The VA Ann Arbor Healthcare System in Michigan is mobilizing telehealth technology for a disaster-relief initiative that aims to connect first responders in the field with medical specialists at the Ann Arbor Medical Center. As reported in Healthcare IT News, the Disaster Relief Telehealth System of Orion, Mich.-based JEMS Technology (www.jemstech.com) enables secure, live-streaming video to be sent to specialists, who can review the video and respond with medical advice.⁵

The Office of Emergency Management at the Ann Arbor VA supports emergency operations from four treatment sites serving 21 counties in Michigan and Ohio, as well as regional disaster preparedness.

In other technology news, the U.S. Army in March awarded a $2.5 million contract to brain-monitoring-device company NeuroWave Systems of Cleveland Heights, Ohio (www.neurowavesystems.com), to develop a wearable, miniaturized brain monitor to assess via electroencephalogram data for traumatic brain injury (TBI) in the field, directly at the point of suspected injury, such as on battlefronts. The device, called SeizTBI, is “small, lightweight, and designed for rapid deployment in austere environments,” explains NeuroWave principal investigator Stephan Bibian, MD. TBI accounted for 22% of U.S. troop casualties in the Iraq and Afghanistan conflicts, but fewer than half were identified in the field.

References

1. Quinn K, Neeman N, Mourad M, Sliwka D. Communication coaching: A multifaceted intervention to improve physician-patient communication [abstract]. J Hosp Med. 2012;7 Suppl 2:S108.
2. Sokol PE, Wynia MK. There and Home Again, Safely: Five Responsibilities of Ambulatory Practices in High Quality Care Transitions. American Medical Association website. http://www.ama-assn.org/resources/doc/patient-safety/ambulatory-practices.pdf. Accessed February 12, 2013.
3. Dharmarajan K, Hsieh AF, Lin Z, et al. Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia. JAMA. 2013;309(4):355-363.
4. JAMA Internal Medicine. Nearly one-third of physicians report missing electronic notification of test results. JAMA Internal Medicine website. Available at: http://media.jamanetwork.com/news-item/nearly-one-third-of-physicians-report-missing-electronic-notification-of-test-results/.Accessed April 8, 2013.
5. Miliard M. VA enlists telehealth for disasters. Healthcare IT News website. http://www.healthcareitnews.com/news/va-enlists-telehealth-disasters. Published February 27, 2013. Accessed April 1, 2013.

The VA Ann Arbor Healthcare System in Michigan is mobilizing telehealth technology for a disaster-relief initiative that aims to connect first responders in the field with medical specialists at the Ann Arbor Medical Center. As reported in Healthcare IT News, the Disaster Relief Telehealth System of Orion, Mich.-based JEMS Technology (www.jemstech.com) enables secure, live-streaming video to be sent to specialists, who can review the video and respond with medical advice.⁵

The Office of Emergency Management at the Ann Arbor VA supports emergency operations from four treatment sites serving 21 counties in Michigan and Ohio, as well as regional disaster preparedness.

In other technology news, the U.S. Army in March awarded a $2.5 million contract to brain-monitoring-device company NeuroWave Systems of Cleveland Heights, Ohio (www.neurowavesystems.com), to develop a wearable, miniaturized brain monitor to assess via electroencephalogram data for traumatic brain injury (TBI) in the field, directly at the point of suspected injury, such as on battlefronts. The device, called SeizTBI, is “small, lightweight, and designed for rapid deployment in austere environments,” explains NeuroWave principal investigator Stephan Bibian, MD. TBI accounted for 22% of U.S. troop casualties in the Iraq and Afghanistan conflicts, but fewer than half were identified in the field.

References

1. Quinn K, Neeman N, Mourad M, Sliwka D. Communication coaching: A multifaceted intervention to improve physician-patient communication [abstract]. J Hosp Med. 2012;7 Suppl 2:S108.
2. Sokol PE, Wynia MK. There and Home Again, Safely: Five Responsibilities of Ambulatory Practices in High Quality Care Transitions. American Medical Association website. http://www.ama-assn.org/resources/doc/patient-safety/ambulatory-practices.pdf. Accessed February 12, 2013.
3. Dharmarajan K, Hsieh AF, Lin Z, et al. Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia. JAMA. 2013;309(4):355-363.
4. JAMA Internal Medicine. Nearly one-third of physicians report missing electronic notification of test results. JAMA Internal Medicine website. Available at: http://media.jamanetwork.com/news-item/nearly-one-third-of-physicians-report-missing-electronic-notification-of-test-results/.Accessed April 8, 2013.
5. Miliard M. VA enlists telehealth for disasters. Healthcare IT News website. http://www.healthcareitnews.com/news/va-enlists-telehealth-disasters. Published February 27, 2013. Accessed April 1, 2013.

