Article

What tests are best for the diagnosis of COVID-19 infection?

Continue to the answer...

The 2 key diagnostic tests for COVID-19 infection are detecting antigen in nasopharyngeal washings or saliva by nucleic acid amplification tests and identifying ground-glass opacities on computed tomography imaging of the chest. (Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med. 2020;383:2451-2460.)

What tests are best for the diagnosis of COVID-19 infection?

Continue to the answer...

The 2 key diagnostic tests for COVID-19 infection are detecting antigen in nasopharyngeal washings or saliva by nucleic acid amplification tests and identifying ground-glass opacities on computed tomography imaging of the chest. (Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med. 2020;383:2451-2460.)

What tests are best for the diagnosis of COVID-19 infection?

Continue to the answer...

The 2 key diagnostic tests for COVID-19 infection are detecting antigen in nasopharyngeal washings or saliva by nucleic acid amplification tests and identifying ground-glass opacities on computed tomography imaging of the chest. (Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med. 2020;383:2451-2460.)

Hundreds of Native American tribes have tentatively settled in what one of the lead attorneys describes as “an epic deal”: The top 3 pharmaceutical distributors in the US and Johnson & Johnson have agreed to pay $665 million for deceptive marketing practices and overdistribution of opioids. Native Americans were among those hardest hit by the opioid epidemic. Between 2006 and 2014, Native Americans were nearly 50% more likely than non-Natives to die of an opioid overdose. In 2014, they ranked number 1 for death by opioid overdose.

Overprescribing was rampant. In some areas, such as southwestern Virginia, eastern Kentucky, and Alabama, prescriptions were 5 to 6 times higher than the national average. The overprescribing was largely due to massive and aggressive billion-dollar marketing campaigns, which misrepresented the safety of opioid medications. Purdue Pharma, for instance, trained sales representatives to claim that the risk of addiction was “less than 1 percent.” In an interview with Smithsonian Magazine, Caleb Alexander, MD, codirector of Johns Hopkins’ Center for Drug Safety and Effectiveness, said, “When I was in residency training, we were taught that one needn’t worry about the addictive potential of opioids if a patient had true pain.” He said it was no accident that physicians were cultivated to overestimate the effectiveness for chronic, noncancer pain while underestimating the risks.

Native Americans were not only in the target group for prescriptions, but also apparently singularly targeted. “We were preyed upon,” said Chickasaw Nation Governor Bill Anoatubby in the Washington Post. “It was unconscionable.” A Washington Post analysis found that, between 2006 and 2014, opioid distributors shipped an average of 36 pills per person in the US. States in the so-called opioid belt (mostly Southern states), received an average of 60 to 66 pills per person. The distributors shipped 57 pills per person to Oklahoma, home to nearly 322,000 Native Americans. (The opioid death rate for Native Americans in Oklahoma from 2006 to 2014 was more than triple the nationwide rate for non-Natives.) In South Dakota as recently as 2015, enough opioids were prescribed to medicate every adult around-the-clock for 19 consecutive days. Native Americans comprise 9% of South Dakota’s population; however, almost 30% of the patients are being treated for opioid use disorder.

In the settlement, which is a first for tribes, McKesson, Cardinal Health, and AmerisourceBergen would pay $515 million over 7 years. Johnson & Johnson would contribute $150 million in 2 years to the federally recognized tribes. “This settlement is a real turning point in history,” said Lloyd Miller, one of the attorneys representing one-third of the litigating tribes.

But the money is still small compensation for ravaging millions of lives. “Flooding the Native community with Western medicine—sedating a population rather than seeking to understand its needs and challenges—is not an acceptable means of handling its trauma,” the Lakota People’s Law Project says in an article on its website. Thus, the money dispersal will be overseen by a panel of tribal health experts, to go toward programs that aid drug users and their communities.

The funds will be managed in a way that will consider the long-term damage, Native American leaders vow. Children, for instance, have not been exempt from the sequelae of the overprescribing. Foster care systems are “overrun” with children of addicted parents, the Law Project says, and the children are placed in homes outside the tribe. “In the long run, this has the potential to curtail tribal membership, break down familial lines, and degrade cultural values.”

Dealing with the problem has drained tribal resources—doubly strained by the COVID-19 epidemic. Chairman Douglas Yankton, of the Spirit Lake Nation in North Dakota, said in a statement, “The dollars that will flow to Tribes under this initial settlement will help fund crucial, on-reservation, culturally appropriate opioid treatment services.”

However, Chairman Kristopher Peters, of the Squaxin Island Tribe in Washington State, told the Washington Post, “There is no amount of money that’s going to solve the generational issues that have been created from this. Our hope is that we can use these funds to help revitalize our culture and help heal our people.”

Johnson & Johnson says it no longer sells prescription opioids in the US

Hundreds of Native American tribes have tentatively settled in what one of the lead attorneys describes as “an epic deal”: The top 3 pharmaceutical distributors in the US and Johnson & Johnson have agreed to pay $665 million for deceptive marketing practices and overdistribution of opioids. Native Americans were among those hardest hit by the opioid epidemic. Between 2006 and 2014, Native Americans were nearly 50% more likely than non-Natives to die of an opioid overdose. In 2014, they ranked number 1 for death by opioid overdose.

Overprescribing was rampant. In some areas, such as southwestern Virginia, eastern Kentucky, and Alabama, prescriptions were 5 to 6 times higher than the national average. The overprescribing was largely due to massive and aggressive billion-dollar marketing campaigns, which misrepresented the safety of opioid medications. Purdue Pharma, for instance, trained sales representatives to claim that the risk of addiction was “less than 1 percent.” In an interview with Smithsonian Magazine, Caleb Alexander, MD, codirector of Johns Hopkins’ Center for Drug Safety and Effectiveness, said, “When I was in residency training, we were taught that one needn’t worry about the addictive potential of opioids if a patient had true pain.” He said it was no accident that physicians were cultivated to overestimate the effectiveness for chronic, noncancer pain while underestimating the risks.

Native Americans were not only in the target group for prescriptions, but also apparently singularly targeted. “We were preyed upon,” said Chickasaw Nation Governor Bill Anoatubby in the Washington Post. “It was unconscionable.” A Washington Post analysis found that, between 2006 and 2014, opioid distributors shipped an average of 36 pills per person in the US. States in the so-called opioid belt (mostly Southern states), received an average of 60 to 66 pills per person. The distributors shipped 57 pills per person to Oklahoma, home to nearly 322,000 Native Americans. (The opioid death rate for Native Americans in Oklahoma from 2006 to 2014 was more than triple the nationwide rate for non-Natives.) In South Dakota as recently as 2015, enough opioids were prescribed to medicate every adult around-the-clock for 19 consecutive days. Native Americans comprise 9% of South Dakota’s population; however, almost 30% of the patients are being treated for opioid use disorder.

In the settlement, which is a first for tribes, McKesson, Cardinal Health, and AmerisourceBergen would pay $515 million over 7 years. Johnson & Johnson would contribute $150 million in 2 years to the federally recognized tribes. “This settlement is a real turning point in history,” said Lloyd Miller, one of the attorneys representing one-third of the litigating tribes.

But the money is still small compensation for ravaging millions of lives. “Flooding the Native community with Western medicine—sedating a population rather than seeking to understand its needs and challenges—is not an acceptable means of handling its trauma,” the Lakota People’s Law Project says in an article on its website. Thus, the money dispersal will be overseen by a panel of tribal health experts, to go toward programs that aid drug users and their communities.

The funds will be managed in a way that will consider the long-term damage, Native American leaders vow. Children, for instance, have not been exempt from the sequelae of the overprescribing. Foster care systems are “overrun” with children of addicted parents, the Law Project says, and the children are placed in homes outside the tribe. “In the long run, this has the potential to curtail tribal membership, break down familial lines, and degrade cultural values.”

Dealing with the problem has drained tribal resources—doubly strained by the COVID-19 epidemic. Chairman Douglas Yankton, of the Spirit Lake Nation in North Dakota, said in a statement, “The dollars that will flow to Tribes under this initial settlement will help fund crucial, on-reservation, culturally appropriate opioid treatment services.”

However, Chairman Kristopher Peters, of the Squaxin Island Tribe in Washington State, told the Washington Post, “There is no amount of money that’s going to solve the generational issues that have been created from this. Our hope is that we can use these funds to help revitalize our culture and help heal our people.”

Johnson & Johnson says it no longer sells prescription opioids in the US

Hundreds of Native American tribes have tentatively settled in what one of the lead attorneys describes as “an epic deal”: The top 3 pharmaceutical distributors in the US and Johnson & Johnson have agreed to pay $665 million for deceptive marketing practices and overdistribution of opioids. Native Americans were among those hardest hit by the opioid epidemic. Between 2006 and 2014, Native Americans were nearly 50% more likely than non-Natives to die of an opioid overdose. In 2014, they ranked number 1 for death by opioid overdose.

Overprescribing was rampant. In some areas, such as southwestern Virginia, eastern Kentucky, and Alabama, prescriptions were 5 to 6 times higher than the national average. The overprescribing was largely due to massive and aggressive billion-dollar marketing campaigns, which misrepresented the safety of opioid medications. Purdue Pharma, for instance, trained sales representatives to claim that the risk of addiction was “less than 1 percent.” In an interview with Smithsonian Magazine, Caleb Alexander, MD, codirector of Johns Hopkins’ Center for Drug Safety and Effectiveness, said, “When I was in residency training, we were taught that one needn’t worry about the addictive potential of opioids if a patient had true pain.” He said it was no accident that physicians were cultivated to overestimate the effectiveness for chronic, noncancer pain while underestimating the risks.

Native Americans were not only in the target group for prescriptions, but also apparently singularly targeted. “We were preyed upon,” said Chickasaw Nation Governor Bill Anoatubby in the Washington Post. “It was unconscionable.” A Washington Post analysis found that, between 2006 and 2014, opioid distributors shipped an average of 36 pills per person in the US. States in the so-called opioid belt (mostly Southern states), received an average of 60 to 66 pills per person. The distributors shipped 57 pills per person to Oklahoma, home to nearly 322,000 Native Americans. (The opioid death rate for Native Americans in Oklahoma from 2006 to 2014 was more than triple the nationwide rate for non-Natives.) In South Dakota as recently as 2015, enough opioids were prescribed to medicate every adult around-the-clock for 19 consecutive days. Native Americans comprise 9% of South Dakota’s population; however, almost 30% of the patients are being treated for opioid use disorder.

In the settlement, which is a first for tribes, McKesson, Cardinal Health, and AmerisourceBergen would pay $515 million over 7 years. Johnson & Johnson would contribute $150 million in 2 years to the federally recognized tribes. “This settlement is a real turning point in history,” said Lloyd Miller, one of the attorneys representing one-third of the litigating tribes.

But the money is still small compensation for ravaging millions of lives. “Flooding the Native community with Western medicine—sedating a population rather than seeking to understand its needs and challenges—is not an acceptable means of handling its trauma,” the Lakota People’s Law Project says in an article on its website. Thus, the money dispersal will be overseen by a panel of tribal health experts, to go toward programs that aid drug users and their communities.

The funds will be managed in a way that will consider the long-term damage, Native American leaders vow. Children, for instance, have not been exempt from the sequelae of the overprescribing. Foster care systems are “overrun” with children of addicted parents, the Law Project says, and the children are placed in homes outside the tribe. “In the long run, this has the potential to curtail tribal membership, break down familial lines, and degrade cultural values.”

Dealing with the problem has drained tribal resources—doubly strained by the COVID-19 epidemic. Chairman Douglas Yankton, of the Spirit Lake Nation in North Dakota, said in a statement, “The dollars that will flow to Tribes under this initial settlement will help fund crucial, on-reservation, culturally appropriate opioid treatment services.”

However, Chairman Kristopher Peters, of the Squaxin Island Tribe in Washington State, told the Washington Post, “There is no amount of money that’s going to solve the generational issues that have been created from this. Our hope is that we can use these funds to help revitalize our culture and help heal our people.”

Johnson & Johnson says it no longer sells prescription opioids in the US

The COVID-19 pandemic largely altered the practice of medicine, including a rapid expansion of telemedicine following the March 2020 World Health Organization guidelines for social distancing, which recommended suspension of all nonurgent in-person visits.¹ Expectedly, COVID-related urgent care visits initially comprised the bulk of the new telemedicine wave: NYU Langone Health (New York, New York), for example, saw a 683% increase in virtual visits between March and April 2020, most (55.3%) of which were for respiratory concerns. In-person visits, on the other hand, concurrently fell by more than 80%. Interestingly, nonurgent ambulatory care specialties also saw a considerable uptick in virtual encounters, from less than 50 visits in a typical day to an average of 7000 in a 10-day stretch.²

As a largely ambulatory specialty that relies on visual examination, dermatology was no exception to the swing toward telemedicine, or teledermatology (TD). Before the COVID-19 pandemic, 14.1% (82 of 582 respondents) of practicing US dermatologists reported having used teledermatology, compared to 96.9% (572/591) during the pandemic.³ Even at my home institution (Massachusetts General Hospital [Boston, Massachusetts] and its 12 affiliated dermatology clinics), the number of in-person visits in April 2020 (n=67) was less than 1% of that in April 2019 (n=7919), whereas there was a total of 1564 virtual visits in April 2020 compared to zero the year prior. Virtual provider-to-provider consults (e-consultations) also saw an increase of more than 20%, suggesting that dermatology’s avid adoption of TD also had improved the perceived accessibility of our specialty.⁴

The adoption and adaptation of TD are projected to continue to grow rapidly across the globe, as digitalization has enhanced access without increasing costs, shortened wait times, and even created opportunities for primary care providers based in rural or overseas locations to learn the diagnosis and treatment of skin disease.⁵ Residents and fellows should be privy to the nuances of training and practicing in this digital era, as our careers inevitably will involve some facet of TD.

The Art of Medicine

Touch, a sense that perhaps ranks second to sight in dermatology, is absent in TD. In either synchronous (live-interactive, face video visits) or asynchronous (store-and-forward, where digital photographs and clinical information sent by patients or referring physicians are assessed at a later time) TD, the skin cannot be rubbed for texture, pinched for thickness, or pushed for blanching. Instead, all we have is vision. Irwin Braverman, MD, Professor Emeritus of Dermatology at Yale University (New Haven, Connecticut), alongside Jacqueline Dolev, MD, dermatologist and Yale graduate, and Linda Friedlaender, curator at the Yale Center for British Art, founded an observational skills workshop in which trainees learn to observe and describe the paintings housed in the museum, noting all memorable details: the color of the sky, the actions of the animals, and the facial expressions of the people. A study of 90 participants over a 2-year period found that following the workshop, the ability to identify key diagnostic details from clinical photography improved by more than 10%.⁶ Other studies also utilizing fine art as a medical training tool to improve “visual literacy” saw similarly increased sophistication in the description of clinical imagery, which translated to better diagnostic acumen.⁷ Confined to video and photographs, TD necessitates trainees and practicing dermatologists to be excellent visual diagnosticians. Although surveyed dermatologists believe TD is presently appropriate for acne, benign lesions, or follow-up appointments,³ conditions for which patients have been examined via TD have included drug eruptions, premalignant or malignant neoplasms, infections, and papulosquamous or inflammatory dermatoses.⁸ At the very least, clinicians should be versed in identifying those conditions that require in-person evaluation, as patients cannot be held responsible to distinguish which situations can and cannot be addressed virtually.

Issues of Patient-Physician Confidentiality

Teledermatology is not without its shortcomings; critics have noted diagnostic challenges with poor quality photographs or videos, inability to perform total-body skin examinations, and socioeconomic limitations due to broadband availability and speed.^5,9 Although most of these shortcomings are outside of our control, a key challenge within the purview of the provider is the protection of patient privacy.

Much of the salient concerns regarding patient-physician confidentiality involve asynchronous TD, where store-and-forward data sharing allows physicians to download patient photographs or information onto their personal email or smartphones.¹⁰ Although some hospital systems provide encryption software or hospital-sponsored devices to ensure security, physicians may opt to use their personal phones or laptops out of convenience or to save time.^10,11 One study found that less than 30% of smartphone users choose to activate user authentication on their devices, even ones as simple as a passphrase.¹¹ The digital exchange of information thus poses an immense risk for compromising protected health information (PHI), as personal devices can be easily lost, stolen, or hacked. Indeed, in 2015, more than 113 million individuals were affected by a breach of PHI, the majority over hacked network servers.¹² With the growing diversity of mediums through which PHI is exchanged, such as videoconferencing and instant messaging, the potential medicolegal risks of information breach continue to climb. The US Department of Health & Human Services urges health care providers to uphold best practices for security, including encrypting data, updating all software including antivirus software, using multifactor authentication, and following local cybersecurity regulations or recommendations.¹³ For synchronous TD, suggested best practices include utilizing headphones during live appointments, avoiding public wireless networks, and ensuring the provider and patient both scan the room with their device’s camera before the start of the visit.¹⁴

On the Horizon of Teledermatology

What can we expect in the coming years? Increased utilization of telemedicine will translate into data that will help address questions surrounding safety, diagnostic accuracy, privacy, and accessibility. One aspect of TD in need of clarity is a guideline on payment and reimbursement, and whether TD can continue to be financially attractive to providers. Starting in 2020, the Centers for Medicare & Medicaid Services removed geographic restrictions for reimbursement of telemedicine visits, enabling even urban-residing patients to enjoy the convenience of TD. This followed a prior relaxation of restrictions, where even prerecorded patient information became eligible for Medicare reimbursement.⁹ However, as virtual visits tend to be shorter with fewer diagnostic services compared to in-person visits, the reimbursement structure of TD must be nuanced, which is the subject of ongoing study and modification in the wake of the COVID-19 pandemic.¹⁵

Another point to consider is the explosion of direct-to-consumer TD, which allows patients to receive virtual dermatologic care or prescription medication without a pre-established relationship with any physician. In 2017, there were 22 direct-to-consumer TD services available to US patients in 45 states, 16 (73%) of which provided dermatologic care for any concern while 6 (27%) were limited to acne or antiaging and were largely prescription oriented. Orchestrated mostly by the for-profit private sector, direct-to-consumer companies are poorly regulated and have raised concerns over questionable practices, such as the use of non–US board-certified physicians, exorbitant fees, and failure to disclose medication side effects.¹⁶ A study of 16 direct-to-consumer telemedicine sites found substantial discordance in the suggested management of the same patient, and many of the services relied heavily on patient-provided self-diagnoses, such as a case where psoriasis medication was dispensed for a psoriasis patient who submitted a photograph of his syphilitic rash.¹⁷ Despite these problems, consumers show a willingness to pay out of pocket to access these services for their shorter waiting times and convenience.¹⁸ Hence, we must learn to ask about direct-to-consumer service use when obtaining a thorough history and be open to counseling our patients on the proper use and potential risks of direct-to-consumer TD.

Final Thoughts

The telemedicine industry is expected to reach more than $130 billion by 2025, with more than 90% of surveyed health care executives planning for the adoption and incorporation of telemedicine into their business models.¹⁹ The COVID-19 pandemic was an impetus for an exponential adoption of TD, and it would behoove current residents to realize that the practice of dermatology will continue to be increasingly digitalized within the coming years. Whether through formal training or self-assessment, we must strive to grow as proficient virtual dermatologists while upholding professionalism, patient safety, and health information privacy.

The COVID-19 pandemic largely altered the practice of medicine, including a rapid expansion of telemedicine following the March 2020 World Health Organization guidelines for social distancing, which recommended suspension of all nonurgent in-person visits.¹ Expectedly, COVID-related urgent care visits initially comprised the bulk of the new telemedicine wave: NYU Langone Health (New York, New York), for example, saw a 683% increase in virtual visits between March and April 2020, most (55.3%) of which were for respiratory concerns. In-person visits, on the other hand, concurrently fell by more than 80%. Interestingly, nonurgent ambulatory care specialties also saw a considerable uptick in virtual encounters, from less than 50 visits in a typical day to an average of 7000 in a 10-day stretch.²

As a largely ambulatory specialty that relies on visual examination, dermatology was no exception to the swing toward telemedicine, or teledermatology (TD). Before the COVID-19 pandemic, 14.1% (82 of 582 respondents) of practicing US dermatologists reported having used teledermatology, compared to 96.9% (572/591) during the pandemic.³ Even at my home institution (Massachusetts General Hospital [Boston, Massachusetts] and its 12 affiliated dermatology clinics), the number of in-person visits in April 2020 (n=67) was less than 1% of that in April 2019 (n=7919), whereas there was a total of 1564 virtual visits in April 2020 compared to zero the year prior. Virtual provider-to-provider consults (e-consultations) also saw an increase of more than 20%, suggesting that dermatology’s avid adoption of TD also had improved the perceived accessibility of our specialty.⁴

The adoption and adaptation of TD are projected to continue to grow rapidly across the globe, as digitalization has enhanced access without increasing costs, shortened wait times, and even created opportunities for primary care providers based in rural or overseas locations to learn the diagnosis and treatment of skin disease.⁵ Residents and fellows should be privy to the nuances of training and practicing in this digital era, as our careers inevitably will involve some facet of TD.

The Art of Medicine

Touch, a sense that perhaps ranks second to sight in dermatology, is absent in TD. In either synchronous (live-interactive, face video visits) or asynchronous (store-and-forward, where digital photographs and clinical information sent by patients or referring physicians are assessed at a later time) TD, the skin cannot be rubbed for texture, pinched for thickness, or pushed for blanching. Instead, all we have is vision. Irwin Braverman, MD, Professor Emeritus of Dermatology at Yale University (New Haven, Connecticut), alongside Jacqueline Dolev, MD, dermatologist and Yale graduate, and Linda Friedlaender, curator at the Yale Center for British Art, founded an observational skills workshop in which trainees learn to observe and describe the paintings housed in the museum, noting all memorable details: the color of the sky, the actions of the animals, and the facial expressions of the people. A study of 90 participants over a 2-year period found that following the workshop, the ability to identify key diagnostic details from clinical photography improved by more than 10%.⁶ Other studies also utilizing fine art as a medical training tool to improve “visual literacy” saw similarly increased sophistication in the description of clinical imagery, which translated to better diagnostic acumen.⁷ Confined to video and photographs, TD necessitates trainees and practicing dermatologists to be excellent visual diagnosticians. Although surveyed dermatologists believe TD is presently appropriate for acne, benign lesions, or follow-up appointments,³ conditions for which patients have been examined via TD have included drug eruptions, premalignant or malignant neoplasms, infections, and papulosquamous or inflammatory dermatoses.⁸ At the very least, clinicians should be versed in identifying those conditions that require in-person evaluation, as patients cannot be held responsible to distinguish which situations can and cannot be addressed virtually.

