Endometriosis

Women with endometriosis often present for medical care for one or more of the following health issues: pelvic pain, infertility, and/or an adnexal cyst (endometrioma). For women with moderate or severe pelvic pain and laparoscopically diagnosed endometriosis, hormone therapy is often necessary to achieve maximal long-term reduction in pain and optimize health. I focus on opportunities to optimize hormonal treatment of endometriosis in this editorial.

When plan A is not working, move expeditiously to plan B

Cyclic or continuous combination estrogen-progestin contraceptives are commonly prescribed to treat pelvic pain caused by endometriosis. Although endometriosis pain may initially improve with estrogen-progestin contraceptives, many women on this medication will eventually report that they have worsening pelvic pain that adversely impacts their daily activities. Surprisingly, clinicians often continue to prescribe estrogen-progestin contraceptives even after the patient reports that the treatment is not effective, and their pain continues to be bothersome.

Patients benefit when they have access to the full range of hormone treatments that have been approved by the FDA for the treatment of moderate to severe pelvic pain caused by endometriosis (TABLE). In the situation where an estrogen-progestin contraceptive is no longer effective at reducing the pelvic pain, I will often offer the patient the option of norethindrone acetate (NEA) or elagolix treatment. My experience is that stopping the estrogen-progestin contraceptive and starting NEA or elagolix will result in a significant decrease in pain symptoms and improvement in the patient’s quality of life.

Continue to: Norethindrone acetate...

NEA 5 mg daily is approved by the FDA to treat endometriosis.¹ NEA was approved at a time when large controlled clinical trials were not routinely required for a medicine to be approved. The data to support NEA treatment of pelvic pain caused by endometriosis is based on cohort studies. In a study of 194 women, median age 21 years with moderate to severe pelvic pain and surgically proven endometriosis, the effect of NEA on pelvic pain was explored.² The initial dose of NEA was 5 mg daily. If the patient did not achieve a reduction in pelvic pain and amenorrhea on the NEA dose of 5 mg daily, the dose was increased by 2.5 mg every 2 weeks, up to a maximum of 15 mg, until amenorrhea and/or a decrease in pelvic pain was achieved. Ninety-five percent of the women in this cohort had previously been treated with an estrogen-progestin contraceptive or a GnRH antagonist and had discontinued those medications because of inadequate control of pelvic pain or because of side effects of the medication.

In this large cohort, 65% of women reported significant improvement in pelvic pain, with a median pain score of 5 before treatment and 0 following NEA treatment. About 55% of the women reported no side effects. The most commonly reported side effects were weight gain (16%; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%). (In this study women could report more than one side effect.)

In another cohort study of 52 women with pelvic pain and surgically confirmed endometriosis, NEA treatment resulted in pain relief in 94% of the women.³ Breakthrough bleeding was a common side effect, reported by 58% of participants. The investigators concluded that NEA treatment was a “cost-effective alternative with relatively mild side effects in the treatment of symptomatic endometriosis.” A conclusion which I endorse.

NEA has been reported to effectively treat ovarian endometriomas and rectovaginal endometriosis.^4,5 In a cohort of 18 women who had previously had the surgical resection of an ovarian endometriosis cyst and had postoperative recurrence of pelvic pain and ovarian endometriosis, treatment was initiated with an escalating NEA regimen.⁴ Treatment was initiated with NEA 5 mg daily, with the dosage increased every 2 weeks by 2.5 mg until amenorrhea was established. Most women achieved amenorrhea with NEA 5 mg daily, and 89% had reduced pelvic pain. The investigators reported complete regression of the endometriosis cyst(s) in 74% of the women. In my experience, NEA does not result in complete regression of endometriosis cysts, but it does cause a reduction in cyst diameter and total volume.

In a retrospective cohort study, 61 women with pelvic pain and rectovaginal endometriosis had 5 years of treatment with NEA 2.5 mg or 5.0 mg daily.⁵ NEA treatment resulted in a decrease in dysmenorrhea, deep dyspareunia, and dyschezia. The most common side effects attributed to NEA treatment were weight gain (30%), vaginal bleeding (23%), decreased libido (11%), headache (9%), bloating or swelling (8%), depression (7%), and acne (5%). In women who had sequential imaging studies, NEA treatment resulted in a decrease in rectovaginal lesion volume, stable disease volume, or an increase in lesion volume in 56%, 32%, and 12% of the women, respectively. The investigators concluded that for women with rectovaginal endometriosis, NEA treatment is a low-cost option for long-term treatment.

In my practice, I do not prescribe NEA at doses greater than 5 mg daily. There are case reports that NEA at a dose of ≥10 mg daily is associated with the development of a hepatic adenoma,⁶ elevated liver transaminase concentration,⁷ and jaundice.⁸ If NEA 5 mg daily is not effective in controlling pelvic pain caused by endometriosis, I stop the NEA and start a GnRH analogue, most often elagolix.

NEA 5 mg is not FDA approved as a contraceptive. However, norethindrone 0.35 mg daily, also known as the “mini-pill”, is approved as a progestin-only contraceptive.⁹ NEA is rapidly and completely deacetylated to norethindrone, and the disposition of oral NEA is indistinguishable from that of norethindrone.¹ Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg has contraceptive properties if taken daily.

Continue to: Elagolix...

Elagolix

Elagolix is FDA approved for the treatment of pelvic pain caused by endometriosis. I reviewed the key studies resulting in FDA approval in the November 2018 issue of OBG Management.¹⁰

In the Elaris Endometriosis-I study, 872 women with endometriosis and pelvic pain were randomly assigned to treatment with 1 of 2 doses of elagolix (high-dose [200 mg twice daily] and low-dose [150 mg once daily]) or placebo.¹¹ After 3 months of therapy, a clinically meaningful reduction in dysmenorrhea pain was reported by 76%, 46%, and 20% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.001 for comparisons of elagolix to placebo). After 3 months of therapy, a clinically meaningful reduction in nonmenstrual pain or decreased or stable use of rescue analgesics was reported by 55%, 50%, and 37% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.01 low-dose elagolix vs placebo and P<.001 high-dose elagolix vs placebo).

Hot flashes that were severe enough to be reported as an adverse event by the study participants were reported by 42%, 24%, and 7% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups. 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 elagolix, low-dose elagolix, and placebo groups, respectively.

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

In my 2018 review,¹⁰ I noted that elagolix dose adjustment can be utilized to attempt to achieve maximal pain relief with minimal vasomotor symptoms. Elagolix at 200 mg twice daily produces a mean estradiol concentration of 12 pg/mL, whereas elagolix at 150 mg daily resulted in a mean estradiol concentration of 41 pg/mL.¹³ The estrogen threshold hypothesis posits that in women with endometriosis a stable estradiol concentration of 20 to 30 pg/mL is often associated with decreased pain and fewer vasomotor events.¹⁴ To achieve the target estradiol range of 20 to 30 pg/mL, I often initiate elagolix treatment with 200 mg twice daily. This enables a rapid onset of amenorrhea and a reduction in pelvic pain. Once amenorrhea has been achieved and a decrease in pelvic pain has occurred, I adjust the dose downward to 200 mg twice daily on even calendar days of each month and 200 mg once daily on odd calendar days each month. Some women will have continued pain relief and amenorrhea when the dose is further decreased to 200 mg once daily. If bothersome bleeding recurs and/or pain symptoms increase in severity, the dose can be increased to 200 mg twice daily or an alternating regimen of 200 mg twice daily and 200 mg once daily, every 2 days. An alternative to dose adjustment is to combine elagolix with NEA, which can reduce the severity of hot flashes and reduce bone loss caused by hypoestrogenism.^15,16

Health insurers and pharmacy benefits managers may require a prior authorization before approving and dispensing elagolix. The prior authorization process can be burdensome for clinicians, consuming limited healthcare resources, contributing to burnout and frustrating patients.¹⁷ Elagolix is less expensive than depot-leuprolide acetate and nafarelin nasal spray and somewhat more expensive than a goserelin implant.^18,19

Elagolix is not approved as a contraceptive. In the Elaris EM-I and -II trials women were advised to use 2 forms of contraception, although pregnancies did occur. There were 6 pregnancies among 475 women taking elagolix 150 mg daily and 2 pregnancies among 477 women taking elagolix 200 mg twice daily.²⁰ Women taking elagolix should be advised to use a contraceptive, but not an estrogen-progestin contraceptive.