The VA Ann Arbor Healthcare System in Michigan is mobilizing telehealth technology for a disaster-relief initiative that aims to connect first responders in the field with medical specialists at the Ann Arbor Medical Center. As reported in Healthcare IT News, the Disaster Relief Telehealth System of Orion, Mich.-based JEMS Technology (www.jemstech.com) enables secure, live-streaming video to be sent to specialists, who can review the video and respond with medical advice.⁵

The Office of Emergency Management at the Ann Arbor VA supports emergency operations from four treatment sites serving 21 counties in Michigan and Ohio, as well as regional disaster preparedness.

In other technology news, the U.S. Army in March awarded a $2.5 million contract to brain-monitoring-device company NeuroWave Systems of Cleveland Heights, Ohio (www.neurowavesystems.com), to develop a wearable, miniaturized brain monitor to assess via electroencephalogram data for traumatic brain injury (TBI) in the field, directly at the point of suspected injury, such as on battlefronts. The device, called SeizTBI, is “small, lightweight, and designed for rapid deployment in austere environments,” explains NeuroWave principal investigator Stephan Bibian, MD. TBI accounted for 22% of U.S. troop casualties in the Iraq and Afghanistan conflicts, but fewer than half were identified in the field.

References

1. Quinn K, Neeman N, Mourad M, Sliwka D. Communication coaching: A multifaceted intervention to improve physician-patient communication [abstract]. J Hosp Med. 2012;7 Suppl 2:S108.
2. Sokol PE, Wynia MK. There and Home Again, Safely: Five Responsibilities of Ambulatory Practices in High Quality Care Transitions. American Medical Association website. http://www.ama-assn.org/resources/doc/patient-safety/ambulatory-practices.pdf. Accessed February 12, 2013.
3. Dharmarajan K, Hsieh AF, Lin Z, et al. Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia. JAMA. 2013;309(4):355-363.
4. JAMA Internal Medicine. Nearly one-third of physicians report missing electronic notification of test results. JAMA Internal Medicine website. Available at: http://media.jamanetwork.com/news-item/nearly-one-third-of-physicians-report-missing-electronic-notification-of-test-results/.Accessed April 8, 2013.
5. Miliard M. VA enlists telehealth for disasters. Healthcare IT News website. http://www.healthcareitnews.com/news/va-enlists-telehealth-disasters. Published February 27, 2013. Accessed April 1, 2013.

The American Medical Association recently released a report developed by a 21-member expert panel proposing a nine-step plan for primary-care-physician (PCP) practices to play an integral role in improving care transitions and preventing avoidable rehospitalizations.² The report recommends focusing on more than just the hospital-admitting diagnosis, conducting a thorough patient health assessment, clarifying the patient’s short- and long-term goals, and coordinating care with other care settings.

With simultaneous research in JAMA concluding that the vast majority of readmissions are for reasons unrelated to the previous hospital stay, coordination between the inpatient and outpatient teams is crucial to successful transitions of care.³ Moreover, a recent survey showed that nearly 30% of PCPs say they miss alerts about patients’ test results from an electronic health record (EHR) notification system.⁴ According to the survey by Hardeep Singh, MD, MPH, and colleagues from the Michael E. DeBakey VA Medical Center in Houston, the doctors received on average 63 such alerts per day. Seventy percent reported that they cannot effectively manage the alerts, and more than half said that the current EHR notification system makes it possible to miss test results.

Larry Beresford is a freelance writer in Oakland, Calif.

References

1. Quinn K, Neeman N, Mourad M, Sliwka D. Communication coaching: A multifaceted intervention to improve physician-patient communication [abstract]. J Hosp Med. 2012;7 Suppl 2:S108.
2. Sokol PE, Wynia MK. There and Home Again, Safely: Five Responsibilities of Ambulatory Practices in High Quality Care Transitions. American Medical Association website. http://www.ama-assn.org/resources/doc/patient-safety/ambulatory-practices.pdf. Accessed February 12, 2013.
3. Dharmarajan K, Hsieh AF, Lin Z, et al. Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia. JAMA. 2013;309(4):355-363.
4. JAMA Internal Medicine. Nearly one-third of physicians report missing electronic notification of test results. JAMA Internal Medicine website. Available at: http://media.jamanetwork.com/news-item/nearly-one-third-of-physicians-report-missing-electronic-notification-of-test-results/.Accessed April 8, 2013.
5. Miliard M. VA enlists telehealth for disasters. Healthcare IT News website. http://www.healthcareitnews.com/news/va-enlists-telehealth-disasters. Published February 27, 2013. Accessed April 1, 2013.

The American Medical Association recently released a report developed by a 21-member expert panel proposing a nine-step plan for primary-care-physician (PCP) practices to play an integral role in improving care transitions and preventing avoidable rehospitalizations.² The report recommends focusing on more than just the hospital-admitting diagnosis, conducting a thorough patient health assessment, clarifying the patient’s short- and long-term goals, and coordinating care with other care settings.