Issues of Patient-Physician Confidentiality

Teledermatology is not without its shortcomings; critics have noted diagnostic challenges with poor quality photographs or videos, inability to perform total-body skin examinations, and socioeconomic limitations due to broadband availability and speed.^5,9 Although most of these shortcomings are outside of our control, a key challenge within the purview of the provider is the protection of patient privacy.

Much of the salient concerns regarding patient-physician confidentiality involve asynchronous TD, where store-and-forward data sharing allows physicians to download patient photographs or information onto their personal email or smartphones.¹⁰ Although some hospital systems provide encryption software or hospital-sponsored devices to ensure security, physicians may opt to use their personal phones or laptops out of convenience or to save time.^10,11 One study found that less than 30% of smartphone users choose to activate user authentication on their devices, even ones as simple as a passphrase.¹¹ The digital exchange of information thus poses an immense risk for compromising protected health information (PHI), as personal devices can be easily lost, stolen, or hacked. Indeed, in 2015, more than 113 million individuals were affected by a breach of PHI, the majority over hacked network servers.¹² With the growing diversity of mediums through which PHI is exchanged, such as videoconferencing and instant messaging, the potential medicolegal risks of information breach continue to climb. The US Department of Health & Human Services urges health care providers to uphold best practices for security, including encrypting data, updating all software including antivirus software, using multifactor authentication, and following local cybersecurity regulations or recommendations.¹³ For synchronous TD, suggested best practices include utilizing headphones during live appointments, avoiding public wireless networks, and ensuring the provider and patient both scan the room with their device’s camera before the start of the visit.¹⁴

On the Horizon of Teledermatology

What can we expect in the coming years? Increased utilization of telemedicine will translate into data that will help address questions surrounding safety, diagnostic accuracy, privacy, and accessibility. One aspect of TD in need of clarity is a guideline on payment and reimbursement, and whether TD can continue to be financially attractive to providers. Starting in 2020, the Centers for Medicare & Medicaid Services removed geographic restrictions for reimbursement of telemedicine visits, enabling even urban-residing patients to enjoy the convenience of TD. This followed a prior relaxation of restrictions, where even prerecorded patient information became eligible for Medicare reimbursement.⁹ However, as virtual visits tend to be shorter with fewer diagnostic services compared to in-person visits, the reimbursement structure of TD must be nuanced, which is the subject of ongoing study and modification in the wake of the COVID-19 pandemic.¹⁵

Another point to consider is the explosion of direct-to-consumer TD, which allows patients to receive virtual dermatologic care or prescription medication without a pre-established relationship with any physician. In 2017, there were 22 direct-to-consumer TD services available to US patients in 45 states, 16 (73%) of which provided dermatologic care for any concern while 6 (27%) were limited to acne or antiaging and were largely prescription oriented. Orchestrated mostly by the for-profit private sector, direct-to-consumer companies are poorly regulated and have raised concerns over questionable practices, such as the use of non–US board-certified physicians, exorbitant fees, and failure to disclose medication side effects.¹⁶ A study of 16 direct-to-consumer telemedicine sites found substantial discordance in the suggested management of the same patient, and many of the services relied heavily on patient-provided self-diagnoses, such as a case where psoriasis medication was dispensed for a psoriasis patient who submitted a photograph of his syphilitic rash.¹⁷ Despite these problems, consumers show a willingness to pay out of pocket to access these services for their shorter waiting times and convenience.¹⁸ Hence, we must learn to ask about direct-to-consumer service use when obtaining a thorough history and be open to counseling our patients on the proper use and potential risks of direct-to-consumer TD.

Final Thoughts

The telemedicine industry is expected to reach more than $130 billion by 2025, with more than 90% of surveyed health care executives planning for the adoption and incorporation of telemedicine into their business models.¹⁹ The COVID-19 pandemic was an impetus for an exponential adoption of TD, and it would behoove current residents to realize that the practice of dermatology will continue to be increasingly digitalized within the coming years. Whether through formal training or self-assessment, we must strive to grow as proficient virtual dermatologists while upholding professionalism, patient safety, and health information privacy.

The COVID-19 pandemic largely altered the practice of medicine, including a rapid expansion of telemedicine following the March 2020 World Health Organization guidelines for social distancing, which recommended suspension of all nonurgent in-person visits.¹ Expectedly, COVID-related urgent care visits initially comprised the bulk of the new telemedicine wave: NYU Langone Health (New York, New York), for example, saw a 683% increase in virtual visits between March and April 2020, most (55.3%) of which were for respiratory concerns. In-person visits, on the other hand, concurrently fell by more than 80%. Interestingly, nonurgent ambulatory care specialties also saw a considerable uptick in virtual encounters, from less than 50 visits in a typical day to an average of 7000 in a 10-day stretch.²

As a largely ambulatory specialty that relies on visual examination, dermatology was no exception to the swing toward telemedicine, or teledermatology (TD). Before the COVID-19 pandemic, 14.1% (82 of 582 respondents) of practicing US dermatologists reported having used teledermatology, compared to 96.9% (572/591) during the pandemic.³ Even at my home institution (Massachusetts General Hospital [Boston, Massachusetts] and its 12 affiliated dermatology clinics), the number of in-person visits in April 2020 (n=67) was less than 1% of that in April 2019 (n=7919), whereas there was a total of 1564 virtual visits in April 2020 compared to zero the year prior. Virtual provider-to-provider consults (e-consultations) also saw an increase of more than 20%, suggesting that dermatology’s avid adoption of TD also had improved the perceived accessibility of our specialty.⁴

The adoption and adaptation of TD are projected to continue to grow rapidly across the globe, as digitalization has enhanced access without increasing costs, shortened wait times, and even created opportunities for primary care providers based in rural or overseas locations to learn the diagnosis and treatment of skin disease.⁵ Residents and fellows should be privy to the nuances of training and practicing in this digital era, as our careers inevitably will involve some facet of TD.

The Art of Medicine

Touch, a sense that perhaps ranks second to sight in dermatology, is absent in TD. In either synchronous (live-interactive, face video visits) or asynchronous (store-and-forward, where digital photographs and clinical information sent by patients or referring physicians are assessed at a later time) TD, the skin cannot be rubbed for texture, pinched for thickness, or pushed for blanching. Instead, all we have is vision. Irwin Braverman, MD, Professor Emeritus of Dermatology at Yale University (New Haven, Connecticut), alongside Jacqueline Dolev, MD, dermatologist and Yale graduate, and Linda Friedlaender, curator at the Yale Center for British Art, founded an observational skills workshop in which trainees learn to observe and describe the paintings housed in the museum, noting all memorable details: the color of the sky, the actions of the animals, and the facial expressions of the people. A study of 90 participants over a 2-year period found that following the workshop, the ability to identify key diagnostic details from clinical photography improved by more than 10%.⁶ Other studies also utilizing fine art as a medical training tool to improve “visual literacy” saw similarly increased sophistication in the description of clinical imagery, which translated to better diagnostic acumen.⁷ Confined to video and photographs, TD necessitates trainees and practicing dermatologists to be excellent visual diagnosticians. Although surveyed dermatologists believe TD is presently appropriate for acne, benign lesions, or follow-up appointments,³ conditions for which patients have been examined via TD have included drug eruptions, premalignant or malignant neoplasms, infections, and papulosquamous or inflammatory dermatoses.⁸ At the very least, clinicians should be versed in identifying those conditions that require in-person evaluation, as patients cannot be held responsible to distinguish which situations can and cannot be addressed virtually.

Issues of Patient-Physician Confidentiality

Teledermatology is not without its shortcomings; critics have noted diagnostic challenges with poor quality photographs or videos, inability to perform total-body skin examinations, and socioeconomic limitations due to broadband availability and speed.^5,9 Although most of these shortcomings are outside of our control, a key challenge within the purview of the provider is the protection of patient privacy.

Much of the salient concerns regarding patient-physician confidentiality involve asynchronous TD, where store-and-forward data sharing allows physicians to download patient photographs or information onto their personal email or smartphones.¹⁰ Although some hospital systems provide encryption software or hospital-sponsored devices to ensure security, physicians may opt to use their personal phones or laptops out of convenience or to save time.^10,11 One study found that less than 30% of smartphone users choose to activate user authentication on their devices, even ones as simple as a passphrase.¹¹ The digital exchange of information thus poses an immense risk for compromising protected health information (PHI), as personal devices can be easily lost, stolen, or hacked. Indeed, in 2015, more than 113 million individuals were affected by a breach of PHI, the majority over hacked network servers.¹² With the growing diversity of mediums through which PHI is exchanged, such as videoconferencing and instant messaging, the potential medicolegal risks of information breach continue to climb. The US Department of Health & Human Services urges health care providers to uphold best practices for security, including encrypting data, updating all software including antivirus software, using multifactor authentication, and following local cybersecurity regulations or recommendations.¹³ For synchronous TD, suggested best practices include utilizing headphones during live appointments, avoiding public wireless networks, and ensuring the provider and patient both scan the room with their device’s camera before the start of the visit.¹⁴

On the Horizon of Teledermatology

What can we expect in the coming years? Increased utilization of telemedicine will translate into data that will help address questions surrounding safety, diagnostic accuracy, privacy, and accessibility. One aspect of TD in need of clarity is a guideline on payment and reimbursement, and whether TD can continue to be financially attractive to providers. Starting in 2020, the Centers for Medicare & Medicaid Services removed geographic restrictions for reimbursement of telemedicine visits, enabling even urban-residing patients to enjoy the convenience of TD. This followed a prior relaxation of restrictions, where even prerecorded patient information became eligible for Medicare reimbursement.⁹ However, as virtual visits tend to be shorter with fewer diagnostic services compared to in-person visits, the reimbursement structure of TD must be nuanced, which is the subject of ongoing study and modification in the wake of the COVID-19 pandemic.¹⁵

Another point to consider is the explosion of direct-to-consumer TD, which allows patients to receive virtual dermatologic care or prescription medication without a pre-established relationship with any physician. In 2017, there were 22 direct-to-consumer TD services available to US patients in 45 states, 16 (73%) of which provided dermatologic care for any concern while 6 (27%) were limited to acne or antiaging and were largely prescription oriented. Orchestrated mostly by the for-profit private sector, direct-to-consumer companies are poorly regulated and have raised concerns over questionable practices, such as the use of non–US board-certified physicians, exorbitant fees, and failure to disclose medication side effects.¹⁶ A study of 16 direct-to-consumer telemedicine sites found substantial discordance in the suggested management of the same patient, and many of the services relied heavily on patient-provided self-diagnoses, such as a case where psoriasis medication was dispensed for a psoriasis patient who submitted a photograph of his syphilitic rash.¹⁷ Despite these problems, consumers show a willingness to pay out of pocket to access these services for their shorter waiting times and convenience.¹⁸ Hence, we must learn to ask about direct-to-consumer service use when obtaining a thorough history and be open to counseling our patients on the proper use and potential risks of direct-to-consumer TD.

Final Thoughts

The telemedicine industry is expected to reach more than $130 billion by 2025, with more than 90% of surveyed health care executives planning for the adoption and incorporation of telemedicine into their business models.¹⁹ The COVID-19 pandemic was an impetus for an exponential adoption of TD, and it would behoove current residents to realize that the practice of dermatology will continue to be increasingly digitalized within the coming years. Whether through formal training or self-assessment, we must strive to grow as proficient virtual dermatologists while upholding professionalism, patient safety, and health information privacy.

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

In this Update, the authors discuss 2 important areas that impact fertility. First, with in vitro fertilization (IVF), successful implantation that leads to live birth requires a normal embryo and a receptive endometrium. While research using advanced molecular array technology has resulted in a clinical test to identify the optimal window of implantation, recent evidence has questioned its clinical effectiveness. Second, recognizing the importance of endometriosis—a common disease with high burden that causes pain, infertility, and other symptoms—the World Health Organization (WHO) last year published an informative fact sheet that highlights the diagnosis, treatment options, and challenges of this significant disease.

Endometrial receptivity array and the quest for optimal endometrial preparation prior to embryo transfer in IVF

Bergin K, Eliner Y, Duvall DW Jr, et al. The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers. Fertil Steril. 2021;116:396-403.

Riestenberg C, Kroener L, Quinn M, et al. Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate. Fertil Steril. 2021;115:1001-1006.

Doyle N, Jahandideh S, Hill MJ, et al. A randomized controlled trial comparing live birth from single euploid frozen blastocyst transfer using standardized timing versus timing by endometrial receptivity analysis. Fertil Steril. 2021;116(suppl):e101.

A successful pregnancy requires optimal crosstalk between the embryo and the endometrium. Over the past several decades, research efforts to improve IVF outcomes have been focused mainly on the embryo factor and methods to improve embryo selection, such as extended culture to blastocyst, time-lapse imaging (morphokinetic assessment), and more notably, preimplantation genetic testing for aneuploidy (PGT-A). However, the other half of the equation, the endometrium, has not garnered the attention that it deserves. Effort has therefore been renewed to optimize the endometrial factor by better diagnosing and treating various forms of endometrial dysfunction that could lead to infertility in general and lack of success with IVF and euploid embryo transfers in particular.

Historical background on endometrial function

Progesterone has long been recognized as the main effector that transforms the estrogen-primed endometrium into a receptive state that results in successful embryo implantation. Progesterone exposure is required at appropriate levels and duration before the endometrium becomes receptive to the embryo. If implantation does not occur soon after the endometrium has attained receptive status (7–10 days after ovulation), further progesterone exposure results in progression of endometrial changes that no longer permit successful implantation.

As early as the 1950s, “luteal phase deficiency” was defined as due to inadequate progesterone secretion and resulted in a short luteal phase. In the 1970s, histologic “dating” of the endometrium became the gold standard for diagnosing luteal phase defects; this relied on a classic histologic appearance of secretory phase endometrium and its changes throughout the luteal phase. Subsequently, however, results of prospective randomized controlled trials published in 2004 cast significant doubt on the accuracy and reproducibility of these endometrial biopsies and did not show any clinical diagnostic benefit or correlation with pregnancy outcomes.

21st century advances: Endometrial dating 2.0

A decade later, with the advancement of molecular biology tools such as microarray technology, researchers were able to study endometrial gene expression patterns at different stages of the menstrual cycle. They identified different phases of endometrial development with molecular profiles, or “signatures,” for the luteal phase, endometriosis, polycystic ovary syndrome, and uterine fibroids.

In 2013, researchers in Spain introduced a diagnostic test called endometrial receptivity array (ERA) with the stated goal of being able to temporally define the receptive endometrium and identify prereceptive as well as postreceptive states.¹ In other words, instead of the histologic dating of the endometrium used in the 1970s, it represented “molecular dating” of the endometrium. Although the initial studies were conducted among women who experienced prior unsuccessful embryo transfers (the so-called recurrent implantation failure, or RIF), the test’s scope was subsequently expanded to include any individual planning on a frozen embryo transfer (FET), regardless of any prior attempts. The term personalized embryo transfer (pET) was coined to suggest the ability to define the best time (up to hours) for embryo transfers on an individual basis. Despite lack of independent validation studies, ERA was then widely adopted by many clinicians (and requested by some patients) with the hope of improving IVF outcomes.

However, not unlike many other novel innovations in assisted reproductive technology, ERA regrettably did not withstand the test of time. Three independent studies in 2021, 1 randomized clinical trial and 2 observational cohort studies, did not show any benefit with regard to implantation rates, pregnancy rates, or live birth rates when ERA was performed in the general infertility population.^2-4

Continue to: Study results...

Study results

The cohort study that matched 133 ERA patients with 353 non-ERA patients showed live birth rates of 49.62% for the ERA group and 54.96% for the non-ERA group (odds ratio [OR], 0.8074; 95% confidence interval [CI], 0.5424–1.2018).² Of note, no difference occurred between subgroups based on the prior number of FETs or the receptivity status (TABLE 1).

Another cohort study from the University of California, Los Angeles, published in 2021 analyzed 228 single euploid FET cycles.³ This study did not show any benefit for routine ERA testing, with a live birth rate of 56.6% in the non-ERA group and 56.5% in the ERA group.

Still, the most convincing evidence for the lack of benefit from routine ERA was noted from the results of the randomized clinical trial.⁴ A total of 767 patients were randomly allocated, 381 to the ERA group and 386 to the control group. There was no difference in ongoing pregnancy rates between the 2 groups. Perhaps more important, even after limiting the analysis to individuals with a nonreceptive ERA result, there was no difference in ongoing pregnancy rates between the 2 groups: 62.5% in the control group (default timing of transfer) and 55.5% in the study group (transfer timing adjusted based on ERA) (rate ratio [RR], 0.9; 95% CI, 0.70–1.14).

ERA usefulness is unsupported in general infertility population

The studies discussed collectively suggest with a high degree of certainty that there is no indication for routine ERA testing in the general infertility population prior to frozen embryo transfers.

Although these studies all were conducted in the general infertility population and did not specifically evaluate the performance of ERA in women with recurrent pregnancy loss or recurrent implantation failure, it is important to acknowledge that if ERA were truly able to define the window of receptivity, one would expect a lower implantation rate if the embryos were transferred outside of the window suggested by the ERA. This was not the case in these studies, as they all showed equivalent pregnancy rates in the control (nonadjusted) groups even when ERA suggested a nonreceptive status.

This observation seriously questions the validity of ERA regarding its ability to temporally define the window of receptivity. On the other hand, as stated earlier, there is still a possibility for ERA to be beneficial for a small subgroup of patients whose window of receptivity may not be as wide as expected in the general population. The challenging question would be how best to identify the particular group with a narrow, or displaced, window of receptivity.

Continue to: WHO raises awareness of endometriosis burden and...

WHO raises awareness of endometriosis burden and highlights need to address diagnosis and treatment for women’s reproductive health

World Health Organization. Endometriosis fact sheet. March 31, 2021. https://www.who.int/news-room /fact-sheets/detail/endometriosis. Accessed January 3, 2022.

The WHO published its first fact sheet on endometriosis in March 2021, recognizing endometriosis as a severe disease that affects almost 190 million women with life-impacting pain, infertility, other symptoms, and especially with chronic, significant emotional sequelae (TABLE 2).⁵ The disease’s variable and broad symptoms result in a lack of awareness and diagnosis by both women and health care providers, especially in low- and middle-income countries and in disadvantaged populations in developed countries. Increased awareness to promote earlier diagnosis, improved training for better management, expanded research for greater understanding, and policies that increase access to quality care are needed to ensure the reproductive health and rights of tens of millions of women with endometriosis.

Endometriosis characteristics and symptoms

Endometriosis is characterized by the presence of tissue resembling endometrium outside the uterus, where it causes a chronic inflammatory reaction that may result in the formation of scar tissue. Endometriotic lesions may be superficial, cystic ovarian endometriomas, or deep lesions, causing a myriad of pain and related symptoms.^6.7

Chronic pain may occur because pain centers in the brain become hyperresponsive over time (central sensitization); this can occur at any point throughout the life course of endometriosis, even when endometriosis lesions are no longer visible. Sometimes, endometriosis is asymptomatic. In addition, endometriosis can cause infertility through anatomic distortion and inflammatory, endocrinologic, and other pathways.

The origins of endometriosis are thought to be multifactorial and include retrograde menstruation, cellular metaplasia, and/or stem cells that spread through blood and lymphatic vessels. Endometriosis is estrogen dependent, but lesion growth also is affected by altered or impaired immunity, localized complex hormonal influences, genetics, and possibly environmental contaminants.

Impact on public health and reproductive rights

Endometriosis has significant social, public health, and economic implications. It can decrease quality of life and prevent girls and women from attending work or school.⁸ Painful sex can affect sexual health. The WHO states that, “Addressing endometriosis will empower those affected by it, by supporting their human right to the highest standard of sexual and reproductive health, quality of life, and overall well-being.”⁵

At present, no known way is available to prevent or cure endometriosis. Early diagnosis and treatment, however, may slow or halt its natural progression and associated symptoms.

Diagnostic steps and treatment options

Early suspicion of endometriosis is the most important factor, followed by a careful history of menstrual symptoms and chronic pelvic pain, early referral to specialists for ultrasonography or other imaging, and sometimes surgical or laparoscopic visualization. Empirical treatment can be begun without histologic or laparoscopic confirmation.

Endometriosis can be treated with medications and/or surgery depending on symptoms, lesions, desired outcome, and patient choice.^5,6 Common therapies include contraceptive steroids, nonsteroidal anti-inflammatory medications, and analgesics. Medical treatments focus on either lowering estrogen or increasing progesterone levels.

Surgery can remove endometriosis lesions, adhesions, and scar tissue. However, success in reducing pain symptoms and increasing pregnancy rates often depends on the extent of disease.

