occur in women with endometriosis.”

“Two concepts may be relevant to why these overlapping pain conditions develop,” Dr. Rapkin continued. “First, visceral sensitization: If one organ or tissue is inflamed and becomes hyperalgesic then other organs in the adjacent region with shared thoracolumbar and sacral innervation can become sensitized through shared cell bodies in the spinal cord, cross-sensitization in the cord, or at higher regions of the CNS. In addition, visceral somatic conversion occurs, whereby somatic tissues such as muscles and subcutaneous tissues with the same nerve supply as the affected organs become sensitized. This process may explain why abdominal wall and pelvic floor muscles become painful. The involvement of surrounding musculature is an important contributor to the pain in many women with endometriosis.”

“Finally, genetic studies of alterations in genes that encode for chemicals affecting the sensitivity and perception of pain are shedding light on the development of chronic pain. Ultimately these studies will advance our understanding of pain related to endometriosis.”

Continue to: Q How have new understandings about the pain mechanisms...

According to Dr. Rapkin, the increased understanding of the mechanisms involved in endometriosis-associated pain gained from these key studies led to a paradigm shift, with endometriosis being viewed not just as a condition with mechanical hypersensitivity due to altered anatomy and inflammation but also as a neurologic condition, or a nerve pain condition with peripheral and central sensitization. “This means there is upregulation or hyperactivity both in the periphery (in the pelvis) and centrally (in the spinal cord and brain),” said Dr. Rapkin.

“In the periphery, the endometriotic lesions develop an afferent sensory innervation and communicate with the brain. Stimulation of these nerves by the inflammatory milieu contributes to pain.” Dr. Rapkin noted research by Maria Adele Giamberardino, which demonstrated that women with endometriosis and pain have a lower threshold for feeling pain in the tissues overlying the pelvis (the abdominal wall and back).¹⁴ This also has been shown by Dr. Berkley in rodents given endometriosis.

“The muscles develop trigger points and tender hyperalgesic points as part of the sensitization process. In addition, distant sensitization develops—women with pelvic pain and endometriosis have a lower threshold for sensing experimental pain in areas outside the pelvis, for example the back, leg, or shoulder. These discoveries clearly reflect up regulation for pain processing in the central nervous system.”

Dr. Rapkin also pointed to research published in 2016 by Sawson As-Sanie, MD, MPH, that showed an association between endometriosis-associated pelvic pain and altered brain chemistry and function.¹⁶ “Dr. As-Sanie demonstrated a decrease in gray matter volume in key neural pain processing areas in the brain in women with pain with endometriosis. This was not found in women with endometriosis who did not have pain,” she said. “Altered connectivity in brain areas related to perception and inhibition of pain is important in maintaining pain. Dr. As-Sanie’s studies also found that these changes are correlated with anxiety, depression, and pain intensity in patients with endometriosis and chronic pain.”

Continue to: Q What are some newer treatment approaches to chronic pain with endometriosis?

Q What are some newer treatment approaches to chronic pain with endometriosis?

“Multidisciplinary approaches to endometriosis-related pain are important,” said Dr. Rapkin. “Although it is important to excise or cauterize endometriosis lesions, or debulk as much as can safely be removed during laparoscopic surgery, it is now standard of care that medical therapy, not surgery, is the first approach to treatment. Endometriosis is a chronic condition. Inflammatory factors will continue to proliferate in patients who menstruate and produce high levels of estrogen with ovulation. The goal of medical therapy is to decrease the levels of estrogen that contribute to maintenance and proliferation of the implants. We want to suppress estrogen in a way that is compatible with long-term quality of life for our patients. Wiping out estrogen and placing patients into a chemical or surgical menopause for most of their reproductive years is not desirable.”

Approaches to hormonally modulate endometriosis include combined hormonal contraceptives and progestin-only medications, such as the levonogestrol-containing IUD, progestin-containing contraceptive implants, injections, or tablets. Second-line medical therapy consists of gonadotropin-releasing hormone agonists and antagonists that can be used for 6 months to 2 years and allows for further lowering of estrogen levels. These may not provide sufficient pain relief for some patients. “There is some evidence from Dr. Giamberadino’s studies that after women with dysmenorrhea were treated with oral contraceptives, the abdominal wall hyperalgesia decreased,” said Dr. Rapkin. “The question is, why don’t we see this in all patients? We come to the realization that endometriosis has to be treated as a neurologically mediated disorder. We have to treat the peripheral and central sensitization in a multidisciplinary way.”

A holistic approach to endometriosis is a new and exciting area for the field, said Dr. Rapkin. “We have to treat ‘bottom-up’, and ‘top-down.’ Bottom-up means we are addressing the peripheral factors that contribute to pain: endometriotic lesions, other pelvic organ pain, myofascial pain, trigger points, the tender points, and the muscle dysfunction in the abdominal wall, the back, and the pelvic floor. Pelvic floor physical therapists help women with pain and endometriosis. Often, women with endometriosis have myofascial pain and pain related to the other comorbid pain conditions they may have developed. Peripheral nerve blocks and medications used for neuropathic pain that alter nerve firing can be helpful in many situations. Pain can be augmented by cognitions and beliefs about pain, and by anxiety and depression. So the top-down approach addresses the cognitions, depression, and anxiety. We do not consider endometriosis a psychosomatic condition, but we know that if you do not address the central upregulation, including anxiety and depression, we may not get anywhere.”

“Interestingly, neurotransmitters and brain regions governing mood contribute to nerve pain. Medications such as tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, anticonvulsants, and calcium channel blocking agents may prove fruitful. Cognitive behavioral therapy is another approach—to stimulate the prefrontal cortex, the area that is involved in pain inhibition, and other areas of the brain that may produce endogenous opioids to help with inhibiting pain. Bringing in complementary approaches is very important—for example, mindfulness-based meditation or yoga. There is growing evidence for acupuncture as well. Physical therapists, pain psychologists, anesthesiologists, or gynecologists who are facile with nerve blocks, to help tone down hyperalgesic tissues, in addition to medical and surgical therapy, have the possibility of really improving the lives of women with endometriosis.”

Q What key pearls would you like to share with readers?

“It is important to evaluate the entire individual,” she said. “Do not just viscerally focus on the uterus, the ovaries, fallopian tubes, and the peritoneum; investigate the adjacent organs and somatic tissues. Think about the abdominal wall, think about the pelvic floor. Learn how to evaluate these structures. There are simple evaluation techniques that gynecologists can learn and should include with every patient with pelvic pain, whether or not they are suspected of having endometriosis. You also want to get a complete history to determine if there are other co-occurring pain conditions. If there are, it is already a sign that there may be central sensitization.”

“Very often, it is necessary to bring in a pain psychologist—not because the disease is psychosomatic but because therapy can help the patient to learn how to use their brain to erase pain memory, and of course to address the concomitant anxiety, depression, and social isolation that happens with pain.”

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Although it has been more than 100 years since endometriosis was first described in the literature, deciphering the mechanisms that cause pain in women with this enigmatic disease is an ongoing pursuit.

Pain is the most debilitating symptom of endometriosis.^1,2 In many cases, it has a profoundly negative impact on a patient’s quality of life, and contributes significantly to disease burden, as well as to personal and societal costs from lost productivity.^3,4 Women with endometriosis often experience chronic pelvic pain, deep dyspareunia, dysmenorrhea, and subfertility.⁵ The majority of women with the disease also have one or more comorbidities, including adenomyosis, adhesive disease, and other pelvic pain conditions such as interstitial cystitis, irritable bowel disease, inflammatory bowel disease, and pelvic floor myalgia.^6-8

Recent studies have yielded new insights into the development of endometriosis-associated pelvic pain. The role of peritoneal inflammation, de novo innervation of endometriosis implants, and changes in the central nervous system are becoming increasingly clear.^5,9,10 These discoveries have important treatment implications.

In this article, Andrea J. Rapkin, MD, Professor of Obstetrics and Gynecology at the University of California, Los Angeles, and Founder and Director of the UCLA Pelvic Pain Center, offers her expert opinion on the findings of key studies and their clinical implications, including the importance of a multidisciplinary treatment approach that focuses on the whole patient.

Q What mechanisms underlie the chronic pain that many women with endometriosis feel?

Although pain is the primary symptom experienced by women with endometriosis, the disease burden and symptom severity do not often correlate.^11,12 “This was the first conundrum presented to clinicians,” noted Dr. Rapkin. “In fact, we do not know the true prevalence of endometriosis because women with endometriosis only come to diagnosis either based on pain or infertility. When infertility is the problem, very often we are surprised by how much disease is present in an individual with either no pain or minimal pain. Conversely, in other individuals with very severe pain, upon laparoscopic surgery, have minimal or mild endometriosis.”

Efforts to solve this clinical puzzle began decades ago. “Dr. Michael Vernon discovered that the small, red, endometriosis implants that looked like petechial hemorrhages produced more prostaglandin E2 (PGE2) in vitro than the older black-brown lesions. PGE2 is a pain-producing (algesic) chemical produced after cytokines stimulation,” said Dr. Rapkin. “This was the first evidence that, yes, there is a reason for pain in many individuals with lower-stage disease.”

“Prostaglandins are known to be a major cause of dysmenorrhea. Prostaglandins induce uterine cramping, sensitize nerve endings, and promote other inflammatory factors responsible for attracting monocytes that become macrophages, further contributing to inflammation,” Dr. Rapkin continued. “PGE2 also stimulates the enzyme aromatase, which allows androgens to be converted to estrogen, which promotes growth of endometriotic lesions. This is a self-feeding aspect of endometriosis.”

Continue to: These discoveries were followed by the realization that deeply infiltrating endometriosis...

Q What other chronic pain conditions might women with endometriosis experience?

Overlapping chronic pain conditions are common in women with endometriosis. “There is a very high co-occurrence of interstitial cystitis/painful bladder syndrome,” said Dr. Rapkin. “Irritable bowel syndrome is more common in women with endometriosis, as is vulvodynia. Fibromyalgia, migraine headache, temporo-mandibular joint pain (TMJ), anxiety, and depression also commonly co-occur in women with endometriosis.”

“Two concepts may be relevant to why these overlapping pain conditions develop,” Dr. Rapkin continued. “First, visceral sensitization: If one organ or tissue is inflamed and becomes hyperalgesic then other organs in the adjacent region with shared thoracolumbar and sacral innervation can become sensitized through shared cell bodies in the spinal cord, cross-sensitization in the cord, or at higher regions of the CNS. In addition, visceral somatic conversion occurs, whereby somatic tissues such as muscles and subcutaneous tissues with the same nerve supply as the affected organs become sensitized. This process may explain why abdominal wall and pelvic floor muscles become painful. The involvement of surrounding musculature is an important contributor to the pain in many women with endometriosis.”

“Finally, genetic studies of alterations in genes that encode for chemicals affecting the sensitivity and perception of pain are shedding light on the development of chronic pain. Ultimately these studies will advance our understanding of pain related to endometriosis.”

Continue to: Q How have new understandings about the pain mechanisms...

According to Dr. Rapkin, the increased understanding of the mechanisms involved in endometriosis-associated pain gained from these key studies led to a paradigm shift, with endometriosis being viewed not just as a condition with mechanical hypersensitivity due to altered anatomy and inflammation but also as a neurologic condition, or a nerve pain condition with peripheral and central sensitization. “This means there is upregulation or hyperactivity both in the periphery (in the pelvis) and centrally (in the spinal cord and brain),” said Dr. Rapkin.

“In the periphery, the endometriotic lesions develop an afferent sensory innervation and communicate with the brain. Stimulation of these nerves by the inflammatory milieu contributes to pain.” Dr. Rapkin noted research by Maria Adele Giamberardino, which demonstrated that women with endometriosis and pain have a lower threshold for feeling pain in the tissues overlying the pelvis (the abdominal wall and back).¹⁴ This also has been shown by Dr. Berkley in rodents given endometriosis.

“The muscles develop trigger points and tender hyperalgesic points as part of the sensitization process. In addition, distant sensitization develops—women with pelvic pain and endometriosis have a lower threshold for sensing experimental pain in areas outside the pelvis, for example the back, leg, or shoulder. These discoveries clearly reflect up regulation for pain processing in the central nervous system.”

Dr. Rapkin also pointed to research published in 2016 by Sawson As-Sanie, MD, MPH, that showed an association between endometriosis-associated pelvic pain and altered brain chemistry and function.¹⁶ “Dr. As-Sanie demonstrated a decrease in gray matter volume in key neural pain processing areas in the brain in women with pain with endometriosis. This was not found in women with endometriosis who did not have pain,” she said. “Altered connectivity in brain areas related to perception and inhibition of pain is important in maintaining pain. Dr. As-Sanie’s studies also found that these changes are correlated with anxiety, depression, and pain intensity in patients with endometriosis and chronic pain.”

Continue to: Q What are some newer treatment approaches to chronic pain with endometriosis?

Q What are some newer treatment approaches to chronic pain with endometriosis?

“Multidisciplinary approaches to endometriosis-related pain are important,” said Dr. Rapkin. “Although it is important to excise or cauterize endometriosis lesions, or debulk as much as can safely be removed during laparoscopic surgery, it is now standard of care that medical therapy, not surgery, is the first approach to treatment. Endometriosis is a chronic condition. Inflammatory factors will continue to proliferate in patients who menstruate and produce high levels of estrogen with ovulation. The goal of medical therapy is to decrease the levels of estrogen that contribute to maintenance and proliferation of the implants. We want to suppress estrogen in a way that is compatible with long-term quality of life for our patients. Wiping out estrogen and placing patients into a chemical or surgical menopause for most of their reproductive years is not desirable.”

Approaches to hormonally modulate endometriosis include combined hormonal contraceptives and progestin-only medications, such as the levonogestrol-containing IUD, progestin-containing contraceptive implants, injections, or tablets. Second-line medical therapy consists of gonadotropin-releasing hormone agonists and antagonists that can be used for 6 months to 2 years and allows for further lowering of estrogen levels. These may not provide sufficient pain relief for some patients. “There is some evidence from Dr. Giamberadino’s studies that after women with dysmenorrhea were treated with oral contraceptives, the abdominal wall hyperalgesia decreased,” said Dr. Rapkin. “The question is, why don’t we see this in all patients? We come to the realization that endometriosis has to be treated as a neurologically mediated disorder. We have to treat the peripheral and central sensitization in a multidisciplinary way.”

A holistic approach to endometriosis is a new and exciting area for the field, said Dr. Rapkin. “We have to treat ‘bottom-up’, and ‘top-down.’ Bottom-up means we are addressing the peripheral factors that contribute to pain: endometriotic lesions, other pelvic organ pain, myofascial pain, trigger points, the tender points, and the muscle dysfunction in the abdominal wall, the back, and the pelvic floor. Pelvic floor physical therapists help women with pain and endometriosis. Often, women with endometriosis have myofascial pain and pain related to the other comorbid pain conditions they may have developed. Peripheral nerve blocks and medications used for neuropathic pain that alter nerve firing can be helpful in many situations. Pain can be augmented by cognitions and beliefs about pain, and by anxiety and depression. So the top-down approach addresses the cognitions, depression, and anxiety. We do not consider endometriosis a psychosomatic condition, but we know that if you do not address the central upregulation, including anxiety and depression, we may not get anywhere.”

“Interestingly, neurotransmitters and brain regions governing mood contribute to nerve pain. Medications such as tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, anticonvulsants, and calcium channel blocking agents may prove fruitful. Cognitive behavioral therapy is another approach—to stimulate the prefrontal cortex, the area that is involved in pain inhibition, and other areas of the brain that may produce endogenous opioids to help with inhibiting pain. Bringing in complementary approaches is very important—for example, mindfulness-based meditation or yoga. There is growing evidence for acupuncture as well. Physical therapists, pain psychologists, anesthesiologists, or gynecologists who are facile with nerve blocks, to help tone down hyperalgesic tissues, in addition to medical and surgical therapy, have the possibility of really improving the lives of women with endometriosis.”

Q What key pearls would you like to share with readers?

“It is important to evaluate the entire individual,” she said. “Do not just viscerally focus on the uterus, the ovaries, fallopian tubes, and the peritoneum; investigate the adjacent organs and somatic tissues. Think about the abdominal wall, think about the pelvic floor. Learn how to evaluate these structures. There are simple evaluation techniques that gynecologists can learn and should include with every patient with pelvic pain, whether or not they are suspected of having endometriosis. You also want to get a complete history to determine if there are other co-occurring pain conditions. If there are, it is already a sign that there may be central sensitization.”

“Very often, it is necessary to bring in a pain psychologist—not because the disease is psychosomatic but because therapy can help the patient to learn how to use their brain to erase pain memory, and of course to address the concomitant anxiety, depression, and social isolation that happens with pain.”