With simultaneous research in JAMA concluding that the vast majority of readmissions are for reasons unrelated to the previous hospital stay, coordination between the inpatient and outpatient teams is crucial to successful transitions of care.³ Moreover, a recent survey showed that nearly 30% of PCPs say they miss alerts about patients’ test results from an electronic health record (EHR) notification system.⁴ According to the survey by Hardeep Singh, MD, MPH, and colleagues from the Michael E. DeBakey VA Medical Center in Houston, the doctors received on average 63 such alerts per day. Seventy percent reported that they cannot effectively manage the alerts, and more than half said that the current EHR notification system makes it possible to miss test results.

Larry Beresford is a freelance writer in Oakland, Calif.

References

1. Quinn K, Neeman N, Mourad M, Sliwka D. Communication coaching: A multifaceted intervention to improve physician-patient communication [abstract]. J Hosp Med. 2012;7 Suppl 2:S108.
2. Sokol PE, Wynia MK. There and Home Again, Safely: Five Responsibilities of Ambulatory Practices in High Quality Care Transitions. American Medical Association website. http://www.ama-assn.org/resources/doc/patient-safety/ambulatory-practices.pdf. Accessed February 12, 2013.
3. Dharmarajan K, Hsieh AF, Lin Z, et al. Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia. JAMA. 2013;309(4):355-363.
4. JAMA Internal Medicine. Nearly one-third of physicians report missing electronic notification of test results. JAMA Internal Medicine website. Available at: http://media.jamanetwork.com/news-item/nearly-one-third-of-physicians-report-missing-electronic-notification-of-test-results/.Accessed April 8, 2013.
5. Miliard M. VA enlists telehealth for disasters. Healthcare IT News website. http://www.healthcareitnews.com/news/va-enlists-telehealth-disasters. Published February 27, 2013. Accessed April 1, 2013.

The American Medical Association recently released a report developed by a 21-member expert panel proposing a nine-step plan for primary-care-physician (PCP) practices to play an integral role in improving care transitions and preventing avoidable rehospitalizations.² The report recommends focusing on more than just the hospital-admitting diagnosis, conducting a thorough patient health assessment, clarifying the patient’s short- and long-term goals, and coordinating care with other care settings.

With simultaneous research in JAMA concluding that the vast majority of readmissions are for reasons unrelated to the previous hospital stay, coordination between the inpatient and outpatient teams is crucial to successful transitions of care.³ Moreover, a recent survey showed that nearly 30% of PCPs say they miss alerts about patients’ test results from an electronic health record (EHR) notification system.⁴ According to the survey by Hardeep Singh, MD, MPH, and colleagues from the Michael E. DeBakey VA Medical Center in Houston, the doctors received on average 63 such alerts per day. Seventy percent reported that they cannot effectively manage the alerts, and more than half said that the current EHR notification system makes it possible to miss test results.

Larry Beresford is a freelance writer in Oakland, Calif.

References

1. Quinn K, Neeman N, Mourad M, Sliwka D. Communication coaching: A multifaceted intervention to improve physician-patient communication [abstract]. J Hosp Med. 2012;7 Suppl 2:S108.
2. Sokol PE, Wynia MK. There and Home Again, Safely: Five Responsibilities of Ambulatory Practices in High Quality Care Transitions. American Medical Association website. http://www.ama-assn.org/resources/doc/patient-safety/ambulatory-practices.pdf. Accessed February 12, 2013.
3. Dharmarajan K, Hsieh AF, Lin Z, et al. Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia. JAMA. 2013;309(4):355-363.
4. JAMA Internal Medicine. Nearly one-third of physicians report missing electronic notification of test results. JAMA Internal Medicine website. Available at: http://media.jamanetwork.com/news-item/nearly-one-third-of-physicians-report-missing-electronic-notification-of-test-results/.Accessed April 8, 2013.
5. Miliard M. VA enlists telehealth for disasters. Healthcare IT News website. http://www.healthcareitnews.com/news/va-enlists-telehealth-disasters. Published February 27, 2013. Accessed April 1, 2013.

In a poster presented at HM12, Kathryn Quinn, MPH, CPPS, FACHE, described how her quality team at the University of California at San Francisco (UCSF) developed a checklist to improve physician communication with patients, then taught it to the attending hospitalist faculty.¹ The project began with a list of 29 best practices for patient-physician interaction, as identified in medical literature. Hospitalists then voted for the elements they felt were most important to their practice, as well as those best able to be measured, and a top-10 list was created.

Quinn, the program manager for quality and safety in the division of hospital medicine at UCSF, says the communication best practices were “chosen by the people whose practices we are trying to change.”

The quality team presented the best practices in one-hour training sessions that included small-group role plays, explains co-investigator and UCSF hospitalist Diane Sliwka, MD. The training extended to outpatient physicians, medical specialists, and chief residents. Participants also were provided a laminated pocket card listing the interventions. They also received feedback from structured observations with patients on service.

Quinn says UCSF hospitalists have improved at knocking and asking permission to enter patient rooms, introducing themselves by name and role, and encouraging questions at the end of the interaction. They have been less successful at inquiring about the patient’s concerns early in the interview and at discussing duration of treatment and next steps.