Continue to: Do not use opioids to treat chronic pelvic pain caused by endometriosis...

Do not use opioids to treat chronic pelvic pain caused by endometriosis

One of the greatest public health tragedies of our era is the opioid misuse epidemic. Hundreds of thousands of deaths have been caused by opioid misuse. The Centers for Disease Control and Prevention reported that for the 12-month period ending in May 2020, there were 81,000 opioid-related deaths, the greatest number ever reported in a 12-month period.²¹ Many authorities believe that in the United States opioid medications have been over-prescribed, contributing to the opioid misuse epidemic. There is little evidence that chronic pelvic pain is optimally managed by chronic treatment with an opioid.^22,23 Prescribing opioids to vulnerable individuals to treat chronic pelvic pain may result in opioid dependency and adversely affect the patient’s health. It is best to pledge not to prescribe an opioid medication for a woman with chronic pelvic pain caused by endometriosis. In situations when pelvic pain is difficult to control with hormonal therapy and nonopioid pain medications, referral to a specialty pain practice may be warranted.

Post–conservative surgery hormone treatment reduces pelvic pain recurrence

In a meta-analysis of 14 studies that reported on endometriosis recurrence rates following conservative surgery, recurrence (defined as recurrent pelvic pain or an imaging study showing recurrent endometriosis) was significantly reduced with the use of hormone treatment compared with expectant management or placebo treatment.²⁴ The postoperative relative risk of endometriosis recurrence was reduced by 83% with progestin treatment, 64% with estrogen-progestin contraceptive treatment, and 38% with GnRH analogue treatment. Overall, the number of patients that needed to be treated to prevent one endometriosis recurrence was 10, assuming a recurrence rate of 25% in the placebo treatment or expectant management groups.

For women with pelvic pain caused by endometriosis who develop a recurrence of pelvic pain while on postoperative hormone treatment, it is important for the prescribing clinician to be flexible and consider changing the hormone regimen. For example, if a postoperative patient is treated with a continuous estrogen-progestin contraceptive and develops recurrent pain, I will stop the contraceptive and initiate treatment with either NEA or elagolix.

Capitalize on opportunities to improve the medical care of women with endometriosis

Early diagnosis of endometriosis can be facilitated by recognizing that the condition is a common cause of moderate to severe dysmenorrhea. In 5 studies involving 1,187 women, the mean length of time from onset of pelvic pain symptoms to diagnosis of endometriosis was 8.6 years.²⁵ If a woman with pelvic pain caused by endometriosis has not had sufficient pain relief with one brand of continuous estrogen-progestin contraceptive, it is best not to prescribe an alternative brand but rather to switch to a progestin-only treatment or a GnRH antagonist. If plan A is not working, move expeditiously to plan B. ●

Women with endometriosis often present for medical care for one or more of the following health issues: pelvic pain, infertility, and/or an adnexal cyst (endometrioma). For women with moderate or severe pelvic pain and laparoscopically diagnosed endometriosis, hormone therapy is often necessary to achieve maximal long-term reduction in pain and optimize health. I focus on opportunities to optimize hormonal treatment of endometriosis in this editorial.

When plan A is not working, move expeditiously to plan B

Cyclic or continuous combination estrogen-progestin contraceptives are commonly prescribed to treat pelvic pain caused by endometriosis. Although endometriosis pain may initially improve with estrogen-progestin contraceptives, many women on this medication will eventually report that they have worsening pelvic pain that adversely impacts their daily activities. Surprisingly, clinicians often continue to prescribe estrogen-progestin contraceptives even after the patient reports that the treatment is not effective, and their pain continues to be bothersome.

Patients benefit when they have access to the full range of hormone treatments that have been approved by the FDA for the treatment of moderate to severe pelvic pain caused by endometriosis (TABLE). In the situation where an estrogen-progestin contraceptive is no longer effective at reducing the pelvic pain, I will often offer the patient the option of norethindrone acetate (NEA) or elagolix treatment. My experience is that stopping the estrogen-progestin contraceptive and starting NEA or elagolix will result in a significant decrease in pain symptoms and improvement in the patient’s quality of life.

Continue to: Norethindrone acetate...

NEA 5 mg daily is approved by the FDA to treat endometriosis.¹ NEA was approved at a time when large controlled clinical trials were not routinely required for a medicine to be approved. The data to support NEA treatment of pelvic pain caused by endometriosis is based on cohort studies. In a study of 194 women, median age 21 years with moderate to severe pelvic pain and surgically proven endometriosis, the effect of NEA on pelvic pain was explored.² The initial dose of NEA was 5 mg daily. If the patient did not achieve a reduction in pelvic pain and amenorrhea on the NEA dose of 5 mg daily, the dose was increased by 2.5 mg every 2 weeks, up to a maximum of 15 mg, until amenorrhea and/or a decrease in pelvic pain was achieved. Ninety-five percent of the women in this cohort had previously been treated with an estrogen-progestin contraceptive or a GnRH antagonist and had discontinued those medications because of inadequate control of pelvic pain or because of side effects of the medication.

In this large cohort, 65% of women reported significant improvement in pelvic pain, with a median pain score of 5 before treatment and 0 following NEA treatment. About 55% of the women reported no side effects. The most commonly reported side effects were weight gain (16%; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%). (In this study women could report more than one side effect.)

In another cohort study of 52 women with pelvic pain and surgically confirmed endometriosis, NEA treatment resulted in pain relief in 94% of the women.³ Breakthrough bleeding was a common side effect, reported by 58% of participants. The investigators concluded that NEA treatment was a “cost-effective alternative with relatively mild side effects in the treatment of symptomatic endometriosis.” A conclusion which I endorse.

NEA has been reported to effectively treat ovarian endometriomas and rectovaginal endometriosis.^4,5 In a cohort of 18 women who had previously had the surgical resection of an ovarian endometriosis cyst and had postoperative recurrence of pelvic pain and ovarian endometriosis, treatment was initiated with an escalating NEA regimen.⁴ Treatment was initiated with NEA 5 mg daily, with the dosage increased every 2 weeks by 2.5 mg until amenorrhea was established. Most women achieved amenorrhea with NEA 5 mg daily, and 89% had reduced pelvic pain. The investigators reported complete regression of the endometriosis cyst(s) in 74% of the women. In my experience, NEA does not result in complete regression of endometriosis cysts, but it does cause a reduction in cyst diameter and total volume.