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

LAS VEGAS – When stage IV endometriosis with obliterated posterior cul-de-sac is discovered during laparoscopic hysterectomy, or suspected beforehand, women should be referred to a minimally invasive gynecologic surgery specialist because the procedure will be much more difficult, investigators said at the meeting sponsored by AAGL.

M. Alexander Otto/MDedge News

They reviewed 333 laparoscopic hysterectomies where endometriosis was discovered in the operating room. The disease is known to increase the complexity of hysterectomy; the investigators wanted to quantify the risk by endometriosis severity. Among their subjects, 237 women (71%) had stage I, II, or III endometriosis; 96 (29%) had stage IV disease, including 55 women (57%) with obliterated posterior cul-de-sacs.

Surgery was longer among stage IV cases (137 vs. 116 minutes), and there was greater blood loss; 66% of stage IV women required laparoscopic-modified radical hysterectomy versus about a quarter of women with stage I-III endometriosis.

Laparoscopic hysterectomy was even more complex when women with stage IV endometriosis had obliterated cul-de-sacs. A total of 93% required modified radical hysterectomies versus 29% of stage IV women with intact cul-de-sacs. Additional procedures were far more likely in this population, including salpingectomy, ureterolysis, enterolysis, cystoscopy, ureteral stenting, proctoscopy, bowel oversew, and anterior resection anastomosis. The differences all were statistically significant.

Among stage IV cases, mean operating time was longer in obliterated cul-de-sac cases (159 vs. 108 minutes), with higher blood loss, 100 mL versus 50 mL.

“Patients with obliterated cul-de-sacs identified intraoperatively should be referred to minimally invasive gynecologic surgeons because of the ... extra training required to safely perform [laparoscopic hysterectomy] with limited morbidity,” said lead investigator Alexandra Melnyk, MD, a University of Pittsburgh ob.gyn resident.

There was no industry funding and the investigators reported no disclosures.

[email protected]

SOURCE: Melnyk A et al. 2018 AAGL Global Congress, Abstract 81.

LAS VEGAS – When stage IV endometriosis with obliterated posterior cul-de-sac is discovered during laparoscopic hysterectomy, or suspected beforehand, women should be referred to a minimally invasive gynecologic surgery specialist because the procedure will be much more difficult, investigators said at the meeting sponsored by AAGL.

M. Alexander Otto/MDedge News

They reviewed 333 laparoscopic hysterectomies where endometriosis was discovered in the operating room. The disease is known to increase the complexity of hysterectomy; the investigators wanted to quantify the risk by endometriosis severity. Among their subjects, 237 women (71%) had stage I, II, or III endometriosis; 96 (29%) had stage IV disease, including 55 women (57%) with obliterated posterior cul-de-sacs.

Surgery was longer among stage IV cases (137 vs. 116 minutes), and there was greater blood loss; 66% of stage IV women required laparoscopic-modified radical hysterectomy versus about a quarter of women with stage I-III endometriosis.

Laparoscopic hysterectomy was even more complex when women with stage IV endometriosis had obliterated cul-de-sacs. A total of 93% required modified radical hysterectomies versus 29% of stage IV women with intact cul-de-sacs. Additional procedures were far more likely in this population, including salpingectomy, ureterolysis, enterolysis, cystoscopy, ureteral stenting, proctoscopy, bowel oversew, and anterior resection anastomosis. The differences all were statistically significant.

Among stage IV cases, mean operating time was longer in obliterated cul-de-sac cases (159 vs. 108 minutes), with higher blood loss, 100 mL versus 50 mL.

“Patients with obliterated cul-de-sacs identified intraoperatively should be referred to minimally invasive gynecologic surgeons because of the ... extra training required to safely perform [laparoscopic hysterectomy] with limited morbidity,” said lead investigator Alexandra Melnyk, MD, a University of Pittsburgh ob.gyn resident.

There was no industry funding and the investigators reported no disclosures.

[email protected]

SOURCE: Melnyk A et al. 2018 AAGL Global Congress, Abstract 81.

LAS VEGAS – When stage IV endometriosis with obliterated posterior cul-de-sac is discovered during laparoscopic hysterectomy, or suspected beforehand, women should be referred to a minimally invasive gynecologic surgery specialist because the procedure will be much more difficult, investigators said at the meeting sponsored by AAGL.

M. Alexander Otto/MDedge News

They reviewed 333 laparoscopic hysterectomies where endometriosis was discovered in the operating room. The disease is known to increase the complexity of hysterectomy; the investigators wanted to quantify the risk by endometriosis severity. Among their subjects, 237 women (71%) had stage I, II, or III endometriosis; 96 (29%) had stage IV disease, including 55 women (57%) with obliterated posterior cul-de-sacs.

Surgery was longer among stage IV cases (137 vs. 116 minutes), and there was greater blood loss; 66% of stage IV women required laparoscopic-modified radical hysterectomy versus about a quarter of women with stage I-III endometriosis.

Laparoscopic hysterectomy was even more complex when women with stage IV endometriosis had obliterated cul-de-sacs. A total of 93% required modified radical hysterectomies versus 29% of stage IV women with intact cul-de-sacs. Additional procedures were far more likely in this population, including salpingectomy, ureterolysis, enterolysis, cystoscopy, ureteral stenting, proctoscopy, bowel oversew, and anterior resection anastomosis. The differences all were statistically significant.

Among stage IV cases, mean operating time was longer in obliterated cul-de-sac cases (159 vs. 108 minutes), with higher blood loss, 100 mL versus 50 mL.

“Patients with obliterated cul-de-sacs identified intraoperatively should be referred to minimally invasive gynecologic surgeons because of the ... extra training required to safely perform [laparoscopic hysterectomy] with limited morbidity,” said lead investigator Alexandra Melnyk, MD, a University of Pittsburgh ob.gyn resident.

There was no industry funding and the investigators reported no disclosures.

[email protected]

SOURCE: Melnyk A et al. 2018 AAGL Global Congress, Abstract 81.

Endometriosis is the presence of tissue resembling endometrial glands and stroma outside of the uterine cavity. Women with endometriosis often present for medical care with at least one of 3 problems: pelvic pain, infertility, and/or an adnexal mass due to endometriosis.¹ Many clinical observations demonstrate that endometriosis lesions require estrogen to grow and maintain their viability, including that: (1) endometriosis is uncommon before puberty or after menopause, (2) surgical removal of both ovaries results in regression of endometriosis lesions, and (3) gonadotropin-releasing hormone (GnRH) analogues cause a hypo‑estrogenic hormonal environment, resulting in regression of endometriosis lesions and improvement in pelvic pain. Since endometriosis lesions require estrogen to maintain their viability, suppressing estradiol is a logical approach to hormonal treatment of the disease.

The estrogen threshold hypothesis

The estradiol concentration that causes endometriosis lesions to grow or regress varies among women, but a concentration less than 20 pg/mL usually causes lesions to regress, and a concentration greater than 60 pg/mL usually supports lesion growth and maintains lesion viability.² Although an estradiol concentration below 20 pg/mL may cause lesions to regress, it also is associated with moderate to severe hot flashes and accelerated bone loss. These adverse effects limit the use of strong suppression of estrogen as a long-term treatment strategy. The estrogen threshold hypothesis posits that gently suppressing estradiol to a concentration between 20 and 45 pg/mL may simultaneously cause endometriosis lesions to regress, resulting in reduced pelvic pain, minimal bone loss, and few hot flashes.²

Building on the estrogen threshold hypothesis, clinicians have two options for treatment of pelvic pain caused by endometriosis:

1. strong suppression of estradiol to a concentration below 20 pg/mL
2. gentle suppression of estradiol to a concentration in the range of 20 to 45 pg/mL.

Strong suppression of estradiol to levels below 20 pg/mL will reliably induce amenorrhea and cause regression of endometriosis lesions, thereby reducing pelvic pain. Strong suppression of estradiol also will cause moderate to severe hot flashes and accelerated bone loss in many women. By contrast, gentle suppression of circulating estradiol to a concentration in the range of 20 to 45 pg/mL may result in amenorrhea or oligomenorrhea, suppression of the growth of endometriosis lesions, a modest reduction in pelvic pain, mild hot flashes, and minimal bone loss.

Recently, the US Food and Drug Administration (FDA) approved elagolix, an oral GnRH antagonist, for treatment of endometriosis.³ Elagolix blocks GnRH receptors in the pituitary gland, resulting in reduced production of luteinizing hormone and follicle stimulating hormone and a decrease in sex steroid secretion in the ovarian follicles, which leads to a reduction in the production and circulating concentration of estradiol. The FDA approved two doses of elagolix: 150 mg once daily for up to 24 months and 200 mg twice daily for up to 6 months. Importantly, elagolix at a dose of 150 mg once daily results in a mean circulating estradiol concentration of 41 pg/mL, indicating gentle suppression of ovarian estradiol production, and 200 mg twice daily results in a mean circulating ovarian estradiol concentration of 12 pg/mL, indicating strong suppression of ovarian estradiol production.³ For clinicians treating women with pelvic pain caused by endometriosis, these two elagolix regimens permit the individualization of hormonal therapy to the unique needs of each woman.

Continue to: Safety information for elagolix

Elagolix benefits and adverse effects

In one large clinical trial (Elaris Endometriosis I), 872 women were randomly assigned to treatment with one of two doses of elagolix (200 mg twice daily [high-dose group] or 150 mgonce daily [low-dose group]) or placebo.⁴ After 3 months of treatment, a clinically meaningful reduction in dysmenorrhea pain was reported by 76%, 46%, and 20% of women in the high-dose, low-dose, and placebo groups, respectively (P<.001 for comparisons of elagolix to placebo). In addition, at 3 months, a clinically meaningful reduction in nonmenstrual pain or decreased or stable use of rescue analgesics was reported by 55%, 50%, and 37% of women in the high-dose, low-dose, and placebo groups, respectively (low-dose vs placebo, P<.01; high-dose vs placebo, P<.001). Hot flashes that were severe enough to be classified as adverse events by study participants were reported by 42%, 24%, and 7% of the women in the high-dose, low-dose, and placebo groups, respectively. Bone density was measured at baseline and after 6 months of treatment. Lumbar bone density changes were -2.61%, -0.32%, and +0.47%, and hip/femoral/neck bone density changes were -1.89%, -0.39%, and +0.02% in the high-dose, low-dose, and placebo groups, respectively.

Another large clinical trial of elagolix for treatment of pelvic pain caused by endometriosis (Elaris II) involving 817 women produced results that were similar to those reported in Elaris I.⁴ The elagolix continuation studies, Elaris III and IV, demonstrated efficacy and safety of elagolix through 12 months of treatment.⁵

Depot leuprolide acetate and nafarelin acetate

Depot leuprolide acetate and nafarelin acetate are GnRH analogues approved by the FDA more than 25 years ago for treatment of pelvic pain caused by endometriosis. Over the past two decades, depot leuprolide acetate has been one of the most commonly used hormonal treatments for endometriosis in the United States. A 3-month formulation of depot leuprolide acetate with an 11.25-mg injection has resulted in mean circulating estradiol concentrations of 8 pg/mL, indicating very strong suppression of estradiol production.⁶ A twice-daily 200-µg dose of nafarelin acetate nasal spray has resulted in a circulating estradiol concentration of approximately 28 pg/mL, indicating gentle suppression of estradiol production.⁷

At current prices, elagolix treatment is substantially less expensive than treatment with leuprolide or nafarelin. In addition, many women in my practice prefer to use an oral medication over an intramuscular injection or a nasal spray medication. It is likely that clinicians and patients will evolve to prioritize and favor elagolix therapy over depot leuprolide or nafarelin treatment.

Continue to: 5 options for using elagolix

There are many potential options for using elagolix in the treatment of pelvic pain caused by endometriosis.

Option 1. Prescribe elagolix 200 mg twice daily for 6 months to achieve strong suppression of estradiol and marked improvement in dysmenorrhea, although at the cost of more hot flashes and greater bone loss.

Option 2. Prescribe elagolix 150 mg once daily for up to 24 months to achieve gentle suppression of estradiol and modest improvement in dysmenorrhea with fewer hot flashes and minimal bone loss.

Options 1 and 2 have been studied in high quality clinical trials involving more than 1,500 women and are approved by the FDA.

Option 3. Initiate treatment with elagolix 200 mg twice daily for 3 months, immediately accruing the benefits of strong suppression of estradiol, and then switch to elagolix 150 mg once daily for up to 24 months to achieve continuing pain control with fewer adverse effects. This regimen combines strong initial suppression of estradiol, which will result in marked improvement in dysmenorrhea, along with long-term gentle suppression of estradiol, which is likely to maintain decreased pain symptoms with minimal long-term bone loss and fewer hot flashes.

Option 4. Prescribe an alternating regimen of elagolix 200 mg twice daily on even days of the month (two pills daily is an even number of pills) and one pill daily on odd days of the month (1 pill daily is an odd number of pills). This regimen should produce a mean estradiol concentration between 12 and 41 pg/mL, resulting in moderate rather than strong or gentle suppression of estradiol.

Options 3 and 4 are based on extrapolation using our knowledge about the hormonal treatment of endometriosis and are not regimens approved by the FDA.

Option 5. Prescribe elagolix 200 mg twice daily and initiate add-back therapy with norethindrone acetate 5 mg once daily. Substantial evidence supports the combination of a GnRH analogue that strongly suppresses estradiol production with norethindrone acetate add-back, which helps mitigate the bone loss that occurs with strong suppression of estradiol and reduces the frequency of moderate to severe hot flashes.

Option 5 is based on extrapolation from high-quality studies of leuprolide acetate depot plus norethindrone acetate add-back.⁸ The combination regimen is approved by the FDA.³

Elagolix availability increases treatment choices for women

Pelvic pain caused by endometriosis is common, affecting approximately 8% of women of reproductive age.⁹ Endometriosis is a vexing disease because diagnosis is often delayed many years after the onset of symptoms, causing great frustration among patients.¹⁰ Some effective hormonal treatment options, including danazol and depot leuprolide, are poorly tolerated by patients because of adverse effects, including weight gain (danazol), hot flashes, and bone loss (depot leuprolide). Combination oral contraceptives used in a continuous or cyclic fashion often result in inadequate improvement in pelvic pain.¹¹ The synthesis of an orally active, small-molecule GnRH antagonist is an innovative advance in endocrine pharmacology. The Elaris Endometriosis clinical trials have demonstrated that elagolix is effective in the treatment of pelvic pain caused by endometriosis.^4,5 A great advantage of elagolix is that dosing can be tailored for each patient to achieve reduction in pain while minimizing unwanted adverse effects such as hot flashes and bone loss. In Elaris Endometriosis I, fewer than 10% of women discontinued elagolix due to adverse effects.⁴ Elagolix is also less expensive than depot leuprolide and nafarelin.

Millions of women in the United States have pelvic pain caused by endometriosis. Obstetrician-gynecologists are the clinicians best trained to care for these women, and patients trust that we will effectively treat their problem.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis is the presence of tissue resembling endometrial glands and stroma outside of the uterine cavity. Women with endometriosis often present for medical care with at least one of 3 problems: pelvic pain, infertility, and/or an adnexal mass due to endometriosis.¹ Many clinical observations demonstrate that endometriosis lesions require estrogen to grow and maintain their viability, including that: (1) endometriosis is uncommon before puberty or after menopause, (2) surgical removal of both ovaries results in regression of endometriosis lesions, and (3) gonadotropin-releasing hormone (GnRH) analogues cause a hypo‑estrogenic hormonal environment, resulting in regression of endometriosis lesions and improvement in pelvic pain. Since endometriosis lesions require estrogen to maintain their viability, suppressing estradiol is a logical approach to hormonal treatment of the disease.

The estrogen threshold hypothesis

The estradiol concentration that causes endometriosis lesions to grow or regress varies among women, but a concentration less than 20 pg/mL usually causes lesions to regress, and a concentration greater than 60 pg/mL usually supports lesion growth and maintains lesion viability.² Although an estradiol concentration below 20 pg/mL may cause lesions to regress, it also is associated with moderate to severe hot flashes and accelerated bone loss. These adverse effects limit the use of strong suppression of estrogen as a long-term treatment strategy. The estrogen threshold hypothesis posits that gently suppressing estradiol to a concentration between 20 and 45 pg/mL may simultaneously cause endometriosis lesions to regress, resulting in reduced pelvic pain, minimal bone loss, and few hot flashes.²

Building on the estrogen threshold hypothesis, clinicians have two options for treatment of pelvic pain caused by endometriosis:

1. strong suppression of estradiol to a concentration below 20 pg/mL
2. gentle suppression of estradiol to a concentration in the range of 20 to 45 pg/mL.