“We learned that it takes more than just talk,” Quinn says. “Just telling physicians how to improve communication doesn’t mean it’s easy to do.”

Still to be determined is the project’s impact on patient satisfaction scores, although the hospitalists reported that they found the training and feedback helpful.

References

1. Quinn K, Neeman N, Mourad M, Sliwka D. Communication coaching: A multifaceted intervention to improve physician-patient communication [abstract]. J Hosp Med. 2012;7 Suppl 2:S108.
2. Sokol PE, Wynia MK. There and Home Again, Safely: Five Responsibilities of Ambulatory Practices in High Quality Care Transitions. American Medical Association website. http://www.ama-assn.org/resources/doc/patient-safety/ambulatory-practices.pdf. Accessed February 12, 2013.
3. Dharmarajan K, Hsieh AF, Lin Z, et al. Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia. JAMA. 2013;309(4):355-363.
4. JAMA Internal Medicine. Nearly one-third of physicians report missing electronic notification of test results. JAMA Internal Medicine website. Available at: http://media.jamanetwork.com/news-item/nearly-one-third-of-physicians-report-missing-electronic-notification-of-test-results/.Accessed April 8, 2013.
5. Miliard M. VA enlists telehealth for disasters. Healthcare IT News website. http://www.healthcareitnews.com/news/va-enlists-telehealth-disasters. Published February 27, 2013. Accessed April 1, 2013.

In a poster presented at HM12, Kathryn Quinn, MPH, CPPS, FACHE, described how her quality team at the University of California at San Francisco (UCSF) developed a checklist to improve physician communication with patients, then taught it to the attending hospitalist faculty.¹ The project began with a list of 29 best practices for patient-physician interaction, as identified in medical literature. Hospitalists then voted for the elements they felt were most important to their practice, as well as those best able to be measured, and a top-10 list was created.

Quinn, the program manager for quality and safety in the division of hospital medicine at UCSF, says the communication best practices were “chosen by the people whose practices we are trying to change.”

The quality team presented the best practices in one-hour training sessions that included small-group role plays, explains co-investigator and UCSF hospitalist Diane Sliwka, MD. The training extended to outpatient physicians, medical specialists, and chief residents. Participants also were provided a laminated pocket card listing the interventions. They also received feedback from structured observations with patients on service.

Quinn says UCSF hospitalists have improved at knocking and asking permission to enter patient rooms, introducing themselves by name and role, and encouraging questions at the end of the interaction. They have been less successful at inquiring about the patient’s concerns early in the interview and at discussing duration of treatment and next steps.

“We learned that it takes more than just talk,” Quinn says. “Just telling physicians how to improve communication doesn’t mean it’s easy to do.”

Still to be determined is the project’s impact on patient satisfaction scores, although the hospitalists reported that they found the training and feedback helpful.

References

1. Quinn K, Neeman N, Mourad M, Sliwka D. Communication coaching: A multifaceted intervention to improve physician-patient communication [abstract]. J Hosp Med. 2012;7 Suppl 2:S108.
2. Sokol PE, Wynia MK. There and Home Again, Safely: Five Responsibilities of Ambulatory Practices in High Quality Care Transitions. American Medical Association website. http://www.ama-assn.org/resources/doc/patient-safety/ambulatory-practices.pdf. Accessed February 12, 2013.
3. Dharmarajan K, Hsieh AF, Lin Z, et al. Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia. JAMA. 2013;309(4):355-363.
4. JAMA Internal Medicine. Nearly one-third of physicians report missing electronic notification of test results. JAMA Internal Medicine website. Available at: http://media.jamanetwork.com/news-item/nearly-one-third-of-physicians-report-missing-electronic-notification-of-test-results/.Accessed April 8, 2013.
5. Miliard M. VA enlists telehealth for disasters. Healthcare IT News website. http://www.healthcareitnews.com/news/va-enlists-telehealth-disasters. Published February 27, 2013. Accessed April 1, 2013.

In a poster presented at HM12, Kathryn Quinn, MPH, CPPS, FACHE, described how her quality team at the University of California at San Francisco (UCSF) developed a checklist to improve physician communication with patients, then taught it to the attending hospitalist faculty.¹ The project began with a list of 29 best practices for patient-physician interaction, as identified in medical literature. Hospitalists then voted for the elements they felt were most important to their practice, as well as those best able to be measured, and a top-10 list was created.

Quinn, the program manager for quality and safety in the division of hospital medicine at UCSF, says the communication best practices were “chosen by the people whose practices we are trying to change.”

The quality team presented the best practices in one-hour training sessions that included small-group role plays, explains co-investigator and UCSF hospitalist Diane Sliwka, MD. The training extended to outpatient physicians, medical specialists, and chief residents. Participants also were provided a laminated pocket card listing the interventions. They also received feedback from structured observations with patients on service.