In a retrospective cohort study, 61 women with pelvic pain and rectovaginal endometriosis had 5 years of treatment with NEA 2.5 mg or 5.0 mg daily.⁵ NEA treatment resulted in a decrease in dysmenorrhea, deep dyspareunia, and dyschezia. The most common side effects attributed to NEA treatment were weight gain (30%), vaginal bleeding (23%), decreased libido (11%), headache (9%), bloating or swelling (8%), depression (7%), and acne (5%). In women who had sequential imaging studies, NEA treatment resulted in a decrease in rectovaginal lesion volume, stable disease volume, or an increase in lesion volume in 56%, 32%, and 12% of the women, respectively. The investigators concluded that for women with rectovaginal endometriosis, NEA treatment is a low-cost option for long-term treatment.

In my practice, I do not prescribe NEA at doses greater than 5 mg daily. There are case reports that NEA at a dose of ≥10 mg daily is associated with the development of a hepatic adenoma,⁶ elevated liver transaminase concentration,⁷ and jaundice.⁸ If NEA 5 mg daily is not effective in controlling pelvic pain caused by endometriosis, I stop the NEA and start a GnRH analogue, most often elagolix.

NEA 5 mg is not FDA approved as a contraceptive. However, norethindrone 0.35 mg daily, also known as the “mini-pill”, is approved as a progestin-only contraceptive.⁹ NEA is rapidly and completely deacetylated to norethindrone, and the disposition of oral NEA is indistinguishable from that of norethindrone.¹ Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg has contraceptive properties if taken daily.

Continue to: Elagolix...

Elagolix

Elagolix is FDA approved for the treatment of pelvic pain caused by endometriosis. I reviewed the key studies resulting in FDA approval in the November 2018 issue of OBG Management.¹⁰

In the Elaris Endometriosis-I study, 872 women with endometriosis and pelvic pain were randomly assigned to treatment with 1 of 2 doses of elagolix (high-dose [200 mg twice daily] and low-dose [150 mg once daily]) or placebo.¹¹ After 3 months of therapy, a clinically meaningful reduction in dysmenorrhea pain was reported by 76%, 46%, and 20% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.001 for comparisons of elagolix to placebo). After 3 months of therapy, a clinically meaningful reduction in nonmenstrual pain or decreased or stable use of rescue analgesics was reported by 55%, 50%, and 37% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.01 low-dose elagolix vs placebo and P<.001 high-dose elagolix vs placebo).

Hot flashes that were severe enough to be reported as an adverse event by the study participants were reported by 42%, 24%, and 7% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups. 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 elagolix, low-dose elagolix, and placebo groups, respectively.

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

In my 2018 review,¹⁰ I noted that elagolix dose adjustment can be utilized to attempt to achieve maximal pain relief with minimal vasomotor symptoms. Elagolix at 200 mg twice daily produces a mean estradiol concentration of 12 pg/mL, whereas elagolix at 150 mg daily resulted in a mean estradiol concentration of 41 pg/mL.¹³ The estrogen threshold hypothesis posits that in women with endometriosis a stable estradiol concentration of 20 to 30 pg/mL is often associated with decreased pain and fewer vasomotor events.¹⁴ To achieve the target estradiol range of 20 to 30 pg/mL, I often initiate elagolix treatment with 200 mg twice daily. This enables a rapid onset of amenorrhea and a reduction in pelvic pain. Once amenorrhea has been achieved and a decrease in pelvic pain has occurred, I adjust the dose downward to 200 mg twice daily on even calendar days of each month and 200 mg once daily on odd calendar days each month. Some women will have continued pain relief and amenorrhea when the dose is further decreased to 200 mg once daily. If bothersome bleeding recurs and/or pain symptoms increase in severity, the dose can be increased to 200 mg twice daily or an alternating regimen of 200 mg twice daily and 200 mg once daily, every 2 days. An alternative to dose adjustment is to combine elagolix with NEA, which can reduce the severity of hot flashes and reduce bone loss caused by hypoestrogenism.^15,16

Health insurers and pharmacy benefits managers may require a prior authorization before approving and dispensing elagolix. The prior authorization process can be burdensome for clinicians, consuming limited healthcare resources, contributing to burnout and frustrating patients.¹⁷ Elagolix is less expensive than depot-leuprolide acetate and nafarelin nasal spray and somewhat more expensive than a goserelin implant.^18,19

Elagolix is not approved as a contraceptive. In the Elaris EM-I and -II trials women were advised to use 2 forms of contraception, although pregnancies did occur. There were 6 pregnancies among 475 women taking elagolix 150 mg daily and 2 pregnancies among 477 women taking elagolix 200 mg twice daily.²⁰ Women taking elagolix should be advised to use a contraceptive, but not an estrogen-progestin contraceptive.

Continue to: Do not use opioids to treat chronic pelvic pain caused by endometriosis...

Do not use opioids to treat chronic pelvic pain caused by endometriosis

One of the greatest public health tragedies of our era is the opioid misuse epidemic. Hundreds of thousands of deaths have been caused by opioid misuse. The Centers for Disease Control and Prevention reported that for the 12-month period ending in May 2020, there were 81,000 opioid-related deaths, the greatest number ever reported in a 12-month period.²¹ Many authorities believe that in the United States opioid medications have been over-prescribed, contributing to the opioid misuse epidemic. There is little evidence that chronic pelvic pain is optimally managed by chronic treatment with an opioid.^22,23 Prescribing opioids to vulnerable individuals to treat chronic pelvic pain may result in opioid dependency and adversely affect the patient’s health. It is best to pledge not to prescribe an opioid medication for a woman with chronic pelvic pain caused by endometriosis. In situations when pelvic pain is difficult to control with hormonal therapy and nonopioid pain medications, referral to a specialty pain practice may be warranted.

Post–conservative surgery hormone treatment reduces pelvic pain recurrence

In a meta-analysis of 14 studies that reported on endometriosis recurrence rates following conservative surgery, recurrence (defined as recurrent pelvic pain or an imaging study showing recurrent endometriosis) was significantly reduced with the use of hormone treatment compared with expectant management or placebo treatment.²⁴ The postoperative relative risk of endometriosis recurrence was reduced by 83% with progestin treatment, 64% with estrogen-progestin contraceptive treatment, and 38% with GnRH analogue treatment. Overall, the number of patients that needed to be treated to prevent one endometriosis recurrence was 10, assuming a recurrence rate of 25% in the placebo treatment or expectant management groups.

For women with pelvic pain caused by endometriosis who develop a recurrence of pelvic pain while on postoperative hormone treatment, it is important for the prescribing clinician to be flexible and consider changing the hormone regimen. For example, if a postoperative patient is treated with a continuous estrogen-progestin contraceptive and develops recurrent pain, I will stop the contraceptive and initiate treatment with either NEA or elagolix.

Capitalize on opportunities to improve the medical care of women with endometriosis

Early diagnosis of endometriosis can be facilitated by recognizing that the condition is a common cause of moderate to severe dysmenorrhea. In 5 studies involving 1,187 women, the mean length of time from onset of pelvic pain symptoms to diagnosis of endometriosis was 8.6 years.²⁵ If a woman with pelvic pain caused by endometriosis has not had sufficient pain relief with one brand of continuous estrogen-progestin contraceptive, it is best not to prescribe an alternative brand but rather to switch to a progestin-only treatment or a GnRH antagonist. If plan A is not working, move expeditiously to plan B. ●

Women with endometriosis often present for medical care for one or more of the following health issues: pelvic pain, infertility, and/or an adnexal cyst (endometrioma). For women with moderate or severe pelvic pain and laparoscopically diagnosed endometriosis, hormone therapy is often necessary to achieve maximal long-term reduction in pain and optimize health. I focus on opportunities to optimize hormonal treatment of endometriosis in this editorial.