Strong suppression of estradiol to levels below 20 pg/mL will reliably induce amenorrhea and cause regression of endometriosis lesions, thereby reducing pelvic pain. Strong suppression of estradiol also will cause moderate to severe hot flashes and accelerated bone loss in many women. By contrast, gentle suppression of circulating estradiol to a concentration in the range of 20 to 45 pg/mL may result in amenorrhea or oligomenorrhea, suppression of the growth of endometriosis lesions, a modest reduction in pelvic pain, mild hot flashes, and minimal bone loss.

Recently, the US Food and Drug Administration (FDA) approved elagolix, an oral GnRH antagonist, for treatment of endometriosis.³ Elagolix blocks GnRH receptors in the pituitary gland, resulting in reduced production of luteinizing hormone and follicle stimulating hormone and a decrease in sex steroid secretion in the ovarian follicles, which leads to a reduction in the production and circulating concentration of estradiol. The FDA approved two doses of elagolix: 150 mg once daily for up to 24 months and 200 mg twice daily for up to 6 months. Importantly, elagolix at a dose of 150 mg once daily results in a mean circulating estradiol concentration of 41 pg/mL, indicating gentle suppression of ovarian estradiol production, and 200 mg twice daily results in a mean circulating ovarian estradiol concentration of 12 pg/mL, indicating strong suppression of ovarian estradiol production.³ For clinicians treating women with pelvic pain caused by endometriosis, these two elagolix regimens permit the individualization of hormonal therapy to the unique needs of each woman.

Continue to: Safety information for elagolix

Elagolix benefits and adverse effects

In one large clinical trial (Elaris Endometriosis I), 872 women were randomly assigned to treatment with one of two doses of elagolix (200 mg twice daily [high-dose group] or 150 mgonce daily [low-dose group]) or placebo.⁴ After 3 months of treatment, a clinically meaningful reduction in dysmenorrhea pain was reported by 76%, 46%, and 20% of women in the high-dose, low-dose, and placebo groups, respectively (P<.001 for comparisons of elagolix to placebo). In addition, at 3 months, a clinically meaningful reduction in nonmenstrual pain or decreased or stable use of rescue analgesics was reported by 55%, 50%, and 37% of women in the high-dose, low-dose, and placebo groups, respectively (low-dose vs placebo, P<.01; high-dose vs placebo, P<.001). Hot flashes that were severe enough to be classified as adverse events by study participants were reported by 42%, 24%, and 7% of the women in the high-dose, low-dose, and placebo groups, respectively. Bone density was measured at baseline and after 6 months of treatment. Lumbar bone density changes were -2.61%, -0.32%, and +0.47%, and hip/femoral/neck bone density changes were -1.89%, -0.39%, and +0.02% in the high-dose, low-dose, and placebo groups, respectively.

Another large clinical trial of elagolix for treatment of pelvic pain caused by endometriosis (Elaris II) involving 817 women produced results that were similar to those reported in Elaris I.⁴ The elagolix continuation studies, Elaris III and IV, demonstrated efficacy and safety of elagolix through 12 months of treatment.⁵

Depot leuprolide acetate and nafarelin acetate

Depot leuprolide acetate and nafarelin acetate are GnRH analogues approved by the FDA more than 25 years ago for treatment of pelvic pain caused by endometriosis. Over the past two decades, depot leuprolide acetate has been one of the most commonly used hormonal treatments for endometriosis in the United States. A 3-month formulation of depot leuprolide acetate with an 11.25-mg injection has resulted in mean circulating estradiol concentrations of 8 pg/mL, indicating very strong suppression of estradiol production.⁶ A twice-daily 200-µg dose of nafarelin acetate nasal spray has resulted in a circulating estradiol concentration of approximately 28 pg/mL, indicating gentle suppression of estradiol production.⁷

At current prices, elagolix treatment is substantially less expensive than treatment with leuprolide or nafarelin. In addition, many women in my practice prefer to use an oral medication over an intramuscular injection or a nasal spray medication. It is likely that clinicians and patients will evolve to prioritize and favor elagolix therapy over depot leuprolide or nafarelin treatment.

Continue to: 5 options for using elagolix

There are many potential options for using elagolix in the treatment of pelvic pain caused by endometriosis.

Option 1. Prescribe elagolix 200 mg twice daily for 6 months to achieve strong suppression of estradiol and marked improvement in dysmenorrhea, although at the cost of more hot flashes and greater bone loss.

Option 2. Prescribe elagolix 150 mg once daily for up to 24 months to achieve gentle suppression of estradiol and modest improvement in dysmenorrhea with fewer hot flashes and minimal bone loss.

Options 1 and 2 have been studied in high quality clinical trials involving more than 1,500 women and are approved by the FDA.

Option 3. Initiate treatment with elagolix 200 mg twice daily for 3 months, immediately accruing the benefits of strong suppression of estradiol, and then switch to elagolix 150 mg once daily for up to 24 months to achieve continuing pain control with fewer adverse effects. This regimen combines strong initial suppression of estradiol, which will result in marked improvement in dysmenorrhea, along with long-term gentle suppression of estradiol, which is likely to maintain decreased pain symptoms with minimal long-term bone loss and fewer hot flashes.

Option 4. Prescribe an alternating regimen of elagolix 200 mg twice daily on even days of the month (two pills daily is an even number of pills) and one pill daily on odd days of the month (1 pill daily is an odd number of pills). This regimen should produce a mean estradiol concentration between 12 and 41 pg/mL, resulting in moderate rather than strong or gentle suppression of estradiol.

Options 3 and 4 are based on extrapolation using our knowledge about the hormonal treatment of endometriosis and are not regimens approved by the FDA.

Option 5. Prescribe elagolix 200 mg twice daily and initiate add-back therapy with norethindrone acetate 5 mg once daily. Substantial evidence supports the combination of a GnRH analogue that strongly suppresses estradiol production with norethindrone acetate add-back, which helps mitigate the bone loss that occurs with strong suppression of estradiol and reduces the frequency of moderate to severe hot flashes.

Option 5 is based on extrapolation from high-quality studies of leuprolide acetate depot plus norethindrone acetate add-back.⁸ The combination regimen is approved by the FDA.³

Elagolix availability increases treatment choices for women

Pelvic pain caused by endometriosis is common, affecting approximately 8% of women of reproductive age.⁹ Endometriosis is a vexing disease because diagnosis is often delayed many years after the onset of symptoms, causing great frustration among patients.¹⁰ Some effective hormonal treatment options, including danazol and depot leuprolide, are poorly tolerated by patients because of adverse effects, including weight gain (danazol), hot flashes, and bone loss (depot leuprolide). Combination oral contraceptives used in a continuous or cyclic fashion often result in inadequate improvement in pelvic pain.¹¹ The synthesis of an orally active, small-molecule GnRH antagonist is an innovative advance in endocrine pharmacology. The Elaris Endometriosis clinical trials have demonstrated that elagolix is effective in the treatment of pelvic pain caused by endometriosis.^4,5 A great advantage of elagolix is that dosing can be tailored for each patient to achieve reduction in pain while minimizing unwanted adverse effects such as hot flashes and bone loss. In Elaris Endometriosis I, fewer than 10% of women discontinued elagolix due to adverse effects.⁴ Elagolix is also less expensive than depot leuprolide and nafarelin.

Millions of women in the United States have pelvic pain caused by endometriosis. Obstetrician-gynecologists are the clinicians best trained to care for these women, and patients trust that we will effectively treat their problem.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis is the presence of tissue resembling endometrial glands and stroma outside of the uterine cavity. Women with endometriosis often present for medical care with at least one of 3 problems: pelvic pain, infertility, and/or an adnexal mass due to endometriosis.¹ Many clinical observations demonstrate that endometriosis lesions require estrogen to grow and maintain their viability, including that: (1) endometriosis is uncommon before puberty or after menopause, (2) surgical removal of both ovaries results in regression of endometriosis lesions, and (3) gonadotropin-releasing hormone (GnRH) analogues cause a hypo‑estrogenic hormonal environment, resulting in regression of endometriosis lesions and improvement in pelvic pain. Since endometriosis lesions require estrogen to maintain their viability, suppressing estradiol is a logical approach to hormonal treatment of the disease.

The estrogen threshold hypothesis

The estradiol concentration that causes endometriosis lesions to grow or regress varies among women, but a concentration less than 20 pg/mL usually causes lesions to regress, and a concentration greater than 60 pg/mL usually supports lesion growth and maintains lesion viability.² Although an estradiol concentration below 20 pg/mL may cause lesions to regress, it also is associated with moderate to severe hot flashes and accelerated bone loss. These adverse effects limit the use of strong suppression of estrogen as a long-term treatment strategy. The estrogen threshold hypothesis posits that gently suppressing estradiol to a concentration between 20 and 45 pg/mL may simultaneously cause endometriosis lesions to regress, resulting in reduced pelvic pain, minimal bone loss, and few hot flashes.²

Building on the estrogen threshold hypothesis, clinicians have two options for treatment of pelvic pain caused by endometriosis:

1. strong suppression of estradiol to a concentration below 20 pg/mL
2. gentle suppression of estradiol to a concentration in the range of 20 to 45 pg/mL.

Strong suppression of estradiol to levels below 20 pg/mL will reliably induce amenorrhea and cause regression of endometriosis lesions, thereby reducing pelvic pain. Strong suppression of estradiol also will cause moderate to severe hot flashes and accelerated bone loss in many women. By contrast, gentle suppression of circulating estradiol to a concentration in the range of 20 to 45 pg/mL may result in amenorrhea or oligomenorrhea, suppression of the growth of endometriosis lesions, a modest reduction in pelvic pain, mild hot flashes, and minimal bone loss.

Recently, the US Food and Drug Administration (FDA) approved elagolix, an oral GnRH antagonist, for treatment of endometriosis.³ Elagolix blocks GnRH receptors in the pituitary gland, resulting in reduced production of luteinizing hormone and follicle stimulating hormone and a decrease in sex steroid secretion in the ovarian follicles, which leads to a reduction in the production and circulating concentration of estradiol. The FDA approved two doses of elagolix: 150 mg once daily for up to 24 months and 200 mg twice daily for up to 6 months. Importantly, elagolix at a dose of 150 mg once daily results in a mean circulating estradiol concentration of 41 pg/mL, indicating gentle suppression of ovarian estradiol production, and 200 mg twice daily results in a mean circulating ovarian estradiol concentration of 12 pg/mL, indicating strong suppression of ovarian estradiol production.³ For clinicians treating women with pelvic pain caused by endometriosis, these two elagolix regimens permit the individualization of hormonal therapy to the unique needs of each woman.

Continue to: Safety information for elagolix

Elagolix benefits and adverse effects

In one large clinical trial (Elaris Endometriosis I), 872 women were randomly assigned to treatment with one of two doses of elagolix (200 mg twice daily [high-dose group] or 150 mgonce daily [low-dose group]) or placebo.⁴ After 3 months of treatment, a clinically meaningful reduction in dysmenorrhea pain was reported by 76%, 46%, and 20% of women in the high-dose, low-dose, and placebo groups, respectively (P<.001 for comparisons of elagolix to placebo). In addition, at 3 months, a clinically meaningful reduction in nonmenstrual pain or decreased or stable use of rescue analgesics was reported by 55%, 50%, and 37% of women in the high-dose, low-dose, and placebo groups, respectively (low-dose vs placebo, P<.01; high-dose vs placebo, P<.001). Hot flashes that were severe enough to be classified as adverse events by study participants were reported by 42%, 24%, and 7% of the women in the high-dose, low-dose, and placebo groups, respectively. Bone density was measured at baseline and after 6 months of treatment. Lumbar bone density changes were -2.61%, -0.32%, and +0.47%, and hip/femoral/neck bone density changes were -1.89%, -0.39%, and +0.02% in the high-dose, low-dose, and placebo groups, respectively.

Another large clinical trial of elagolix for treatment of pelvic pain caused by endometriosis (Elaris II) involving 817 women produced results that were similar to those reported in Elaris I.⁴ The elagolix continuation studies, Elaris III and IV, demonstrated efficacy and safety of elagolix through 12 months of treatment.⁵

Depot leuprolide acetate and nafarelin acetate

Depot leuprolide acetate and nafarelin acetate are GnRH analogues approved by the FDA more than 25 years ago for treatment of pelvic pain caused by endometriosis. Over the past two decades, depot leuprolide acetate has been one of the most commonly used hormonal treatments for endometriosis in the United States. A 3-month formulation of depot leuprolide acetate with an 11.25-mg injection has resulted in mean circulating estradiol concentrations of 8 pg/mL, indicating very strong suppression of estradiol production.⁶ A twice-daily 200-µg dose of nafarelin acetate nasal spray has resulted in a circulating estradiol concentration of approximately 28 pg/mL, indicating gentle suppression of estradiol production.⁷

At current prices, elagolix treatment is substantially less expensive than treatment with leuprolide or nafarelin. In addition, many women in my practice prefer to use an oral medication over an intramuscular injection or a nasal spray medication. It is likely that clinicians and patients will evolve to prioritize and favor elagolix therapy over depot leuprolide or nafarelin treatment.

Continue to: 5 options for using elagolix

There are many potential options for using elagolix in the treatment of pelvic pain caused by endometriosis.

Option 1. Prescribe elagolix 200 mg twice daily for 6 months to achieve strong suppression of estradiol and marked improvement in dysmenorrhea, although at the cost of more hot flashes and greater bone loss.

Option 2. Prescribe elagolix 150 mg once daily for up to 24 months to achieve gentle suppression of estradiol and modest improvement in dysmenorrhea with fewer hot flashes and minimal bone loss.

Options 1 and 2 have been studied in high quality clinical trials involving more than 1,500 women and are approved by the FDA.

Option 3. Initiate treatment with elagolix 200 mg twice daily for 3 months, immediately accruing the benefits of strong suppression of estradiol, and then switch to elagolix 150 mg once daily for up to 24 months to achieve continuing pain control with fewer adverse effects. This regimen combines strong initial suppression of estradiol, which will result in marked improvement in dysmenorrhea, along with long-term gentle suppression of estradiol, which is likely to maintain decreased pain symptoms with minimal long-term bone loss and fewer hot flashes.

Option 4. Prescribe an alternating regimen of elagolix 200 mg twice daily on even days of the month (two pills daily is an even number of pills) and one pill daily on odd days of the month (1 pill daily is an odd number of pills). This regimen should produce a mean estradiol concentration between 12 and 41 pg/mL, resulting in moderate rather than strong or gentle suppression of estradiol.

Options 3 and 4 are based on extrapolation using our knowledge about the hormonal treatment of endometriosis and are not regimens approved by the FDA.

Option 5. Prescribe elagolix 200 mg twice daily and initiate add-back therapy with norethindrone acetate 5 mg once daily. Substantial evidence supports the combination of a GnRH analogue that strongly suppresses estradiol production with norethindrone acetate add-back, which helps mitigate the bone loss that occurs with strong suppression of estradiol and reduces the frequency of moderate to severe hot flashes.

Option 5 is based on extrapolation from high-quality studies of leuprolide acetate depot plus norethindrone acetate add-back.⁸ The combination regimen is approved by the FDA.³

Elagolix availability increases treatment choices for women

Pelvic pain caused by endometriosis is common, affecting approximately 8% of women of reproductive age.⁹ Endometriosis is a vexing disease because diagnosis is often delayed many years after the onset of symptoms, causing great frustration among patients.¹⁰ Some effective hormonal treatment options, including danazol and depot leuprolide, are poorly tolerated by patients because of adverse effects, including weight gain (danazol), hot flashes, and bone loss (depot leuprolide). Combination oral contraceptives used in a continuous or cyclic fashion often result in inadequate improvement in pelvic pain.¹¹ The synthesis of an orally active, small-molecule GnRH antagonist is an innovative advance in endocrine pharmacology. The Elaris Endometriosis clinical trials have demonstrated that elagolix is effective in the treatment of pelvic pain caused by endometriosis.^4,5 A great advantage of elagolix is that dosing can be tailored for each patient to achieve reduction in pain while minimizing unwanted adverse effects such as hot flashes and bone loss. In Elaris Endometriosis I, fewer than 10% of women discontinued elagolix due to adverse effects.⁴ Elagolix is also less expensive than depot leuprolide and nafarelin.

Millions of women in the United States have pelvic pain caused by endometriosis. Obstetrician-gynecologists are the clinicians best trained to care for these women, and patients trust that we will effectively treat their problem.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis can mean living with symptoms, multiple surgeries, and infertility for the estimated 10% of U.S. women who experience it, according to a new survey by Health Union, a family of online health communities.

Advances in support and understanding have been made through research and dissemination of information via the Internet, but complete control of endometriosis remains elusive, as only 13% of the 1,239 women surveyed from June 13 to July 14, 2018, said that their condition was under control with their current treatment plan.