For infertility due to endometriosis, treatment options include laparoscopic surgical removal of endometriosis, ovarian stimulation with intrauterine insemination (IUI), and IVF. Multidisciplinary treatment addressing different symptoms and overall health often requires referral to pain experts and other specialists.⁹

The WHO perspective on endometriosis

Recognizing the importance of endometriosis and its impact on people’s sexual and reproductive health, quality of life, and overall well-being, the WHO is taking action to improve awareness, diagnosis, and treatment of endometriosis (TABLE 3).⁵ ●

CASE Embryo mix-up with 2 couples

A lawsuit was recently filed in California by a couple after the woman carried and gave birth to “the wrong child.” This was the second full-term pregnancy for the couple. The couple had undergone an unsuccessful in vitro fertilization (IVF) cycle in October 2018. The next IVF cycle in 2019 led to the birth of a daughter on September 24, 2019, who is the subject of this case.¹

At the time of birth, the couple suspected something was wrong because the baby had “jet-black hair and a complexion that was darker” than their complexions. The couple eventually obtained a DNA test, which confirmed in November 2019 that this was not their biological child.¹

A few weeks later, they learned that another woman who went to the same IVF clinic gave birth to a female baby 1 week after their daughter was born. Similarly, that baby did not resemble the parents, and DNA testing confirmed the baby belonged to the first couple. The couples ultimately exchanged the babies.¹

The legal claim filed against the IVF center and its owner (an obstetrician) was for breach of contract, medical malpractice, and infliction of emotional distress, including experiencing “disassociation” on the part of the couple(s). Each couple felt they did not get to experience the birth of their biological child, and, of course there was considerable distress in the process of learning that the child was not theirs and exchanging the birth child for the biological child. In addition, the couple who filed the suit had another child (now age 7 years), who begged them to keep the baby to whom they gave birth. The couple also reported experiencing panic attacks as a result of the events.¹

Medical considerations

As of 2018, more than 8 million IVF babies had been born, with the first in 1978 in the United Kingdom.² Advances in science and technology have improved the process. Storage tanks now have alarms and several safeguards to monitor the level of liquid nitrogen and immediately notify key personnel if levels are low (FIGURES 1 and 2). Preimplantation genetic testing is also readily available to assess the embryo prior to transfer into the uterus and identify various genetic problems.

Guidelines for embryo straw labelling are provided by the College of American Pathologists and the Centers for Disease Control and Prevention. The American Society for Reproductive Medicine (ASRM) also provides guidelines. When an error occurs, disclosure is recommended and ethical and legal counsel should be involved. Failing to disclose can lead to professional penalties.⁴

Unfortunately, despite these advances and guidelines, embryo mix-ups like the one in the above case do occur and receive public notice (See “Cross country embryo mix-up cases”).^5,6 A report from the University of Nevada assessed liability for embryo mix-ups in US fertility practices from 2000 to 2020.⁷ They evaluated 184,015 IVF cycles with 176 claims. Payments were made to plaintiffs in 21 cases, resulting in $15 million of awarded damages (average award was $199,188).⁷ The most common problem was in the embryology laboratory with an overall incidence of 0.03% of the total number of IVF cycles.⁷ To avoid damages, the authors emphasized the importance of following labeling guidelines when storing embryos, considering a 2-step read-back method prior to embryo transfer, and offering genetic testing when a discrepancy is noted in the record (TABLE).⁷

Other medical liability considerations

Embryo mix-ups are not the only source of problems and potential liability in IVF. At the 2021 Association of Sexual and Reproductive Medicine Annual Meeting, Applebaum et al presented results from a comprehensive review of malpractice litigation involving IVF in the United States.⁸ Using the legal database NEXIS Uni they identified 50 cases between 1986 and 2020 (32% of which were filed in New York state). Common thematic elements among patient allegations were embryology errors (eg, lost or destroyed embryos or incorrect sperm or egg donor), errors in preimplantation genetics, surgical or medical errors/complications, or misdiagnosis (eg, sexually transmitted disease screening or malignancy).⁸ Overall, the most common plaintiff complaint was negligence (26 cases) due to informed consent–related issues (9 cases), wrongful life or birth (9 cases), or negligent or intentional infliction of emotional distress (5 cases).⁸

In 48% of cases, the verdict was in favor of the defendant; it was for the plaintiff in 36% of cases and ongoing proceedings or partial judgement accounted for the remaining cases.⁸ Damages ranged from $4,171.45 to $50 million. The authors emphasized specific defense strategies, including the importance of careful labeling and handling of embryos, prompt disclosure when an error does occur, and awareness of the specific state statute(s) of limitations for medical malpractice claims.⁸

Continue to: Legal considerations...

The case at the beginning of this article is a “mix-up” case, in which an IVF center implanted the wrong embryo, resulting in the birth parents not being the biological parents.¹ As in that case, there may be (but are not always)^6,9 2 mix-ups, so that 2 couples have each other’s biological children. These cases may go unnoticed by the birth parent if the physical appearance is not unexpected and the parents never do genetic testing, or if the IVF center does not discover the error and inform the parents. Infrequently the cases make the news or the courts.^10,11

News accounts are not trials, and we do not suggest that all the facts discussed in news reports on the case described here are complete—or even accurate in the details reported. They are generally 1-sided, so there are other perspectives. To consider the legal issues, however, we will assume for discussion only that the facts are as they have been reported in the news coverage—with the understanding that the discovery and trial processes would undoubtedly bring to light many other important facts or corrections.

Negligence

Although there are several potential bases for liability (ie, contract or warranty claims, a form of product liability/defect) in mix-up and other artificial reproductive technology (ART), negligence or malpractice seem most likely.¹² “Negligence” here is intended to be simple negligence but may also include gross negligence or recklessness.

Although the incidence of errors in ART is unknown, there is limited evidence that suggests it is not a rare event. One study suggested >20% of fertility clinics knew of errors in processing or handling donor samples and embryos for implantation.¹³ Another study in the United Kingdom found that 1 in 1,000 IVF embryos were implanted in the wrong woman.¹⁴

Was there negligence? The first question in a malpractice or negligence-type action is, was there a professional relationship between the plaintiff who is claiming harm and the professional or organization defendant? The next question is whether the defendant was reasonably careful given the circumstances—that is, did the physician meet the “standard of care”? This is sometimes described as whether the professional’s actions would be acceptable (ie, reasonably prudent within the profession or specialty). If there was negligence, then the next question is, did that negligence cause an injury to the plaintiff?¹⁵

Determining the standard of care. The nature of the expected standard of care is dependent, in part, on the potential consequences of an error. For example, the care required when there is a significant risk of death from an error would be considerably more cautious than for an error that might result in small property damage. In this case study, a mix-up error is likely to be less severe than death, but is very substantial in terms of emotional harm and disruption. Thus, considerable care and attention would be expected to avoid these errors. They should be a “never” event. Institutions and physicians should give considerable attention to their processes and procedures to avoid the possibility of a mix-up error.¹⁶

Where did the negligence occur? There is an old tort doctrine “Res ipsa loquitor” (RIL) that means, “The thing speaks for itself.” Although there are several technical rules around the application of RIL as a presumption of negligence, it comes down to the proposition that some injuries do not occur without negligence. A traditional medical example is the sponge left in a patient during surgery—ordinarily that does not happen without some negligence. For RIL to be applied, usually the mechanism by which the injury occurred had to be under the control of the defendant (or the agents of the defendant).

The “mix-up” of embryos is an example of the kind of error that would not likely occur without negligence.¹⁷ But the embryo may not be in the exclusive control of any 1 institution. For example, the mistake could be made by the IVF center (or its employees), a separate facility that has processed or cryogenically stored the genetic materials, and independent physicians (not employees or agents of the center). Therefore, it is necessary to pinpoint where the negligence occurred and who is legally responsible. In some cases, a health care provider must take steps to ensure that its contractors have sufficient safeguards to avoid unnecessary harms. For example, an IVF center that uses an external cryogenic storage facility may have some obligation to know that the genetic material returned to the center is the same material that the center provided the storage facility in the first place and is properly identified.¹⁸

Assessing damages

From the facts as we have them, it appears that there must have been negligence that caused the mix-up of the embryos in the original case. It also appears reasonably clear that the negligence resulted in harm to both sets of parents and their families. This would suggest that the families should recover substantial damages. But that, somewhat surprisingly, may not be the case.¹⁹ Several legal principles may limit the availability or size of damages in mix-up cases. Also, it is worth remembering that there are differences in how states treat the different types of damages in these cases. Although the case was filed in California, we’ll take a more national view of the damages issue.

Not all harm is treated as equal. The first problem facing plaintiffs in mix-up cases may be the fact that they have suffered only emotional harm, without any physical injury. Traditionally, the courts have been reluctant to allow recovery in negligence for purely emotional injuries. Also “intentional” infliction of emotional distress does permit financial recovery, but generally “negligent” infliction of emotional harm traditionally has not. In part, this was because of the fear of unwarranted (and difficult-to-assess) claims of emotional harm that are not related to a physical harm. Some states developed a “zone of danger” exception (eg, where someone was almost hit by a car) or allowed some emotional injury recovery if there were “physical manifestations” of the emotional harm. In short, depending on the state’s rules, negligence that causes purely emotional harm may not be compensable.²⁰

State-based malpractice “caps.” Another limitation on emotional injuries is the “caps” on malpractice damages enacted by several states (including California, where this mix-up case occurred). Therefore, if a mix-up case is determined to be a malpractice case under state law, emotional suffering damages (which are non-economic damages) may be limited to the cap—$250,000 in California, for example—even if the state allows damages for emotional injuries without physical injuries.

The rare exception. Very careless labeling or handling of the identity of the embryo could at the extreme be considered gross negligence or recklessness. There are relatively inexpensive and easy procedures that could easily avoid what is likely to be significant harm to families (including emotional upset).²¹ Institutions that callously fail to use those procedures might be seen by some courts as reckless, or in outrageous cases, even intentional. An example would be the University of California Irvine Center for Reproductive Health case, in which physicians intentionally (without consent) used patients’ ova, fertilized them, and then implanted them in other patients, with at least 15 births, many lawsuits, and multimillion dollar settlements.²² In “intentional” cases, limitations on emotional injuries would usually not be major barriers to recovery of damages. However, those are legal stretches, and recovery is the exception rather than the rule.²³

Continue to: Additional legal concerns with IVF...

Additional legal concerns with IVF

Reproduction negligence cases include a large range of errors and injuries—not just embryo mix-ups. Courts have struggled with when it is appropriate to allow damages, even when there have been clear injuries. For the most part courts have been reluctant to find liability in many areas of new IVF technology.¹² One problem in determining how to assess damages is determining how incidental benefits should be used to offset some or all of the damages. For example, how should the joy of having a child offset the costs of raising the child?

There are more than a dozen kinds of current and likely future claims arising from problems with ART. It is tempting to conclude, “Oh, what a tangled legal web we weave when first we practice to artificially conceive.” There are various groupings of such claims, with several examples of cases presented in this article. It is not possible to consider those in detail in this article. As a general proposition, however, “our legal system treats wrongfully disrupted plans concerning reproduction like one of those life adversities that people are expected to abide without remedy.”²⁴

This is not to say, however, that there is no compensation for IVF-related injuries. Applebaum and colleagues found more than 100 cases in the 35 years covered by the study (1984-2020).⁸ However, only 50 of those cases fit the criteria for inclusion in their data. The successful cases for the plaintiffs involved medical or surgical error, while it appeared that various forms of wrongful life or birth were much less successful. It would be a mistake to conclude from these data that there are not, and will not be, meaningful risks of liability in the areas of IVF and ART more generally.

First, claims that fit with existing legal doctrine are producing liability. About half of the claims (25 over the 34 years) examined by Applebaum et al resulted in liability. Admittedly, that number was small because ART use was increasing. Where the claims fit well-recognized legal forms of damages and forms of action (primarily negligence), the liability could be substantial. A remarkable example of this is the case of Wuth v Lab. Corp (see “Liability for genetic testing errors”),²⁵ which was the largest verdict ($50 million) in the Applebaum and colleagues’ study.⁸ The large verdict was due to the failure of the testing company and a medical center to properly perform and assess a genetic test, which resulted in the birth of a child with an unbalanced chromosome translocation.^8,25 The child’s serious disabilities would require a great deal of expensive care. Although the jury held the testing laboratory and medical center liable, they did not find liability against the physician.²⁵ Ultimately, this case would be considered a failure of genetic testing rather than an IVF case.

Future challenges

The future is likely to bring substantially expanded IVF/ART liability for several reasons. ART is becoming more common. Although courts have struggled with how to apply existing liability rules to the new technologies and related novel legal claims, the absence of established legal principles into which IVF injuries fit will not last forever. The legal system eventually finds ways of adjusting old rules or adopting new ones to cover injuries from new technology.

Although IVF injuries that most people feel deserve compensation currently are not cognizable in law, that will undoubtedly change. Either the courts will find new ways of assessing ART claims, or state legislatures and Congress will step in with legislation. To date, Congress has been relatively “hands off” on the ART processes, with the Fertility Clinic Success Rate and Certification Act of 1992 being a notable exception.²⁴ This law requires ART programs to report success rates and directs the Centers for Disease Control and Prevention (CDC) to publish reported success rates and laboratory incidents. It also establishes a model state laboratory certification program.²⁴ The CDC has an outline of the work under the statute,²⁶ as well as state-specific data regarding ART²⁷ and lists of publications in key areas.²⁸ In addition there are various state laws related to recordkeeping, donor qualifications, licensing, and family law issues.²⁹ Ultimately, physicians, scientists, and legal professionals can perform a valuable role in helping to fashion IVF liability principles that are workable and reasonable, that will not interfere with the progress of medicine, and that will ensure that those injured through carelessness or bad medicine receive compensation. ●

CASE Embryo mix-up with 2 couples

A lawsuit was recently filed in California by a couple after the woman carried and gave birth to “the wrong child.” This was the second full-term pregnancy for the couple. The couple had undergone an unsuccessful in vitro fertilization (IVF) cycle in October 2018. The next IVF cycle in 2019 led to the birth of a daughter on September 24, 2019, who is the subject of this case.¹

At the time of birth, the couple suspected something was wrong because the baby had “jet-black hair and a complexion that was darker” than their complexions. The couple eventually obtained a DNA test, which confirmed in November 2019 that this was not their biological child.¹

A few weeks later, they learned that another woman who went to the same IVF clinic gave birth to a female baby 1 week after their daughter was born. Similarly, that baby did not resemble the parents, and DNA testing confirmed the baby belonged to the first couple. The couples ultimately exchanged the babies.¹

The legal claim filed against the IVF center and its owner (an obstetrician) was for breach of contract, medical malpractice, and infliction of emotional distress, including experiencing “disassociation” on the part of the couple(s). Each couple felt they did not get to experience the birth of their biological child, and, of course there was considerable distress in the process of learning that the child was not theirs and exchanging the birth child for the biological child. In addition, the couple who filed the suit had another child (now age 7 years), who begged them to keep the baby to whom they gave birth. The couple also reported experiencing panic attacks as a result of the events.¹

Medical considerations

As of 2018, more than 8 million IVF babies had been born, with the first in 1978 in the United Kingdom.² Advances in science and technology have improved the process. Storage tanks now have alarms and several safeguards to monitor the level of liquid nitrogen and immediately notify key personnel if levels are low (FIGURES 1 and 2). Preimplantation genetic testing is also readily available to assess the embryo prior to transfer into the uterus and identify various genetic problems.

Guidelines for embryo straw labelling are provided by the College of American Pathologists and the Centers for Disease Control and Prevention. The American Society for Reproductive Medicine (ASRM) also provides guidelines. When an error occurs, disclosure is recommended and ethical and legal counsel should be involved. Failing to disclose can lead to professional penalties.⁴

Unfortunately, despite these advances and guidelines, embryo mix-ups like the one in the above case do occur and receive public notice (See “Cross country embryo mix-up cases”).^5,6 A report from the University of Nevada assessed liability for embryo mix-ups in US fertility practices from 2000 to 2020.⁷ They evaluated 184,015 IVF cycles with 176 claims. Payments were made to plaintiffs in 21 cases, resulting in $15 million of awarded damages (average award was $199,188).⁷ The most common problem was in the embryology laboratory with an overall incidence of 0.03% of the total number of IVF cycles.⁷ To avoid damages, the authors emphasized the importance of following labeling guidelines when storing embryos, considering a 2-step read-back method prior to embryo transfer, and offering genetic testing when a discrepancy is noted in the record (TABLE).⁷

Other medical liability considerations

Embryo mix-ups are not the only source of problems and potential liability in IVF. At the 2021 Association of Sexual and Reproductive Medicine Annual Meeting, Applebaum et al presented results from a comprehensive review of malpractice litigation involving IVF in the United States.⁸ Using the legal database NEXIS Uni they identified 50 cases between 1986 and 2020 (32% of which were filed in New York state). Common thematic elements among patient allegations were embryology errors (eg, lost or destroyed embryos or incorrect sperm or egg donor), errors in preimplantation genetics, surgical or medical errors/complications, or misdiagnosis (eg, sexually transmitted disease screening or malignancy).⁸ Overall, the most common plaintiff complaint was negligence (26 cases) due to informed consent–related issues (9 cases), wrongful life or birth (9 cases), or negligent or intentional infliction of emotional distress (5 cases).⁸

In 48% of cases, the verdict was in favor of the defendant; it was for the plaintiff in 36% of cases and ongoing proceedings or partial judgement accounted for the remaining cases.⁸ Damages ranged from $4,171.45 to $50 million. The authors emphasized specific defense strategies, including the importance of careful labeling and handling of embryos, prompt disclosure when an error does occur, and awareness of the specific state statute(s) of limitations for medical malpractice claims.⁸

Continue to: Legal considerations...

The case at the beginning of this article is a “mix-up” case, in which an IVF center implanted the wrong embryo, resulting in the birth parents not being the biological parents.¹ As in that case, there may be (but are not always)^6,9 2 mix-ups, so that 2 couples have each other’s biological children. These cases may go unnoticed by the birth parent if the physical appearance is not unexpected and the parents never do genetic testing, or if the IVF center does not discover the error and inform the parents. Infrequently the cases make the news or the courts.^10,11

News accounts are not trials, and we do not suggest that all the facts discussed in news reports on the case described here are complete—or even accurate in the details reported. They are generally 1-sided, so there are other perspectives. To consider the legal issues, however, we will assume for discussion only that the facts are as they have been reported in the news coverage—with the understanding that the discovery and trial processes would undoubtedly bring to light many other important facts or corrections.

Negligence

Although there are several potential bases for liability (ie, contract or warranty claims, a form of product liability/defect) in mix-up and other artificial reproductive technology (ART), negligence or malpractice seem most likely.¹² “Negligence” here is intended to be simple negligence but may also include gross negligence or recklessness.

Although the incidence of errors in ART is unknown, there is limited evidence that suggests it is not a rare event. One study suggested >20% of fertility clinics knew of errors in processing or handling donor samples and embryos for implantation.¹³ Another study in the United Kingdom found that 1 in 1,000 IVF embryos were implanted in the wrong woman.¹⁴

Was there negligence? The first question in a malpractice or negligence-type action is, was there a professional relationship between the plaintiff who is claiming harm and the professional or organization defendant? The next question is whether the defendant was reasonably careful given the circumstances—that is, did the physician meet the “standard of care”? This is sometimes described as whether the professional’s actions would be acceptable (ie, reasonably prudent within the profession or specialty). If there was negligence, then the next question is, did that negligence cause an injury to the plaintiff?¹⁵

Determining the standard of care. The nature of the expected standard of care is dependent, in part, on the potential consequences of an error. For example, the care required when there is a significant risk of death from an error would be considerably more cautious than for an error that might result in small property damage. In this case study, a mix-up error is likely to be less severe than death, but is very substantial in terms of emotional harm and disruption. Thus, considerable care and attention would be expected to avoid these errors. They should be a “never” event. Institutions and physicians should give considerable attention to their processes and procedures to avoid the possibility of a mix-up error.¹⁶

Where did the negligence occur? There is an old tort doctrine “Res ipsa loquitor” (RIL) that means, “The thing speaks for itself.” Although there are several technical rules around the application of RIL as a presumption of negligence, it comes down to the proposition that some injuries do not occur without negligence. A traditional medical example is the sponge left in a patient during surgery—ordinarily that does not happen without some negligence. For RIL to be applied, usually the mechanism by which the injury occurred had to be under the control of the defendant (or the agents of the defendant).

The “mix-up” of embryos is an example of the kind of error that would not likely occur without negligence.¹⁷ But the embryo may not be in the exclusive control of any 1 institution. For example, the mistake could be made by the IVF center (or its employees), a separate facility that has processed or cryogenically stored the genetic materials, and independent physicians (not employees or agents of the center). Therefore, it is necessary to pinpoint where the negligence occurred and who is legally responsible. In some cases, a health care provider must take steps to ensure that its contractors have sufficient safeguards to avoid unnecessary harms. For example, an IVF center that uses an external cryogenic storage facility may have some obligation to know that the genetic material returned to the center is the same material that the center provided the storage facility in the first place and is properly identified.¹⁸

Assessing damages

From the facts as we have them, it appears that there must have been negligence that caused the mix-up of the embryos in the original case. It also appears reasonably clear that the negligence resulted in harm to both sets of parents and their families. This would suggest that the families should recover substantial damages. But that, somewhat surprisingly, may not be the case.¹⁹ Several legal principles may limit the availability or size of damages in mix-up cases. Also, it is worth remembering that there are differences in how states treat the different types of damages in these cases. Although the case was filed in California, we’ll take a more national view of the damages issue.

Not all harm is treated as equal. The first problem facing plaintiffs in mix-up cases may be the fact that they have suffered only emotional harm, without any physical injury. Traditionally, the courts have been reluctant to allow recovery in negligence for purely emotional injuries. Also “intentional” infliction of emotional distress does permit financial recovery, but generally “negligent” infliction of emotional harm traditionally has not. In part, this was because of the fear of unwarranted (and difficult-to-assess) claims of emotional harm that are not related to a physical harm. Some states developed a “zone of danger” exception (eg, where someone was almost hit by a car) or allowed some emotional injury recovery if there were “physical manifestations” of the emotional harm. In short, depending on the state’s rules, negligence that causes purely emotional harm may not be compensable.²⁰

State-based malpractice “caps.” Another limitation on emotional injuries is the “caps” on malpractice damages enacted by several states (including California, where this mix-up case occurred). Therefore, if a mix-up case is determined to be a malpractice case under state law, emotional suffering damages (which are non-economic damages) may be limited to the cap—$250,000 in California, for example—even if the state allows damages for emotional injuries without physical injuries.