When plan A is not working, move expeditiously to plan B

Cyclic or continuous combination estrogen-progestin contraceptives are commonly prescribed to treat pelvic pain caused by endometriosis. Although endometriosis pain may initially improve with estrogen-progestin contraceptives, many women on this medication will eventually report that they have worsening pelvic pain that adversely impacts their daily activities. Surprisingly, clinicians often continue to prescribe estrogen-progestin contraceptives even after the patient reports that the treatment is not effective, and their pain continues to be bothersome.

Patients benefit when they have access to the full range of hormone treatments that have been approved by the FDA for the treatment of moderate to severe pelvic pain caused by endometriosis (TABLE). In the situation where an estrogen-progestin contraceptive is no longer effective at reducing the pelvic pain, I will often offer the patient the option of norethindrone acetate (NEA) or elagolix treatment. My experience is that stopping the estrogen-progestin contraceptive and starting NEA or elagolix will result in a significant decrease in pain symptoms and improvement in the patient’s quality of life.

Continue to: Norethindrone acetate...

NEA 5 mg daily is approved by the FDA to treat endometriosis.¹ NEA was approved at a time when large controlled clinical trials were not routinely required for a medicine to be approved. The data to support NEA treatment of pelvic pain caused by endometriosis is based on cohort studies. In a study of 194 women, median age 21 years with moderate to severe pelvic pain and surgically proven endometriosis, the effect of NEA on pelvic pain was explored.² The initial dose of NEA was 5 mg daily. If the patient did not achieve a reduction in pelvic pain and amenorrhea on the NEA dose of 5 mg daily, the dose was increased by 2.5 mg every 2 weeks, up to a maximum of 15 mg, until amenorrhea and/or a decrease in pelvic pain was achieved. Ninety-five percent of the women in this cohort had previously been treated with an estrogen-progestin contraceptive or a GnRH antagonist and had discontinued those medications because of inadequate control of pelvic pain or because of side effects of the medication.

In this large cohort, 65% of women reported significant improvement in pelvic pain, with a median pain score of 5 before treatment and 0 following NEA treatment. About 55% of the women reported no side effects. The most commonly reported side effects were weight gain (16%; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%). (In this study women could report more than one side effect.)

In another cohort study of 52 women with pelvic pain and surgically confirmed endometriosis, NEA treatment resulted in pain relief in 94% of the women.³ Breakthrough bleeding was a common side effect, reported by 58% of participants. The investigators concluded that NEA treatment was a “cost-effective alternative with relatively mild side effects in the treatment of symptomatic endometriosis.” A conclusion which I endorse.

NEA has been reported to effectively treat ovarian endometriomas and rectovaginal endometriosis.^4,5 In a cohort of 18 women who had previously had the surgical resection of an ovarian endometriosis cyst and had postoperative recurrence of pelvic pain and ovarian endometriosis, treatment was initiated with an escalating NEA regimen.⁴ Treatment was initiated with NEA 5 mg daily, with the dosage increased every 2 weeks by 2.5 mg until amenorrhea was established. Most women achieved amenorrhea with NEA 5 mg daily, and 89% had reduced pelvic pain. The investigators reported complete regression of the endometriosis cyst(s) in 74% of the women. In my experience, NEA does not result in complete regression of endometriosis cysts, but it does cause a reduction in cyst diameter and total volume.

In a retrospective cohort study, 61 women with pelvic pain and rectovaginal endometriosis had 5 years of treatment with NEA 2.5 mg or 5.0 mg daily.⁵ NEA treatment resulted in a decrease in dysmenorrhea, deep dyspareunia, and dyschezia. The most common side effects attributed to NEA treatment were weight gain (30%), vaginal bleeding (23%), decreased libido (11%), headache (9%), bloating or swelling (8%), depression (7%), and acne (5%). In women who had sequential imaging studies, NEA treatment resulted in a decrease in rectovaginal lesion volume, stable disease volume, or an increase in lesion volume in 56%, 32%, and 12% of the women, respectively. The investigators concluded that for women with rectovaginal endometriosis, NEA treatment is a low-cost option for long-term treatment.

In my practice, I do not prescribe NEA at doses greater than 5 mg daily. There are case reports that NEA at a dose of ≥10 mg daily is associated with the development of a hepatic adenoma,⁶ elevated liver transaminase concentration,⁷ and jaundice.⁸ If NEA 5 mg daily is not effective in controlling pelvic pain caused by endometriosis, I stop the NEA and start a GnRH analogue, most often elagolix.

NEA 5 mg is not FDA approved as a contraceptive. However, norethindrone 0.35 mg daily, also known as the “mini-pill”, is approved as a progestin-only contraceptive.⁹ NEA is rapidly and completely deacetylated to norethindrone, and the disposition of oral NEA is indistinguishable from that of norethindrone.¹ Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg has contraceptive properties if taken daily.

Continue to: Elagolix...

Elagolix

Elagolix is FDA approved for the treatment of pelvic pain caused by endometriosis. I reviewed the key studies resulting in FDA approval in the November 2018 issue of OBG Management.¹⁰

In the Elaris Endometriosis-I study, 872 women with endometriosis and pelvic pain were randomly assigned to treatment with 1 of 2 doses of elagolix (high-dose [200 mg twice daily] and low-dose [150 mg once daily]) or placebo.¹¹ After 3 months of therapy, a clinically meaningful reduction in dysmenorrhea pain was reported by 76%, 46%, and 20% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.001 for comparisons of elagolix to placebo). After 3 months of therapy, a clinically meaningful reduction in nonmenstrual pain or decreased or stable use of rescue analgesics was reported by 55%, 50%, and 37% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.01 low-dose elagolix vs placebo and P<.001 high-dose elagolix vs placebo).

Hot flashes that were severe enough to be reported as an adverse event by the study participants were reported by 42%, 24%, and 7% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups. 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 elagolix, low-dose elagolix, and placebo groups, respectively.

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

In my 2018 review,¹⁰ I noted that elagolix dose adjustment can be utilized to attempt to achieve maximal pain relief with minimal vasomotor symptoms. Elagolix at 200 mg twice daily produces a mean estradiol concentration of 12 pg/mL, whereas elagolix at 150 mg daily resulted in a mean estradiol concentration of 41 pg/mL.¹³ The estrogen threshold hypothesis posits that in women with endometriosis a stable estradiol concentration of 20 to 30 pg/mL is often associated with decreased pain and fewer vasomotor events.¹⁴ To achieve the target estradiol range of 20 to 30 pg/mL, I often initiate elagolix treatment with 200 mg twice daily. This enables a rapid onset of amenorrhea and a reduction in pelvic pain. Once amenorrhea has been achieved and a decrease in pelvic pain has occurred, I adjust the dose downward to 200 mg twice daily on even calendar days of each month and 200 mg once daily on odd calendar days each month. Some women will have continued pain relief and amenorrhea when the dose is further decreased to 200 mg once daily. If bothersome bleeding recurs and/or pain symptoms increase in severity, the dose can be increased to 200 mg twice daily or an alternating regimen of 200 mg twice daily and 200 mg once daily, every 2 days. An alternative to dose adjustment is to combine elagolix with NEA, which can reduce the severity of hot flashes and reduce bone loss caused by hypoestrogenism.^15,16

Health insurers and pharmacy benefits managers may require a prior authorization before approving and dispensing elagolix. The prior authorization process can be burdensome for clinicians, consuming limited healthcare resources, contributing to burnout and frustrating patients.¹⁷ Elagolix is less expensive than depot-leuprolide acetate and nafarelin nasal spray and somewhat more expensive than a goserelin implant.^18,19

Elagolix is not approved as a contraceptive. In the Elaris EM-I and -II trials women were advised to use 2 forms of contraception, although pregnancies did occur. There were 6 pregnancies among 475 women taking elagolix 150 mg daily and 2 pregnancies among 477 women taking elagolix 200 mg twice daily.²⁰ Women taking elagolix should be advised to use a contraceptive, but not an estrogen-progestin contraceptive.