Quinn says UCSF hospitalists have improved at knocking and asking permission to enter patient rooms, introducing themselves by name and role, and encouraging questions at the end of the interaction. They have been less successful at inquiring about the patient’s concerns early in the interview and at discussing duration of treatment and next steps.

“We learned that it takes more than just talk,” Quinn says. “Just telling physicians how to improve communication doesn’t mean it’s easy to do.”

Still to be determined is the project’s impact on patient satisfaction scores, although the hospitalists reported that they found the training and feedback helpful.

References

1. Quinn K, Neeman N, Mourad M, Sliwka D. Communication coaching: A multifaceted intervention to improve physician-patient communication [abstract]. J Hosp Med. 2012;7 Suppl 2:S108.
2. Sokol PE, Wynia MK. There and Home Again, Safely: Five Responsibilities of Ambulatory Practices in High Quality Care Transitions. American Medical Association website. http://www.ama-assn.org/resources/doc/patient-safety/ambulatory-practices.pdf. Accessed February 12, 2013.
3. Dharmarajan K, Hsieh AF, Lin Z, et al. Diagnoses and timing of 30-day readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia. JAMA. 2013;309(4):355-363.
4. JAMA Internal Medicine. Nearly one-third of physicians report missing electronic notification of test results. JAMA Internal Medicine website. Available at: http://media.jamanetwork.com/news-item/nearly-one-third-of-physicians-report-missing-electronic-notification-of-test-results/.Accessed April 8, 2013.
5. Miliard M. VA enlists telehealth for disasters. Healthcare IT News website. http://www.healthcareitnews.com/news/va-enlists-telehealth-disasters. Published February 27, 2013. Accessed April 1, 2013.

Are you a hospitalist who, on daily rounds, often thinks, “There’s got to be a better way to do this”? You might be just the type of person who can carve a niche for yourself in hospital quality and patient safety—and advance your career in the process.

Successful navigation of the quality-improvement (QI) and patient-safety domains, according to three veteran hospitalists, requires an initial passion and an incremental approach. Now is an especially good time, they agree, for young hospitalists to engage in these types of initiatives.

Why Do It?

In her capacity as president of the Mid-Atlantic Business Unit for Brentwood, Tenn.-based CogentHMG, Julia Wright, MD, SFHM, FACP, often encourages young recruits to consider participation in QI and patient-safety initiatives. She admits that the transition from residency to a busy HM practice, with its higher patient volumes and a faster pace, can be daunting at first. Still, she tries to cultivate interest in initiatives and establish a realistic timeframe for involvement.

There are many reasons to consider this as a career step. Dr. Wright says that quality and patient safety dovetail with hospitalists’ initial reasons for choosing medicine: to improve patients’ lives.

Janet Nagamine, RN, MD, SFHM, former patient safety officer and assistant chief of quality at Kaiser Permanente in Santa Clara, Calif., describes the fit this way: “I might be a good doctor, but as a hospitalist, I rely on many others within the system to deliver, so my patients can’t get good care until the entire system is running well,” she says. “There are all kinds of opportunities to fix our [hospital] system, and I really believe that hospitalists cannot separate themselves from that engagement.”

Elizabeth Gundersen, MD, FHM, of Fort Lauderdale, Fla., agrees that it’s a natural step to think about the ways to make a difference on a larger level. At her former institution, the University of Massachusetts (UMass) Medical School in Worcester, she parlayed her interest in QI to work her way up from ground-level hospitalist to associate chief of her division and quality officer for the hospital. “Physicians get a lot of satisfaction from helping individual patients,” she says. “One thing I really liked about getting involved with quality improvement was being able to make a difference for patients on a systems level.”

An Incremental Path

The path to her current position began with a very specific issue for Dr. Nagamine, an SHM board member who also serves as a Project BOOST co-investigator. “Although I have been doing patient safety since before they had a name for it, I didn’t start out saying that I wanted a career in quality and safety,” she says. “I was trying to take better care of my patients with diabetes, but controlling their glucose was extremely challenging because all the related variables—timing and amount of their insulin dosage, when and how much they had eaten—were charted in different places. This made it hard to adjust their insulin appropriately.”

It quickly became clear to Dr. Nagamine that the solution had to be systemic. She realized that something as basic as taking care of her patients with diabetes required multiple departments (i.e. dietary, nursing, and pharmacy) to furnish information in an integrated manner. So she joined the diabetes committee and went to work on the issue. She helped devise a flow chart that could be used by all relevant departments. A further evolution on the path emanated from one of her patients receiving the wrong medication. She joined the medication safety committee, became chair, “and the next thing you know, I’m in charge of patient safety, and an assistant chief of quality.”

Training Is Necessary

QI and patient-safety methodologies have become sophisticated disciplines in the past two decades, Dr. Wright says. Access to training in QI basics now is readily available to early-career hospitalists. For example, CogentHMG offers program support for QI so that anyone interested “doesn’t have to start from scratch anymore; we can help show them the way and support them in doing it.”