Before control, of course, comes diagnosis, and the average gap between onset of symptoms and diagnosis was 8.6 years. Such a gap “can lead to delayed treatment and a potentially negative impact on quality of life,” Health Union said in a written statement. Those years of delays often involved visits to multiple physicians: 44% of respondents saw 3-5 physicians before receiving a diagnosis and 11% had to see 10 or more physicians.

“When comparing differences between symptom onset-to-diagnosis groups, there are some significant findings that suggest a fair amount of progress has been made, for the better,” Health Union said, noting that women who received a diagnosis in less than 5 years “were significantly less likely to think their symptoms were related to their menstrual cycles than those with a longer symptoms-to-diagnosis gap.” Respondents who had a gap of less than 2 years “were more likely to seek medical care as soon as possible” and to have used hormone therapies than those with longer gaps, the group said.

The most common diagnostic tests were laparoscopy, reported by 85% of respondents, and pelvic/transvaginal ultrasound, reported by 46%. Of the women who did not have a laparoscopy, 43% were undergoing a surgical procedure for another condition when their endometriosis was discovered. Laparoscopy also was by far the most common surgery to treat endometriosis, with a 79% prevalence among respondents, compared with 16% for laparotomy and 12% for oophorectomy, Health Union reported in Endometriosis in America 2018.

Common nonsurgical tactics to improve symptoms included increased water intake (79%), use of a heating pad (75%), and increased fresh fruit (64%) or green vegetables (62%) in the diet. Three-quarters of respondents also tried alternative and complementary therapies such as vitamins, exercise, and acupuncture, the report showed.

“Living with endometriosis is much easier now than it was not even a decade ago, as the Internet and social media have definitely increased knowledge about the disease,” said Endometriosis.net (one of the Health Union online communities) patient advocate Laura Kiesel. “When I first suspected I had the disease, in the mid-90s, hardly anyone had heard about it, and those aware of it didn’t think it was very serious. All these years later, I get a lot more sympathy and support – both online and in person – and people understand how serious, painful, and life altering it could be.”

[email protected]

Endometriosis can mean living with symptoms, multiple surgeries, and infertility for the estimated 10% of U.S. women who experience it, according to a new survey by Health Union, a family of online health communities.

Advances in support and understanding have been made through research and dissemination of information via the Internet, but complete control of endometriosis remains elusive, as only 13% of the 1,239 women surveyed from June 13 to July 14, 2018, said that their condition was under control with their current treatment plan.

Before control, of course, comes diagnosis, and the average gap between onset of symptoms and diagnosis was 8.6 years. Such a gap “can lead to delayed treatment and a potentially negative impact on quality of life,” Health Union said in a written statement. Those years of delays often involved visits to multiple physicians: 44% of respondents saw 3-5 physicians before receiving a diagnosis and 11% had to see 10 or more physicians.

“When comparing differences between symptom onset-to-diagnosis groups, there are some significant findings that suggest a fair amount of progress has been made, for the better,” Health Union said, noting that women who received a diagnosis in less than 5 years “were significantly less likely to think their symptoms were related to their menstrual cycles than those with a longer symptoms-to-diagnosis gap.” Respondents who had a gap of less than 2 years “were more likely to seek medical care as soon as possible” and to have used hormone therapies than those with longer gaps, the group said.

The most common diagnostic tests were laparoscopy, reported by 85% of respondents, and pelvic/transvaginal ultrasound, reported by 46%. Of the women who did not have a laparoscopy, 43% were undergoing a surgical procedure for another condition when their endometriosis was discovered. Laparoscopy also was by far the most common surgery to treat endometriosis, with a 79% prevalence among respondents, compared with 16% for laparotomy and 12% for oophorectomy, Health Union reported in Endometriosis in America 2018.

Common nonsurgical tactics to improve symptoms included increased water intake (79%), use of a heating pad (75%), and increased fresh fruit (64%) or green vegetables (62%) in the diet. Three-quarters of respondents also tried alternative and complementary therapies such as vitamins, exercise, and acupuncture, the report showed.

“Living with endometriosis is much easier now than it was not even a decade ago, as the Internet and social media have definitely increased knowledge about the disease,” said Endometriosis.net (one of the Health Union online communities) patient advocate Laura Kiesel. “When I first suspected I had the disease, in the mid-90s, hardly anyone had heard about it, and those aware of it didn’t think it was very serious. All these years later, I get a lot more sympathy and support – both online and in person – and people understand how serious, painful, and life altering it could be.”

[email protected]

Endometriosis can mean living with symptoms, multiple surgeries, and infertility for the estimated 10% of U.S. women who experience it, according to a new survey by Health Union, a family of online health communities.

Advances in support and understanding have been made through research and dissemination of information via the Internet, but complete control of endometriosis remains elusive, as only 13% of the 1,239 women surveyed from June 13 to July 14, 2018, said that their condition was under control with their current treatment plan.

Before control, of course, comes diagnosis, and the average gap between onset of symptoms and diagnosis was 8.6 years. Such a gap “can lead to delayed treatment and a potentially negative impact on quality of life,” Health Union said in a written statement. Those years of delays often involved visits to multiple physicians: 44% of respondents saw 3-5 physicians before receiving a diagnosis and 11% had to see 10 or more physicians.

“When comparing differences between symptom onset-to-diagnosis groups, there are some significant findings that suggest a fair amount of progress has been made, for the better,” Health Union said, noting that women who received a diagnosis in less than 5 years “were significantly less likely to think their symptoms were related to their menstrual cycles than those with a longer symptoms-to-diagnosis gap.” Respondents who had a gap of less than 2 years “were more likely to seek medical care as soon as possible” and to have used hormone therapies than those with longer gaps, the group said.

The most common diagnostic tests were laparoscopy, reported by 85% of respondents, and pelvic/transvaginal ultrasound, reported by 46%. Of the women who did not have a laparoscopy, 43% were undergoing a surgical procedure for another condition when their endometriosis was discovered. Laparoscopy also was by far the most common surgery to treat endometriosis, with a 79% prevalence among respondents, compared with 16% for laparotomy and 12% for oophorectomy, Health Union reported in Endometriosis in America 2018.

Common nonsurgical tactics to improve symptoms included increased water intake (79%), use of a heating pad (75%), and increased fresh fruit (64%) or green vegetables (62%) in the diet. Three-quarters of respondents also tried alternative and complementary therapies such as vitamins, exercise, and acupuncture, the report showed.

“Living with endometriosis is much easier now than it was not even a decade ago, as the Internet and social media have definitely increased knowledge about the disease,” said Endometriosis.net (one of the Health Union online communities) patient advocate Laura Kiesel. “When I first suspected I had the disease, in the mid-90s, hardly anyone had heard about it, and those aware of it didn’t think it was very serious. All these years later, I get a lot more sympathy and support – both online and in person – and people understand how serious, painful, and life altering it could be.”

[email protected]

CASE Endometriosis pain increases despite hormonal treatment

A 25-year-old woman (G0) with severe dysmenorrhea had a laparoscopy showing endometriosis in the cul-de-sac and a peritoneal window near the left uterosacral ligament. Biopsy of a cul-de-sac lesion showed endometriosis on histopathology. The patient was treated with a continuous low-dose estrogen-progestin contraceptive. Initially, the treatment helped relieve her pain symptoms. Over the next year, while on that treatment, her pain gradually increased in severity until it was disabling. At an office visit, the primary clinician renewed the estrogen-progestin contraceptive for another year, even though it was not relieving the patient’s pain. The patient sought a second opinion.

We are the experts in the management of pelvic pain caused by endometriosis

Women’s health clinicians are the specialists best trained to care for patients with severe pain caused by endometriosis. Low-dose continuous estrogen-progestin contraceptives are commonly prescribed as a first-line hormonal treatment for pain caused by endometriosis. My observation is that estrogen-progestincontraceptives are often effective when initially prescribed, but with continued use over years, pain often recurs. Estrogen is known to stimulate endometriosis disease activity. Progestins at high doses suppress endometriosis disease activity. However, endometriosis implants often manifest decreased responsiveness to progestins, permitting the estrogen in the combination contraceptive to exert its disease-stimulating effect.^1,2 I frequently see women with pelvic pain caused by endometriosis, who initially had a significant decrease in pain with continuous estrogen-progestin contraceptive treatment but who develop increasing pain with continued use of the medication. In this clinical situation, it is useful to consider stopping the estrogen-progestin therapy and to prescribe a hormone with a different mechanism of action (TABLE).

Progestin-only medications

Progestin-only medications are often effective in the treatment of pain caused by endometriosis. High-dose progestin-only medications suppress pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby suppressing ovarian synthesis of estrogen, resulting in low circulating levels of estrogen. This removes the estrogen stimulus that exacerbates endometriosis disease activity. High-dose progestins also directly suppress cellular activity in endometriosis implants. High-dose progestins often overcome the relative resistance of endometriosis lesions to progestin suppression of disease activity. Hence, high-dose progestin-only medications have two mechanisms of action: suppression of estrogen synthesis through pituitary suppression of LH and FSH, and direct inhibition of cellular activity in the endometriosis lesions. High-dose progestin-only treatments include:

• oral norethindrone acetate 5 mg daily
• oral medroxyprogesterone acetate (MPA) 20 to 40 mg daily
• subcutaneous, or depot MPA
• levonorgestrel-releasing intrauterine device (LNG-IUD).

In my practice, I frequently use oral norethindrone acetate 5 mg daily to treat pelvic pain caused by endometriosis. In one randomized trial, 90 women with pelvic pain and rectovaginal endometriosis were randomly assigned to treatment with norethindrone acetate 2.5 mg daily or an estrogen-progestin contraceptive. After 12 months of treatment, satisfaction with treatment was reported by 73% and 62% of the women in the norethindrone acetate and estrogen-progestin groups, respectively.³ The most common adverse effects reported by women taking norethindrone acetate were weight gain (27%) and decreased libido (9%).

Oral MPA at doses of 30 mg to 100 mg daily has been reported to be effective for the treatment of pelvic pain caused by endometriosis. MPA treatment can induce atrophy and pseudodecidualization in endometrium and endometriosis implants. In my practice I typically prescribe doses in the range of 20 mg to 40 mg daily. With oral MPA treatment, continued uterine bleeding may occur in up to 30% of women, somewhat limiting its efficacy.^4–7

Subcutaneous and depot MPA have been reported to be effective in the treatment of pelvic pain caused by endometriosis.^4,8 In some resource-limited countries, depot MPA may be the most available progestin for the treatment of pelvic pain caused by endometriosis.

The LNG-IUD, inserted after surgery for endometriosis, has been reported to result in decreased pelvic pain in studies with a modest number of participants.^9–11

GnRH analogue medications

Gonadotropin-releasing hormone (GnRH) analogues, including both GnRH agonists (nafarelin, leuprolide, and goserelin) and GnRH antagonists (elagolix) reduce pelvic pain caused by endometriosis by suppressing pituitary secretion of LH and FSH, thereby reducing ovarian synthesis of estradiol. In the absence of estradiol stimulation, cellular activity in endometriosis lesions decreases and pain symptoms improve. In my practice, I frequently use either nafarelin¹² or leuprolide acetate depot plus norethindrone add-back.¹³ I generally avoid the use of leuprolide depot monotherapy because in many women it causes severe vasomotor symptoms.

At standard doses, nafarelin therapy generally results in serum estradiol levels in the range of 20 to 30 pg/mL, a “sweet spot” associated with modest vasomotor symptoms and reduced cellular activity in endometriosis implants.^12,14 In many women who become amenorrheic on nafarelin two sprays daily, the dose can be reduced with maintenance of pain control and ovarian suppression.¹⁵ Leuprolide acetate depot monotherapy results in serum estradiol levels in the range of 5 to 10 pg/mL, causing severe vasomotor symptoms and reduction in cellular activity in endometriosis lesions. To reduce the adverse effects of leuprolide acetate depot monotherapy, I generally initiate concomitant add-back therapy with norethindrone acetate.¹³ A little recognized pharmacokinetic observation is that a very small amount of norethindrone acetate, generally less than 1%, is metabolized to ethinyl estradiol.¹⁶

The oral GnRH antagonist, elagolix, 150 mg daily for up to 24 months or 200 mg twice daily for 6 months, was approved by the US Food and Drug Administration (FDA) in July 2018. It is now available in pharmacies. Elagolix treatment results in significant reduction in pain caused by endometriosis, but only moderately bothersome vasomotor symptoms.^17,18 Elagolix likely will become a widely used medication because of the simplicity of oral administration, efficacy against endometriosis, and acceptable adverse-effect profile. A major disadvantage of the GnRH analogue-class of medications is that they are more expensive than the progestin medications mentioned above. Among the GnRH analogue class of medications, elagolix and goserelin are the least expensive.

Androgens

Estrogen stimulates cellular activity in endometriosis lesions. Androgen and high-dose progestins inhibit cellular activity in endometriosis lesions. Danazol, an attenuated androgen and a progestin is effectivein treating pelvic pain caused by endometriosis.^19,20 However, many women decline to use danazol because it is often associated with weight gain. As an androgen, danazol can permanently change a woman’s voice pitch and should not be used by professional singers or speech therapists.

Aromatase Inhibitors

Estrogen is a critically important stimulus of cell activity in endometriosis lesions. Aromatase inhibitors, which block the synthesis of estrogen, have been explored in the treatment of endometriosis that has proven to be resistant to other therapies. Although the combination of an aromatase inhibitor plus a high-dose progestin or GnRH analogue may be effective, more data are needed before widely using the aromatase inhibitors in clinical practice.²¹

Don’t get stuck in a rut

When treating pelvic pain caused by endometriosis, if the patient’s hormone regimen is not working, prescribe a medication from another class of hormones. In the case presented above, a woman with pelvic pain and surgically proven endometriosis reported inadequate control of her pain symptoms with a continuous estrogen-progestin medication. Her physician prescribed another year of the same estrogen-progestin medication. Instead of renewing the medication, the physician could have offered the patient a hormone medication from another drug class: 1) progestin only, 2) GnRH analogue, or 3) danazol. By using every available hormonal agent, physicians will improve the treatment of pelvic pain caused by endometriosis. Millions of women in our country have pelvic pain caused by endometriosis. They are counting on us, women’s health specialists, to effectively treat their disease.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE Endometriosis pain increases despite hormonal treatment

A 25-year-old woman (G0) with severe dysmenorrhea had a laparoscopy showing endometriosis in the cul-de-sac and a peritoneal window near the left uterosacral ligament. Biopsy of a cul-de-sac lesion showed endometriosis on histopathology. The patient was treated with a continuous low-dose estrogen-progestin contraceptive. Initially, the treatment helped relieve her pain symptoms. Over the next year, while on that treatment, her pain gradually increased in severity until it was disabling. At an office visit, the primary clinician renewed the estrogen-progestin contraceptive for another year, even though it was not relieving the patient’s pain. The patient sought a second opinion.

We are the experts in the management of pelvic pain caused by endometriosis

Women’s health clinicians are the specialists best trained to care for patients with severe pain caused by endometriosis. Low-dose continuous estrogen-progestin contraceptives are commonly prescribed as a first-line hormonal treatment for pain caused by endometriosis. My observation is that estrogen-progestincontraceptives are often effective when initially prescribed, but with continued use over years, pain often recurs. Estrogen is known to stimulate endometriosis disease activity. Progestins at high doses suppress endometriosis disease activity. However, endometriosis implants often manifest decreased responsiveness to progestins, permitting the estrogen in the combination contraceptive to exert its disease-stimulating effect.^1,2 I frequently see women with pelvic pain caused by endometriosis, who initially had a significant decrease in pain with continuous estrogen-progestin contraceptive treatment but who develop increasing pain with continued use of the medication. In this clinical situation, it is useful to consider stopping the estrogen-progestin therapy and to prescribe a hormone with a different mechanism of action (TABLE).

Progestin-only medications

Progestin-only medications are often effective in the treatment of pain caused by endometriosis. High-dose progestin-only medications suppress pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby suppressing ovarian synthesis of estrogen, resulting in low circulating levels of estrogen. This removes the estrogen stimulus that exacerbates endometriosis disease activity. High-dose progestins also directly suppress cellular activity in endometriosis implants. High-dose progestins often overcome the relative resistance of endometriosis lesions to progestin suppression of disease activity. Hence, high-dose progestin-only medications have two mechanisms of action: suppression of estrogen synthesis through pituitary suppression of LH and FSH, and direct inhibition of cellular activity in the endometriosis lesions. High-dose progestin-only treatments include:

• oral norethindrone acetate 5 mg daily
• oral medroxyprogesterone acetate (MPA) 20 to 40 mg daily
• subcutaneous, or depot MPA
• levonorgestrel-releasing intrauterine device (LNG-IUD).