Continue to: Do not use opioids to treat chronic pelvic pain caused by endometriosis...

Do not use opioids to treat chronic pelvic pain caused by endometriosis

One of the greatest public health tragedies of our era is the opioid misuse epidemic. Hundreds of thousands of deaths have been caused by opioid misuse. The Centers for Disease Control and Prevention reported that for the 12-month period ending in May 2020, there were 81,000 opioid-related deaths, the greatest number ever reported in a 12-month period.²¹ Many authorities believe that in the United States opioid medications have been over-prescribed, contributing to the opioid misuse epidemic. There is little evidence that chronic pelvic pain is optimally managed by chronic treatment with an opioid.^22,23 Prescribing opioids to vulnerable individuals to treat chronic pelvic pain may result in opioid dependency and adversely affect the patient’s health. It is best to pledge not to prescribe an opioid medication for a woman with chronic pelvic pain caused by endometriosis. In situations when pelvic pain is difficult to control with hormonal therapy and nonopioid pain medications, referral to a specialty pain practice may be warranted.

Post–conservative surgery hormone treatment reduces pelvic pain recurrence

In a meta-analysis of 14 studies that reported on endometriosis recurrence rates following conservative surgery, recurrence (defined as recurrent pelvic pain or an imaging study showing recurrent endometriosis) was significantly reduced with the use of hormone treatment compared with expectant management or placebo treatment.²⁴ The postoperative relative risk of endometriosis recurrence was reduced by 83% with progestin treatment, 64% with estrogen-progestin contraceptive treatment, and 38% with GnRH analogue treatment. Overall, the number of patients that needed to be treated to prevent one endometriosis recurrence was 10, assuming a recurrence rate of 25% in the placebo treatment or expectant management groups.

For women with pelvic pain caused by endometriosis who develop a recurrence of pelvic pain while on postoperative hormone treatment, it is important for the prescribing clinician to be flexible and consider changing the hormone regimen. For example, if a postoperative patient is treated with a continuous estrogen-progestin contraceptive and develops recurrent pain, I will stop the contraceptive and initiate treatment with either NEA or elagolix.

Capitalize on opportunities to improve the medical care of women with endometriosis

Early diagnosis of endometriosis can be facilitated by recognizing that the condition is a common cause of moderate to severe dysmenorrhea. In 5 studies involving 1,187 women, the mean length of time from onset of pelvic pain symptoms to diagnosis of endometriosis was 8.6 years.²⁵ If a woman with pelvic pain caused by endometriosis has not had sufficient pain relief with one brand of continuous estrogen-progestin contraceptive, it is best not to prescribe an alternative brand but rather to switch to a progestin-only treatment or a GnRH antagonist. If plan A is not working, move expeditiously to plan B. ●

Can you provide some background on endometriosis and the importance of early diagnosis?

Dr. Goldstein: Endometriosis is an inflammatory condition, characterized by endometrial tissue at sites outside the uterus—this definition comes from the World Endometriosis Society.

Endometriosis is said to affect about 10% of women of reproductive age, and if you look at a group, a subset of women with pelvic pain or infertility, the numbers rise to the range of 35% to 50%. It can present in a multitude of locations, mainly in the pelvis, although occasionally even in places like the lung. When it occurs in the uterus, it is known as adenomyosis; when it occurs inside the ovary, it can cause an endometrioma (or what is sometimes referred to as chocolate cyst of the ovary), but you can see endometriotic implants anywhere in the peritoneum—along the urinary tract, rectum, uterosacral ligaments, rectovaginal septum, and even the vaginal wall occasionally.

What I am really interested in is an earlier diagnosis of superficial endometriosis, and it should be apparent to the reader why this is important—the quality of life from pain from endometriosis can be debilitating. It can be a source of infertility, a source of menstrual irregularities, and a source of not only quality of life but also economic consequences. Many women can also undergo as much as a 7-year delay in diagnosis, so the need for a timely diagnosis and initiation of treatment is extremely important.

What is the role of ultrasound in endometriosis diagnostics?

Dr. Goldstein: In an article that I authored 31 years ago, I wrote that there was a difference between an ultrasound examination by referral and examining one’s patients with ultrasound. I coined a phrase: the “ultrasound-enhanced bimanual exam.” I believed that this term should become a routine part of the overall gynecologic exam. I wanted people to think about the bimanual that we had done for at least half a century, which, in my opinion, consists of 2 components:

1. An objective component: Is this uterus normal? Is it enlarged or irregular in contour, suggesting maybe fibroids? Is an ovary enlarged? If so, does it feel cystic or solid?
2. A subjective component: Does this patient have tenderness through the pelvis. Is there normal mobility of the pelvic organs?

Part of the thesis was that the objective portion could be replaced by an image that could be produced in seconds, dependent on the operator’s training and availability of equipment. The subjective portion, however, depended on the experience and, often, nuance of the examiner. Lately, I have been seeking to expand that thesis by having the imager use examination as part of their overall imaging—this is the concept of dynamic imaging.

Can you expand on the concept of dynamic ultrasound in this setting?

Dr. Goldstein: Presently, most imagers take a multitude of pictures, what I would call 2-dimensional snapshots, to illustrate anatomy. This is usually done by a sonographer, or a technician, who collects the images for viewing by the physician, who then often does so without holding the transducer. Increasing utilization of remote tools like teleradiology only makes this more likely, and for a minority of people who may use video clips instead of still images, they are still simply representations of anatomy. The guidelines for pelvic ultrasound are the underpinning of the expectation of those who are scanning the female pelvis. With dynamic imaging, the operator uses their other hand on the abdomen as well as some motion with the probe to see if they can elicit pain with the vaginal probe, checking for mobility, asking the patient to bear down. Whether you are a sonographer, a radiologist, or an ObGyn, dynamic imaging can bring the examination process into the imager’s hands.

Can you tell us more about the indications for pelvic sonography for endometriosis and what data can you give to support this?

Dr. Goldstein: There is a document titled “Ultrasound Examination of the Female Pelvis,” that was originally developed by the American Institute of Ultrasound in Medicine (AIUM). In this document, there are about 19 different indications for pelvic sonography (in no defined order), and it is interesting that the first indication listed is evaluation of pelvic pain. Well, I would ask you, how do you evaluate pelvic pain with a series of anatomic images? If you have a classic ovarian endometrioma, or you have a classic hydrosalpinx, you can surmise that these are the source of the pain that the patient is reporting. But how do you properly evaluate pain with just an anatomic image? Thus, the need to use dynamic assessment.

There was a concept first introduced by my colleague, Dr. Ilan Timor, known as the sliding organ sign, that was mainly used to determine if 2 structures were adherent or separate. This involved use of the abdominal hand, liberal use of the probe moving in and out, and under real-time vision, examining the patient with the ultrasound transducer; this is the concept of dynamic ultrasound. This practice can be expanded to verify if there is pelvic tenderness and can be a significant part of the nonlaparoscopic, presumptive diagnosis of endometriosis, even when there is no ovarian endometrioma.