This month, HM13 (www.hospital medicine2013.org)—just outside Washington, D.C.—will offer multiple sessions on quality, as well as the “Initiating Quality Improvement Projects with Built-In Sustainment” workshop, led by Center for Comprehensive Access and Delivery Research and Evaluation (CADRE) core investigator Peter Kaboli, MD, MS, who will address sustainability.

Beyond methodological tools, success in quality and patient safety requires the ability to motivate people, often across multiple disciplines, Dr. Nagamine says. “If you want things to work better, you must invite the right people to the table. For example, we often forget to include key nonclinical stakeholders,” she adds.

When working with hospitals across the country to implement rapid-response tTeams, Dr. Nagamine often reminds them to invite the operators, or “key people,” in the process.

“If you put patient safety at the core of your initiative and create the context for that, most people will agree that it’s the right thing to do and will get on board, even if it’s an extra step for them,” she says. “Know your audience, listen to their perspective, and learn what matters to them. And to most people, it matters that they give good patient care.”

Gretchen Henkel is a freelance writer in California.

Branch Out: QI and Patient-Safety Initiatives

Pick a passion. It’s best to choose an issue that’s important to you. “It has to be a

passion because much of the time it’s an uphill battle,” says Dr. Gundersen. She started with the issue of reducing readmissions, and with two colleagues pitched the idea of involving the UMass HM group in SHM’s Project BOOST. After that, she set out to become an expert on reducing readmissions, applying what she had learned to other successful initiatives.

Learn the lingo. Dr. Wright advises learning some of the most basic principles, such as Shewhart’s PDCA (Plan-Do-Check-Act) or Deming’s adaptation PDSA (Plan-Do-Study-Act) cycles; the quality tripod; and accessing resources made available from SHM. A member of SHM’s Hospital Quality and Patient Safety Committee, Dr. Wright says a subcommittee for leadership engagement has been created and furnishes tools and training for advancing quality initiatives. The Institute for Healthcare Improvement (www.ihi.org) also offers a wealth of measures, speaker series, and white papers on improvement in health care.

It’s important to put in time at the start of a project to demonstrate your value, but if you’re constantly staying up late working on a project, consider pitching a compensated role to your boss.

Start small. You can test your ability to work with interdisciplinary departments, often a prerequisite of many quality initiatives, by first joining a committee, Dr. Nagamine advises. “See how effective or persuasive you are in pitching an idea and seeing it through with other departments,” she says.

Brace for a marathon. “Most people,” Dr. Gundersen says, “do not hand you 100% of their cooperation and a budget you can work with.” It takes time to get buy-in, especially if you’re doing interdisciplinary initiatives. If possible, break your projects into achievable units. “Start with some quick wins. Small payoffs here and there can re-energize your team and eventually yield a larger payoff,” she says.

Limit sweat equity. It’s important to put in time at the start of a project to demonstrate your value, but if you’re constantly staying up late working on a project, consider pitching a compensated role to your boss. “Being a good citizen and volunteering for committees is one thing,” Dr. Nagamine cautions, “but taking on leadership roles in too many projects, without dedicated time, is not sustainable and can jeopardize the success of your projects.”

—Gretchen Henkel

Are you a hospitalist who, on daily rounds, often thinks, “There’s got to be a better way to do this”? You might be just the type of person who can carve a niche for yourself in hospital quality and patient safety—and advance your career in the process.

Successful navigation of the quality-improvement (QI) and patient-safety domains, according to three veteran hospitalists, requires an initial passion and an incremental approach. Now is an especially good time, they agree, for young hospitalists to engage in these types of initiatives.

Why Do It?

In her capacity as president of the Mid-Atlantic Business Unit for Brentwood, Tenn.-based CogentHMG, Julia Wright, MD, SFHM, FACP, often encourages young recruits to consider participation in QI and patient-safety initiatives. She admits that the transition from residency to a busy HM practice, with its higher patient volumes and a faster pace, can be daunting at first. Still, she tries to cultivate interest in initiatives and establish a realistic timeframe for involvement.

There are many reasons to consider this as a career step. Dr. Wright says that quality and patient safety dovetail with hospitalists’ initial reasons for choosing medicine: to improve patients’ lives.

Janet Nagamine, RN, MD, SFHM, former patient safety officer and assistant chief of quality at Kaiser Permanente in Santa Clara, Calif., describes the fit this way: “I might be a good doctor, but as a hospitalist, I rely on many others within the system to deliver, so my patients can’t get good care until the entire system is running well,” she says. “There are all kinds of opportunities to fix our [hospital] system, and I really believe that hospitalists cannot separate themselves from that engagement.”

Elizabeth Gundersen, MD, FHM, of Fort Lauderdale, Fla., agrees that it’s a natural step to think about the ways to make a difference on a larger level. At her former institution, the University of Massachusetts (UMass) Medical School in Worcester, she parlayed her interest in QI to work her way up from ground-level hospitalist to associate chief of her division and quality officer for the hospital. “Physicians get a lot of satisfaction from helping individual patients,” she says. “One thing I really liked about getting involved with quality improvement was being able to make a difference for patients on a systems level.”