In my practice, I frequently use oral norethindrone acetate 5 mg daily to treat pelvic pain caused by endometriosis. In one randomized trial, 90 women with pelvic pain and rectovaginal endometriosis were randomly assigned to treatment with norethindrone acetate 2.5 mg daily or an estrogen-progestin contraceptive. After 12 months of treatment, satisfaction with treatment was reported by 73% and 62% of the women in the norethindrone acetate and estrogen-progestin groups, respectively.³ The most common adverse effects reported by women taking norethindrone acetate were weight gain (27%) and decreased libido (9%).

Oral MPA at doses of 30 mg to 100 mg daily has been reported to be effective for the treatment of pelvic pain caused by endometriosis. MPA treatment can induce atrophy and pseudodecidualization in endometrium and endometriosis implants. In my practice I typically prescribe doses in the range of 20 mg to 40 mg daily. With oral MPA treatment, continued uterine bleeding may occur in up to 30% of women, somewhat limiting its efficacy.^4–7

Subcutaneous and depot MPA have been reported to be effective in the treatment of pelvic pain caused by endometriosis.^4,8 In some resource-limited countries, depot MPA may be the most available progestin for the treatment of pelvic pain caused by endometriosis.

The LNG-IUD, inserted after surgery for endometriosis, has been reported to result in decreased pelvic pain in studies with a modest number of participants.^9–11

GnRH analogue medications

Gonadotropin-releasing hormone (GnRH) analogues, including both GnRH agonists (nafarelin, leuprolide, and goserelin) and GnRH antagonists (elagolix) reduce pelvic pain caused by endometriosis by suppressing pituitary secretion of LH and FSH, thereby reducing ovarian synthesis of estradiol. In the absence of estradiol stimulation, cellular activity in endometriosis lesions decreases and pain symptoms improve. In my practice, I frequently use either nafarelin¹² or leuprolide acetate depot plus norethindrone add-back.¹³ I generally avoid the use of leuprolide depot monotherapy because in many women it causes severe vasomotor symptoms.

At standard doses, nafarelin therapy generally results in serum estradiol levels in the range of 20 to 30 pg/mL, a “sweet spot” associated with modest vasomotor symptoms and reduced cellular activity in endometriosis implants.^12,14 In many women who become amenorrheic on nafarelin two sprays daily, the dose can be reduced with maintenance of pain control and ovarian suppression.¹⁵ Leuprolide acetate depot monotherapy results in serum estradiol levels in the range of 5 to 10 pg/mL, causing severe vasomotor symptoms and reduction in cellular activity in endometriosis lesions. To reduce the adverse effects of leuprolide acetate depot monotherapy, I generally initiate concomitant add-back therapy with norethindrone acetate.¹³ A little recognized pharmacokinetic observation is that a very small amount of norethindrone acetate, generally less than 1%, is metabolized to ethinyl estradiol.¹⁶

The oral GnRH antagonist, elagolix, 150 mg daily for up to 24 months or 200 mg twice daily for 6 months, was approved by the US Food and Drug Administration (FDA) in July 2018. It is now available in pharmacies. Elagolix treatment results in significant reduction in pain caused by endometriosis, but only moderately bothersome vasomotor symptoms.^17,18 Elagolix likely will become a widely used medication because of the simplicity of oral administration, efficacy against endometriosis, and acceptable adverse-effect profile. A major disadvantage of the GnRH analogue-class of medications is that they are more expensive than the progestin medications mentioned above. Among the GnRH analogue class of medications, elagolix and goserelin are the least expensive.

Androgens

Estrogen stimulates cellular activity in endometriosis lesions. Androgen and high-dose progestins inhibit cellular activity in endometriosis lesions. Danazol, an attenuated androgen and a progestin is effectivein treating pelvic pain caused by endometriosis.^19,20 However, many women decline to use danazol because it is often associated with weight gain. As an androgen, danazol can permanently change a woman’s voice pitch and should not be used by professional singers or speech therapists.

Aromatase Inhibitors

Estrogen is a critically important stimulus of cell activity in endometriosis lesions. Aromatase inhibitors, which block the synthesis of estrogen, have been explored in the treatment of endometriosis that has proven to be resistant to other therapies. Although the combination of an aromatase inhibitor plus a high-dose progestin or GnRH analogue may be effective, more data are needed before widely using the aromatase inhibitors in clinical practice.²¹

Don’t get stuck in a rut

When treating pelvic pain caused by endometriosis, if the patient’s hormone regimen is not working, prescribe a medication from another class of hormones. In the case presented above, a woman with pelvic pain and surgically proven endometriosis reported inadequate control of her pain symptoms with a continuous estrogen-progestin medication. Her physician prescribed another year of the same estrogen-progestin medication. Instead of renewing the medication, the physician could have offered the patient a hormone medication from another drug class: 1) progestin only, 2) GnRH analogue, or 3) danazol. By using every available hormonal agent, physicians will improve the treatment of pelvic pain caused by endometriosis. Millions of women in our country have pelvic pain caused by endometriosis. They are counting on us, women’s health specialists, to effectively treat their disease.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE Endometriosis pain increases despite hormonal treatment

A 25-year-old woman (G0) with severe dysmenorrhea had a laparoscopy showing endometriosis in the cul-de-sac and a peritoneal window near the left uterosacral ligament. Biopsy of a cul-de-sac lesion showed endometriosis on histopathology. The patient was treated with a continuous low-dose estrogen-progestin contraceptive. Initially, the treatment helped relieve her pain symptoms. Over the next year, while on that treatment, her pain gradually increased in severity until it was disabling. At an office visit, the primary clinician renewed the estrogen-progestin contraceptive for another year, even though it was not relieving the patient’s pain. The patient sought a second opinion.

We are the experts in the management of pelvic pain caused by endometriosis

Women’s health clinicians are the specialists best trained to care for patients with severe pain caused by endometriosis. Low-dose continuous estrogen-progestin contraceptives are commonly prescribed as a first-line hormonal treatment for pain caused by endometriosis. My observation is that estrogen-progestincontraceptives are often effective when initially prescribed, but with continued use over years, pain often recurs. Estrogen is known to stimulate endometriosis disease activity. Progestins at high doses suppress endometriosis disease activity. However, endometriosis implants often manifest decreased responsiveness to progestins, permitting the estrogen in the combination contraceptive to exert its disease-stimulating effect.^1,2 I frequently see women with pelvic pain caused by endometriosis, who initially had a significant decrease in pain with continuous estrogen-progestin contraceptive treatment but who develop increasing pain with continued use of the medication. In this clinical situation, it is useful to consider stopping the estrogen-progestin therapy and to prescribe a hormone with a different mechanism of action (TABLE).

Progestin-only medications

Progestin-only medications are often effective in the treatment of pain caused by endometriosis. High-dose progestin-only medications suppress pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), thereby suppressing ovarian synthesis of estrogen, resulting in low circulating levels of estrogen. This removes the estrogen stimulus that exacerbates endometriosis disease activity. High-dose progestins also directly suppress cellular activity in endometriosis implants. High-dose progestins often overcome the relative resistance of endometriosis lesions to progestin suppression of disease activity. Hence, high-dose progestin-only medications have two mechanisms of action: suppression of estrogen synthesis through pituitary suppression of LH and FSH, and direct inhibition of cellular activity in the endometriosis lesions. High-dose progestin-only treatments include:

• oral norethindrone acetate 5 mg daily
• oral medroxyprogesterone acetate (MPA) 20 to 40 mg daily
• subcutaneous, or depot MPA
• levonorgestrel-releasing intrauterine device (LNG-IUD).

In my practice, I frequently use oral norethindrone acetate 5 mg daily to treat pelvic pain caused by endometriosis. In one randomized trial, 90 women with pelvic pain and rectovaginal endometriosis were randomly assigned to treatment with norethindrone acetate 2.5 mg daily or an estrogen-progestin contraceptive. After 12 months of treatment, satisfaction with treatment was reported by 73% and 62% of the women in the norethindrone acetate and estrogen-progestin groups, respectively.³ The most common adverse effects reported by women taking norethindrone acetate were weight gain (27%) and decreased libido (9%).

Oral MPA at doses of 30 mg to 100 mg daily has been reported to be effective for the treatment of pelvic pain caused by endometriosis. MPA treatment can induce atrophy and pseudodecidualization in endometrium and endometriosis implants. In my practice I typically prescribe doses in the range of 20 mg to 40 mg daily. With oral MPA treatment, continued uterine bleeding may occur in up to 30% of women, somewhat limiting its efficacy.^4–7

Subcutaneous and depot MPA have been reported to be effective in the treatment of pelvic pain caused by endometriosis.^4,8 In some resource-limited countries, depot MPA may be the most available progestin for the treatment of pelvic pain caused by endometriosis.

The LNG-IUD, inserted after surgery for endometriosis, has been reported to result in decreased pelvic pain in studies with a modest number of participants.^9–11

GnRH analogue medications

Gonadotropin-releasing hormone (GnRH) analogues, including both GnRH agonists (nafarelin, leuprolide, and goserelin) and GnRH antagonists (elagolix) reduce pelvic pain caused by endometriosis by suppressing pituitary secretion of LH and FSH, thereby reducing ovarian synthesis of estradiol. In the absence of estradiol stimulation, cellular activity in endometriosis lesions decreases and pain symptoms improve. In my practice, I frequently use either nafarelin¹² or leuprolide acetate depot plus norethindrone add-back.¹³ I generally avoid the use of leuprolide depot monotherapy because in many women it causes severe vasomotor symptoms.

At standard doses, nafarelin therapy generally results in serum estradiol levels in the range of 20 to 30 pg/mL, a “sweet spot” associated with modest vasomotor symptoms and reduced cellular activity in endometriosis implants.^12,14 In many women who become amenorrheic on nafarelin two sprays daily, the dose can be reduced with maintenance of pain control and ovarian suppression.¹⁵ Leuprolide acetate depot monotherapy results in serum estradiol levels in the range of 5 to 10 pg/mL, causing severe vasomotor symptoms and reduction in cellular activity in endometriosis lesions. To reduce the adverse effects of leuprolide acetate depot monotherapy, I generally initiate concomitant add-back therapy with norethindrone acetate.¹³ A little recognized pharmacokinetic observation is that a very small amount of norethindrone acetate, generally less than 1%, is metabolized to ethinyl estradiol.¹⁶

The oral GnRH antagonist, elagolix, 150 mg daily for up to 24 months or 200 mg twice daily for 6 months, was approved by the US Food and Drug Administration (FDA) in July 2018. It is now available in pharmacies. Elagolix treatment results in significant reduction in pain caused by endometriosis, but only moderately bothersome vasomotor symptoms.^17,18 Elagolix likely will become a widely used medication because of the simplicity of oral administration, efficacy against endometriosis, and acceptable adverse-effect profile. A major disadvantage of the GnRH analogue-class of medications is that they are more expensive than the progestin medications mentioned above. Among the GnRH analogue class of medications, elagolix and goserelin are the least expensive.

Androgens

Estrogen stimulates cellular activity in endometriosis lesions. Androgen and high-dose progestins inhibit cellular activity in endometriosis lesions. Danazol, an attenuated androgen and a progestin is effectivein treating pelvic pain caused by endometriosis.^19,20 However, many women decline to use danazol because it is often associated with weight gain. As an androgen, danazol can permanently change a woman’s voice pitch and should not be used by professional singers or speech therapists.

Aromatase Inhibitors

Estrogen is a critically important stimulus of cell activity in endometriosis lesions. Aromatase inhibitors, which block the synthesis of estrogen, have been explored in the treatment of endometriosis that has proven to be resistant to other therapies. Although the combination of an aromatase inhibitor plus a high-dose progestin or GnRH analogue may be effective, more data are needed before widely using the aromatase inhibitors in clinical practice.²¹

Don’t get stuck in a rut

When treating pelvic pain caused by endometriosis, if the patient’s hormone regimen is not working, prescribe a medication from another class of hormones. In the case presented above, a woman with pelvic pain and surgically proven endometriosis reported inadequate control of her pain symptoms with a continuous estrogen-progestin medication. Her physician prescribed another year of the same estrogen-progestin medication. Instead of renewing the medication, the physician could have offered the patient a hormone medication from another drug class: 1) progestin only, 2) GnRH analogue, or 3) danazol. By using every available hormonal agent, physicians will improve the treatment of pelvic pain caused by endometriosis. Millions of women in our country have pelvic pain caused by endometriosis. They are counting on us, women’s health specialists, to effectively treat their disease.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis affects up to 10% of women of reproductive age or, conservatively, about 6.5 million women in the United States.^1,2 There are 3 types of endometriosis—superficial, ovarian, and deep—and in the past each of these was assumed to have a distinct pathogenesis.³ Deep infiltrating endometriosis (DIE) is the presence of one or more endometriotic nodules deeper than 5 mm. In a study at a large tertiary-care center, 40% of patients with endometriosis had deep disease.⁴ DIE is associated with more severe pain and infertility.⁵ In patients with endometriosis, diagnosis is commonly made 7 to 9 years after the initial pelvic pain presentation.⁶ For these reasons, well-directed history taking and proper evaluation and treatment should be pursued to relieve pain and optimize outcomes.

CASE Young woman with intensifying pelvic pain

Mary is a 26-year-old social worker who presents to her ObGyn with symptoms of worsening pain during as well as outside her periods. What additional information would you want to obtain from Mary, given her chief symptom of pain?

Investigate the type of pain

It is important to ask the patient about her menstrual and sexual history, her thoughts regarding near- and long-term fertility, and the type and severity of her pain symptoms. The 5 pain symptoms specific to pelvic pain are dysmenorrhea, dyspareunia, dysuria, dyschezia, and noncyclic pelvic pain. A visual analog scale (VAS) for pain as well as pelvic pain questionnaires can be used to guide evaluation options and monitor treatment outcomes. In addition, it is of paramount importance to understand the differential diagnoses that can present as pelvic pain (TABLE).

CASE Continued: Mary’s history

Mary reports that she always has had painful periods and that she was started on oral contraceptive pills for pain control and regulation of her periods soon after the onset of menses, when she was 12 years old. In college, she was prescribed oral contraceptive pills for contraception. Recently engaged, she is interested in becoming pregnant in 3 years.

A year ago, Mary discontinued the pills because of their adverse effects. Now she has severe pain during (VAS score, 8/10) and outside (VAS score, 7) her monthly periods. Because of this pain, she has taken time off from work twice within the past 6 months. She has pain during intercourse (VAS score, 7) and some pain with bowel movements during her menses (VAS score, 4). Pelvic examination reveals a normal-sized uterus and adnexa as well as a tender nodule in the rectovaginal septum.

What diagnostic tests and imaging would you obtain?

Imaging’s role in diagnosis

At many advanced centers for endometriosis, DIE is successfully diagnosed with specific magnetic resonance imaging (MRI) or transvaginal ultrasound (TVUS) protocols. In a recent review, MRI’s pooled sensitivity and specificity for rectosigmoid endometriosis were 92% and 96%, respectively.⁷ Choice of imaging for DIE depends on the skills and experience of the clinicians at each center. At a large referral center in São Paulo, Brazil, TVUS with bowel preparation had better sensitivity and specificity for deep retrocervical and rectosigmoid disease compared with MRI and digital pelvic examination.⁸ In addition, at a center in the United States, we found that proficiency in performing TVUS for DIE was achieved after 70 to 75 cases, and the exam took an average of only 20 minutes.⁹

Despite recent advances in imaging, most gynecologic societies still hold that endometriosis is to be definitively diagnosed with histologic confirmation from tissue biopsies during surgery. Although surgery remains the diagnostic gold standard, it does not mean that all patients with pelvic pain should undergo diagnostic laparoscopy with tissue biopsies.

The combination of compelling clinical signs, symptoms, and imaging findings (such as absence of findings for ovarian and deep endometriosis) can be used to make a presumptive nonsurgical (that is, clinical) diagnosis of endometriosis. Major societies recommend empiric medical therapy (for example, combination oral contraceptives) for the pain associated with superficial endometriosis.^10,11 When there is no response to treatment, or when a patient declines or has contraindications to medical therapy, diagnostic laparoscopy with excision of endometriosis should be considered.

CASE Continued: Diagnosis

Mary undergoes TVUS with bowel preparation, which reveals a normal uterus and adnexa and the presence of 2 lesions, a 2×1.5-cm retrocervical lesion and a 1.8×2-cm rectosigmoid lesion 9 cm above the anal verge. The rectosigmoid lesion involves the external muscularis and compromises 30% of the bowel circumference.

How would you manage the bowel DIE?

Read about management options and individualized care.

Management options: Factor in the variables

DIE can involve the ureters and bladder, the retrocervical and rectovaginal spaces, the appendix, and the bowel. Lesions can be single or multifocal. Although our institutions’ imaging with MRI and TVUS is highly accurate, we additionally recommend the use of colonoscopy (with directed biopsies if appropriate) to evaluate patients who present with rectal bleeding, large endometriotic rectal nodules, or have a family history of bowel cancer.