To support this theory, I would point you toward a classic article by E Okaro and colleagues in the British Journal of OB-GYN. This study took 120 consecutive women with chronic pelvic pain who were scheduled for laparoscopy, but performed a transvaginal ultrasound prior, and they looked for anatomic abnormalities and divided this into hard markers and soft markers. Hard markers were obvious endometriomas and hydrosalpinges, while soft markers included things like reduced ovarian mobility, site-specific pelvic tenderness, and presence of loculated peritoneal fluid in the pelvis. These were typical of chronic pelvic pain patients that ranged from late teens to almost menopausal, as the average age was about 30 years old.

Patients had experienced pain for anywhere from 6 months to 12 years, but the average was about 4 years. At laparoscopy, 58% of these patients had pelvic pathology, and 42% had a normal pelvis. Of the 58% with pathology, the overwhelming majority—about 51 of 70 women—had endometriosis alone, and another 7 had endometriosis with adhesions. A normal ultrasound, based on the absence of hard markers, was found in 96 of 120 women. Thus, 24 of the 120 women had an abnormal scan based on the presence of these hard markers. At laparoscopy, all 24 women had abnormal laparoscopies. Of those 96 women who would have had a normal ultrasound, based on the anatomic absence of some pathology, 53% had an abnormal scan based on the presence of these soft markers while the remaining women had no soft- or hard-markers suggesting any pelvic pathology. At laparoscopy, 73% of the patients with soft markers had pelvic pathology and 27% had a normal laparoscopy. Of 45 patients who had a normal, transvaginal ultrasound, 9 were found to have small evidence of endometriosis without discrete endometriomas at laparoscopy.

To summarize the study data, 100% of patients with hard markers and chronic pelvic pain had abnormal anatomy at laparoscopy, but 73% of patients who had soft markers but otherwise would have been interpreted as normal anatomic findings had evidence of pelvic pathology. Such an approach, if used, could lead to a reduction in the number of unnecessary laparoscopies.

What it really boils down to is, if you have 100 women with chronic pelvic pain, are you willing to treat 100 patients without laparoscopy, knowing that 73 are going to have a positive laparoscopy and will require treatment anyway? You would treat 27% with a pharmaceutical agent that may provide relief of their pain, or may not, depending on what the true etiology was. I would be willing to do so, as a positive predictive value of 73% makes doing that worthwhile, and I believe a majority of clinicians would agree.

Do you have any other tips or ways to improve the reader’s understanding of transvaginal ultrasound?

Dr. Goldstein: Pelvic organs have mobility. If a premenopausal woman is examined in lithotomy position, if the ovaries are freely mobile, by gravity, they are going to go lateral to the uterus and are seen immediately adjacent to the iliac vessels. But remember, iliac vessels are retroperitoneal as they are outside the peritoneal cavity. If you were to turn that patient onto all fours, so that the ovaries are freely mobile, they are going to move somewhat toward the anterior abdominal wall. When an ovary is seen in a nonanatomic position, it could be normal or it could be held up by a loop of bowel, but it may indicate adhesions. This is where this sliding organ sign and liberal use of the other hand on the lower abdomen can be extremely important. The reader should also understand that our ability to localize ovaries on ultrasound depends on the amount of folliculogenesis. Follicles are black circles that are sonolucent, because they contain fluid, so they make it easy to localize ovaries, but also their anatomic position relative to the iliac vessels. However, there is a caveat—which is, sometimes an ovary might look like it is behind the uterus and not in its normal anatomic location. When dynamic imaging is used, you are able to cajole that ovary to move lateral and sit on top of the iliac vessels, which can enable you make the proper diagnosis.

Can you provide some background on endometriosis and the importance of early diagnosis?

Dr. Goldstein: Endometriosis is an inflammatory condition, characterized by endometrial tissue at sites outside the uterus—this definition comes from the World Endometriosis Society.

Endometriosis is said to affect about 10% of women of reproductive age, and if you look at a group, a subset of women with pelvic pain or infertility, the numbers rise to the range of 35% to 50%. It can present in a multitude of locations, mainly in the pelvis, although occasionally even in places like the lung. When it occurs in the uterus, it is known as adenomyosis; when it occurs inside the ovary, it can cause an endometrioma (or what is sometimes referred to as chocolate cyst of the ovary), but you can see endometriotic implants anywhere in the peritoneum—along the urinary tract, rectum, uterosacral ligaments, rectovaginal septum, and even the vaginal wall occasionally.

What I am really interested in is an earlier diagnosis of superficial endometriosis, and it should be apparent to the reader why this is important—the quality of life from pain from endometriosis can be debilitating. It can be a source of infertility, a source of menstrual irregularities, and a source of not only quality of life but also economic consequences. Many women can also undergo as much as a 7-year delay in diagnosis, so the need for a timely diagnosis and initiation of treatment is extremely important.

What is the role of ultrasound in endometriosis diagnostics?

Dr. Goldstein: In an article that I authored 31 years ago, I wrote that there was a difference between an ultrasound examination by referral and examining one’s patients with ultrasound. I coined a phrase: the “ultrasound-enhanced bimanual exam.” I believed that this term should become a routine part of the overall gynecologic exam. I wanted people to think about the bimanual that we had done for at least half a century, which, in my opinion, consists of 2 components:

1. An objective component: Is this uterus normal? Is it enlarged or irregular in contour, suggesting maybe fibroids? Is an ovary enlarged? If so, does it feel cystic or solid?
2. A subjective component: Does this patient have tenderness through the pelvis. Is there normal mobility of the pelvic organs?

Part of the thesis was that the objective portion could be replaced by an image that could be produced in seconds, dependent on the operator’s training and availability of equipment. The subjective portion, however, depended on the experience and, often, nuance of the examiner. Lately, I have been seeking to expand that thesis by having the imager use examination as part of their overall imaging—this is the concept of dynamic imaging.

Can you expand on the concept of dynamic ultrasound in this setting?

Dr. Goldstein: Presently, most imagers take a multitude of pictures, what I would call 2-dimensional snapshots, to illustrate anatomy. This is usually done by a sonographer, or a technician, who collects the images for viewing by the physician, who then often does so without holding the transducer. Increasing utilization of remote tools like teleradiology only makes this more likely, and for a minority of people who may use video clips instead of still images, they are still simply representations of anatomy. The guidelines for pelvic ultrasound are the underpinning of the expectation of those who are scanning the female pelvis. With dynamic imaging, the operator uses their other hand on the abdomen as well as some motion with the probe to see if they can elicit pain with the vaginal probe, checking for mobility, asking the patient to bear down. Whether you are a sonographer, a radiologist, or an ObGyn, dynamic imaging can bring the examination process into the imager’s hands.

Can you tell us more about the indications for pelvic sonography for endometriosis and what data can you give to support this?

Dr. Goldstein: There is a document titled “Ultrasound Examination of the Female Pelvis,” that was originally developed by the American Institute of Ultrasound in Medicine (AIUM). In this document, there are about 19 different indications for pelvic sonography (in no defined order), and it is interesting that the first indication listed is evaluation of pelvic pain. Well, I would ask you, how do you evaluate pelvic pain with a series of anatomic images? If you have a classic ovarian endometrioma, or you have a classic hydrosalpinx, you can surmise that these are the source of the pain that the patient is reporting. But how do you properly evaluate pain with just an anatomic image? Thus, the need to use dynamic assessment.