The rare exception. Very careless labeling or handling of the identity of the embryo could at the extreme be considered gross negligence or recklessness. There are relatively inexpensive and easy procedures that could easily avoid what is likely to be significant harm to families (including emotional upset).²¹ Institutions that callously fail to use those procedures might be seen by some courts as reckless, or in outrageous cases, even intentional. An example would be the University of California Irvine Center for Reproductive Health case, in which physicians intentionally (without consent) used patients’ ova, fertilized them, and then implanted them in other patients, with at least 15 births, many lawsuits, and multimillion dollar settlements.²² In “intentional” cases, limitations on emotional injuries would usually not be major barriers to recovery of damages. However, those are legal stretches, and recovery is the exception rather than the rule.²³

Continue to: Additional legal concerns with IVF...

Additional legal concerns with IVF

Reproduction negligence cases include a large range of errors and injuries—not just embryo mix-ups. Courts have struggled with when it is appropriate to allow damages, even when there have been clear injuries. For the most part courts have been reluctant to find liability in many areas of new IVF technology.¹² One problem in determining how to assess damages is determining how incidental benefits should be used to offset some or all of the damages. For example, how should the joy of having a child offset the costs of raising the child?

There are more than a dozen kinds of current and likely future claims arising from problems with ART. It is tempting to conclude, “Oh, what a tangled legal web we weave when first we practice to artificially conceive.” There are various groupings of such claims, with several examples of cases presented in this article. It is not possible to consider those in detail in this article. As a general proposition, however, “our legal system treats wrongfully disrupted plans concerning reproduction like one of those life adversities that people are expected to abide without remedy.”²⁴

This is not to say, however, that there is no compensation for IVF-related injuries. Applebaum and colleagues found more than 100 cases in the 35 years covered by the study (1984-2020).⁸ However, only 50 of those cases fit the criteria for inclusion in their data. The successful cases for the plaintiffs involved medical or surgical error, while it appeared that various forms of wrongful life or birth were much less successful. It would be a mistake to conclude from these data that there are not, and will not be, meaningful risks of liability in the areas of IVF and ART more generally.

First, claims that fit with existing legal doctrine are producing liability. About half of the claims (25 over the 34 years) examined by Applebaum et al resulted in liability. Admittedly, that number was small because ART use was increasing. Where the claims fit well-recognized legal forms of damages and forms of action (primarily negligence), the liability could be substantial. A remarkable example of this is the case of Wuth v Lab. Corp (see “Liability for genetic testing errors”),²⁵ which was the largest verdict ($50 million) in the Applebaum and colleagues’ study.⁸ The large verdict was due to the failure of the testing company and a medical center to properly perform and assess a genetic test, which resulted in the birth of a child with an unbalanced chromosome translocation.^8,25 The child’s serious disabilities would require a great deal of expensive care. Although the jury held the testing laboratory and medical center liable, they did not find liability against the physician.²⁵ Ultimately, this case would be considered a failure of genetic testing rather than an IVF case.

Future challenges

The future is likely to bring substantially expanded IVF/ART liability for several reasons. ART is becoming more common. Although courts have struggled with how to apply existing liability rules to the new technologies and related novel legal claims, the absence of established legal principles into which IVF injuries fit will not last forever. The legal system eventually finds ways of adjusting old rules or adopting new ones to cover injuries from new technology.

Although IVF injuries that most people feel deserve compensation currently are not cognizable in law, that will undoubtedly change. Either the courts will find new ways of assessing ART claims, or state legislatures and Congress will step in with legislation. To date, Congress has been relatively “hands off” on the ART processes, with the Fertility Clinic Success Rate and Certification Act of 1992 being a notable exception.²⁴ This law requires ART programs to report success rates and directs the Centers for Disease Control and Prevention (CDC) to publish reported success rates and laboratory incidents. It also establishes a model state laboratory certification program.²⁴ The CDC has an outline of the work under the statute,²⁶ as well as state-specific data regarding ART²⁷ and lists of publications in key areas.²⁸ In addition there are various state laws related to recordkeeping, donor qualifications, licensing, and family law issues.²⁹ Ultimately, physicians, scientists, and legal professionals can perform a valuable role in helping to fashion IVF liability principles that are workable and reasonable, that will not interfere with the progress of medicine, and that will ensure that those injured through carelessness or bad medicine receive compensation. ●

CASE Embryo mix-up with 2 couples

A lawsuit was recently filed in California by a couple after the woman carried and gave birth to “the wrong child.” This was the second full-term pregnancy for the couple. The couple had undergone an unsuccessful in vitro fertilization (IVF) cycle in October 2018. The next IVF cycle in 2019 led to the birth of a daughter on September 24, 2019, who is the subject of this case.¹

At the time of birth, the couple suspected something was wrong because the baby had “jet-black hair and a complexion that was darker” than their complexions. The couple eventually obtained a DNA test, which confirmed in November 2019 that this was not their biological child.¹

A few weeks later, they learned that another woman who went to the same IVF clinic gave birth to a female baby 1 week after their daughter was born. Similarly, that baby did not resemble the parents, and DNA testing confirmed the baby belonged to the first couple. The couples ultimately exchanged the babies.¹

The legal claim filed against the IVF center and its owner (an obstetrician) was for breach of contract, medical malpractice, and infliction of emotional distress, including experiencing “disassociation” on the part of the couple(s). Each couple felt they did not get to experience the birth of their biological child, and, of course there was considerable distress in the process of learning that the child was not theirs and exchanging the birth child for the biological child. In addition, the couple who filed the suit had another child (now age 7 years), who begged them to keep the baby to whom they gave birth. The couple also reported experiencing panic attacks as a result of the events.¹

Medical considerations

As of 2018, more than 8 million IVF babies had been born, with the first in 1978 in the United Kingdom.² Advances in science and technology have improved the process. Storage tanks now have alarms and several safeguards to monitor the level of liquid nitrogen and immediately notify key personnel if levels are low (FIGURES 1 and 2). Preimplantation genetic testing is also readily available to assess the embryo prior to transfer into the uterus and identify various genetic problems.

Guidelines for embryo straw labelling are provided by the College of American Pathologists and the Centers for Disease Control and Prevention. The American Society for Reproductive Medicine (ASRM) also provides guidelines. When an error occurs, disclosure is recommended and ethical and legal counsel should be involved. Failing to disclose can lead to professional penalties.⁴

Unfortunately, despite these advances and guidelines, embryo mix-ups like the one in the above case do occur and receive public notice (See “Cross country embryo mix-up cases”).^5,6 A report from the University of Nevada assessed liability for embryo mix-ups in US fertility practices from 2000 to 2020.⁷ They evaluated 184,015 IVF cycles with 176 claims. Payments were made to plaintiffs in 21 cases, resulting in $15 million of awarded damages (average award was $199,188).⁷ The most common problem was in the embryology laboratory with an overall incidence of 0.03% of the total number of IVF cycles.⁷ To avoid damages, the authors emphasized the importance of following labeling guidelines when storing embryos, considering a 2-step read-back method prior to embryo transfer, and offering genetic testing when a discrepancy is noted in the record (TABLE).⁷

Other medical liability considerations

Embryo mix-ups are not the only source of problems and potential liability in IVF. At the 2021 Association of Sexual and Reproductive Medicine Annual Meeting, Applebaum et al presented results from a comprehensive review of malpractice litigation involving IVF in the United States.⁸ Using the legal database NEXIS Uni they identified 50 cases between 1986 and 2020 (32% of which were filed in New York state). Common thematic elements among patient allegations were embryology errors (eg, lost or destroyed embryos or incorrect sperm or egg donor), errors in preimplantation genetics, surgical or medical errors/complications, or misdiagnosis (eg, sexually transmitted disease screening or malignancy).⁸ Overall, the most common plaintiff complaint was negligence (26 cases) due to informed consent–related issues (9 cases), wrongful life or birth (9 cases), or negligent or intentional infliction of emotional distress (5 cases).⁸

In 48% of cases, the verdict was in favor of the defendant; it was for the plaintiff in 36% of cases and ongoing proceedings or partial judgement accounted for the remaining cases.⁸ Damages ranged from $4,171.45 to $50 million. The authors emphasized specific defense strategies, including the importance of careful labeling and handling of embryos, prompt disclosure when an error does occur, and awareness of the specific state statute(s) of limitations for medical malpractice claims.⁸

Continue to: Legal considerations...

The case at the beginning of this article is a “mix-up” case, in which an IVF center implanted the wrong embryo, resulting in the birth parents not being the biological parents.¹ As in that case, there may be (but are not always)^6,9 2 mix-ups, so that 2 couples have each other’s biological children. These cases may go unnoticed by the birth parent if the physical appearance is not unexpected and the parents never do genetic testing, or if the IVF center does not discover the error and inform the parents. Infrequently the cases make the news or the courts.^10,11

News accounts are not trials, and we do not suggest that all the facts discussed in news reports on the case described here are complete—or even accurate in the details reported. They are generally 1-sided, so there are other perspectives. To consider the legal issues, however, we will assume for discussion only that the facts are as they have been reported in the news coverage—with the understanding that the discovery and trial processes would undoubtedly bring to light many other important facts or corrections.

Negligence

Although there are several potential bases for liability (ie, contract or warranty claims, a form of product liability/defect) in mix-up and other artificial reproductive technology (ART), negligence or malpractice seem most likely.¹² “Negligence” here is intended to be simple negligence but may also include gross negligence or recklessness.

Although the incidence of errors in ART is unknown, there is limited evidence that suggests it is not a rare event. One study suggested >20% of fertility clinics knew of errors in processing or handling donor samples and embryos for implantation.¹³ Another study in the United Kingdom found that 1 in 1,000 IVF embryos were implanted in the wrong woman.¹⁴

Was there negligence? The first question in a malpractice or negligence-type action is, was there a professional relationship between the plaintiff who is claiming harm and the professional or organization defendant? The next question is whether the defendant was reasonably careful given the circumstances—that is, did the physician meet the “standard of care”? This is sometimes described as whether the professional’s actions would be acceptable (ie, reasonably prudent within the profession or specialty). If there was negligence, then the next question is, did that negligence cause an injury to the plaintiff?¹⁵

Determining the standard of care. The nature of the expected standard of care is dependent, in part, on the potential consequences of an error. For example, the care required when there is a significant risk of death from an error would be considerably more cautious than for an error that might result in small property damage. In this case study, a mix-up error is likely to be less severe than death, but is very substantial in terms of emotional harm and disruption. Thus, considerable care and attention would be expected to avoid these errors. They should be a “never” event. Institutions and physicians should give considerable attention to their processes and procedures to avoid the possibility of a mix-up error.¹⁶

Where did the negligence occur? There is an old tort doctrine “Res ipsa loquitor” (RIL) that means, “The thing speaks for itself.” Although there are several technical rules around the application of RIL as a presumption of negligence, it comes down to the proposition that some injuries do not occur without negligence. A traditional medical example is the sponge left in a patient during surgery—ordinarily that does not happen without some negligence. For RIL to be applied, usually the mechanism by which the injury occurred had to be under the control of the defendant (or the agents of the defendant).

The “mix-up” of embryos is an example of the kind of error that would not likely occur without negligence.¹⁷ But the embryo may not be in the exclusive control of any 1 institution. For example, the mistake could be made by the IVF center (or its employees), a separate facility that has processed or cryogenically stored the genetic materials, and independent physicians (not employees or agents of the center). Therefore, it is necessary to pinpoint where the negligence occurred and who is legally responsible. In some cases, a health care provider must take steps to ensure that its contractors have sufficient safeguards to avoid unnecessary harms. For example, an IVF center that uses an external cryogenic storage facility may have some obligation to know that the genetic material returned to the center is the same material that the center provided the storage facility in the first place and is properly identified.¹⁸

Assessing damages

From the facts as we have them, it appears that there must have been negligence that caused the mix-up of the embryos in the original case. It also appears reasonably clear that the negligence resulted in harm to both sets of parents and their families. This would suggest that the families should recover substantial damages. But that, somewhat surprisingly, may not be the case.¹⁹ Several legal principles may limit the availability or size of damages in mix-up cases. Also, it is worth remembering that there are differences in how states treat the different types of damages in these cases. Although the case was filed in California, we’ll take a more national view of the damages issue.

Not all harm is treated as equal. The first problem facing plaintiffs in mix-up cases may be the fact that they have suffered only emotional harm, without any physical injury. Traditionally, the courts have been reluctant to allow recovery in negligence for purely emotional injuries. Also “intentional” infliction of emotional distress does permit financial recovery, but generally “negligent” infliction of emotional harm traditionally has not. In part, this was because of the fear of unwarranted (and difficult-to-assess) claims of emotional harm that are not related to a physical harm. Some states developed a “zone of danger” exception (eg, where someone was almost hit by a car) or allowed some emotional injury recovery if there were “physical manifestations” of the emotional harm. In short, depending on the state’s rules, negligence that causes purely emotional harm may not be compensable.²⁰

State-based malpractice “caps.” Another limitation on emotional injuries is the “caps” on malpractice damages enacted by several states (including California, where this mix-up case occurred). Therefore, if a mix-up case is determined to be a malpractice case under state law, emotional suffering damages (which are non-economic damages) may be limited to the cap—$250,000 in California, for example—even if the state allows damages for emotional injuries without physical injuries.

The rare exception. Very careless labeling or handling of the identity of the embryo could at the extreme be considered gross negligence or recklessness. There are relatively inexpensive and easy procedures that could easily avoid what is likely to be significant harm to families (including emotional upset).²¹ Institutions that callously fail to use those procedures might be seen by some courts as reckless, or in outrageous cases, even intentional. An example would be the University of California Irvine Center for Reproductive Health case, in which physicians intentionally (without consent) used patients’ ova, fertilized them, and then implanted them in other patients, with at least 15 births, many lawsuits, and multimillion dollar settlements.²² In “intentional” cases, limitations on emotional injuries would usually not be major barriers to recovery of damages. However, those are legal stretches, and recovery is the exception rather than the rule.²³

Continue to: Additional legal concerns with IVF...

Additional legal concerns with IVF

Reproduction negligence cases include a large range of errors and injuries—not just embryo mix-ups. Courts have struggled with when it is appropriate to allow damages, even when there have been clear injuries. For the most part courts have been reluctant to find liability in many areas of new IVF technology.¹² One problem in determining how to assess damages is determining how incidental benefits should be used to offset some or all of the damages. For example, how should the joy of having a child offset the costs of raising the child?

There are more than a dozen kinds of current and likely future claims arising from problems with ART. It is tempting to conclude, “Oh, what a tangled legal web we weave when first we practice to artificially conceive.” There are various groupings of such claims, with several examples of cases presented in this article. It is not possible to consider those in detail in this article. As a general proposition, however, “our legal system treats wrongfully disrupted plans concerning reproduction like one of those life adversities that people are expected to abide without remedy.”²⁴

This is not to say, however, that there is no compensation for IVF-related injuries. Applebaum and colleagues found more than 100 cases in the 35 years covered by the study (1984-2020).⁸ However, only 50 of those cases fit the criteria for inclusion in their data. The successful cases for the plaintiffs involved medical or surgical error, while it appeared that various forms of wrongful life or birth were much less successful. It would be a mistake to conclude from these data that there are not, and will not be, meaningful risks of liability in the areas of IVF and ART more generally.

First, claims that fit with existing legal doctrine are producing liability. About half of the claims (25 over the 34 years) examined by Applebaum et al resulted in liability. Admittedly, that number was small because ART use was increasing. Where the claims fit well-recognized legal forms of damages and forms of action (primarily negligence), the liability could be substantial. A remarkable example of this is the case of Wuth v Lab. Corp (see “Liability for genetic testing errors”),²⁵ which was the largest verdict ($50 million) in the Applebaum and colleagues’ study.⁸ The large verdict was due to the failure of the testing company and a medical center to properly perform and assess a genetic test, which resulted in the birth of a child with an unbalanced chromosome translocation.^8,25 The child’s serious disabilities would require a great deal of expensive care. Although the jury held the testing laboratory and medical center liable, they did not find liability against the physician.²⁵ Ultimately, this case would be considered a failure of genetic testing rather than an IVF case.

Future challenges

The future is likely to bring substantially expanded IVF/ART liability for several reasons. ART is becoming more common. Although courts have struggled with how to apply existing liability rules to the new technologies and related novel legal claims, the absence of established legal principles into which IVF injuries fit will not last forever. The legal system eventually finds ways of adjusting old rules or adopting new ones to cover injuries from new technology.

Although IVF injuries that most people feel deserve compensation currently are not cognizable in law, that will undoubtedly change. Either the courts will find new ways of assessing ART claims, or state legislatures and Congress will step in with legislation. To date, Congress has been relatively “hands off” on the ART processes, with the Fertility Clinic Success Rate and Certification Act of 1992 being a notable exception.²⁴ This law requires ART programs to report success rates and directs the Centers for Disease Control and Prevention (CDC) to publish reported success rates and laboratory incidents. It also establishes a model state laboratory certification program.²⁴ The CDC has an outline of the work under the statute,²⁶ as well as state-specific data regarding ART²⁷ and lists of publications in key areas.²⁸ In addition there are various state laws related to recordkeeping, donor qualifications, licensing, and family law issues.²⁹ Ultimately, physicians, scientists, and legal professionals can perform a valuable role in helping to fashion IVF liability principles that are workable and reasonable, that will not interfere with the progress of medicine, and that will ensure that those injured through carelessness or bad medicine receive compensation. ●

Women who undergo bilateral salpingo-oophorectomy (BSO) for various indications prior to menopause experience a rapid decline in ovarian hormone levels and consequent vasomotor and other menopausal symptoms. In addition, the resulting estrogen deprivation is associated with such long-term adverse outcomes as osteoporosis and cardiovascular morbidity.

OBG Management convened a roundtable with 3 experts who discussed health considerations in women who have undergone BSO prior to the age of natural menopause¹ to further explore the issues involved in managing hormone therapy (HT) in these patients. Stephanie Faubion, MD, MBA, NCMP, moderated the exchange.

Surgical vs natural menopause

Stephanie Faubion, MD, MBA, NCMP: Since the Women’s Health Initiative study was published in 2002,² many clinicians have been fearful of using systemic HT in menopausal women, and HT use has declined dramatically such that only about 4% to 6% of menopausal women are now receiving systemic HT. Importantly, however, a group of younger menopausal women also are not receiving HT, and that is women who undergo BSO before they reach the average age of menopause, which in the United States is about age 52; this is sometimes referred to as surgical menopause or early surgical menopause. Early surgical menopause has different connotations for long-term health risks than natural menopause at the average age, and we are here to discuss these health effects and their management.

My name is Stephanie Faubion, and I am a women’s health internist and the Chair of the Department of Medicine at Mayo Clinic in Jacksonville, Florida, and Director of Mayo Clinic Women’s Health. I am here with 2 of my esteemed colleagues, Dr. Andrew Kaunitz and Dr. Ekta Kapoor.

Andrew M. Kaunitz, MD, NCMP: Hello, I am an ObGyn with the University of Florida College of Medicine in Jacksonville, with particular interests in contraception, menopause, and gynecologic ultrasonography.

Ekta Kapoor, MBBS, NCMP: And I am an endocrinologist at Mayo Clinic in Rochester with a specific interest in menopause and hormone therapy. I am also the Assistant Director for Mayo Clinic Women’s Health.

Higher-than-standard estrogen doses needed in younger menopausal women

Dr. Faubion: Let’s consider a couple of cases so that we can illustrate some important points regarding hormone management in women who have undergone BSO before the age of natural menopause.

Our first case patient is a woman who is 41 years of age and, because of adenomyosis, she will undergo a hysterectomy. She tells her clinician that she is very concerned about ovarian cancer risk because one of her good friends recently was diagnosed with ovarian cancer, and together they decide to remove her ovaries at the time of hysterectomy. Notably, her ovaries were healthy.

The patient is now menopausal postsurgery, and she is having significant hot flashes and night sweats. She visits her local internist, who is concerned about initiating HT. She is otherwise a healthy woman and does not have any contraindications to HT. Dr. Kaunitz, what would you tell her internist?

Dr. Kaunitz: We are dealing with 2 different issues in terms of decision making about systemic HT for this 41-year-old who has undergone BSO. First, as you mentioned, Dr. Faubion, she has bothersome hot flashes, or vasomotor symptoms. Unless there are contraindications, systemic HT would be appropriate. Although I might start treatment at standard doses, and the accompanying TABLE depicts standard doses for the 2 most common oral estrogen formulations as well as transdermal estradiol, it’s important to recognize that younger menopausal women often will need to use higher-than-standard doses.

For example, for a 53-year-old woman who has been menopausal for a year or 2 and now has bothersome symptoms, I might start her on estradiol 1 mg tablets with progestin if a uterus is present. However, in this 41-year-old case patient, while I might start treatment at a standard dose, I would anticipate increasing to higher doses, such as 1.5 or 2 mg of daily estradiol until she feels her menopausal symptoms are adequately addressed.

Dr. Faubion: It is important to note that sometimes women with early BSO tend to have more severe vasomotor symptoms. Do you find that sometimes a higher dose is required just to manage symptoms, Dr. Kaunitz?

Dr. Kaunitz: Absolutely, yes. The decision whether or not to use systemic HT might be considered discretionary or elective in the classic 53-year-old woman recently menopausal with hot flashes, a so-called spontaneously or naturally menopausal woman. But my perspective is that unless there are clear contraindications, the decision to start systemic HT in the 41-year-old BSO case patient is actually not discretionary. Unless contraindications are present, it is important not only to treat symptoms but also to prevent an array of chronic major health concerns that are more likely if we don’t prescribe systemic HT.