While many studies have found that surgical resection of DIE improves pain and quality of life, surgery can have significant complications.¹² Observation is adequate for asymptomatic patients with DIE. Medical treatment may be offered to patients with mild pain (there is no evidence of a reduction in lesion size with medical therapy). In cases of surgical treatment, we encourage the involvement of a multidisciplinary surgical team to reduce complications and optimize outcomes.

Patients with DIE, significant pain (VAS score, >7), and multiple failed in vitro fertilization treatments are candidates for surgery. When bowel endometriosis is noted on imaging, factors such as size, depth, number of lesions, circumferential involvement, and distance from the anal verge are all used to determine the surgical approach. Rectosigmoid lesions smaller than 3 cm can be treated more conservatively—for example, with shaving or anterior resection with manual repair using disk staplers. Segmental resection generally is indicated for rectosigmoid lesions larger than 3 cm, involvement deeper than the submucosal layer, multiple lesions, circumferential involvement of more than 40%, and the presence of obstructed bowel symptoms.^13,14

In patients with DIE who present with both infertility and pain, antimüllerian hormone level and TVUS follicular count are used to evaluate ovarian reserve. As surgical treatment may further reduce ovarian reserve in patients with DIE and infertility, we counsel them regarding assisted reproductive technology options before surgery.

CASE Resolved

After thorough discussion, Mary opts to try a different combination oral contraceptive pill formulation. The pills improve her pain symptoms significantly (VAS score, 4), and she decides to forgo surgery. She will be followed up closely on an outpatient basis with serial TVUS imaging.

Individualize management based on patient parameters

Imaging has been used for the nonsurgical diagnosis of DIE for many years, and this practice increasingly is being accepted and adopted. A presumptive nonsurgical diagnosis of endometriosis can be made based on the clinical signs and symptoms obtained from a thorough history and physical examination, in addition to the absence of imaging findings for ovarian and deep endometriosis.

According to guidelines from major ObGyn societies, such as the American College of Obstetricians and Gynecologists and the European Society of Human Reproduction and Embryology, empiric medical therapy (including combination oral contraceptives, progesterone-containing formulations, and gonadotropin-releasing hormone agonists) can be considered for patients with presumed endometriosis presenting with pain.¹⁵

When surgery is chosen, the surgeon must obtain crucial information on the characteristics of the lesion(s) and involve a multidisciplinary team to achieve the best outcomes for the patient.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis affects up to 10% of women of reproductive age or, conservatively, about 6.5 million women in the United States.^1,2 There are 3 types of endometriosis—superficial, ovarian, and deep—and in the past each of these was assumed to have a distinct pathogenesis.³ Deep infiltrating endometriosis (DIE) is the presence of one or more endometriotic nodules deeper than 5 mm. In a study at a large tertiary-care center, 40% of patients with endometriosis had deep disease.⁴ DIE is associated with more severe pain and infertility.⁵ In patients with endometriosis, diagnosis is commonly made 7 to 9 years after the initial pelvic pain presentation.⁶ For these reasons, well-directed history taking and proper evaluation and treatment should be pursued to relieve pain and optimize outcomes.

CASE Young woman with intensifying pelvic pain

Mary is a 26-year-old social worker who presents to her ObGyn with symptoms of worsening pain during as well as outside her periods. What additional information would you want to obtain from Mary, given her chief symptom of pain?

Investigate the type of pain

It is important to ask the patient about her menstrual and sexual history, her thoughts regarding near- and long-term fertility, and the type and severity of her pain symptoms. The 5 pain symptoms specific to pelvic pain are dysmenorrhea, dyspareunia, dysuria, dyschezia, and noncyclic pelvic pain. A visual analog scale (VAS) for pain as well as pelvic pain questionnaires can be used to guide evaluation options and monitor treatment outcomes. In addition, it is of paramount importance to understand the differential diagnoses that can present as pelvic pain (TABLE).

CASE Continued: Mary’s history

Mary reports that she always has had painful periods and that she was started on oral contraceptive pills for pain control and regulation of her periods soon after the onset of menses, when she was 12 years old. In college, she was prescribed oral contraceptive pills for contraception. Recently engaged, she is interested in becoming pregnant in 3 years.

A year ago, Mary discontinued the pills because of their adverse effects. Now she has severe pain during (VAS score, 8/10) and outside (VAS score, 7) her monthly periods. Because of this pain, she has taken time off from work twice within the past 6 months. She has pain during intercourse (VAS score, 7) and some pain with bowel movements during her menses (VAS score, 4). Pelvic examination reveals a normal-sized uterus and adnexa as well as a tender nodule in the rectovaginal septum.

What diagnostic tests and imaging would you obtain?

Imaging’s role in diagnosis

At many advanced centers for endometriosis, DIE is successfully diagnosed with specific magnetic resonance imaging (MRI) or transvaginal ultrasound (TVUS) protocols. In a recent review, MRI’s pooled sensitivity and specificity for rectosigmoid endometriosis were 92% and 96%, respectively.⁷ Choice of imaging for DIE depends on the skills and experience of the clinicians at each center. At a large referral center in São Paulo, Brazil, TVUS with bowel preparation had better sensitivity and specificity for deep retrocervical and rectosigmoid disease compared with MRI and digital pelvic examination.⁸ In addition, at a center in the United States, we found that proficiency in performing TVUS for DIE was achieved after 70 to 75 cases, and the exam took an average of only 20 minutes.⁹

Despite recent advances in imaging, most gynecologic societies still hold that endometriosis is to be definitively diagnosed with histologic confirmation from tissue biopsies during surgery. Although surgery remains the diagnostic gold standard, it does not mean that all patients with pelvic pain should undergo diagnostic laparoscopy with tissue biopsies.

The combination of compelling clinical signs, symptoms, and imaging findings (such as absence of findings for ovarian and deep endometriosis) can be used to make a presumptive nonsurgical (that is, clinical) diagnosis of endometriosis. Major societies recommend empiric medical therapy (for example, combination oral contraceptives) for the pain associated with superficial endometriosis.^10,11 When there is no response to treatment, or when a patient declines or has contraindications to medical therapy, diagnostic laparoscopy with excision of endometriosis should be considered.

CASE Continued: Diagnosis

Mary undergoes TVUS with bowel preparation, which reveals a normal uterus and adnexa and the presence of 2 lesions, a 2×1.5-cm retrocervical lesion and a 1.8×2-cm rectosigmoid lesion 9 cm above the anal verge. The rectosigmoid lesion involves the external muscularis and compromises 30% of the bowel circumference.

How would you manage the bowel DIE?

Read about management options and individualized care.

Management options: Factor in the variables

DIE can involve the ureters and bladder, the retrocervical and rectovaginal spaces, the appendix, and the bowel. Lesions can be single or multifocal. Although our institutions’ imaging with MRI and TVUS is highly accurate, we additionally recommend the use of colonoscopy (with directed biopsies if appropriate) to evaluate patients who present with rectal bleeding, large endometriotic rectal nodules, or have a family history of bowel cancer.

While many studies have found that surgical resection of DIE improves pain and quality of life, surgery can have significant complications.¹² Observation is adequate for asymptomatic patients with DIE. Medical treatment may be offered to patients with mild pain (there is no evidence of a reduction in lesion size with medical therapy). In cases of surgical treatment, we encourage the involvement of a multidisciplinary surgical team to reduce complications and optimize outcomes.

Patients with DIE, significant pain (VAS score, >7), and multiple failed in vitro fertilization treatments are candidates for surgery. When bowel endometriosis is noted on imaging, factors such as size, depth, number of lesions, circumferential involvement, and distance from the anal verge are all used to determine the surgical approach. Rectosigmoid lesions smaller than 3 cm can be treated more conservatively—for example, with shaving or anterior resection with manual repair using disk staplers. Segmental resection generally is indicated for rectosigmoid lesions larger than 3 cm, involvement deeper than the submucosal layer, multiple lesions, circumferential involvement of more than 40%, and the presence of obstructed bowel symptoms.^13,14

In patients with DIE who present with both infertility and pain, antimüllerian hormone level and TVUS follicular count are used to evaluate ovarian reserve. As surgical treatment may further reduce ovarian reserve in patients with DIE and infertility, we counsel them regarding assisted reproductive technology options before surgery.

CASE Resolved

After thorough discussion, Mary opts to try a different combination oral contraceptive pill formulation. The pills improve her pain symptoms significantly (VAS score, 4), and she decides to forgo surgery. She will be followed up closely on an outpatient basis with serial TVUS imaging.

Individualize management based on patient parameters

Imaging has been used for the nonsurgical diagnosis of DIE for many years, and this practice increasingly is being accepted and adopted. A presumptive nonsurgical diagnosis of endometriosis can be made based on the clinical signs and symptoms obtained from a thorough history and physical examination, in addition to the absence of imaging findings for ovarian and deep endometriosis.

According to guidelines from major ObGyn societies, such as the American College of Obstetricians and Gynecologists and the European Society of Human Reproduction and Embryology, empiric medical therapy (including combination oral contraceptives, progesterone-containing formulations, and gonadotropin-releasing hormone agonists) can be considered for patients with presumed endometriosis presenting with pain.¹⁵

When surgery is chosen, the surgeon must obtain crucial information on the characteristics of the lesion(s) and involve a multidisciplinary team to achieve the best outcomes for the patient.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis affects up to 10% of women of reproductive age or, conservatively, about 6.5 million women in the United States.^1,2 There are 3 types of endometriosis—superficial, ovarian, and deep—and in the past each of these was assumed to have a distinct pathogenesis.³ Deep infiltrating endometriosis (DIE) is the presence of one or more endometriotic nodules deeper than 5 mm. In a study at a large tertiary-care center, 40% of patients with endometriosis had deep disease.⁴ DIE is associated with more severe pain and infertility.⁵ In patients with endometriosis, diagnosis is commonly made 7 to 9 years after the initial pelvic pain presentation.⁶ For these reasons, well-directed history taking and proper evaluation and treatment should be pursued to relieve pain and optimize outcomes.

CASE Young woman with intensifying pelvic pain

Mary is a 26-year-old social worker who presents to her ObGyn with symptoms of worsening pain during as well as outside her periods. What additional information would you want to obtain from Mary, given her chief symptom of pain?

Investigate the type of pain

It is important to ask the patient about her menstrual and sexual history, her thoughts regarding near- and long-term fertility, and the type and severity of her pain symptoms. The 5 pain symptoms specific to pelvic pain are dysmenorrhea, dyspareunia, dysuria, dyschezia, and noncyclic pelvic pain. A visual analog scale (VAS) for pain as well as pelvic pain questionnaires can be used to guide evaluation options and monitor treatment outcomes. In addition, it is of paramount importance to understand the differential diagnoses that can present as pelvic pain (TABLE).

CASE Continued: Mary’s history

Mary reports that she always has had painful periods and that she was started on oral contraceptive pills for pain control and regulation of her periods soon after the onset of menses, when she was 12 years old. In college, she was prescribed oral contraceptive pills for contraception. Recently engaged, she is interested in becoming pregnant in 3 years.

A year ago, Mary discontinued the pills because of their adverse effects. Now she has severe pain during (VAS score, 8/10) and outside (VAS score, 7) her monthly periods. Because of this pain, she has taken time off from work twice within the past 6 months. She has pain during intercourse (VAS score, 7) and some pain with bowel movements during her menses (VAS score, 4). Pelvic examination reveals a normal-sized uterus and adnexa as well as a tender nodule in the rectovaginal septum.

What diagnostic tests and imaging would you obtain?

Imaging’s role in diagnosis

At many advanced centers for endometriosis, DIE is successfully diagnosed with specific magnetic resonance imaging (MRI) or transvaginal ultrasound (TVUS) protocols. In a recent review, MRI’s pooled sensitivity and specificity for rectosigmoid endometriosis were 92% and 96%, respectively.⁷ Choice of imaging for DIE depends on the skills and experience of the clinicians at each center. At a large referral center in São Paulo, Brazil, TVUS with bowel preparation had better sensitivity and specificity for deep retrocervical and rectosigmoid disease compared with MRI and digital pelvic examination.⁸ In addition, at a center in the United States, we found that proficiency in performing TVUS for DIE was achieved after 70 to 75 cases, and the exam took an average of only 20 minutes.⁹

Despite recent advances in imaging, most gynecologic societies still hold that endometriosis is to be definitively diagnosed with histologic confirmation from tissue biopsies during surgery. Although surgery remains the diagnostic gold standard, it does not mean that all patients with pelvic pain should undergo diagnostic laparoscopy with tissue biopsies.

The combination of compelling clinical signs, symptoms, and imaging findings (such as absence of findings for ovarian and deep endometriosis) can be used to make a presumptive nonsurgical (that is, clinical) diagnosis of endometriosis. Major societies recommend empiric medical therapy (for example, combination oral contraceptives) for the pain associated with superficial endometriosis.^10,11 When there is no response to treatment, or when a patient declines or has contraindications to medical therapy, diagnostic laparoscopy with excision of endometriosis should be considered.

CASE Continued: Diagnosis

Mary undergoes TVUS with bowel preparation, which reveals a normal uterus and adnexa and the presence of 2 lesions, a 2×1.5-cm retrocervical lesion and a 1.8×2-cm rectosigmoid lesion 9 cm above the anal verge. The rectosigmoid lesion involves the external muscularis and compromises 30% of the bowel circumference.

How would you manage the bowel DIE?

Read about management options and individualized care.

Management options: Factor in the variables

DIE can involve the ureters and bladder, the retrocervical and rectovaginal spaces, the appendix, and the bowel. Lesions can be single or multifocal. Although our institutions’ imaging with MRI and TVUS is highly accurate, we additionally recommend the use of colonoscopy (with directed biopsies if appropriate) to evaluate patients who present with rectal bleeding, large endometriotic rectal nodules, or have a family history of bowel cancer.

While many studies have found that surgical resection of DIE improves pain and quality of life, surgery can have significant complications.¹² Observation is adequate for asymptomatic patients with DIE. Medical treatment may be offered to patients with mild pain (there is no evidence of a reduction in lesion size with medical therapy). In cases of surgical treatment, we encourage the involvement of a multidisciplinary surgical team to reduce complications and optimize outcomes.

Patients with DIE, significant pain (VAS score, >7), and multiple failed in vitro fertilization treatments are candidates for surgery. When bowel endometriosis is noted on imaging, factors such as size, depth, number of lesions, circumferential involvement, and distance from the anal verge are all used to determine the surgical approach. Rectosigmoid lesions smaller than 3 cm can be treated more conservatively—for example, with shaving or anterior resection with manual repair using disk staplers. Segmental resection generally is indicated for rectosigmoid lesions larger than 3 cm, involvement deeper than the submucosal layer, multiple lesions, circumferential involvement of more than 40%, and the presence of obstructed bowel symptoms.^13,14

In patients with DIE who present with both infertility and pain, antimüllerian hormone level and TVUS follicular count are used to evaluate ovarian reserve. As surgical treatment may further reduce ovarian reserve in patients with DIE and infertility, we counsel them regarding assisted reproductive technology options before surgery.

CASE Resolved

After thorough discussion, Mary opts to try a different combination oral contraceptive pill formulation. The pills improve her pain symptoms significantly (VAS score, 4), and she decides to forgo surgery. She will be followed up closely on an outpatient basis with serial TVUS imaging.

Individualize management based on patient parameters

Imaging has been used for the nonsurgical diagnosis of DIE for many years, and this practice increasingly is being accepted and adopted. A presumptive nonsurgical diagnosis of endometriosis can be made based on the clinical signs and symptoms obtained from a thorough history and physical examination, in addition to the absence of imaging findings for ovarian and deep endometriosis.

According to guidelines from major ObGyn societies, such as the American College of Obstetricians and Gynecologists and the European Society of Human Reproduction and Embryology, empiric medical therapy (including combination oral contraceptives, progesterone-containing formulations, and gonadotropin-releasing hormone agonists) can be considered for patients with presumed endometriosis presenting with pain.¹⁵

When surgery is chosen, the surgeon must obtain crucial information on the characteristics of the lesion(s) and involve a multidisciplinary team to achieve the best outcomes for the patient.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis is one of the more daunting diagnoses that gynecologists treat. In this roundtable discussion, moderated by OBG Management Board Member Arnold P. Advincula, MD, 2 leading surgeons discuss endometriosis diagnosis as well as medical and surgical management.

First-time evaluation

Arnold P. Advincula, MD: When a patient presents to your practice for the first time and you suspect endometriosis, what considerations tailor your evaluation, and what does that evaluation involve?