An Incremental Path

The path to her current position began with a very specific issue for Dr. Nagamine, an SHM board member who also serves as a Project BOOST co-investigator. “Although I have been doing patient safety since before they had a name for it, I didn’t start out saying that I wanted a career in quality and safety,” she says. “I was trying to take better care of my patients with diabetes, but controlling their glucose was extremely challenging because all the related variables—timing and amount of their insulin dosage, when and how much they had eaten—were charted in different places. This made it hard to adjust their insulin appropriately.”

It quickly became clear to Dr. Nagamine that the solution had to be systemic. She realized that something as basic as taking care of her patients with diabetes required multiple departments (i.e. dietary, nursing, and pharmacy) to furnish information in an integrated manner. So she joined the diabetes committee and went to work on the issue. She helped devise a flow chart that could be used by all relevant departments. A further evolution on the path emanated from one of her patients receiving the wrong medication. She joined the medication safety committee, became chair, “and the next thing you know, I’m in charge of patient safety, and an assistant chief of quality.”

Training Is Necessary

QI and patient-safety methodologies have become sophisticated disciplines in the past two decades, Dr. Wright says. Access to training in QI basics now is readily available to early-career hospitalists. For example, CogentHMG offers program support for QI so that anyone interested “doesn’t have to start from scratch anymore; we can help show them the way and support them in doing it.”

This month, HM13 (www.hospital medicine2013.org)—just outside Washington, D.C.—will offer multiple sessions on quality, as well as the “Initiating Quality Improvement Projects with Built-In Sustainment” workshop, led by Center for Comprehensive Access and Delivery Research and Evaluation (CADRE) core investigator Peter Kaboli, MD, MS, who will address sustainability.

Beyond methodological tools, success in quality and patient safety requires the ability to motivate people, often across multiple disciplines, Dr. Nagamine says. “If you want things to work better, you must invite the right people to the table. For example, we often forget to include key nonclinical stakeholders,” she adds.

When working with hospitals across the country to implement rapid-response tTeams, Dr. Nagamine often reminds them to invite the operators, or “key people,” in the process.

“If you put patient safety at the core of your initiative and create the context for that, most people will agree that it’s the right thing to do and will get on board, even if it’s an extra step for them,” she says. “Know your audience, listen to their perspective, and learn what matters to them. And to most people, it matters that they give good patient care.”

Gretchen Henkel is a freelance writer in California.

Branch Out: QI and Patient-Safety Initiatives

Pick a passion. It’s best to choose an issue that’s important to you. “It has to be a

passion because much of the time it’s an uphill battle,” says Dr. Gundersen. She started with the issue of reducing readmissions, and with two colleagues pitched the idea of involving the UMass HM group in SHM’s Project BOOST. After that, she set out to become an expert on reducing readmissions, applying what she had learned to other successful initiatives.

Learn the lingo. Dr. Wright advises learning some of the most basic principles, such as Shewhart’s PDCA (Plan-Do-Check-Act) or Deming’s adaptation PDSA (Plan-Do-Study-Act) cycles; the quality tripod; and accessing resources made available from SHM. A member of SHM’s Hospital Quality and Patient Safety Committee, Dr. Wright says a subcommittee for leadership engagement has been created and furnishes tools and training for advancing quality initiatives. The Institute for Healthcare Improvement (www.ihi.org) also offers a wealth of measures, speaker series, and white papers on improvement in health care.

It’s important to put in time at the start of a project to demonstrate your value, but if you’re constantly staying up late working on a project, consider pitching a compensated role to your boss.

Start small. You can test your ability to work with interdisciplinary departments, often a prerequisite of many quality initiatives, by first joining a committee, Dr. Nagamine advises. “See how effective or persuasive you are in pitching an idea and seeing it through with other departments,” she says.

Brace for a marathon. “Most people,” Dr. Gundersen says, “do not hand you 100% of their cooperation and a budget you can work with.” It takes time to get buy-in, especially if you’re doing interdisciplinary initiatives. If possible, break your projects into achievable units. “Start with some quick wins. Small payoffs here and there can re-energize your team and eventually yield a larger payoff,” she says.

Limit sweat equity. It’s important to put in time at the start of a project to demonstrate your value, but if you’re constantly staying up late working on a project, consider pitching a compensated role to your boss. “Being a good citizen and volunteering for committees is one thing,” Dr. Nagamine cautions, “but taking on leadership roles in too many projects, without dedicated time, is not sustainable and can jeopardize the success of your projects.”

—Gretchen Henkel

Are you a hospitalist who, on daily rounds, often thinks, “There’s got to be a better way to do this”? You might be just the type of person who can carve a niche for yourself in hospital quality and patient safety—and advance your career in the process.