Continue to: Health effects of not using HT...

Dr. Faubion: Dr. Kapoor, can you describe the potential long-term adverse health consequences of not using estrogen therapy? Say the same 41-year-old woman does not have many bothersome symptoms. What would you do?

Dr. Kapoor: Thank you for that important question. Building on what Dr. Kaunitz said, in these patients there are really 2 issues that can seem to be independent but are not: The first relates to the immediate consequences of lack of estrogen, ie, the menopause-related symptoms, but the second and perhaps the bigger issue is the long-term risk associated with estrogen deprivation.

The symptoms in these women are often obvious as they can be quite severe and abrupt; one day these women have normal hormone levels and the next day, after BSO, suddenly their hormones are very low. So if symptoms occur, they are usually hard to miss, simply because they are very drastic and very severe.

Historically, patients and their clinicians have targeted these symptoms. Patients experience menopausal symptoms, they seek treatment, and then the clinicians basically titrate the treatment to manage these symptoms. That misses the bigger issue, however, which is that premature estrogen deprivation leads to a host of chronic health conditions, as Dr. Kaunitz mentioned. These mainly include increased risk for cardiovascular disease, diabetes, hypertension, dyslipidemia, increased risk of mortality, dementia, and osteoporosis.

Fairly strong observational evidence suggests that use of estrogen therapy given in replacement doses—doses higher than those typically used in women after natural menopause, therefore considered replacement doses—helps mitigate the risk of some of these adverse health conditions.

In these women, the bigger goal really is to reinstate the hormonal milieu that exists prior to menopause. To your point, Dr. Faubion, if I have a patient who is younger than 46 years, who has her ovaries taken out, and even if she has zero symptoms (and sometimes that does happen), I would still make a case for this patient to utilize hormone therapy unless there is a contraindication such as breast cancer or other estrogen-sensitive cancers.

Dr. Faubion: Again, would you aim for those higher doses rather than treat with the “lowest dose”?

Dr. Kapoor: Absolutely. My punchline to the patients and clinicians in these discussions is that the rules of the game are different for these women. We cannot extrapolate the risks and benefits of HT use in women after natural menopause to younger women who have surgical menopause. Those rules just do not apply with respect to both benefits and risks.

Dr. Faubion: I think it’s important to say that these same “rules” would apply if the women were to go through premature menopause for any other reason, too, such as chemotherapy, radiation therapy, or premature ovarian insufficiency for any number of reasons, including toxic, metabolic, or genetic causes and so on. Would that be true?

Dr. Kapoor: Yes, absolutely so.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: In terms of practical or clinical issues regarding systemic HT management, for the woman in her early 50s who has experienced normal or natural spontaneous menopause, a starting dose of transdermal estradiol would be, for instance, a 0.05-mg patch, which is a patch that over 24 hours releases 0.05 mg of estradiol daily; or standard oral estrogen, including conjugated equine estrogen, a 0.625-mg tablet daily, or estradiol, a 1-mg tablet daily.

But in younger patients, we want to use higher doses. For a patch, for instance, I would aim for a 0.075- or 0.1-mg estradiol patch, which releases a higher daily dose of estradiol than the standard dose. For oral estrogen, the dose would be 0.9- or even 1.25-mg tablets of conjugated equine estrogen or 1.5 mg, which is a 1-mg plus a 0.5-mg estradiol tablet, or a 2-mg estradiol tablet. Estradiol does come in a 2-mg strength.

For oral estrogen, I prefer estradiol because it’s available as a generic medication and often available at a very low cost, sometimes as low as $4 a month from chain pharmacies.

Continue to: Usefulness of monitoring estradiol levels for dosage adjustment...

Dr. Faubion: That’s a great point, and again it is important to emphasize that we are aiming to recreate the premenopausal hormonal milieu. If you were to check estradiol levels, that would be aiming for a premenopausal range of approximately 80 to 120 pg per mL. Dr. Kapoor, is there utility in monitoring estrogen levels?

Dr. Kapoor: Great question, Dr. Faubion, and as you know it’s a loaded one. We base this on empiric evidence. We know that if the hormonal milieu in a young patient is changed to a postmenopausal one, her risk for many chronic conditions is increased. So if we were to reinstate a premenopausal hormonal milieu, that risk would probably be reduced. It makes good sense to target an empiric goal of 80 to 120 pg per mL of estradiol, which is the average estradiol level in a premenopausal woman. If you were to ask me, however, are there randomized, controlled trial data to support this practice—that is, if you target that level, can you make sure that the risk of diabetes is lower or that the risk of heart disease is lower—that study has yet to be done, and it may not ever be done on a large scale. However, it intuitively makes good sense to target premenopausal estradiol levels.

Dr. Faubion: When might you check an estradiol level in this population? For example, if you are treating a patient with a 0.1-mg estradiol patch and she still has significant hot flashes, would it be useful to check the level?

Dr. Kapoor: It would. In my practice, I check estradiol levels on these patients on an annual basis, regardless of symptoms, but definitely in the patient who has symptoms. It makes good sense, because sometimes these patients don’t absorb the estrogen well, particularly if administered by the transdermal route.

A general rule of thumb is that in the average population, if a patient is on the 0.1-mg patch, for example, you would expect her level to be around 100. If it is much lower than that, which sometimes happens, that speaks for poor absorption. Options at that point would be to treat her with a higher dose patch, depending on what the level is, or switch to a different formulation, such as oral.

In instances in which I have treated patients with a 0.1-mg patch for example, and their estradiol levels are undetectable, that speaks for very poor absorption. For such patients I make a case for switching them to oral therapy. Most definitely that makes sense in a patient who is symptomatic despite treatment. But even for patients who don’t have symptoms, I like to target that level, acknowledging that there is no evidence as such to support this practice.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: Yes, a few practical points. Although patches are available in a wider array of doses than oral estrogen formulations, the highest dose available is 0.1 mg. It’s important for clinicians to recognize that while checking serum levels when indicated can be performed in women using transdermal estradiol or patches, in women who are using oral estrogen, checking blood levels is not going to work well because serum estrogen levels have a daily peak and valley in women who use oral versus transdermal estradiol.

I also wanted to talk about progestins. Although many patients who have had a BSO prior to spontaneous menopause also have had a hysterectomy, others have an intact uterus associated with their BSO, so progestins must be used along with estrogen. And if we are using higher-than-standard doses of estrogen, we also need to use higher-than-standard doses of progestin.

In that classic 53-year-old woman I referred to who had spontaneous normal menopause, if she is taking 1 mg of estradiol daily, or a 0.05-mg patch, or 0.625 mg of conjugated equine estrogen, 2.5 mg of medroxyprogesterone is fine. In fact, that showed excellent progestational protection of the endometrium in the Women’s Health Initiative and in other studies.

However, if we are going to use double the estrogen dose, we should increase the progestin dose too. In some of my patients on higher estrogen doses who have an intact uterus, I’ll use 5 or even 10 mg of daily medroxyprogesterone acetate to ensure adequate progestational suppression.

Dr. Faubion: Another practical tip is that if one is using conjugated equine estrogens, measuring the serum estradiol levels is not useful either.

Dr. Kaunitz: I agree.

Continue to: Oral contraceptives as replacement HT...

Dr. Faubion: Would you comment on use of a birth control pill in this circumstance? Would it be optimal to use a postmenopausal HT regimen as opposed to a birth control pill or combined hormonal contraception?

Dr. Kapoor: In this younger population, sometimes it seems like a more socially acceptable decision to be on a birth control option than on menopausal HT. But there are some issues with being on a contraceptive regimen. One is that we end up using estrogen doses much higher than what is really needed for replacement purposes. It is also a nonphysiologic way of replacement in another sense—as opposed to estradiol, which is the main hormone made by the ovaries, the hormonal contraceptive regimens contain the synthetic estrogen ethinyl estradiol for the most part.

The other issue that is based on some weak evidence is that it appears that the bone health outcomes are probably inferior with combined hormonal contraception. For these reasons, regimens that are based on replacement doses of estradiol are preferred.

Dr. Faubion: Right, although the data are somewhat weak, I agree that thus far it seems optimal to utilize a postmenopausal regimen for various reasons. Dr. Kaunitz, anything to add?

Dr. Kaunitz: Yes, to underscore Dr. Kapoor’s point, a common oral contraceptive that contains 20 µg of ethinyl estradiol is substantially more estrogenic than 1.0 or 2.0 mg of micronized oral estradiol.

Also consider that a 20-µg ethinyl estradiol oral contraceptive may increase the risk of venous thromboembolism more than menopausal doses of oral estradiol, whether it be a micronized estradiol or conjugated equine estrogen.

Dr. Faubion: So the risk may be greater with oral combined hormonal contraception as well?

Dr. Kaunitz: One thing we can do is explain to our patients that their ovaries, prior to surgery or prior to induced menopause, were making substantial quantities of estradiol. Whether we prescribe a patch or oral micronized estradiol, this estrogen is identical to the hormone that their ovaries were making prior to surgery or induced menopause.

Breast cancer concerns

Dr. Faubion: Let’s consider a more complicated case. A 35-year-old woman has an identified BRCA1 mutation; she has not had any cancers but has undergone risk-reducing BSO and her uterus remains. Is this woman a candidate for HT? At what dose, and for how long? Dr. Kaunitz, why don’t you start.

Dr. Kaunitz: That is a challenging case but one that I think our readers will find interesting and maybe even provocative.

We know that women with BRCA1 mutations, the more common of the 2 BRCA mutations, have a very high risk of developing epithelial ovarian cancer at a young age. For this reason, our colleagues in medical oncology who specialize in hereditary ovarian/breast cancer syndromes recommend prophylactic risk-reducing—and I would also say lifesaving—BSO with or without hysterectomy for women with BRCA1 mutations.

However, over the years there has been tremendous reluctance among physicians caring for BRCA patients and the women themselves—I use the term “previvors” to describe BRCA carriers who have not been diagnosed with breast or ovarian cancer—to use HT after BSO because of concerns that HT might increase breast cancer risk in women who are already at high risk for breast cancer.

I assume, Dr. Faubion, that in this case the woman had gynecologic surgery but continues to have intact breasts. Is that correct?

Dr. Faubion: That is correct.

Dr. Kaunitz: Although the assumption has been that it is not safe to prescribe HT in this setting, in fact, the reported cohort studies that have looked at this issue have not found an elevated risk of breast cancer when replacement estrogen, with or without progestin, is prescribed to BRCA1 previvors with intact breasts.

Given what Dr. Kapoor said regarding the morbidity that is associated with BSO without replacement of physiologic estrogen, and also given the severe symptoms that so many of these young menopausal women experience, in my practice I do prescribe estrogen or estrogen-progestin therapy and focus on the higher target doses that we discussed for the earlier case patient who had a hysterectomy for abnormal uterine bleeding with adenomyosis.

Dr. Faubion: Dr. Kapoor, do you agree with this approach? How long would you continue therapy?

Dr. Kapoor: First, in this BRCA1 case we need to appreciate that the indication for the BSO is a legitimate one, in contrast to the first case in which the ovaries were removed in a patient whose average risk of ovarian cancer was low. It is important to recognize that surgery performed in this context is the right thing to do because it does significantly reduce the risk of ovarian cancer.

The second thing to appreciate is that while we reduce the risk of ovarian cancer significantly and make sure that these patients survive longer, it’s striking a fine balance in that you want to make sure that their morbidity is not increased as a result of premature estrogen deprivation.

As Dr. Kaunitz told us, the evidence that we have so far, which granted is not very robust but is fairly strong observational evidence, suggests that the risk of breast cancer is not elevated when these patients are treated with replacement doses of HT.

Having said that, I do have very strong discussions with my patients in this category about having the risk-reducing bilateral mastectomy also, because if they were to get breast cancer because of their increased genetic predisposition, the cancer is likely to grow faster if the patient is on HT. So one of my counseling points to patients is that they strongly consider bilateral mastectomy, which reduces their breast cancer risk by more than 90%. At the same time, I also strongly endorse using HT in replacement doses for the reasons that we have already stated.

Dr. Faubion: Continue HT until age 50 or 52?

Dr. Kapoor: Definitely until that age, and possibly longer, depending on their symptoms. The indications for treating beyond the age of natural menopause are much the same as for women who experience natural menopause.

Dr. Faubion: That is assuming they had a bilateral mastectomy?

Dr. Kapoor: Yes.

Continue to: Continuing HT until the age of natural menopause...

Dr. Kaunitz: Dr. Kapoor brings up the important point of duration of systemic HT. I agree that similar considerations apply both to the healthy 41-year-old who had a hysterectomy for abnormal uterine bleeding and to the 35-year-old who had risk-reducing surgery because of her BRCA1 mutation.

In the 2 cases, both to treat symptoms and to prevent chronic diseases, it makes sense to continue HT at least until the age of natural menopause. That is consistent with 2017 guidance from The North American Menopause Society (NAMS) position statement on the use of systemic HT, that is, continuing systemic HT at least until the age of natural menopause.³ Then at that point, continuing or discontinuing systemic HT becomes discretionary, and that would be true for both cases. If the patient is slender or has a strong family history of osteoporosis, that tends to push the patient more in terms of continuing systemic HT. Those are just some examples, and Dr. Kapoor may want to detail other relevant considerations.

Dr. Kapoor: I completely agree. The decision is driven by symptoms that are not otherwise well managed, for example, with nonhormone strategies. If we have any concerns utilizing HT beyond the age of natural menopause, then nonhormonal options can be considered; but sometimes those are not as effective. And bone health is very important. You want to avoid using bisphosphonates in younger women and reserve them for older patients in their late 60s and 70s. Hormone therapy use is a very reasonable strategy to prevent bone loss.

Dr. Kaunitz: It is also worth mentioning that sometimes the woman involved in shared decision making with her clinician decides to stop systemic HT. In that setting, should the patient start developing new-onset dyspareunia, vaginal dryness, or other genital or sexuality-related concerns, it takes very little for me to advise that she start low-dose local vaginal estrogen therapy.

Dr. Faubion: In either scenario, if a woman were to develop symptoms consistent with genitourinary syndrome of menopause (GSM), would you use vaginal estrogen in addition to the systemic estrogen or alone after the woman elected to discontinue systemic therapy?

Dr. Kapoor: Yes to both, I would say.

Dr. Kaunitz: As my patients using systemic HT age, often I will lower the dose. For instance, the dose I use in a 53-year-old will be higher than when she is 59 or 62. At the same time, as we lower the dose of systemic estrogen therapy, symptoms of vaginal atrophy or GSM often will appear, and these can be effectively treated by adding low-dose vaginal estrogen therapy. A number of my patients, particularly those who are on lower-than-standard doses of systemic HT, are also using low-dose vaginal estrogen therapy.

There is a “hybrid” product available: the 90-day estradiol vaginal ring. Estring is a low-dose, 2-mg, 90-day estradiol ring that is very useful, but it is effective only for treating GSM or vaginal atrophy. A second menopausal vaginal estradiol ring, Femring, is available in 2 doses: 0.05 mg/day and 0.1 mg/day. These are very effective in treating both systemic issues, such as vasomotor symptoms or prevention of osteoporosis, and very effective in treating GSM or vaginal atrophy. One problem is that Femring, depending on insurance coverage, can be very expensive. It’s not available as a generic, so for insurance or financial reasons I don’t often prescribe it. If I could remove those financial barriers, I would prescribe Femring more often because it is very useful.

Dr. Faubion: You raise an important point, and that is, for women who have been on HT for some time, clinicians often feel the need to slowly reduce the dose. Would you do that same thing, Dr. Kapoor, for a 40-year-old woman? Would you reduce the dose as she approaches age 50? Is there pressure that “she shouldn’t be on that much estrogen”?

Dr. Kapoor: No, I would not feel pressured until the patient turns at least 46. I bring up age 46 because the average age range for menopause is 46 to 55. After that, if there is any concern, we can decrease the dose to half and keep the patient on that until she turns 50 or 51. But most of my patients are on replacement doses until the average age of menopause, which is around 51 years, and that’s when you reduce the dose to that of the typical HT regimens used after natural menopause.

Sometimes patients are told something by a friend or they have read something and they worry about the risk of 2 things. One is breast cancer and the other is venous thromboembolism (VTE), and that may be why they want to be on a lower dose. I counsel patients that while the risk of VTE is real with HT, it is the women after natural menopause who are at risk—because age itself is a risk for VTE—and it also has to do with the kind of HT regimen that a patient is on. High doses of oral estrogens and certain progestogens increase the risk. But again, for estradiol used in replacement doses and the more common progestogens that we now use in practice, such as micronized progesterone, the risk is not the same. The same goes for breast cancer. My biggest message to patients and clinicians who take care of these patients is that the rules that apply to women after natural menopause just do not apply to this very different patient population.

Dr. Faubion: Thank you, Dr. Kaunitz and Dr. Kapoor, for sharing your knowledge and experience. ●

Women who undergo bilateral salpingo-oophorectomy (BSO) for various indications prior to menopause experience a rapid decline in ovarian hormone levels and consequent vasomotor and other menopausal symptoms. In addition, the resulting estrogen deprivation is associated with such long-term adverse outcomes as osteoporosis and cardiovascular morbidity.

OBG Management convened a roundtable with 3 experts who discussed health considerations in women who have undergone BSO prior to the age of natural menopause¹ to further explore the issues involved in managing hormone therapy (HT) in these patients. Stephanie Faubion, MD, MBA, NCMP, moderated the exchange.

Surgical vs natural menopause

Stephanie Faubion, MD, MBA, NCMP: Since the Women’s Health Initiative study was published in 2002,² many clinicians have been fearful of using systemic HT in menopausal women, and HT use has declined dramatically such that only about 4% to 6% of menopausal women are now receiving systemic HT. Importantly, however, a group of younger menopausal women also are not receiving HT, and that is women who undergo BSO before they reach the average age of menopause, which in the United States is about age 52; this is sometimes referred to as surgical menopause or early surgical menopause. Early surgical menopause has different connotations for long-term health risks than natural menopause at the average age, and we are here to discuss these health effects and their management.

My name is Stephanie Faubion, and I am a women’s health internist and the Chair of the Department of Medicine at Mayo Clinic in Jacksonville, Florida, and Director of Mayo Clinic Women’s Health. I am here with 2 of my esteemed colleagues, Dr. Andrew Kaunitz and Dr. Ekta Kapoor.

Andrew M. Kaunitz, MD, NCMP: Hello, I am an ObGyn with the University of Florida College of Medicine in Jacksonville, with particular interests in contraception, menopause, and gynecologic ultrasonography.

Ekta Kapoor, MBBS, NCMP: And I am an endocrinologist at Mayo Clinic in Rochester with a specific interest in menopause and hormone therapy. I am also the Assistant Director for Mayo Clinic Women’s Health.

Higher-than-standard estrogen doses needed in younger menopausal women

Dr. Faubion: Let’s consider a couple of cases so that we can illustrate some important points regarding hormone management in women who have undergone BSO before the age of natural menopause.

Our first case patient is a woman who is 41 years of age and, because of adenomyosis, she will undergo a hysterectomy. She tells her clinician that she is very concerned about ovarian cancer risk because one of her good friends recently was diagnosed with ovarian cancer, and together they decide to remove her ovaries at the time of hysterectomy. Notably, her ovaries were healthy.

The patient is now menopausal postsurgery, and she is having significant hot flashes and night sweats. She visits her local internist, who is concerned about initiating HT. She is otherwise a healthy woman and does not have any contraindications to HT. Dr. Kaunitz, what would you tell her internist?

Dr. Kaunitz: We are dealing with 2 different issues in terms of decision making about systemic HT for this 41-year-old who has undergone BSO. First, as you mentioned, Dr. Faubion, she has bothersome hot flashes, or vasomotor symptoms. Unless there are contraindications, systemic HT would be appropriate. Although I might start treatment at standard doses, and the accompanying TABLE depicts standard doses for the 2 most common oral estrogen formulations as well as transdermal estradiol, it’s important to recognize that younger menopausal women often will need to use higher-than-standard doses.

For example, for a 53-year-old woman who has been menopausal for a year or 2 and now has bothersome symptoms, I might start her on estradiol 1 mg tablets with progestin if a uterus is present. However, in this 41-year-old case patient, while I might start treatment at a standard dose, I would anticipate increasing to higher doses, such as 1.5 or 2 mg of daily estradiol until she feels her menopausal symptoms are adequately addressed.

Dr. Faubion: It is important to note that sometimes women with early BSO tend to have more severe vasomotor symptoms. Do you find that sometimes a higher dose is required just to manage symptoms, Dr. Kaunitz?

Dr. Kaunitz: Absolutely, yes. The decision whether or not to use systemic HT might be considered discretionary or elective in the classic 53-year-old woman recently menopausal with hot flashes, a so-called spontaneously or naturally menopausal woman. But my perspective is that unless there are clear contraindications, the decision to start systemic HT in the 41-year-old BSO case patient is actually not discretionary. Unless contraindications are present, it is important not only to treat symptoms but also to prevent an array of chronic major health concerns that are more likely if we don’t prescribe systemic HT.

Continue to: Health effects of not using HT...

Dr. Faubion: Dr. Kapoor, can you describe the potential long-term adverse health consequences of not using estrogen therapy? Say the same 41-year-old woman does not have many bothersome symptoms. What would you do?

Dr. Kapoor: Thank you for that important question. Building on what Dr. Kaunitz said, in these patients there are really 2 issues that can seem to be independent but are not: The first relates to the immediate consequences of lack of estrogen, ie, the menopause-related symptoms, but the second and perhaps the bigger issue is the long-term risk associated with estrogen deprivation.

The symptoms in these women are often obvious as they can be quite severe and abrupt; one day these women have normal hormone levels and the next day, after BSO, suddenly their hormones are very low. So if symptoms occur, they are usually hard to miss, simply because they are very drastic and very severe.