There was a concept first introduced by my colleague, Dr. Ilan Timor, known as the sliding organ sign, that was mainly used to determine if 2 structures were adherent or separate. This involved use of the abdominal hand, liberal use of the probe moving in and out, and under real-time vision, examining the patient with the ultrasound transducer; this is the concept of dynamic ultrasound. This practice can be expanded to verify if there is pelvic tenderness and can be a significant part of the nonlaparoscopic, presumptive diagnosis of endometriosis, even when there is no ovarian endometrioma.

To support this theory, I would point you toward a classic article by E Okaro and colleagues in the British Journal of OB-GYN. This study took 120 consecutive women with chronic pelvic pain who were scheduled for laparoscopy, but performed a transvaginal ultrasound prior, and they looked for anatomic abnormalities and divided this into hard markers and soft markers. Hard markers were obvious endometriomas and hydrosalpinges, while soft markers included things like reduced ovarian mobility, site-specific pelvic tenderness, and presence of loculated peritoneal fluid in the pelvis. These were typical of chronic pelvic pain patients that ranged from late teens to almost menopausal, as the average age was about 30 years old.

Patients had experienced pain for anywhere from 6 months to 12 years, but the average was about 4 years. At laparoscopy, 58% of these patients had pelvic pathology, and 42% had a normal pelvis. Of the 58% with pathology, the overwhelming majority—about 51 of 70 women—had endometriosis alone, and another 7 had endometriosis with adhesions. A normal ultrasound, based on the absence of hard markers, was found in 96 of 120 women. Thus, 24 of the 120 women had an abnormal scan based on the presence of these hard markers. At laparoscopy, all 24 women had abnormal laparoscopies. Of those 96 women who would have had a normal ultrasound, based on the anatomic absence of some pathology, 53% had an abnormal scan based on the presence of these soft markers while the remaining women had no soft- or hard-markers suggesting any pelvic pathology. At laparoscopy, 73% of the patients with soft markers had pelvic pathology and 27% had a normal laparoscopy. Of 45 patients who had a normal, transvaginal ultrasound, 9 were found to have small evidence of endometriosis without discrete endometriomas at laparoscopy.

To summarize the study data, 100% of patients with hard markers and chronic pelvic pain had abnormal anatomy at laparoscopy, but 73% of patients who had soft markers but otherwise would have been interpreted as normal anatomic findings had evidence of pelvic pathology. Such an approach, if used, could lead to a reduction in the number of unnecessary laparoscopies.

What it really boils down to is, if you have 100 women with chronic pelvic pain, are you willing to treat 100 patients without laparoscopy, knowing that 73 are going to have a positive laparoscopy and will require treatment anyway? You would treat 27% with a pharmaceutical agent that may provide relief of their pain, or may not, depending on what the true etiology was. I would be willing to do so, as a positive predictive value of 73% makes doing that worthwhile, and I believe a majority of clinicians would agree.

Do you have any other tips or ways to improve the reader’s understanding of transvaginal ultrasound?

Dr. Goldstein: Pelvic organs have mobility. If a premenopausal woman is examined in lithotomy position, if the ovaries are freely mobile, by gravity, they are going to go lateral to the uterus and are seen immediately adjacent to the iliac vessels. But remember, iliac vessels are retroperitoneal as they are outside the peritoneal cavity. If you were to turn that patient onto all fours, so that the ovaries are freely mobile, they are going to move somewhat toward the anterior abdominal wall. When an ovary is seen in a nonanatomic position, it could be normal or it could be held up by a loop of bowel, but it may indicate adhesions. This is where this sliding organ sign and liberal use of the other hand on the lower abdomen can be extremely important. The reader should also understand that our ability to localize ovaries on ultrasound depends on the amount of folliculogenesis. Follicles are black circles that are sonolucent, because they contain fluid, so they make it easy to localize ovaries, but also their anatomic position relative to the iliac vessels. However, there is a caveat—which is, sometimes an ovary might look like it is behind the uterus and not in its normal anatomic location. When dynamic imaging is used, you are able to cajole that ovary to move lateral and sit on top of the iliac vessels, which can enable you make the proper diagnosis.

Can you provide some background on endometriosis and the importance of early diagnosis?

Dr. Goldstein: Endometriosis is an inflammatory condition, characterized by endometrial tissue at sites outside the uterus—this definition comes from the World Endometriosis Society.

Endometriosis is said to affect about 10% of women of reproductive age, and if you look at a group, a subset of women with pelvic pain or infertility, the numbers rise to the range of 35% to 50%. It can present in a multitude of locations, mainly in the pelvis, although occasionally even in places like the lung. When it occurs in the uterus, it is known as adenomyosis; when it occurs inside the ovary, it can cause an endometrioma (or what is sometimes referred to as chocolate cyst of the ovary), but you can see endometriotic implants anywhere in the peritoneum—along the urinary tract, rectum, uterosacral ligaments, rectovaginal septum, and even the vaginal wall occasionally.

What I am really interested in is an earlier diagnosis of superficial endometriosis, and it should be apparent to the reader why this is important—the quality of life from pain from endometriosis can be debilitating. It can be a source of infertility, a source of menstrual irregularities, and a source of not only quality of life but also economic consequences. Many women can also undergo as much as a 7-year delay in diagnosis, so the need for a timely diagnosis and initiation of treatment is extremely important.

What is the role of ultrasound in endometriosis diagnostics?

Dr. Goldstein: In an article that I authored 31 years ago, I wrote that there was a difference between an ultrasound examination by referral and examining one’s patients with ultrasound. I coined a phrase: the “ultrasound-enhanced bimanual exam.” I believed that this term should become a routine part of the overall gynecologic exam. I wanted people to think about the bimanual that we had done for at least half a century, which, in my opinion, consists of 2 components:

1. An objective component: Is this uterus normal? Is it enlarged or irregular in contour, suggesting maybe fibroids? Is an ovary enlarged? If so, does it feel cystic or solid?
2. A subjective component: Does this patient have tenderness through the pelvis. Is there normal mobility of the pelvic organs?

Part of the thesis was that the objective portion could be replaced by an image that could be produced in seconds, dependent on the operator’s training and availability of equipment. The subjective portion, however, depended on the experience and, often, nuance of the examiner. Lately, I have been seeking to expand that thesis by having the imager use examination as part of their overall imaging—this is the concept of dynamic imaging.

Can you expand on the concept of dynamic ultrasound in this setting?

Dr. Goldstein: Presently, most imagers take a multitude of pictures, what I would call 2-dimensional snapshots, to illustrate anatomy. This is usually done by a sonographer, or a technician, who collects the images for viewing by the physician, who then often does so without holding the transducer. Increasing utilization of remote tools like teleradiology only makes this more likely, and for a minority of people who may use video clips instead of still images, they are still simply representations of anatomy. The guidelines for pelvic ultrasound are the underpinning of the expectation of those who are scanning the female pelvis. With dynamic imaging, the operator uses their other hand on the abdomen as well as some motion with the probe to see if they can elicit pain with the vaginal probe, checking for mobility, asking the patient to bear down. Whether you are a sonographer, a radiologist, or an ObGyn, dynamic imaging can bring the examination process into the imager’s hands.

Can you tell us more about the indications for pelvic sonography for endometriosis and what data can you give to support this?

Dr. Goldstein: There is a document titled “Ultrasound Examination of the Female Pelvis,” that was originally developed by the American Institute of Ultrasound in Medicine (AIUM). In this document, there are about 19 different indications for pelvic sonography (in no defined order), and it is interesting that the first indication listed is evaluation of pelvic pain. Well, I would ask you, how do you evaluate pelvic pain with a series of anatomic images? If you have a classic ovarian endometrioma, or you have a classic hydrosalpinx, you can surmise that these are the source of the pain that the patient is reporting. But how do you properly evaluate pain with just an anatomic image? Thus, the need to use dynamic assessment.