Hye-Chun Hur, MD, MPH: The diagnosis is contingent on a patient’s presenting profile. How symptomatic is she? How old is she? What are her reproductive goals? The gold standard for diagnosis is a histologic diagnosis, which is surgical. Depending on the age profile, however, and how close she is to menopause, the patient may be managed medically. Even women in the young reproductive age group may be managed medically if symptoms are responsive to medical treatment.

Douglas N. Brown, MD: I agree. When a patient presents without a laparoscopy, or a tissue diagnosis, but the symptoms are consistent with likely endometriosis (depending on where she is in her reproductive cycle and what her goals are), I think treating with a first-line therapy—hormonal treatments such as progestin-only oral contraceptive pills—is acceptable. I usually conduct a treatment trial period of 3 to 6 months to see if she obtains any symptom relief.

If that first-line treatment fails, generally you can move to a second-line treatment.

I have a discussion in which I either offer a second-line treatment, such as medroxyprogesterone (Depo-Provera) or leuprolide acetate (Lupron Depot), or get a tissue diagnosis, if possible, by performing laparoscopy. If first-line or even second-line therapy fails, you need to consider doing a diagnostic laparoscopy to confirm or deny the diagnosis.

Dr. Advincula: Are there any points in the evaluation of a patient who visits your practice for the first time where you would immediately offer a surgical approach, as opposed to starting with medical management?

Dr. Hur: A large percentage of my patients undergo surgical evaluation, as surgical diagnosis is the gold standard. If you look at the literature, even among surgeons, the accuracy of visual diagnosis is not great.^1,2 I target individuals who are either not responsive to medical treatment or who have never tried medical treatment but are trying to conceive, so they are not medical candidates, or individuals who genuinely want a diagnosis for surgical management—sometimes even before first-line medical treatment.

Dr. Brown: Your examination sometimes also dictates your approach. A patient may never have had a laparoscopy or hormone therapy, but if you find uterosacral ligament nodularity, extreme pain on examination, and suspicious findings on ultrasound or otherwise, a diagnostic laparoscopy may be warranted to confirm the diagnosis.

Endometrioma management

Dr. Advincula: Let’s jump ahead. You have decided to proceed with laparoscopy and you encounter an endometrioma. What is your management strategy, particularly in a fertility-desiring patient?

Dr. Hur: Even if a woman has not undergone first-line medical treatment, if she is trying to conceive or presents with infertility, it’s a different balancing act for approaching the patient. When a woman presents, either with an ultrasound finding or an intraoperative finding of an endometrioma, I am a strong advocate of treating symptomatic disease, which means complete cyst excision. Good clinical data suggest that reproductive outcomes are improved for spontaneous pregnancy rates when you excise an endometrioma.^3-6

Dr. Advincula: What are the risks of excision of an endometrioma cyst that patients need to know about?

Dr. Brown: Current standard of care is cystectomy, stripping the cyst wall away from the ovarian cortex. There is some concern that the stripping process, depending on how long the endometrioma has been present within the ovary, can cause some destruction to the underlying oocytes and perhaps impact that ovary’s ability to produce viable eggs.

Some studies, from France in particular, have investigated different energy sources, such as plasma energy, that make it possible to remove part of the cyst and then use the plasma energy to vaporize the rest of the cyst wall that may be lying on the cortex. Researchers looked at anti-Müllerian hormone levels, and there does seem to be a difference in terms of how you remove the cyst.^7-9 This energy source is not available to everyone; it’s similar to laser but does not have as much penetration. Standard of care is still ovarian stripping.

The conversation with the patient—if she is already infertile and this cyst is a problem—would be that it likely needs to be removed. There is a chance that she may need assisted reproduction; she might not be able to get pregnant on her own due either to the presence of the endometrioma or to the surgical process of removing it and stripping.

Dr. Advincula: How soon after surgery can a patient start to pursue trying to get pregnant?

Dr. Hur: I think there is no time restraint outside of recovery. As long as the patient has a routine postoperative course, she can try to conceive, spontaneously or with assisted reproduction. Some data suggest, however, that ovarian reserve is diminished immediately after surgery.^10–12 If you look at the spontaneous clinical pregnancy outcomes, they are comparable 3 to 6 months postsurgery.^4,12–14

Dr. Brown: I agree. Time is of the essence with a lot of patients, many of whom present after age 35.

Dr. Hur: It’s also important to highlight that there are 2 presentations with endometrioma: the symptomatic patient and the asymptomatic patient. In the asymptomatic patient, her age, reproductive goals, and the bilaterality (whether it is present on both sides or on one side) of the endometrioma are important in deciding on a patient-centered surgical plan. For someone with a smaller cyst, unilateral presentation, and maybe older age at presentation, it may or may not impact assisted reproductive outcomes.

If the patient is not symptomatic and she is older with bilateral endometriomas less than 4 cm, some data suggest that patient might be better served in a conservative fashion.^6,15–17 Then, once she is done with assisted reproduction, we might be more aggressive surgically by treating the finding that would not resolve spontaneously without surgical management. It is important to highlight that endometriomas do not resolve on their own; they require surgical management.

Read about managing endometriosis for the patient not seeking fertility

Endometriosis management for the patient not seeking fertility

Dr. Advincula: Let’s now consider a patient on whom you have performed laparoscopy not only to diagnose and confirm the evidence of endometriosis but also to treat endometriosis, an endometrioma, and potentially deeply infiltrative disease. But this person is not trying to get pregnant. Postoperatively, what is your approach?

Dr. Brown: Suppressive therapy for this patient could be first-line or second-line therapy, such as a Lupron Depot or Depo-Provera. We keep the patient on suppressive therapy (whatever treatments work for her), until she’s ready to get pregnant; then we take her off. Hopefully she gets pregnant. After she delivers, we reinitiate suppressive therapy. I will follow these women throughout their reproductive cycle, and I think having a team of physicians who are all on the same page can help this patient manage her disease through her reproductive years.

Dr. Hur: If a patient presented warranting surgical management once, and she is not menopausal, the likelihood that disease will recur is quite high. Understanding the nature and the pathology of the disease, hormonal suppression would be warranted. Suppression is not just for between pregnancies, it’s until the patient reaches natural menopause. It’s also in the hopes of suppressing the disease so she does not need recurrent surgeries.

We typically do not operate unless patients have recurrence of symptoms that no longer respond to medical therapy. Our hope is to buy them more time closer to the age of natural menopause so that medical repercussions do not result in hysterectomy and ovary removal, which have other nongynecologic manifestations, including negative impact on bone and cardiac health.

The role of the LNG-IUD

Dr. Advincula: Something that often comes up is the role of a levonorgestrel-releasing intrauterine device (LNG-IUD) as one therapy option, either preoperatively or postoperatively. What is your perspective?

Dr. Hur: I reserve the LNG-IUD as a second-line therapy for patients, predominantly because it allows direct delivery of the medication to the womb (rather than systemic exposure of the medication). For patients who experience adverse effects due to systemic exposure to first-line treatments, it might be a great option. However, I do not believe that it consistently suppresses the ovaries, which we understand feeds the pathology of the hormonal stimulation, and so typically I will reserve it as a second-line treatment.

Dr. Brown: I utilize the LNG-IUD in a similar fashion. I may have patients who have had a diagnostic laparoscopy somewhere else and were referred to me because they now have known stage 3 or 4 endometriosis without endometriomas. Those patients, if they are going to need suppressive therapy after surgery and are not ready to get pregnant, do very well with the LNG-IUD, and I will place it during surgery under anesthesia. If a patient has endometriomas seen at the time of surgery, we could still place an LNG-IUD at the time of surgery. We may need to add on an additional medication, however, like another oral progesterone. I do have patients that use both an IUD and either combined oral contraceptive pills and/or oral progestins. Those patients usually have complicated cases with very deep infiltrative disease.

Read about managing endometriosis involving the bowel

Managing endometriosis involving the bowel

Dr. Advincula: Patients often are quite concerned when the words “endometriosis” and “bowel” come together. How do you manage disease that involves the bowel?

Illustration: Kimberly Martens for OBG Management

Dr. Hur: A lot of patients with endometriosis have what I call neighboring disease—it’s not limited just to the pelvis, but it involves the neighboring organs including the bowel and bladder. Patients can present with symptoms related to those adjacent organs. However, not all disease involving the bowel or bladder manifests with symptoms, and patients with symptoms may not have visible disease.

Typically, when a patient presents with symptoms of bowel involvement, where the bowel lumen is narrowed to more than 50% and/or she has functional manifestations (signs of obstruction that result in abnormal bowel function), we have serious conversations about a bowel resection. If she has full-thickness disease without significant bowel dysfunction—other than blood in her stool—sometimes we talk about more conservative treatment because of the long-term manifestations that a bowel resection could have.

Dr. Brown: I agree completely. It is important to have a good relationship with our colorectal surgeons. If I suspect that the patient has narrowing of the lumen of the large bowel or she actually has symptoms such as bloody diarrhea during menstruation—which is suggestive of deep, infiltrative and penetrative disease—I will often order a colonoscopy ahead of time to get confirmed biopsies. Then the patient discussion occurs with our colorectal surgeon, who operates with me jointly if we decide to proceed with a bowel resection. It’s important to have subspecialty colleagues involved in this care, because a low anterior resection is a very big surgery and there can be down-the-stream complications.

The importance of multidisciplinary care

Dr. Advincula: What are your perspectives on a multidisciplinary or interdisciplinary approach to the patient with endometriosis?

Dr. Brown: As I previously mentioned, it is important to develop a good relationship with colorectal surgery/urology. In addition, behavioral therapists may be involved in the care of patients with endometriosis, for a number of reasons. The disease process is fluid. It will change during the patient’s reproductive years, and you need to manage it accordingly based on her symptoms. Sometimes the diagnosis is not made for 5 to 10 years, and that can lead to other issues: depression, fibromyalgia, or irritable bowel syndrome.

The patient may have multiple issues plus endometriosis. I think having specialists such as gastroenterologists and behavioral therapists on board, as well as colorectal and urological surgeons who can perform these complex surgeries, is very beneficial to the patient. That way, she benefits from the team’s focus and is cared for from start to finish.

Dr. Hur: I like to call the abdomen a studio. It does not have separate compartments for each organ system. It’s one big room, and often the neighboring organs are involved, including the bowel and bladder. I think Dr. Brown’s observation—the multidisciplinary approach to a patient’s comprehensive care—is critical. Like any surgery, preoperative planning and preoperative assessment are essential, and these steps should include the patient. The discussion should cover not only the surgical outcomes that the surgeons expect, but also what the patient expects to be improved. For example, for patients with extensive disease and bowel involvement, a bowel resection is not always the right approach because it can have potential long-term sequelae. Balancing the risks associated with surgery with the long-term benefits is an important part of the discussion.

Dr. Advincula: Those are both excellent perspectives. Endometriosis is a very complicated disease state, does require a multidisciplinary approach to management, and there are implications and strategies that involve both the medical approach to management and the surgical approach.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis is one of the more daunting diagnoses that gynecologists treat. In this roundtable discussion, moderated by OBG Management Board Member Arnold P. Advincula, MD, 2 leading surgeons discuss endometriosis diagnosis as well as medical and surgical management.

First-time evaluation

Arnold P. Advincula, MD: When a patient presents to your practice for the first time and you suspect endometriosis, what considerations tailor your evaluation, and what does that evaluation involve?

Hye-Chun Hur, MD, MPH: The diagnosis is contingent on a patient’s presenting profile. How symptomatic is she? How old is she? What are her reproductive goals? The gold standard for diagnosis is a histologic diagnosis, which is surgical. Depending on the age profile, however, and how close she is to menopause, the patient may be managed medically. Even women in the young reproductive age group may be managed medically if symptoms are responsive to medical treatment.

Douglas N. Brown, MD: I agree. When a patient presents without a laparoscopy, or a tissue diagnosis, but the symptoms are consistent with likely endometriosis (depending on where she is in her reproductive cycle and what her goals are), I think treating with a first-line therapy—hormonal treatments such as progestin-only oral contraceptive pills—is acceptable. I usually conduct a treatment trial period of 3 to 6 months to see if she obtains any symptom relief.

If that first-line treatment fails, generally you can move to a second-line treatment.

I have a discussion in which I either offer a second-line treatment, such as medroxyprogesterone (Depo-Provera) or leuprolide acetate (Lupron Depot), or get a tissue diagnosis, if possible, by performing laparoscopy. If first-line or even second-line therapy fails, you need to consider doing a diagnostic laparoscopy to confirm or deny the diagnosis.

Dr. Advincula: Are there any points in the evaluation of a patient who visits your practice for the first time where you would immediately offer a surgical approach, as opposed to starting with medical management?

Dr. Hur: A large percentage of my patients undergo surgical evaluation, as surgical diagnosis is the gold standard. If you look at the literature, even among surgeons, the accuracy of visual diagnosis is not great.^1,2 I target individuals who are either not responsive to medical treatment or who have never tried medical treatment but are trying to conceive, so they are not medical candidates, or individuals who genuinely want a diagnosis for surgical management—sometimes even before first-line medical treatment.

Dr. Brown: Your examination sometimes also dictates your approach. A patient may never have had a laparoscopy or hormone therapy, but if you find uterosacral ligament nodularity, extreme pain on examination, and suspicious findings on ultrasound or otherwise, a diagnostic laparoscopy may be warranted to confirm the diagnosis.

Endometrioma management

Dr. Advincula: Let’s jump ahead. You have decided to proceed with laparoscopy and you encounter an endometrioma. What is your management strategy, particularly in a fertility-desiring patient?

Dr. Hur: Even if a woman has not undergone first-line medical treatment, if she is trying to conceive or presents with infertility, it’s a different balancing act for approaching the patient. When a woman presents, either with an ultrasound finding or an intraoperative finding of an endometrioma, I am a strong advocate of treating symptomatic disease, which means complete cyst excision. Good clinical data suggest that reproductive outcomes are improved for spontaneous pregnancy rates when you excise an endometrioma.^3-6

Dr. Advincula: What are the risks of excision of an endometrioma cyst that patients need to know about?

Dr. Brown: Current standard of care is cystectomy, stripping the cyst wall away from the ovarian cortex. There is some concern that the stripping process, depending on how long the endometrioma has been present within the ovary, can cause some destruction to the underlying oocytes and perhaps impact that ovary’s ability to produce viable eggs.

Some studies, from France in particular, have investigated different energy sources, such as plasma energy, that make it possible to remove part of the cyst and then use the plasma energy to vaporize the rest of the cyst wall that may be lying on the cortex. Researchers looked at anti-Müllerian hormone levels, and there does seem to be a difference in terms of how you remove the cyst.^7-9 This energy source is not available to everyone; it’s similar to laser but does not have as much penetration. Standard of care is still ovarian stripping.

The conversation with the patient—if she is already infertile and this cyst is a problem—would be that it likely needs to be removed. There is a chance that she may need assisted reproduction; she might not be able to get pregnant on her own due either to the presence of the endometrioma or to the surgical process of removing it and stripping.

Dr. Advincula: How soon after surgery can a patient start to pursue trying to get pregnant?

Dr. Hur: I think there is no time restraint outside of recovery. As long as the patient has a routine postoperative course, she can try to conceive, spontaneously or with assisted reproduction. Some data suggest, however, that ovarian reserve is diminished immediately after surgery.^10–12 If you look at the spontaneous clinical pregnancy outcomes, they are comparable 3 to 6 months postsurgery.^4,12–14

Dr. Brown: I agree. Time is of the essence with a lot of patients, many of whom present after age 35.

Dr. Hur: It’s also important to highlight that there are 2 presentations with endometrioma: the symptomatic patient and the asymptomatic patient. In the asymptomatic patient, her age, reproductive goals, and the bilaterality (whether it is present on both sides or on one side) of the endometrioma are important in deciding on a patient-centered surgical plan. For someone with a smaller cyst, unilateral presentation, and maybe older age at presentation, it may or may not impact assisted reproductive outcomes.

If the patient is not symptomatic and she is older with bilateral endometriomas less than 4 cm, some data suggest that patient might be better served in a conservative fashion.^6,15–17 Then, once she is done with assisted reproduction, we might be more aggressive surgically by treating the finding that would not resolve spontaneously without surgical management. It is important to highlight that endometriomas do not resolve on their own; they require surgical management.

Read about managing endometriosis for the patient not seeking fertility

Endometriosis management for the patient not seeking fertility

Dr. Advincula: Let’s now consider a patient on whom you have performed laparoscopy not only to diagnose and confirm the evidence of endometriosis but also to treat endometriosis, an endometrioma, and potentially deeply infiltrative disease. But this person is not trying to get pregnant. Postoperatively, what is your approach?