Historically, patients and their clinicians have targeted these symptoms. Patients experience menopausal symptoms, they seek treatment, and then the clinicians basically titrate the treatment to manage these symptoms. That misses the bigger issue, however, which is that premature estrogen deprivation leads to a host of chronic health conditions, as Dr. Kaunitz mentioned. These mainly include increased risk for cardiovascular disease, diabetes, hypertension, dyslipidemia, increased risk of mortality, dementia, and osteoporosis.

Fairly strong observational evidence suggests that use of estrogen therapy given in replacement doses—doses higher than those typically used in women after natural menopause, therefore considered replacement doses—helps mitigate the risk of some of these adverse health conditions.

In these women, the bigger goal really is to reinstate the hormonal milieu that exists prior to menopause. To your point, Dr. Faubion, if I have a patient who is younger than 46 years, who has her ovaries taken out, and even if she has zero symptoms (and sometimes that does happen), I would still make a case for this patient to utilize hormone therapy unless there is a contraindication such as breast cancer or other estrogen-sensitive cancers.

Dr. Faubion: Again, would you aim for those higher doses rather than treat with the “lowest dose”?

Dr. Kapoor: Absolutely. My punchline to the patients and clinicians in these discussions is that the rules of the game are different for these women. We cannot extrapolate the risks and benefits of HT use in women after natural menopause to younger women who have surgical menopause. Those rules just do not apply with respect to both benefits and risks.

Dr. Faubion: I think it’s important to say that these same “rules” would apply if the women were to go through premature menopause for any other reason, too, such as chemotherapy, radiation therapy, or premature ovarian insufficiency for any number of reasons, including toxic, metabolic, or genetic causes and so on. Would that be true?

Dr. Kapoor: Yes, absolutely so.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: In terms of practical or clinical issues regarding systemic HT management, for the woman in her early 50s who has experienced normal or natural spontaneous menopause, a starting dose of transdermal estradiol would be, for instance, a 0.05-mg patch, which is a patch that over 24 hours releases 0.05 mg of estradiol daily; or standard oral estrogen, including conjugated equine estrogen, a 0.625-mg tablet daily, or estradiol, a 1-mg tablet daily.

But in younger patients, we want to use higher doses. For a patch, for instance, I would aim for a 0.075- or 0.1-mg estradiol patch, which releases a higher daily dose of estradiol than the standard dose. For oral estrogen, the dose would be 0.9- or even 1.25-mg tablets of conjugated equine estrogen or 1.5 mg, which is a 1-mg plus a 0.5-mg estradiol tablet, or a 2-mg estradiol tablet. Estradiol does come in a 2-mg strength.

For oral estrogen, I prefer estradiol because it’s available as a generic medication and often available at a very low cost, sometimes as low as $4 a month from chain pharmacies.

Continue to: Usefulness of monitoring estradiol levels for dosage adjustment...

Dr. Faubion: That’s a great point, and again it is important to emphasize that we are aiming to recreate the premenopausal hormonal milieu. If you were to check estradiol levels, that would be aiming for a premenopausal range of approximately 80 to 120 pg per mL. Dr. Kapoor, is there utility in monitoring estrogen levels?

Dr. Kapoor: Great question, Dr. Faubion, and as you know it’s a loaded one. We base this on empiric evidence. We know that if the hormonal milieu in a young patient is changed to a postmenopausal one, her risk for many chronic conditions is increased. So if we were to reinstate a premenopausal hormonal milieu, that risk would probably be reduced. It makes good sense to target an empiric goal of 80 to 120 pg per mL of estradiol, which is the average estradiol level in a premenopausal woman. If you were to ask me, however, are there randomized, controlled trial data to support this practice—that is, if you target that level, can you make sure that the risk of diabetes is lower or that the risk of heart disease is lower—that study has yet to be done, and it may not ever be done on a large scale. However, it intuitively makes good sense to target premenopausal estradiol levels.

Dr. Faubion: When might you check an estradiol level in this population? For example, if you are treating a patient with a 0.1-mg estradiol patch and she still has significant hot flashes, would it be useful to check the level?

Dr. Kapoor: It would. In my practice, I check estradiol levels on these patients on an annual basis, regardless of symptoms, but definitely in the patient who has symptoms. It makes good sense, because sometimes these patients don’t absorb the estrogen well, particularly if administered by the transdermal route.

A general rule of thumb is that in the average population, if a patient is on the 0.1-mg patch, for example, you would expect her level to be around 100. If it is much lower than that, which sometimes happens, that speaks for poor absorption. Options at that point would be to treat her with a higher dose patch, depending on what the level is, or switch to a different formulation, such as oral.

In instances in which I have treated patients with a 0.1-mg patch for example, and their estradiol levels are undetectable, that speaks for very poor absorption. For such patients I make a case for switching them to oral therapy. Most definitely that makes sense in a patient who is symptomatic despite treatment. But even for patients who don’t have symptoms, I like to target that level, acknowledging that there is no evidence as such to support this practice.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: Yes, a few practical points. Although patches are available in a wider array of doses than oral estrogen formulations, the highest dose available is 0.1 mg. It’s important for clinicians to recognize that while checking serum levels when indicated can be performed in women using transdermal estradiol or patches, in women who are using oral estrogen, checking blood levels is not going to work well because serum estrogen levels have a daily peak and valley in women who use oral versus transdermal estradiol.

I also wanted to talk about progestins. Although many patients who have had a BSO prior to spontaneous menopause also have had a hysterectomy, others have an intact uterus associated with their BSO, so progestins must be used along with estrogen. And if we are using higher-than-standard doses of estrogen, we also need to use higher-than-standard doses of progestin.

In that classic 53-year-old woman I referred to who had spontaneous normal menopause, if she is taking 1 mg of estradiol daily, or a 0.05-mg patch, or 0.625 mg of conjugated equine estrogen, 2.5 mg of medroxyprogesterone is fine. In fact, that showed excellent progestational protection of the endometrium in the Women’s Health Initiative and in other studies.

However, if we are going to use double the estrogen dose, we should increase the progestin dose too. In some of my patients on higher estrogen doses who have an intact uterus, I’ll use 5 or even 10 mg of daily medroxyprogesterone acetate to ensure adequate progestational suppression.

Dr. Faubion: Another practical tip is that if one is using conjugated equine estrogens, measuring the serum estradiol levels is not useful either.

Dr. Kaunitz: I agree.

Continue to: Oral contraceptives as replacement HT...

Dr. Faubion: Would you comment on use of a birth control pill in this circumstance? Would it be optimal to use a postmenopausal HT regimen as opposed to a birth control pill or combined hormonal contraception?

Dr. Kapoor: In this younger population, sometimes it seems like a more socially acceptable decision to be on a birth control option than on menopausal HT. But there are some issues with being on a contraceptive regimen. One is that we end up using estrogen doses much higher than what is really needed for replacement purposes. It is also a nonphysiologic way of replacement in another sense—as opposed to estradiol, which is the main hormone made by the ovaries, the hormonal contraceptive regimens contain the synthetic estrogen ethinyl estradiol for the most part.

The other issue that is based on some weak evidence is that it appears that the bone health outcomes are probably inferior with combined hormonal contraception. For these reasons, regimens that are based on replacement doses of estradiol are preferred.

Dr. Faubion: Right, although the data are somewhat weak, I agree that thus far it seems optimal to utilize a postmenopausal regimen for various reasons. Dr. Kaunitz, anything to add?

Dr. Kaunitz: Yes, to underscore Dr. Kapoor’s point, a common oral contraceptive that contains 20 µg of ethinyl estradiol is substantially more estrogenic than 1.0 or 2.0 mg of micronized oral estradiol.

Also consider that a 20-µg ethinyl estradiol oral contraceptive may increase the risk of venous thromboembolism more than menopausal doses of oral estradiol, whether it be a micronized estradiol or conjugated equine estrogen.

Dr. Faubion: So the risk may be greater with oral combined hormonal contraception as well?

Dr. Kaunitz: One thing we can do is explain to our patients that their ovaries, prior to surgery or prior to induced menopause, were making substantial quantities of estradiol. Whether we prescribe a patch or oral micronized estradiol, this estrogen is identical to the hormone that their ovaries were making prior to surgery or induced menopause.

Breast cancer concerns

Dr. Faubion: Let’s consider a more complicated case. A 35-year-old woman has an identified BRCA1 mutation; she has not had any cancers but has undergone risk-reducing BSO and her uterus remains. Is this woman a candidate for HT? At what dose, and for how long? Dr. Kaunitz, why don’t you start.

Dr. Kaunitz: That is a challenging case but one that I think our readers will find interesting and maybe even provocative.

We know that women with BRCA1 mutations, the more common of the 2 BRCA mutations, have a very high risk of developing epithelial ovarian cancer at a young age. For this reason, our colleagues in medical oncology who specialize in hereditary ovarian/breast cancer syndromes recommend prophylactic risk-reducing—and I would also say lifesaving—BSO with or without hysterectomy for women with BRCA1 mutations.

However, over the years there has been tremendous reluctance among physicians caring for BRCA patients and the women themselves—I use the term “previvors” to describe BRCA carriers who have not been diagnosed with breast or ovarian cancer—to use HT after BSO because of concerns that HT might increase breast cancer risk in women who are already at high risk for breast cancer.

I assume, Dr. Faubion, that in this case the woman had gynecologic surgery but continues to have intact breasts. Is that correct?

Dr. Faubion: That is correct.

Dr. Kaunitz: Although the assumption has been that it is not safe to prescribe HT in this setting, in fact, the reported cohort studies that have looked at this issue have not found an elevated risk of breast cancer when replacement estrogen, with or without progestin, is prescribed to BRCA1 previvors with intact breasts.

Given what Dr. Kapoor said regarding the morbidity that is associated with BSO without replacement of physiologic estrogen, and also given the severe symptoms that so many of these young menopausal women experience, in my practice I do prescribe estrogen or estrogen-progestin therapy and focus on the higher target doses that we discussed for the earlier case patient who had a hysterectomy for abnormal uterine bleeding with adenomyosis.

Dr. Faubion: Dr. Kapoor, do you agree with this approach? How long would you continue therapy?

Dr. Kapoor: First, in this BRCA1 case we need to appreciate that the indication for the BSO is a legitimate one, in contrast to the first case in which the ovaries were removed in a patient whose average risk of ovarian cancer was low. It is important to recognize that surgery performed in this context is the right thing to do because it does significantly reduce the risk of ovarian cancer.

The second thing to appreciate is that while we reduce the risk of ovarian cancer significantly and make sure that these patients survive longer, it’s striking a fine balance in that you want to make sure that their morbidity is not increased as a result of premature estrogen deprivation.

As Dr. Kaunitz told us, the evidence that we have so far, which granted is not very robust but is fairly strong observational evidence, suggests that the risk of breast cancer is not elevated when these patients are treated with replacement doses of HT.

Having said that, I do have very strong discussions with my patients in this category about having the risk-reducing bilateral mastectomy also, because if they were to get breast cancer because of their increased genetic predisposition, the cancer is likely to grow faster if the patient is on HT. So one of my counseling points to patients is that they strongly consider bilateral mastectomy, which reduces their breast cancer risk by more than 90%. At the same time, I also strongly endorse using HT in replacement doses for the reasons that we have already stated.

Dr. Faubion: Continue HT until age 50 or 52?

Dr. Kapoor: Definitely until that age, and possibly longer, depending on their symptoms. The indications for treating beyond the age of natural menopause are much the same as for women who experience natural menopause.

Dr. Faubion: That is assuming they had a bilateral mastectomy?

Dr. Kapoor: Yes.

Continue to: Continuing HT until the age of natural menopause...

Dr. Kaunitz: Dr. Kapoor brings up the important point of duration of systemic HT. I agree that similar considerations apply both to the healthy 41-year-old who had a hysterectomy for abnormal uterine bleeding and to the 35-year-old who had risk-reducing surgery because of her BRCA1 mutation.

In the 2 cases, both to treat symptoms and to prevent chronic diseases, it makes sense to continue HT at least until the age of natural menopause. That is consistent with 2017 guidance from The North American Menopause Society (NAMS) position statement on the use of systemic HT, that is, continuing systemic HT at least until the age of natural menopause.³ Then at that point, continuing or discontinuing systemic HT becomes discretionary, and that would be true for both cases. If the patient is slender or has a strong family history of osteoporosis, that tends to push the patient more in terms of continuing systemic HT. Those are just some examples, and Dr. Kapoor may want to detail other relevant considerations.

Dr. Kapoor: I completely agree. The decision is driven by symptoms that are not otherwise well managed, for example, with nonhormone strategies. If we have any concerns utilizing HT beyond the age of natural menopause, then nonhormonal options can be considered; but sometimes those are not as effective. And bone health is very important. You want to avoid using bisphosphonates in younger women and reserve them for older patients in their late 60s and 70s. Hormone therapy use is a very reasonable strategy to prevent bone loss.

Dr. Kaunitz: It is also worth mentioning that sometimes the woman involved in shared decision making with her clinician decides to stop systemic HT. In that setting, should the patient start developing new-onset dyspareunia, vaginal dryness, or other genital or sexuality-related concerns, it takes very little for me to advise that she start low-dose local vaginal estrogen therapy.

Dr. Faubion: In either scenario, if a woman were to develop symptoms consistent with genitourinary syndrome of menopause (GSM), would you use vaginal estrogen in addition to the systemic estrogen or alone after the woman elected to discontinue systemic therapy?

Dr. Kapoor: Yes to both, I would say.

Dr. Kaunitz: As my patients using systemic HT age, often I will lower the dose. For instance, the dose I use in a 53-year-old will be higher than when she is 59 or 62. At the same time, as we lower the dose of systemic estrogen therapy, symptoms of vaginal atrophy or GSM often will appear, and these can be effectively treated by adding low-dose vaginal estrogen therapy. A number of my patients, particularly those who are on lower-than-standard doses of systemic HT, are also using low-dose vaginal estrogen therapy.

There is a “hybrid” product available: the 90-day estradiol vaginal ring. Estring is a low-dose, 2-mg, 90-day estradiol ring that is very useful, but it is effective only for treating GSM or vaginal atrophy. A second menopausal vaginal estradiol ring, Femring, is available in 2 doses: 0.05 mg/day and 0.1 mg/day. These are very effective in treating both systemic issues, such as vasomotor symptoms or prevention of osteoporosis, and very effective in treating GSM or vaginal atrophy. One problem is that Femring, depending on insurance coverage, can be very expensive. It’s not available as a generic, so for insurance or financial reasons I don’t often prescribe it. If I could remove those financial barriers, I would prescribe Femring more often because it is very useful.

Dr. Faubion: You raise an important point, and that is, for women who have been on HT for some time, clinicians often feel the need to slowly reduce the dose. Would you do that same thing, Dr. Kapoor, for a 40-year-old woman? Would you reduce the dose as she approaches age 50? Is there pressure that “she shouldn’t be on that much estrogen”?

Dr. Kapoor: No, I would not feel pressured until the patient turns at least 46. I bring up age 46 because the average age range for menopause is 46 to 55. After that, if there is any concern, we can decrease the dose to half and keep the patient on that until she turns 50 or 51. But most of my patients are on replacement doses until the average age of menopause, which is around 51 years, and that’s when you reduce the dose to that of the typical HT regimens used after natural menopause.

Sometimes patients are told something by a friend or they have read something and they worry about the risk of 2 things. One is breast cancer and the other is venous thromboembolism (VTE), and that may be why they want to be on a lower dose. I counsel patients that while the risk of VTE is real with HT, it is the women after natural menopause who are at risk—because age itself is a risk for VTE—and it also has to do with the kind of HT regimen that a patient is on. High doses of oral estrogens and certain progestogens increase the risk. But again, for estradiol used in replacement doses and the more common progestogens that we now use in practice, such as micronized progesterone, the risk is not the same. The same goes for breast cancer. My biggest message to patients and clinicians who take care of these patients is that the rules that apply to women after natural menopause just do not apply to this very different patient population.

Dr. Faubion: Thank you, Dr. Kaunitz and Dr. Kapoor, for sharing your knowledge and experience. ●

Women who undergo bilateral salpingo-oophorectomy (BSO) for various indications prior to menopause experience a rapid decline in ovarian hormone levels and consequent vasomotor and other menopausal symptoms. In addition, the resulting estrogen deprivation is associated with such long-term adverse outcomes as osteoporosis and cardiovascular morbidity.

OBG Management convened a roundtable with 3 experts who discussed health considerations in women who have undergone BSO prior to the age of natural menopause¹ to further explore the issues involved in managing hormone therapy (HT) in these patients. Stephanie Faubion, MD, MBA, NCMP, moderated the exchange.

Surgical vs natural menopause

Stephanie Faubion, MD, MBA, NCMP: Since the Women’s Health Initiative study was published in 2002,² many clinicians have been fearful of using systemic HT in menopausal women, and HT use has declined dramatically such that only about 4% to 6% of menopausal women are now receiving systemic HT. Importantly, however, a group of younger menopausal women also are not receiving HT, and that is women who undergo BSO before they reach the average age of menopause, which in the United States is about age 52; this is sometimes referred to as surgical menopause or early surgical menopause. Early surgical menopause has different connotations for long-term health risks than natural menopause at the average age, and we are here to discuss these health effects and their management.

My name is Stephanie Faubion, and I am a women’s health internist and the Chair of the Department of Medicine at Mayo Clinic in Jacksonville, Florida, and Director of Mayo Clinic Women’s Health. I am here with 2 of my esteemed colleagues, Dr. Andrew Kaunitz and Dr. Ekta Kapoor.

Andrew M. Kaunitz, MD, NCMP: Hello, I am an ObGyn with the University of Florida College of Medicine in Jacksonville, with particular interests in contraception, menopause, and gynecologic ultrasonography.

Ekta Kapoor, MBBS, NCMP: And I am an endocrinologist at Mayo Clinic in Rochester with a specific interest in menopause and hormone therapy. I am also the Assistant Director for Mayo Clinic Women’s Health.

Higher-than-standard estrogen doses needed in younger menopausal women

Dr. Faubion: Let’s consider a couple of cases so that we can illustrate some important points regarding hormone management in women who have undergone BSO before the age of natural menopause.

Our first case patient is a woman who is 41 years of age and, because of adenomyosis, she will undergo a hysterectomy. She tells her clinician that she is very concerned about ovarian cancer risk because one of her good friends recently was diagnosed with ovarian cancer, and together they decide to remove her ovaries at the time of hysterectomy. Notably, her ovaries were healthy.

The patient is now menopausal postsurgery, and she is having significant hot flashes and night sweats. She visits her local internist, who is concerned about initiating HT. She is otherwise a healthy woman and does not have any contraindications to HT. Dr. Kaunitz, what would you tell her internist?

Dr. Kaunitz: We are dealing with 2 different issues in terms of decision making about systemic HT for this 41-year-old who has undergone BSO. First, as you mentioned, Dr. Faubion, she has bothersome hot flashes, or vasomotor symptoms. Unless there are contraindications, systemic HT would be appropriate. Although I might start treatment at standard doses, and the accompanying TABLE depicts standard doses for the 2 most common oral estrogen formulations as well as transdermal estradiol, it’s important to recognize that younger menopausal women often will need to use higher-than-standard doses.

For example, for a 53-year-old woman who has been menopausal for a year or 2 and now has bothersome symptoms, I might start her on estradiol 1 mg tablets with progestin if a uterus is present. However, in this 41-year-old case patient, while I might start treatment at a standard dose, I would anticipate increasing to higher doses, such as 1.5 or 2 mg of daily estradiol until she feels her menopausal symptoms are adequately addressed.

Dr. Faubion: It is important to note that sometimes women with early BSO tend to have more severe vasomotor symptoms. Do you find that sometimes a higher dose is required just to manage symptoms, Dr. Kaunitz?

Dr. Kaunitz: Absolutely, yes. The decision whether or not to use systemic HT might be considered discretionary or elective in the classic 53-year-old woman recently menopausal with hot flashes, a so-called spontaneously or naturally menopausal woman. But my perspective is that unless there are clear contraindications, the decision to start systemic HT in the 41-year-old BSO case patient is actually not discretionary. Unless contraindications are present, it is important not only to treat symptoms but also to prevent an array of chronic major health concerns that are more likely if we don’t prescribe systemic HT.

Continue to: Health effects of not using HT...

Dr. Faubion: Dr. Kapoor, can you describe the potential long-term adverse health consequences of not using estrogen therapy? Say the same 41-year-old woman does not have many bothersome symptoms. What would you do?

Dr. Kapoor: Thank you for that important question. Building on what Dr. Kaunitz said, in these patients there are really 2 issues that can seem to be independent but are not: The first relates to the immediate consequences of lack of estrogen, ie, the menopause-related symptoms, but the second and perhaps the bigger issue is the long-term risk associated with estrogen deprivation.

The symptoms in these women are often obvious as they can be quite severe and abrupt; one day these women have normal hormone levels and the next day, after BSO, suddenly their hormones are very low. So if symptoms occur, they are usually hard to miss, simply because they are very drastic and very severe.

Historically, patients and their clinicians have targeted these symptoms. Patients experience menopausal symptoms, they seek treatment, and then the clinicians basically titrate the treatment to manage these symptoms. That misses the bigger issue, however, which is that premature estrogen deprivation leads to a host of chronic health conditions, as Dr. Kaunitz mentioned. These mainly include increased risk for cardiovascular disease, diabetes, hypertension, dyslipidemia, increased risk of mortality, dementia, and osteoporosis.

Fairly strong observational evidence suggests that use of estrogen therapy given in replacement doses—doses higher than those typically used in women after natural menopause, therefore considered replacement doses—helps mitigate the risk of some of these adverse health conditions.

In these women, the bigger goal really is to reinstate the hormonal milieu that exists prior to menopause. To your point, Dr. Faubion, if I have a patient who is younger than 46 years, who has her ovaries taken out, and even if she has zero symptoms (and sometimes that does happen), I would still make a case for this patient to utilize hormone therapy unless there is a contraindication such as breast cancer or other estrogen-sensitive cancers.