There was a concept first introduced by my colleague, Dr. Ilan Timor, known as the sliding organ sign, that was mainly used to determine if 2 structures were adherent or separate. This involved use of the abdominal hand, liberal use of the probe moving in and out, and under real-time vision, examining the patient with the ultrasound transducer; this is the concept of dynamic ultrasound. This practice can be expanded to verify if there is pelvic tenderness and can be a significant part of the nonlaparoscopic, presumptive diagnosis of endometriosis, even when there is no ovarian endometrioma.

To support this theory, I would point you toward a classic article by E Okaro and colleagues in the British Journal of OB-GYN. This study took 120 consecutive women with chronic pelvic pain who were scheduled for laparoscopy, but performed a transvaginal ultrasound prior, and they looked for anatomic abnormalities and divided this into hard markers and soft markers. Hard markers were obvious endometriomas and hydrosalpinges, while soft markers included things like reduced ovarian mobility, site-specific pelvic tenderness, and presence of loculated peritoneal fluid in the pelvis. These were typical of chronic pelvic pain patients that ranged from late teens to almost menopausal, as the average age was about 30 years old.

Patients had experienced pain for anywhere from 6 months to 12 years, but the average was about 4 years. At laparoscopy, 58% of these patients had pelvic pathology, and 42% had a normal pelvis. Of the 58% with pathology, the overwhelming majority—about 51 of 70 women—had endometriosis alone, and another 7 had endometriosis with adhesions. A normal ultrasound, based on the absence of hard markers, was found in 96 of 120 women. Thus, 24 of the 120 women had an abnormal scan based on the presence of these hard markers. At laparoscopy, all 24 women had abnormal laparoscopies. Of those 96 women who would have had a normal ultrasound, based on the anatomic absence of some pathology, 53% had an abnormal scan based on the presence of these soft markers while the remaining women had no soft- or hard-markers suggesting any pelvic pathology. At laparoscopy, 73% of the patients with soft markers had pelvic pathology and 27% had a normal laparoscopy. Of 45 patients who had a normal, transvaginal ultrasound, 9 were found to have small evidence of endometriosis without discrete endometriomas at laparoscopy.

To summarize the study data, 100% of patients with hard markers and chronic pelvic pain had abnormal anatomy at laparoscopy, but 73% of patients who had soft markers but otherwise would have been interpreted as normal anatomic findings had evidence of pelvic pathology. Such an approach, if used, could lead to a reduction in the number of unnecessary laparoscopies.

What it really boils down to is, if you have 100 women with chronic pelvic pain, are you willing to treat 100 patients without laparoscopy, knowing that 73 are going to have a positive laparoscopy and will require treatment anyway? You would treat 27% with a pharmaceutical agent that may provide relief of their pain, or may not, depending on what the true etiology was. I would be willing to do so, as a positive predictive value of 73% makes doing that worthwhile, and I believe a majority of clinicians would agree.

Do you have any other tips or ways to improve the reader’s understanding of transvaginal ultrasound?

Dr. Goldstein: Pelvic organs have mobility. If a premenopausal woman is examined in lithotomy position, if the ovaries are freely mobile, by gravity, they are going to go lateral to the uterus and are seen immediately adjacent to the iliac vessels. But remember, iliac vessels are retroperitoneal as they are outside the peritoneal cavity. If you were to turn that patient onto all fours, so that the ovaries are freely mobile, they are going to move somewhat toward the anterior abdominal wall. When an ovary is seen in a nonanatomic position, it could be normal or it could be held up by a loop of bowel, but it may indicate adhesions. This is where this sliding organ sign and liberal use of the other hand on the lower abdomen can be extremely important. The reader should also understand that our ability to localize ovaries on ultrasound depends on the amount of folliculogenesis. Follicles are black circles that are sonolucent, because they contain fluid, so they make it easy to localize ovaries, but also their anatomic position relative to the iliac vessels. However, there is a caveat—which is, sometimes an ovary might look like it is behind the uterus and not in its normal anatomic location. When dynamic imaging is used, you are able to cajole that ovary to move lateral and sit on top of the iliac vessels, which can enable you make the proper diagnosis.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

References

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

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

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

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

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

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

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

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

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

Gene dysregulation contributes to fibroid development

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

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

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

Estrogen and progesterone influence fibroid size and cell activity

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

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

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

Continue to: Leuprolide acetate...

Leuprolide acetate

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

Elagolix plus estradiol plus norethindrone acetate (Oriahnn)

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

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

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

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

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

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

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

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

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

AUB caused by fibroids is a common problem in gyn practice

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

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

Gene dysregulation contributes to fibroid development

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

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

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

Estrogen and progesterone influence fibroid size and cell activity

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

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

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

Continue to: Leuprolide acetate...

Leuprolide acetate

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

Elagolix plus estradiol plus norethindrone acetate (Oriahnn)

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

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

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

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

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

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

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

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

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

AUB caused by fibroids is a common problem in gyn practice

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

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

Gene dysregulation contributes to fibroid development

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

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

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

Estrogen and progesterone influence fibroid size and cell activity

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

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

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

Continue to: Leuprolide acetate...

Leuprolide acetate

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

Elagolix plus estradiol plus norethindrone acetate (Oriahnn)

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

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

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

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

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

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

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

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

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

AUB caused by fibroids is a common problem in gyn practice

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

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

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

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

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

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

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

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

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

iStockphoto.com

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

iStockphoto.com

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

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

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

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

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

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

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

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

iStockphoto.com

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

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

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

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

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

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

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

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

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

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

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

[email protected]

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

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

Expert Commentary

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

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

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

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

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

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

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

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

Continue to: Details about the study...

Details about the study

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

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

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

Effects on bone density

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

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

Continue to: Study strengths and limitations...

Study strengths and limitations

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

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

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

Expert Commentary

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

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

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

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

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

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

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

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

Continue to: Details about the study...

Details about the study

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

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

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

Effects on bone density

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

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

Continue to: Study strengths and limitations...

Study strengths and limitations

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

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

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

Expert Commentary

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

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

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

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

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

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

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

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

Continue to: Details about the study...

Details about the study

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

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

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

Effects on bone density

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

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

Continue to: Study strengths and limitations...

Study strengths and limitations

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

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

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

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

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

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

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

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

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

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

Less pain

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

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

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

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

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

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

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

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

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

“Compelling” findings but early days

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

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

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

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

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

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

This article first appeared on Medscape.com.

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

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

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

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

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

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

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

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

Less pain

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

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

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

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

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

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

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

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

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

“Compelling” findings but early days

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

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

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

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

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

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

This article first appeared on Medscape.com.

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

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

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

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

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

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

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

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

Less pain

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

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

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

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

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

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

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

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

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

“Compelling” findings but early days

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

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

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

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

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

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

This article first appeared on Medscape.com.

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

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

Phase 3 study details

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

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



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

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

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

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

Phase 3 study details

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

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



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

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

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

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

Phase 3 study details

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

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



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

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

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

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

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

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

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

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

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

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

Dr. Leonardi reported no relevant financial disclosures

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

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

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

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

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

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

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

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

Dr. Leonardi reported no relevant financial disclosures

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

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

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

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

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

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

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

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

Dr. Leonardi reported no relevant financial disclosures