Dr. Brown: Suppressive therapy for this patient could be first-line or second-line therapy, such as a Lupron Depot or Depo-Provera. We keep the patient on suppressive therapy (whatever treatments work for her), until she’s ready to get pregnant; then we take her off. Hopefully she gets pregnant. After she delivers, we reinitiate suppressive therapy. I will follow these women throughout their reproductive cycle, and I think having a team of physicians who are all on the same page can help this patient manage her disease through her reproductive years.

Dr. Hur: If a patient presented warranting surgical management once, and she is not menopausal, the likelihood that disease will recur is quite high. Understanding the nature and the pathology of the disease, hormonal suppression would be warranted. Suppression is not just for between pregnancies, it’s until the patient reaches natural menopause. It’s also in the hopes of suppressing the disease so she does not need recurrent surgeries.

We typically do not operate unless patients have recurrence of symptoms that no longer respond to medical therapy. Our hope is to buy them more time closer to the age of natural menopause so that medical repercussions do not result in hysterectomy and ovary removal, which have other nongynecologic manifestations, including negative impact on bone and cardiac health.

The role of the LNG-IUD

Dr. Advincula: Something that often comes up is the role of a levonorgestrel-releasing intrauterine device (LNG-IUD) as one therapy option, either preoperatively or postoperatively. What is your perspective?

Dr. Hur: I reserve the LNG-IUD as a second-line therapy for patients, predominantly because it allows direct delivery of the medication to the womb (rather than systemic exposure of the medication). For patients who experience adverse effects due to systemic exposure to first-line treatments, it might be a great option. However, I do not believe that it consistently suppresses the ovaries, which we understand feeds the pathology of the hormonal stimulation, and so typically I will reserve it as a second-line treatment.

Dr. Brown: I utilize the LNG-IUD in a similar fashion. I may have patients who have had a diagnostic laparoscopy somewhere else and were referred to me because they now have known stage 3 or 4 endometriosis without endometriomas. Those patients, if they are going to need suppressive therapy after surgery and are not ready to get pregnant, do very well with the LNG-IUD, and I will place it during surgery under anesthesia. If a patient has endometriomas seen at the time of surgery, we could still place an LNG-IUD at the time of surgery. We may need to add on an additional medication, however, like another oral progesterone. I do have patients that use both an IUD and either combined oral contraceptive pills and/or oral progestins. Those patients usually have complicated cases with very deep infiltrative disease.

Read about managing endometriosis involving the bowel

Managing endometriosis involving the bowel

Dr. Advincula: Patients often are quite concerned when the words “endometriosis” and “bowel” come together. How do you manage disease that involves the bowel?

Illustration: Kimberly Martens for OBG Management

Dr. Hur: A lot of patients with endometriosis have what I call neighboring disease—it’s not limited just to the pelvis, but it involves the neighboring organs including the bowel and bladder. Patients can present with symptoms related to those adjacent organs. However, not all disease involving the bowel or bladder manifests with symptoms, and patients with symptoms may not have visible disease.

Typically, when a patient presents with symptoms of bowel involvement, where the bowel lumen is narrowed to more than 50% and/or she has functional manifestations (signs of obstruction that result in abnormal bowel function), we have serious conversations about a bowel resection. If she has full-thickness disease without significant bowel dysfunction—other than blood in her stool—sometimes we talk about more conservative treatment because of the long-term manifestations that a bowel resection could have.

Dr. Brown: I agree completely. It is important to have a good relationship with our colorectal surgeons. If I suspect that the patient has narrowing of the lumen of the large bowel or she actually has symptoms such as bloody diarrhea during menstruation—which is suggestive of deep, infiltrative and penetrative disease—I will often order a colonoscopy ahead of time to get confirmed biopsies. Then the patient discussion occurs with our colorectal surgeon, who operates with me jointly if we decide to proceed with a bowel resection. It’s important to have subspecialty colleagues involved in this care, because a low anterior resection is a very big surgery and there can be down-the-stream complications.

The importance of multidisciplinary care

Dr. Advincula: What are your perspectives on a multidisciplinary or interdisciplinary approach to the patient with endometriosis?

Dr. Brown: As I previously mentioned, it is important to develop a good relationship with colorectal surgery/urology. In addition, behavioral therapists may be involved in the care of patients with endometriosis, for a number of reasons. The disease process is fluid. It will change during the patient’s reproductive years, and you need to manage it accordingly based on her symptoms. Sometimes the diagnosis is not made for 5 to 10 years, and that can lead to other issues: depression, fibromyalgia, or irritable bowel syndrome.

The patient may have multiple issues plus endometriosis. I think having specialists such as gastroenterologists and behavioral therapists on board, as well as colorectal and urological surgeons who can perform these complex surgeries, is very beneficial to the patient. That way, she benefits from the team’s focus and is cared for from start to finish.

Dr. Hur: I like to call the abdomen a studio. It does not have separate compartments for each organ system. It’s one big room, and often the neighboring organs are involved, including the bowel and bladder. I think Dr. Brown’s observation—the multidisciplinary approach to a patient’s comprehensive care—is critical. Like any surgery, preoperative planning and preoperative assessment are essential, and these steps should include the patient. The discussion should cover not only the surgical outcomes that the surgeons expect, but also what the patient expects to be improved. For example, for patients with extensive disease and bowel involvement, a bowel resection is not always the right approach because it can have potential long-term sequelae. Balancing the risks associated with surgery with the long-term benefits is an important part of the discussion.

Dr. Advincula: Those are both excellent perspectives. Endometriosis is a very complicated disease state, does require a multidisciplinary approach to management, and there are implications and strategies that involve both the medical approach to management and the surgical approach.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Endometriosis is one of the more daunting diagnoses that gynecologists treat. In this roundtable discussion, moderated by OBG Management Board Member Arnold P. Advincula, MD, 2 leading surgeons discuss endometriosis diagnosis as well as medical and surgical management.

First-time evaluation

Arnold P. Advincula, MD: When a patient presents to your practice for the first time and you suspect endometriosis, what considerations tailor your evaluation, and what does that evaluation involve?

Hye-Chun Hur, MD, MPH: The diagnosis is contingent on a patient’s presenting profile. How symptomatic is she? How old is she? What are her reproductive goals? The gold standard for diagnosis is a histologic diagnosis, which is surgical. Depending on the age profile, however, and how close she is to menopause, the patient may be managed medically. Even women in the young reproductive age group may be managed medically if symptoms are responsive to medical treatment.

Douglas N. Brown, MD: I agree. When a patient presents without a laparoscopy, or a tissue diagnosis, but the symptoms are consistent with likely endometriosis (depending on where she is in her reproductive cycle and what her goals are), I think treating with a first-line therapy—hormonal treatments such as progestin-only oral contraceptive pills—is acceptable. I usually conduct a treatment trial period of 3 to 6 months to see if she obtains any symptom relief.

If that first-line treatment fails, generally you can move to a second-line treatment.

I have a discussion in which I either offer a second-line treatment, such as medroxyprogesterone (Depo-Provera) or leuprolide acetate (Lupron Depot), or get a tissue diagnosis, if possible, by performing laparoscopy. If first-line or even second-line therapy fails, you need to consider doing a diagnostic laparoscopy to confirm or deny the diagnosis.

Dr. Advincula: Are there any points in the evaluation of a patient who visits your practice for the first time where you would immediately offer a surgical approach, as opposed to starting with medical management?

Dr. Hur: A large percentage of my patients undergo surgical evaluation, as surgical diagnosis is the gold standard. If you look at the literature, even among surgeons, the accuracy of visual diagnosis is not great.^1,2 I target individuals who are either not responsive to medical treatment or who have never tried medical treatment but are trying to conceive, so they are not medical candidates, or individuals who genuinely want a diagnosis for surgical management—sometimes even before first-line medical treatment.

Dr. Brown: Your examination sometimes also dictates your approach. A patient may never have had a laparoscopy or hormone therapy, but if you find uterosacral ligament nodularity, extreme pain on examination, and suspicious findings on ultrasound or otherwise, a diagnostic laparoscopy may be warranted to confirm the diagnosis.

Endometrioma management

Dr. Advincula: Let’s jump ahead. You have decided to proceed with laparoscopy and you encounter an endometrioma. What is your management strategy, particularly in a fertility-desiring patient?

Dr. Hur: Even if a woman has not undergone first-line medical treatment, if she is trying to conceive or presents with infertility, it’s a different balancing act for approaching the patient. When a woman presents, either with an ultrasound finding or an intraoperative finding of an endometrioma, I am a strong advocate of treating symptomatic disease, which means complete cyst excision. Good clinical data suggest that reproductive outcomes are improved for spontaneous pregnancy rates when you excise an endometrioma.^3-6

Dr. Advincula: What are the risks of excision of an endometrioma cyst that patients need to know about?

Dr. Brown: Current standard of care is cystectomy, stripping the cyst wall away from the ovarian cortex. There is some concern that the stripping process, depending on how long the endometrioma has been present within the ovary, can cause some destruction to the underlying oocytes and perhaps impact that ovary’s ability to produce viable eggs.

Some studies, from France in particular, have investigated different energy sources, such as plasma energy, that make it possible to remove part of the cyst and then use the plasma energy to vaporize the rest of the cyst wall that may be lying on the cortex. Researchers looked at anti-Müllerian hormone levels, and there does seem to be a difference in terms of how you remove the cyst.^7-9 This energy source is not available to everyone; it’s similar to laser but does not have as much penetration. Standard of care is still ovarian stripping.

The conversation with the patient—if she is already infertile and this cyst is a problem—would be that it likely needs to be removed. There is a chance that she may need assisted reproduction; she might not be able to get pregnant on her own due either to the presence of the endometrioma or to the surgical process of removing it and stripping.

Dr. Advincula: How soon after surgery can a patient start to pursue trying to get pregnant?

Dr. Hur: I think there is no time restraint outside of recovery. As long as the patient has a routine postoperative course, she can try to conceive, spontaneously or with assisted reproduction. Some data suggest, however, that ovarian reserve is diminished immediately after surgery.^10–12 If you look at the spontaneous clinical pregnancy outcomes, they are comparable 3 to 6 months postsurgery.^4,12–14

Dr. Brown: I agree. Time is of the essence with a lot of patients, many of whom present after age 35.

Dr. Hur: It’s also important to highlight that there are 2 presentations with endometrioma: the symptomatic patient and the asymptomatic patient. In the asymptomatic patient, her age, reproductive goals, and the bilaterality (whether it is present on both sides or on one side) of the endometrioma are important in deciding on a patient-centered surgical plan. For someone with a smaller cyst, unilateral presentation, and maybe older age at presentation, it may or may not impact assisted reproductive outcomes.

If the patient is not symptomatic and she is older with bilateral endometriomas less than 4 cm, some data suggest that patient might be better served in a conservative fashion.^6,15–17 Then, once she is done with assisted reproduction, we might be more aggressive surgically by treating the finding that would not resolve spontaneously without surgical management. It is important to highlight that endometriomas do not resolve on their own; they require surgical management.

Read about managing endometriosis for the patient not seeking fertility

Endometriosis management for the patient not seeking fertility

Dr. Advincula: Let’s now consider a patient on whom you have performed laparoscopy not only to diagnose and confirm the evidence of endometriosis but also to treat endometriosis, an endometrioma, and potentially deeply infiltrative disease. But this person is not trying to get pregnant. Postoperatively, what is your approach?

Dr. Brown: Suppressive therapy for this patient could be first-line or second-line therapy, such as a Lupron Depot or Depo-Provera. We keep the patient on suppressive therapy (whatever treatments work for her), until she’s ready to get pregnant; then we take her off. Hopefully she gets pregnant. After she delivers, we reinitiate suppressive therapy. I will follow these women throughout their reproductive cycle, and I think having a team of physicians who are all on the same page can help this patient manage her disease through her reproductive years.

Dr. Hur: If a patient presented warranting surgical management once, and she is not menopausal, the likelihood that disease will recur is quite high. Understanding the nature and the pathology of the disease, hormonal suppression would be warranted. Suppression is not just for between pregnancies, it’s until the patient reaches natural menopause. It’s also in the hopes of suppressing the disease so she does not need recurrent surgeries.

We typically do not operate unless patients have recurrence of symptoms that no longer respond to medical therapy. Our hope is to buy them more time closer to the age of natural menopause so that medical repercussions do not result in hysterectomy and ovary removal, which have other nongynecologic manifestations, including negative impact on bone and cardiac health.

The role of the LNG-IUD

Dr. Advincula: Something that often comes up is the role of a levonorgestrel-releasing intrauterine device (LNG-IUD) as one therapy option, either preoperatively or postoperatively. What is your perspective?

Dr. Hur: I reserve the LNG-IUD as a second-line therapy for patients, predominantly because it allows direct delivery of the medication to the womb (rather than systemic exposure of the medication). For patients who experience adverse effects due to systemic exposure to first-line treatments, it might be a great option. However, I do not believe that it consistently suppresses the ovaries, which we understand feeds the pathology of the hormonal stimulation, and so typically I will reserve it as a second-line treatment.

Dr. Brown: I utilize the LNG-IUD in a similar fashion. I may have patients who have had a diagnostic laparoscopy somewhere else and were referred to me because they now have known stage 3 or 4 endometriosis without endometriomas. Those patients, if they are going to need suppressive therapy after surgery and are not ready to get pregnant, do very well with the LNG-IUD, and I will place it during surgery under anesthesia. If a patient has endometriomas seen at the time of surgery, we could still place an LNG-IUD at the time of surgery. We may need to add on an additional medication, however, like another oral progesterone. I do have patients that use both an IUD and either combined oral contraceptive pills and/or oral progestins. Those patients usually have complicated cases with very deep infiltrative disease.

Read about managing endometriosis involving the bowel

Managing endometriosis involving the bowel

Dr. Advincula: Patients often are quite concerned when the words “endometriosis” and “bowel” come together. How do you manage disease that involves the bowel?

Illustration: Kimberly Martens for OBG Management

Dr. Hur: A lot of patients with endometriosis have what I call neighboring disease—it’s not limited just to the pelvis, but it involves the neighboring organs including the bowel and bladder. Patients can present with symptoms related to those adjacent organs. However, not all disease involving the bowel or bladder manifests with symptoms, and patients with symptoms may not have visible disease.

Typically, when a patient presents with symptoms of bowel involvement, where the bowel lumen is narrowed to more than 50% and/or she has functional manifestations (signs of obstruction that result in abnormal bowel function), we have serious conversations about a bowel resection. If she has full-thickness disease without significant bowel dysfunction—other than blood in her stool—sometimes we talk about more conservative treatment because of the long-term manifestations that a bowel resection could have.

Dr. Brown: I agree completely. It is important to have a good relationship with our colorectal surgeons. If I suspect that the patient has narrowing of the lumen of the large bowel or she actually has symptoms such as bloody diarrhea during menstruation—which is suggestive of deep, infiltrative and penetrative disease—I will often order a colonoscopy ahead of time to get confirmed biopsies. Then the patient discussion occurs with our colorectal surgeon, who operates with me jointly if we decide to proceed with a bowel resection. It’s important to have subspecialty colleagues involved in this care, because a low anterior resection is a very big surgery and there can be down-the-stream complications.

The importance of multidisciplinary care

Dr. Advincula: What are your perspectives on a multidisciplinary or interdisciplinary approach to the patient with endometriosis?

Dr. Brown: As I previously mentioned, it is important to develop a good relationship with colorectal surgery/urology. In addition, behavioral therapists may be involved in the care of patients with endometriosis, for a number of reasons. The disease process is fluid. It will change during the patient’s reproductive years, and you need to manage it accordingly based on her symptoms. Sometimes the diagnosis is not made for 5 to 10 years, and that can lead to other issues: depression, fibromyalgia, or irritable bowel syndrome.

The patient may have multiple issues plus endometriosis. I think having specialists such as gastroenterologists and behavioral therapists on board, as well as colorectal and urological surgeons who can perform these complex surgeries, is very beneficial to the patient. That way, she benefits from the team’s focus and is cared for from start to finish.

Dr. Hur: I like to call the abdomen a studio. It does not have separate compartments for each organ system. It’s one big room, and often the neighboring organs are involved, including the bowel and bladder. I think Dr. Brown’s observation—the multidisciplinary approach to a patient’s comprehensive care—is critical. Like any surgery, preoperative planning and preoperative assessment are essential, and these steps should include the patient. The discussion should cover not only the surgical outcomes that the surgeons expect, but also what the patient expects to be improved. For example, for patients with extensive disease and bowel involvement, a bowel resection is not always the right approach because it can have potential long-term sequelae. Balancing the risks associated with surgery with the long-term benefits is an important part of the discussion.

Dr. Advincula: Those are both excellent perspectives. Endometriosis is a very complicated disease state, does require a multidisciplinary approach to management, and there are implications and strategies that involve both the medical approach to management and the surgical approach.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.