Dr. Faubion: Again, would you aim for those higher doses rather than treat with the “lowest dose”?

Dr. Kapoor: Absolutely. My punchline to the patients and clinicians in these discussions is that the rules of the game are different for these women. We cannot extrapolate the risks and benefits of HT use in women after natural menopause to younger women who have surgical menopause. Those rules just do not apply with respect to both benefits and risks.

Dr. Faubion: I think it’s important to say that these same “rules” would apply if the women were to go through premature menopause for any other reason, too, such as chemotherapy, radiation therapy, or premature ovarian insufficiency for any number of reasons, including toxic, metabolic, or genetic causes and so on. Would that be true?

Dr. Kapoor: Yes, absolutely so.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: In terms of practical or clinical issues regarding systemic HT management, for the woman in her early 50s who has experienced normal or natural spontaneous menopause, a starting dose of transdermal estradiol would be, for instance, a 0.05-mg patch, which is a patch that over 24 hours releases 0.05 mg of estradiol daily; or standard oral estrogen, including conjugated equine estrogen, a 0.625-mg tablet daily, or estradiol, a 1-mg tablet daily.

But in younger patients, we want to use higher doses. For a patch, for instance, I would aim for a 0.075- or 0.1-mg estradiol patch, which releases a higher daily dose of estradiol than the standard dose. For oral estrogen, the dose would be 0.9- or even 1.25-mg tablets of conjugated equine estrogen or 1.5 mg, which is a 1-mg plus a 0.5-mg estradiol tablet, or a 2-mg estradiol tablet. Estradiol does come in a 2-mg strength.

For oral estrogen, I prefer estradiol because it’s available as a generic medication and often available at a very low cost, sometimes as low as $4 a month from chain pharmacies.

Continue to: Usefulness of monitoring estradiol levels for dosage adjustment...

Dr. Faubion: That’s a great point, and again it is important to emphasize that we are aiming to recreate the premenopausal hormonal milieu. If you were to check estradiol levels, that would be aiming for a premenopausal range of approximately 80 to 120 pg per mL. Dr. Kapoor, is there utility in monitoring estrogen levels?

Dr. Kapoor: Great question, Dr. Faubion, and as you know it’s a loaded one. We base this on empiric evidence. We know that if the hormonal milieu in a young patient is changed to a postmenopausal one, her risk for many chronic conditions is increased. So if we were to reinstate a premenopausal hormonal milieu, that risk would probably be reduced. It makes good sense to target an empiric goal of 80 to 120 pg per mL of estradiol, which is the average estradiol level in a premenopausal woman. If you were to ask me, however, are there randomized, controlled trial data to support this practice—that is, if you target that level, can you make sure that the risk of diabetes is lower or that the risk of heart disease is lower—that study has yet to be done, and it may not ever be done on a large scale. However, it intuitively makes good sense to target premenopausal estradiol levels.

Dr. Faubion: When might you check an estradiol level in this population? For example, if you are treating a patient with a 0.1-mg estradiol patch and she still has significant hot flashes, would it be useful to check the level?

Dr. Kapoor: It would. In my practice, I check estradiol levels on these patients on an annual basis, regardless of symptoms, but definitely in the patient who has symptoms. It makes good sense, because sometimes these patients don’t absorb the estrogen well, particularly if administered by the transdermal route.

A general rule of thumb is that in the average population, if a patient is on the 0.1-mg patch, for example, you would expect her level to be around 100. If it is much lower than that, which sometimes happens, that speaks for poor absorption. Options at that point would be to treat her with a higher dose patch, depending on what the level is, or switch to a different formulation, such as oral.

In instances in which I have treated patients with a 0.1-mg patch for example, and their estradiol levels are undetectable, that speaks for very poor absorption. For such patients I make a case for switching them to oral therapy. Most definitely that makes sense in a patient who is symptomatic despite treatment. But even for patients who don’t have symptoms, I like to target that level, acknowledging that there is no evidence as such to support this practice.

Dr. Faubion: Dr. Kaunitz, do you want to add anything?

Dr. Kaunitz: Yes, a few practical points. Although patches are available in a wider array of doses than oral estrogen formulations, the highest dose available is 0.1 mg. It’s important for clinicians to recognize that while checking serum levels when indicated can be performed in women using transdermal estradiol or patches, in women who are using oral estrogen, checking blood levels is not going to work well because serum estrogen levels have a daily peak and valley in women who use oral versus transdermal estradiol.

I also wanted to talk about progestins. Although many patients who have had a BSO prior to spontaneous menopause also have had a hysterectomy, others have an intact uterus associated with their BSO, so progestins must be used along with estrogen. And if we are using higher-than-standard doses of estrogen, we also need to use higher-than-standard doses of progestin.

In that classic 53-year-old woman I referred to who had spontaneous normal menopause, if she is taking 1 mg of estradiol daily, or a 0.05-mg patch, or 0.625 mg of conjugated equine estrogen, 2.5 mg of medroxyprogesterone is fine. In fact, that showed excellent progestational protection of the endometrium in the Women’s Health Initiative and in other studies.

However, if we are going to use double the estrogen dose, we should increase the progestin dose too. In some of my patients on higher estrogen doses who have an intact uterus, I’ll use 5 or even 10 mg of daily medroxyprogesterone acetate to ensure adequate progestational suppression.

Dr. Faubion: Another practical tip is that if one is using conjugated equine estrogens, measuring the serum estradiol levels is not useful either.

Dr. Kaunitz: I agree.

Continue to: Oral contraceptives as replacement HT...

Dr. Faubion: Would you comment on use of a birth control pill in this circumstance? Would it be optimal to use a postmenopausal HT regimen as opposed to a birth control pill or combined hormonal contraception?

Dr. Kapoor: In this younger population, sometimes it seems like a more socially acceptable decision to be on a birth control option than on menopausal HT. But there are some issues with being on a contraceptive regimen. One is that we end up using estrogen doses much higher than what is really needed for replacement purposes. It is also a nonphysiologic way of replacement in another sense—as opposed to estradiol, which is the main hormone made by the ovaries, the hormonal contraceptive regimens contain the synthetic estrogen ethinyl estradiol for the most part.

The other issue that is based on some weak evidence is that it appears that the bone health outcomes are probably inferior with combined hormonal contraception. For these reasons, regimens that are based on replacement doses of estradiol are preferred.

Dr. Faubion: Right, although the data are somewhat weak, I agree that thus far it seems optimal to utilize a postmenopausal regimen for various reasons. Dr. Kaunitz, anything to add?

Dr. Kaunitz: Yes, to underscore Dr. Kapoor’s point, a common oral contraceptive that contains 20 µg of ethinyl estradiol is substantially more estrogenic than 1.0 or 2.0 mg of micronized oral estradiol.

Also consider that a 20-µg ethinyl estradiol oral contraceptive may increase the risk of venous thromboembolism more than menopausal doses of oral estradiol, whether it be a micronized estradiol or conjugated equine estrogen.

Dr. Faubion: So the risk may be greater with oral combined hormonal contraception as well?

Dr. Kaunitz: One thing we can do is explain to our patients that their ovaries, prior to surgery or prior to induced menopause, were making substantial quantities of estradiol. Whether we prescribe a patch or oral micronized estradiol, this estrogen is identical to the hormone that their ovaries were making prior to surgery or induced menopause.

Breast cancer concerns

Dr. Faubion: Let’s consider a more complicated case. A 35-year-old woman has an identified BRCA1 mutation; she has not had any cancers but has undergone risk-reducing BSO and her uterus remains. Is this woman a candidate for HT? At what dose, and for how long? Dr. Kaunitz, why don’t you start.

Dr. Kaunitz: That is a challenging case but one that I think our readers will find interesting and maybe even provocative.

We know that women with BRCA1 mutations, the more common of the 2 BRCA mutations, have a very high risk of developing epithelial ovarian cancer at a young age. For this reason, our colleagues in medical oncology who specialize in hereditary ovarian/breast cancer syndromes recommend prophylactic risk-reducing—and I would also say lifesaving—BSO with or without hysterectomy for women with BRCA1 mutations.

However, over the years there has been tremendous reluctance among physicians caring for BRCA patients and the women themselves—I use the term “previvors” to describe BRCA carriers who have not been diagnosed with breast or ovarian cancer—to use HT after BSO because of concerns that HT might increase breast cancer risk in women who are already at high risk for breast cancer.

I assume, Dr. Faubion, that in this case the woman had gynecologic surgery but continues to have intact breasts. Is that correct?

Dr. Faubion: That is correct.

Dr. Kaunitz: Although the assumption has been that it is not safe to prescribe HT in this setting, in fact, the reported cohort studies that have looked at this issue have not found an elevated risk of breast cancer when replacement estrogen, with or without progestin, is prescribed to BRCA1 previvors with intact breasts.

Given what Dr. Kapoor said regarding the morbidity that is associated with BSO without replacement of physiologic estrogen, and also given the severe symptoms that so many of these young menopausal women experience, in my practice I do prescribe estrogen or estrogen-progestin therapy and focus on the higher target doses that we discussed for the earlier case patient who had a hysterectomy for abnormal uterine bleeding with adenomyosis.

Dr. Faubion: Dr. Kapoor, do you agree with this approach? How long would you continue therapy?

Dr. Kapoor: First, in this BRCA1 case we need to appreciate that the indication for the BSO is a legitimate one, in contrast to the first case in which the ovaries were removed in a patient whose average risk of ovarian cancer was low. It is important to recognize that surgery performed in this context is the right thing to do because it does significantly reduce the risk of ovarian cancer.

The second thing to appreciate is that while we reduce the risk of ovarian cancer significantly and make sure that these patients survive longer, it’s striking a fine balance in that you want to make sure that their morbidity is not increased as a result of premature estrogen deprivation.

As Dr. Kaunitz told us, the evidence that we have so far, which granted is not very robust but is fairly strong observational evidence, suggests that the risk of breast cancer is not elevated when these patients are treated with replacement doses of HT.

Having said that, I do have very strong discussions with my patients in this category about having the risk-reducing bilateral mastectomy also, because if they were to get breast cancer because of their increased genetic predisposition, the cancer is likely to grow faster if the patient is on HT. So one of my counseling points to patients is that they strongly consider bilateral mastectomy, which reduces their breast cancer risk by more than 90%. At the same time, I also strongly endorse using HT in replacement doses for the reasons that we have already stated.

Dr. Faubion: Continue HT until age 50 or 52?

Dr. Kapoor: Definitely until that age, and possibly longer, depending on their symptoms. The indications for treating beyond the age of natural menopause are much the same as for women who experience natural menopause.

Dr. Faubion: That is assuming they had a bilateral mastectomy?

Dr. Kapoor: Yes.

Continue to: Continuing HT until the age of natural menopause...

Dr. Kaunitz: Dr. Kapoor brings up the important point of duration of systemic HT. I agree that similar considerations apply both to the healthy 41-year-old who had a hysterectomy for abnormal uterine bleeding and to the 35-year-old who had risk-reducing surgery because of her BRCA1 mutation.

In the 2 cases, both to treat symptoms and to prevent chronic diseases, it makes sense to continue HT at least until the age of natural menopause. That is consistent with 2017 guidance from The North American Menopause Society (NAMS) position statement on the use of systemic HT, that is, continuing systemic HT at least until the age of natural menopause.³ Then at that point, continuing or discontinuing systemic HT becomes discretionary, and that would be true for both cases. If the patient is slender or has a strong family history of osteoporosis, that tends to push the patient more in terms of continuing systemic HT. Those are just some examples, and Dr. Kapoor may want to detail other relevant considerations.

Dr. Kapoor: I completely agree. The decision is driven by symptoms that are not otherwise well managed, for example, with nonhormone strategies. If we have any concerns utilizing HT beyond the age of natural menopause, then nonhormonal options can be considered; but sometimes those are not as effective. And bone health is very important. You want to avoid using bisphosphonates in younger women and reserve them for older patients in their late 60s and 70s. Hormone therapy use is a very reasonable strategy to prevent bone loss.

Dr. Kaunitz: It is also worth mentioning that sometimes the woman involved in shared decision making with her clinician decides to stop systemic HT. In that setting, should the patient start developing new-onset dyspareunia, vaginal dryness, or other genital or sexuality-related concerns, it takes very little for me to advise that she start low-dose local vaginal estrogen therapy.

Dr. Faubion: In either scenario, if a woman were to develop symptoms consistent with genitourinary syndrome of menopause (GSM), would you use vaginal estrogen in addition to the systemic estrogen or alone after the woman elected to discontinue systemic therapy?

Dr. Kapoor: Yes to both, I would say.

Dr. Kaunitz: As my patients using systemic HT age, often I will lower the dose. For instance, the dose I use in a 53-year-old will be higher than when she is 59 or 62. At the same time, as we lower the dose of systemic estrogen therapy, symptoms of vaginal atrophy or GSM often will appear, and these can be effectively treated by adding low-dose vaginal estrogen therapy. A number of my patients, particularly those who are on lower-than-standard doses of systemic HT, are also using low-dose vaginal estrogen therapy.

There is a “hybrid” product available: the 90-day estradiol vaginal ring. Estring is a low-dose, 2-mg, 90-day estradiol ring that is very useful, but it is effective only for treating GSM or vaginal atrophy. A second menopausal vaginal estradiol ring, Femring, is available in 2 doses: 0.05 mg/day and 0.1 mg/day. These are very effective in treating both systemic issues, such as vasomotor symptoms or prevention of osteoporosis, and very effective in treating GSM or vaginal atrophy. One problem is that Femring, depending on insurance coverage, can be very expensive. It’s not available as a generic, so for insurance or financial reasons I don’t often prescribe it. If I could remove those financial barriers, I would prescribe Femring more often because it is very useful.

Dr. Faubion: You raise an important point, and that is, for women who have been on HT for some time, clinicians often feel the need to slowly reduce the dose. Would you do that same thing, Dr. Kapoor, for a 40-year-old woman? Would you reduce the dose as she approaches age 50? Is there pressure that “she shouldn’t be on that much estrogen”?

Dr. Kapoor: No, I would not feel pressured until the patient turns at least 46. I bring up age 46 because the average age range for menopause is 46 to 55. After that, if there is any concern, we can decrease the dose to half and keep the patient on that until she turns 50 or 51. But most of my patients are on replacement doses until the average age of menopause, which is around 51 years, and that’s when you reduce the dose to that of the typical HT regimens used after natural menopause.

Sometimes patients are told something by a friend or they have read something and they worry about the risk of 2 things. One is breast cancer and the other is venous thromboembolism (VTE), and that may be why they want to be on a lower dose. I counsel patients that while the risk of VTE is real with HT, it is the women after natural menopause who are at risk—because age itself is a risk for VTE—and it also has to do with the kind of HT regimen that a patient is on. High doses of oral estrogens and certain progestogens increase the risk. But again, for estradiol used in replacement doses and the more common progestogens that we now use in practice, such as micronized progesterone, the risk is not the same. The same goes for breast cancer. My biggest message to patients and clinicians who take care of these patients is that the rules that apply to women after natural menopause just do not apply to this very different patient population.

Dr. Faubion: Thank you, Dr. Kaunitz and Dr. Kapoor, for sharing your knowledge and experience. ●

Koning 3D Breast CT

Koning expects to submit trial data for their ongoing screening study to the FDA in Q1 2022.

For more information, visit https://www.koninghealth.com/en/

New STI treatment resources

Healthcare Effectiveness and Data Information Set (HEDIS) measures are performance improvement measures used for health plans to track various dimensions of care. In 2019, the HEDIS measure for chlamydia screening showed that commercial and Medicaid health plans had an average 52% screening rate among sexually active 16- to 24-year-old women. In an effort to increase screening rates among young women, the Centers for Disease Control and Prevention has implemented opt-out, or universal screening, for chlamydia. In order to aid clinicians in implementing this opt-out screening into their practices, the American Sexual Health Association and the National Chlamydia Coalition created resources that offer guidance, including using normalizing language with patients to explain the screening strategy. Providers can access these resources online (http://chlamydiacoalition.org/opt-out-screening/). Videos are offered and include case examples of how to speak with patients about universal screening, and printable documents are included that expand on ways that practices can improve screening rates.

For more information, visit http://chlamydiacoalition.org/opt-out-screening/.

Koning 3D Breast CT

Koning expects to submit trial data for their ongoing screening study to the FDA in Q1 2022.

For more information, visit https://www.koninghealth.com/en/

New STI treatment resources

Healthcare Effectiveness and Data Information Set (HEDIS) measures are performance improvement measures used for health plans to track various dimensions of care. In 2019, the HEDIS measure for chlamydia screening showed that commercial and Medicaid health plans had an average 52% screening rate among sexually active 16- to 24-year-old women. In an effort to increase screening rates among young women, the Centers for Disease Control and Prevention has implemented opt-out, or universal screening, for chlamydia. In order to aid clinicians in implementing this opt-out screening into their practices, the American Sexual Health Association and the National Chlamydia Coalition created resources that offer guidance, including using normalizing language with patients to explain the screening strategy. Providers can access these resources online (http://chlamydiacoalition.org/opt-out-screening/). Videos are offered and include case examples of how to speak with patients about universal screening, and printable documents are included that expand on ways that practices can improve screening rates.

For more information, visit http://chlamydiacoalition.org/opt-out-screening/.

Koning 3D Breast CT

Koning expects to submit trial data for their ongoing screening study to the FDA in Q1 2022.

For more information, visit https://www.koninghealth.com/en/

New STI treatment resources

Healthcare Effectiveness and Data Information Set (HEDIS) measures are performance improvement measures used for health plans to track various dimensions of care. In 2019, the HEDIS measure for chlamydia screening showed that commercial and Medicaid health plans had an average 52% screening rate among sexually active 16- to 24-year-old women. In an effort to increase screening rates among young women, the Centers for Disease Control and Prevention has implemented opt-out, or universal screening, for chlamydia. In order to aid clinicians in implementing this opt-out screening into their practices, the American Sexual Health Association and the National Chlamydia Coalition created resources that offer guidance, including using normalizing language with patients to explain the screening strategy. Providers can access these resources online (http://chlamydiacoalition.org/opt-out-screening/). Videos are offered and include case examples of how to speak with patients about universal screening, and printable documents are included that expand on ways that practices can improve screening rates.

For more information, visit http://chlamydiacoalition.org/opt-out-screening/.

Contraception and family planning have improved the health of all people by reducing maternal mortality, improving maternal and child health through birth spacing, supporting full education attainment, and advancing workforce participation.¹ Contraception is cost-effective and should be supported by all health insurers. One economic study reported that depending on the contraceptive method utilized, up to $7 of health care costs were saved for each dollar spent on contraceptive services and supplies.²

Progestin-only pills (POPs) are an important contraceptive option for people in the following situations who³:

• have a contraindication to estrogen-containing contraceptives
• are actively breastfeeding
• are less than 21 days since birth
• have a preference to avoid estrogen.

POPs are contraindicated for women who have breast cancer, abnormal uterine bleeding, or active liver disease and for women who are pregnant. A history of bariatric surgery with a malabsorption procedure (Roux-en-Y and biliopancreatic diversion) and the use of antiepileptic medications that are strong enzyme inducers are additional situations where the risk of POP may outweigh the benefit.³ Alternative progestin-only options include the subdermal etonogestrel implant, depot medroxyprogesterone acetate, and levonorgestrel-releasing intrauterine devices. These 3 options provide superior contraceptive efficacy to POP.

As a contraceptive, norethindrone at a dose of 0.35 mg daily has two major flaws:

• it does not reliably inhibit ovulation
• it has a short half-life.

In clinical studies, norethindrone inhibits ovulation in approximately 50% of cycles.^4,5 Because norethindrone at a dose of 0.35 mg does not reliably inhibit ovulation it relies on additional mechanisms for contraceptive efficacy, including thickening of the cervical mucus to block sperm entry into the upper reproductive tract, reduced fallopian tube motility, and thinning of the endometrium.⁶

Norethindrone POP is formulated in packs of 28 pills containing 0.35 mg intended for daily continuous administration and no medication-free intervals. One rationale for the low dose of 0.35 mg in norethindrone POP is that it approximates the lowest dose with contraceptive efficacy for breastfeeding women, which has the benefit of minimizing exposure of the baby to the medication. Estrogen-progestin birth control pills containing norethindrone as the progestin reliably inhibit ovulation and have a minimum of 1 mg of norethindrone in each hormone pill. A POP with 1 mg of norethindrone per pill would likely have greater contraceptive efficacy. When taken daily, norethindrone acetate 5 mg (Aygestin) suppresses ovarian estrogen production, ovulation, and often causes cessation of uterine bleeding.⁷ The short half-life of norethindrone (7.7 hours) further exacerbates the problem of an insufficient daily dose.⁶ The standard guidance is that norethindrone must be taken at the same time every day, a goal that is nearly impossible to achieve. If a dose of norethindrone is taken >3 hours late, backup contraception is recommended for 48 hours.⁶

Drospirenone is a chemical analogue of spironolactone. Drospirenone is a progestin that suppresses LH and FSH and has anti-androgenic and partial anti-mineralocorticoid effects.⁸ Drospirenone POP contains 4 mg of a nonmicronized formulation that is believed to provide a pharmacologically similar area under the curve in drug metabolism studies to the 3 mg of micronized drospirenone, present in drospirenone-containing estrogen-progestin contraceptives.⁸ It is provided in a pack of 28 pills with 24 drospirenone pills and 4 pills without hormone. Drospirenone has a long half-life of 30 to 34 hours.⁸ If ≥2 drospirenone pills are missed, backup contraception is recommended for 7 days.⁹ The contraceptive effectiveness of drospirenone POP is thought to be similar to estrogen-progestin pills.⁸ Theoretically, drospirenone, acting as an anti-mineralocorticoid, can cause hyperkalemia. People with renal and adrenal insufficiency are most vulnerable to this adverse effect and should not be prescribed drospirenone. Women taking drospirenone and a medication that strongly inhibits CYP3A4, an enzyme involved in drospirenone degradation—including ketoconazole, indinavir, boceprevir, and clarithromycin—may have increased circulating levels of drospirenone and be at an increased risk of hyperkalemia. The US Food and Drug Administration (FDA) suggests that clinicians consider monitoring potassium concentration in women taking drospirenone who are also prescribed a strong CYP3A4 inhibitor.⁹ In people with normal renal and adrenal function, drospirenone-induced hyperkalemia is not commonly observed.⁹

Drospirenone 4 mg has been reported to not affect the natural balance of pro- and anti-coagulation factors in women.¹⁰ Drospirenone 4 mg daily has been reported to cause a modest decrease in systolic (-8 mm Hg) and diastolic (-5 mm Hg) blood pressure for women with a baseline blood pressure ≥130 mm Hg. Drospirenone 4 mg daily did not change blood pressure measurement in women with a baseline systolic blood pressure <130 mm Hg.¹¹ For women using drospirenone POP, circulating estradiol concentration is usually >30 pg/mL, with a mean concentration of 51 pg/mL.^12,13 Drospirenone POP does not result in a significant change in body weight.¹⁴ Preliminary studies suggest that drospirenone is an effective contraceptive in women with a BMI >30 kg/m².^14,15 Drospirenone enters breast milk and the relative infant dose is reported to be 1.5%.⁹ In general, breastfeeding is considered reasonably safe when the relative infant dose of a medication is <10%.¹⁶

The most common adverse effect reported with both norethindrone and drospirenone POP is unscheduled uterine bleeding. With norethindrone POP about 50% of users have a relatively preserved monthly bleeding pattern and approximately 50% have bleeding between periods, spotting and/or prolonged bleeding.^17,18 A similar frequency of unscheduled uterine bleeding has been reported with drospirenone POP.^14,19 Unscheduled and bothersome uterine bleeding is a common reason people discontinue POP. For drospirenone POP, the FDA reports a Pearl Index of 4.⁹ Other studies report a Pearl Index of 0.73 (95% confidence interval [CI], 0.31 to 1.43) for drospirenone POP.¹⁴ For norethindrone POP, the FDA reports that in typical use about 5% of people using the contraceptive method would become pregnant.⁶ The TABLE provides a comparison of the key features of the two available POP contraceptives. My assessment is that drospirenone has superior contraceptive properties over norethindrone POP. However, a head-to-head clinical trial would be necessary to determine the relative contraceptive effectiveness of drospirenone versus norethindrone POP.

Maintaining contraception access

Access to contraception without a copayment is an important component of a comprehensive and equitable insurance program.²⁰ The American College of Obstetricians and Gynecologists (ACOG) advocates that all people “should have unhindered and affordable access to all U.S. Food and Drug Administration-approved contraceptives.”²¹ ACOG also calls for the “full implementation of the Affordable Care Act requirement that new and revised private health insurance plans cover all U.S. Food and Drug Administration approved contraceptives without cost sharing, including nonequivalent options within one method category.” The National Women’s Law Center²² provides helpful resources to ensure access to legislated contraceptive benefits, including a phone script for speaking with an insurance benefits agent²³ and a toolkit for advocating for your contraceptive choice.²⁴ We need to ensure that people have unfettered access to all FDA-approved contraceptives because access to contraception is an important component of public health. Although drospirenone is more costly than norethindrone POP, drospirenone contraception should be available to all patients seeking POP contraception. ●

Contraception and family planning have improved the health of all people by reducing maternal mortality, improving maternal and child health through birth spacing, supporting full education attainment, and advancing workforce participation.¹ Contraception is cost-effective and should be supported by all health insurers. One economic study reported that depending on the contraceptive method utilized, up to $7 of health care costs were saved for each dollar spent on contraceptive services and supplies.²

Progestin-only pills (POPs) are an important contraceptive option for people in the following situations who³:

• have a contraindication to estrogen-containing contraceptives
• are actively breastfeeding
• are less than 21 days since birth
• have a preference to avoid estrogen.

POPs are contraindicated for women who have breast cancer, abnormal uterine bleeding, or active liver disease and for women who are pregnant. A history of bariatric surgery with a malabsorption procedure (Roux-en-Y and biliopancreatic diversion) and the use of antiepileptic medications that are strong enzyme inducers are additional situations where the risk of POP may outweigh the benefit.³ Alternative progestin-only options include the subdermal etonogestrel implant, depot medroxyprogesterone acetate, and levonorgestrel-releasing intrauterine devices. These 3 options provide superior contraceptive efficacy to POP.

As a contraceptive, norethindrone at a dose of 0.35 mg daily has two major flaws:

• it does not reliably inhibit ovulation
• it has a short half-life.

In clinical studies, norethindrone inhibits ovulation in approximately 50% of cycles.^4,5 Because norethindrone at a dose of 0.35 mg does not reliably inhibit ovulation it relies on additional mechanisms for contraceptive efficacy, including thickening of the cervical mucus to block sperm entry into the upper reproductive tract, reduced fallopian tube motility, and thinning of the endometrium.⁶

Norethindrone POP is formulated in packs of 28 pills containing 0.35 mg intended for daily continuous administration and no medication-free intervals. One rationale for the low dose of 0.35 mg in norethindrone POP is that it approximates the lowest dose with contraceptive efficacy for breastfeeding women, which has the benefit of minimizing exposure of the baby to the medication. Estrogen-progestin birth control pills containing norethindrone as the progestin reliably inhibit ovulation and have a minimum of 1 mg of norethindrone in each hormone pill. A POP with 1 mg of norethindrone per pill would likely have greater contraceptive efficacy. When taken daily, norethindrone acetate 5 mg (Aygestin) suppresses ovarian estrogen production, ovulation, and often causes cessation of uterine bleeding.⁷ The short half-life of norethindrone (7.7 hours) further exacerbates the problem of an insufficient daily dose.⁶ The standard guidance is that norethindrone must be taken at the same time every day, a goal that is nearly impossible to achieve. If a dose of norethindrone is taken >3 hours late, backup contraception is recommended for 48 hours.⁶

Drospirenone is a chemical analogue of spironolactone. Drospirenone is a progestin that suppresses LH and FSH and has anti-androgenic and partial anti-mineralocorticoid effects.⁸ Drospirenone POP contains 4 mg of a nonmicronized formulation that is believed to provide a pharmacologically similar area under the curve in drug metabolism studies to the 3 mg of micronized drospirenone, present in drospirenone-containing estrogen-progestin contraceptives.⁸ It is provided in a pack of 28 pills with 24 drospirenone pills and 4 pills without hormone. Drospirenone has a long half-life of 30 to 34 hours.⁸ If ≥2 drospirenone pills are missed, backup contraception is recommended for 7 days.⁹ The contraceptive effectiveness of drospirenone POP is thought to be similar to estrogen-progestin pills.⁸ Theoretically, drospirenone, acting as an anti-mineralocorticoid, can cause hyperkalemia. People with renal and adrenal insufficiency are most vulnerable to this adverse effect and should not be prescribed drospirenone. Women taking drospirenone and a medication that strongly inhibits CYP3A4, an enzyme involved in drospirenone degradation—including ketoconazole, indinavir, boceprevir, and clarithromycin—may have increased circulating levels of drospirenone and be at an increased risk of hyperkalemia. The US Food and Drug Administration (FDA) suggests that clinicians consider monitoring potassium concentration in women taking drospirenone who are also prescribed a strong CYP3A4 inhibitor.⁹ In people with normal renal and adrenal function, drospirenone-induced hyperkalemia is not commonly observed.⁹

Drospirenone 4 mg has been reported to not affect the natural balance of pro- and anti-coagulation factors in women.¹⁰ Drospirenone 4 mg daily has been reported to cause a modest decrease in systolic (-8 mm Hg) and diastolic (-5 mm Hg) blood pressure for women with a baseline blood pressure ≥130 mm Hg. Drospirenone 4 mg daily did not change blood pressure measurement in women with a baseline systolic blood pressure <130 mm Hg.¹¹ For women using drospirenone POP, circulating estradiol concentration is usually >30 pg/mL, with a mean concentration of 51 pg/mL.^12,13 Drospirenone POP does not result in a significant change in body weight.¹⁴ Preliminary studies suggest that drospirenone is an effective contraceptive in women with a BMI >30 kg/m².^14,15 Drospirenone enters breast milk and the relative infant dose is reported to be 1.5%.⁹ In general, breastfeeding is considered reasonably safe when the relative infant dose of a medication is <10%.¹⁶

The most common adverse effect reported with both norethindrone and drospirenone POP is unscheduled uterine bleeding. With norethindrone POP about 50% of users have a relatively preserved monthly bleeding pattern and approximately 50% have bleeding between periods, spotting and/or prolonged bleeding.^17,18 A similar frequency of unscheduled uterine bleeding has been reported with drospirenone POP.^14,19 Unscheduled and bothersome uterine bleeding is a common reason people discontinue POP. For drospirenone POP, the FDA reports a Pearl Index of 4.⁹ Other studies report a Pearl Index of 0.73 (95% confidence interval [CI], 0.31 to 1.43) for drospirenone POP.¹⁴ For norethindrone POP, the FDA reports that in typical use about 5% of people using the contraceptive method would become pregnant.⁶ The TABLE provides a comparison of the key features of the two available POP contraceptives. My assessment is that drospirenone has superior contraceptive properties over norethindrone POP. However, a head-to-head clinical trial would be necessary to determine the relative contraceptive effectiveness of drospirenone versus norethindrone POP.

Maintaining contraception access

Access to contraception without a copayment is an important component of a comprehensive and equitable insurance program.²⁰ The American College of Obstetricians and Gynecologists (ACOG) advocates that all people “should have unhindered and affordable access to all U.S. Food and Drug Administration-approved contraceptives.”²¹ ACOG also calls for the “full implementation of the Affordable Care Act requirement that new and revised private health insurance plans cover all U.S. Food and Drug Administration approved contraceptives without cost sharing, including nonequivalent options within one method category.” The National Women’s Law Center²² provides helpful resources to ensure access to legislated contraceptive benefits, including a phone script for speaking with an insurance benefits agent²³ and a toolkit for advocating for your contraceptive choice.²⁴ We need to ensure that people have unfettered access to all FDA-approved contraceptives because access to contraception is an important component of public health. Although drospirenone is more costly than norethindrone POP, drospirenone contraception should be available to all patients seeking POP contraception. ●

Contraception and family planning have improved the health of all people by reducing maternal mortality, improving maternal and child health through birth spacing, supporting full education attainment, and advancing workforce participation.¹ Contraception is cost-effective and should be supported by all health insurers. One economic study reported that depending on the contraceptive method utilized, up to $7 of health care costs were saved for each dollar spent on contraceptive services and supplies.²

Progestin-only pills (POPs) are an important contraceptive option for people in the following situations who³:

• have a contraindication to estrogen-containing contraceptives
• are actively breastfeeding
• are less than 21 days since birth
• have a preference to avoid estrogen.

POPs are contraindicated for women who have breast cancer, abnormal uterine bleeding, or active liver disease and for women who are pregnant. A history of bariatric surgery with a malabsorption procedure (Roux-en-Y and biliopancreatic diversion) and the use of antiepileptic medications that are strong enzyme inducers are additional situations where the risk of POP may outweigh the benefit.³ Alternative progestin-only options include the subdermal etonogestrel implant, depot medroxyprogesterone acetate, and levonorgestrel-releasing intrauterine devices. These 3 options provide superior contraceptive efficacy to POP.

As a contraceptive, norethindrone at a dose of 0.35 mg daily has two major flaws:

• it does not reliably inhibit ovulation
• it has a short half-life.

In clinical studies, norethindrone inhibits ovulation in approximately 50% of cycles.^4,5 Because norethindrone at a dose of 0.35 mg does not reliably inhibit ovulation it relies on additional mechanisms for contraceptive efficacy, including thickening of the cervical mucus to block sperm entry into the upper reproductive tract, reduced fallopian tube motility, and thinning of the endometrium.⁶

Norethindrone POP is formulated in packs of 28 pills containing 0.35 mg intended for daily continuous administration and no medication-free intervals. One rationale for the low dose of 0.35 mg in norethindrone POP is that it approximates the lowest dose with contraceptive efficacy for breastfeeding women, which has the benefit of minimizing exposure of the baby to the medication. Estrogen-progestin birth control pills containing norethindrone as the progestin reliably inhibit ovulation and have a minimum of 1 mg of norethindrone in each hormone pill. A POP with 1 mg of norethindrone per pill would likely have greater contraceptive efficacy. When taken daily, norethindrone acetate 5 mg (Aygestin) suppresses ovarian estrogen production, ovulation, and often causes cessation of uterine bleeding.⁷ The short half-life of norethindrone (7.7 hours) further exacerbates the problem of an insufficient daily dose.⁶ The standard guidance is that norethindrone must be taken at the same time every day, a goal that is nearly impossible to achieve. If a dose of norethindrone is taken >3 hours late, backup contraception is recommended for 48 hours.⁶

Drospirenone is a chemical analogue of spironolactone. Drospirenone is a progestin that suppresses LH and FSH and has anti-androgenic and partial anti-mineralocorticoid effects.⁸ Drospirenone POP contains 4 mg of a nonmicronized formulation that is believed to provide a pharmacologically similar area under the curve in drug metabolism studies to the 3 mg of micronized drospirenone, present in drospirenone-containing estrogen-progestin contraceptives.⁸ It is provided in a pack of 28 pills with 24 drospirenone pills and 4 pills without hormone. Drospirenone has a long half-life of 30 to 34 hours.⁸ If ≥2 drospirenone pills are missed, backup contraception is recommended for 7 days.⁹ The contraceptive effectiveness of drospirenone POP is thought to be similar to estrogen-progestin pills.⁸ Theoretically, drospirenone, acting as an anti-mineralocorticoid, can cause hyperkalemia. People with renal and adrenal insufficiency are most vulnerable to this adverse effect and should not be prescribed drospirenone. Women taking drospirenone and a medication that strongly inhibits CYP3A4, an enzyme involved in drospirenone degradation—including ketoconazole, indinavir, boceprevir, and clarithromycin—may have increased circulating levels of drospirenone and be at an increased risk of hyperkalemia. The US Food and Drug Administration (FDA) suggests that clinicians consider monitoring potassium concentration in women taking drospirenone who are also prescribed a strong CYP3A4 inhibitor.⁹ In people with normal renal and adrenal function, drospirenone-induced hyperkalemia is not commonly observed.⁹

Drospirenone 4 mg has been reported to not affect the natural balance of pro- and anti-coagulation factors in women.¹⁰ Drospirenone 4 mg daily has been reported to cause a modest decrease in systolic (-8 mm Hg) and diastolic (-5 mm Hg) blood pressure for women with a baseline blood pressure ≥130 mm Hg. Drospirenone 4 mg daily did not change blood pressure measurement in women with a baseline systolic blood pressure <130 mm Hg.¹¹ For women using drospirenone POP, circulating estradiol concentration is usually >30 pg/mL, with a mean concentration of 51 pg/mL.^12,13 Drospirenone POP does not result in a significant change in body weight.¹⁴ Preliminary studies suggest that drospirenone is an effective contraceptive in women with a BMI >30 kg/m².^14,15 Drospirenone enters breast milk and the relative infant dose is reported to be 1.5%.⁹ In general, breastfeeding is considered reasonably safe when the relative infant dose of a medication is <10%.¹⁶

The most common adverse effect reported with both norethindrone and drospirenone POP is unscheduled uterine bleeding. With norethindrone POP about 50% of users have a relatively preserved monthly bleeding pattern and approximately 50% have bleeding between periods, spotting and/or prolonged bleeding.^17,18 A similar frequency of unscheduled uterine bleeding has been reported with drospirenone POP.^14,19 Unscheduled and bothersome uterine bleeding is a common reason people discontinue POP. For drospirenone POP, the FDA reports a Pearl Index of 4.⁹ Other studies report a Pearl Index of 0.73 (95% confidence interval [CI], 0.31 to 1.43) for drospirenone POP.¹⁴ For norethindrone POP, the FDA reports that in typical use about 5% of people using the contraceptive method would become pregnant.⁶ The TABLE provides a comparison of the key features of the two available POP contraceptives. My assessment is that drospirenone has superior contraceptive properties over norethindrone POP. However, a head-to-head clinical trial would be necessary to determine the relative contraceptive effectiveness of drospirenone versus norethindrone POP.

Maintaining contraception access

Access to contraception without a copayment is an important component of a comprehensive and equitable insurance program.²⁰ The American College of Obstetricians and Gynecologists (ACOG) advocates that all people “should have unhindered and affordable access to all U.S. Food and Drug Administration-approved contraceptives.”²¹ ACOG also calls for the “full implementation of the Affordable Care Act requirement that new and revised private health insurance plans cover all U.S. Food and Drug Administration approved contraceptives without cost sharing, including nonequivalent options within one method category.” The National Women’s Law Center²² provides helpful resources to ensure access to legislated contraceptive benefits, including a phone script for speaking with an insurance benefits agent²³ and a toolkit for advocating for your contraceptive choice.²⁴ We need to ensure that people have unfettered access to all FDA-approved contraceptives because access to contraception is an important component of public health. Although drospirenone is more costly than norethindrone POP, drospirenone contraception should be available to all patients seeking POP contraception. ●

Tardive dyskinesia (TD) is a delayed movement disorder resulting from treatment with dopamine receptor–blocking medications, Dr Karen Anderson of Georgetown University School of Medicine explains. TD is most commonly associated with long-term use of antipsychotic drugs. 

TD is characterized by involuntary, jerking movements of the tongue, lips, face, trunk, extremities, or the whole body. Although its characteristic movements are sometimes viewed as cosmetic, TD can interfere with patients’ quality of life and add to the stigma of mental illness. 

The sooner TD is diagnosed, the more likely it is for patients to achieve remission spontaneously and without treatment. To that end, patients who are prescribed antipsychotic medication should be evaluated at baseline and regularly thereafter using the Abnormal Involuntary Movement Scale (AIMS), which rates abnormal movements. 

The optimal first step in TD management is to stop the dopamine receptor–blocking medication, but this option may not be possible in patients with chronic conditions, such as manic depression and schizophrenia. In these patients, dose reduction or switching to a newer antipsychotic may provide relief.  

Two vesicular monoamine transporter 2 (VMAT2) inhibitors are approved to treat TD and have been found to not worsen patients’ underlying psychiatric condition. Dr Anderson cautions that patients treated with a VMAT2 inhibitor will require monitoring because side effects of these agents include suicidal ideation. 

--

Karen Anderson, MD, Professor, Department of Psychiatry and Neurology, Georgetown University School of Medicine; Washington, DC 

Karen Anderson, MD, has disclosed the following relevant financial relationships: 
 
Received income in an amount equal to or greater than $250 from: Neurocrine; Teva 

Tardive dyskinesia (TD) is a delayed movement disorder resulting from treatment with dopamine receptor–blocking medications, Dr Karen Anderson of Georgetown University School of Medicine explains. TD is most commonly associated with long-term use of antipsychotic drugs. 

TD is characterized by involuntary, jerking movements of the tongue, lips, face, trunk, extremities, or the whole body. Although its characteristic movements are sometimes viewed as cosmetic, TD can interfere with patients’ quality of life and add to the stigma of mental illness. 

The sooner TD is diagnosed, the more likely it is for patients to achieve remission spontaneously and without treatment. To that end, patients who are prescribed antipsychotic medication should be evaluated at baseline and regularly thereafter using the Abnormal Involuntary Movement Scale (AIMS), which rates abnormal movements. 

The optimal first step in TD management is to stop the dopamine receptor–blocking medication, but this option may not be possible in patients with chronic conditions, such as manic depression and schizophrenia. In these patients, dose reduction or switching to a newer antipsychotic may provide relief.  

Two vesicular monoamine transporter 2 (VMAT2) inhibitors are approved to treat TD and have been found to not worsen patients’ underlying psychiatric condition. Dr Anderson cautions that patients treated with a VMAT2 inhibitor will require monitoring because side effects of these agents include suicidal ideation. 

--

Karen Anderson, MD, Professor, Department of Psychiatry and Neurology, Georgetown University School of Medicine; Washington, DC 

Karen Anderson, MD, has disclosed the following relevant financial relationships: 
 
Received income in an amount equal to or greater than $250 from: Neurocrine; Teva 

Tardive dyskinesia (TD) is a delayed movement disorder resulting from treatment with dopamine receptor–blocking medications, Dr Karen Anderson of Georgetown University School of Medicine explains. TD is most commonly associated with long-term use of antipsychotic drugs. 

TD is characterized by involuntary, jerking movements of the tongue, lips, face, trunk, extremities, or the whole body. Although its characteristic movements are sometimes viewed as cosmetic, TD can interfere with patients’ quality of life and add to the stigma of mental illness. 

The sooner TD is diagnosed, the more likely it is for patients to achieve remission spontaneously and without treatment. To that end, patients who are prescribed antipsychotic medication should be evaluated at baseline and regularly thereafter using the Abnormal Involuntary Movement Scale (AIMS), which rates abnormal movements. 

The optimal first step in TD management is to stop the dopamine receptor–blocking medication, but this option may not be possible in patients with chronic conditions, such as manic depression and schizophrenia. In these patients, dose reduction or switching to a newer antipsychotic may provide relief.  

Two vesicular monoamine transporter 2 (VMAT2) inhibitors are approved to treat TD and have been found to not worsen patients’ underlying psychiatric condition. Dr Anderson cautions that patients treated with a VMAT2 inhibitor will require monitoring because side effects of these agents include suicidal ideation. 

--

Karen Anderson, MD, Professor, Department of Psychiatry and Neurology, Georgetown University School of Medicine; Washington, DC 

Karen Anderson, MD, has disclosed the following relevant financial relationships: 
 
Received income in an amount equal to or greater than $250 from: Neurocrine; Teva 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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