Successful navigation of the quality-improvement (QI) and patient-safety domains, according to three veteran hospitalists, requires an initial passion and an incremental approach. Now is an especially good time, they agree, for young hospitalists to engage in these types of initiatives.

Why Do It?

In her capacity as president of the Mid-Atlantic Business Unit for Brentwood, Tenn.-based CogentHMG, Julia Wright, MD, SFHM, FACP, often encourages young recruits to consider participation in QI and patient-safety initiatives. She admits that the transition from residency to a busy HM practice, with its higher patient volumes and a faster pace, can be daunting at first. Still, she tries to cultivate interest in initiatives and establish a realistic timeframe for involvement.

There are many reasons to consider this as a career step. Dr. Wright says that quality and patient safety dovetail with hospitalists’ initial reasons for choosing medicine: to improve patients’ lives.

Janet Nagamine, RN, MD, SFHM, former patient safety officer and assistant chief of quality at Kaiser Permanente in Santa Clara, Calif., describes the fit this way: “I might be a good doctor, but as a hospitalist, I rely on many others within the system to deliver, so my patients can’t get good care until the entire system is running well,” she says. “There are all kinds of opportunities to fix our [hospital] system, and I really believe that hospitalists cannot separate themselves from that engagement.”

Elizabeth Gundersen, MD, FHM, of Fort Lauderdale, Fla., agrees that it’s a natural step to think about the ways to make a difference on a larger level. At her former institution, the University of Massachusetts (UMass) Medical School in Worcester, she parlayed her interest in QI to work her way up from ground-level hospitalist to associate chief of her division and quality officer for the hospital. “Physicians get a lot of satisfaction from helping individual patients,” she says. “One thing I really liked about getting involved with quality improvement was being able to make a difference for patients on a systems level.”

An Incremental Path

The path to her current position began with a very specific issue for Dr. Nagamine, an SHM board member who also serves as a Project BOOST co-investigator. “Although I have been doing patient safety since before they had a name for it, I didn’t start out saying that I wanted a career in quality and safety,” she says. “I was trying to take better care of my patients with diabetes, but controlling their glucose was extremely challenging because all the related variables—timing and amount of their insulin dosage, when and how much they had eaten—were charted in different places. This made it hard to adjust their insulin appropriately.”

It quickly became clear to Dr. Nagamine that the solution had to be systemic. She realized that something as basic as taking care of her patients with diabetes required multiple departments (i.e. dietary, nursing, and pharmacy) to furnish information in an integrated manner. So she joined the diabetes committee and went to work on the issue. She helped devise a flow chart that could be used by all relevant departments. A further evolution on the path emanated from one of her patients receiving the wrong medication. She joined the medication safety committee, became chair, “and the next thing you know, I’m in charge of patient safety, and an assistant chief of quality.”

Training Is Necessary

QI and patient-safety methodologies have become sophisticated disciplines in the past two decades, Dr. Wright says. Access to training in QI basics now is readily available to early-career hospitalists. For example, CogentHMG offers program support for QI so that anyone interested “doesn’t have to start from scratch anymore; we can help show them the way and support them in doing it.”

This month, HM13 (www.hospital medicine2013.org)—just outside Washington, D.C.—will offer multiple sessions on quality, as well as the “Initiating Quality Improvement Projects with Built-In Sustainment” workshop, led by Center for Comprehensive Access and Delivery Research and Evaluation (CADRE) core investigator Peter Kaboli, MD, MS, who will address sustainability.

Beyond methodological tools, success in quality and patient safety requires the ability to motivate people, often across multiple disciplines, Dr. Nagamine says. “If you want things to work better, you must invite the right people to the table. For example, we often forget to include key nonclinical stakeholders,” she adds.

When working with hospitals across the country to implement rapid-response tTeams, Dr. Nagamine often reminds them to invite the operators, or “key people,” in the process.

“If you put patient safety at the core of your initiative and create the context for that, most people will agree that it’s the right thing to do and will get on board, even if it’s an extra step for them,” she says. “Know your audience, listen to their perspective, and learn what matters to them. And to most people, it matters that they give good patient care.”

Gretchen Henkel is a freelance writer in California.

Branch Out: QI and Patient-Safety Initiatives

Pick a passion. It’s best to choose an issue that’s important to you. “It has to be a

passion because much of the time it’s an uphill battle,” says Dr. Gundersen. She started with the issue of reducing readmissions, and with two colleagues pitched the idea of involving the UMass HM group in SHM’s Project BOOST. After that, she set out to become an expert on reducing readmissions, applying what she had learned to other successful initiatives.

Learn the lingo. Dr. Wright advises learning some of the most basic principles, such as Shewhart’s PDCA (Plan-Do-Check-Act) or Deming’s adaptation PDSA (Plan-Do-Study-Act) cycles; the quality tripod; and accessing resources made available from SHM. A member of SHM’s Hospital Quality and Patient Safety Committee, Dr. Wright says a subcommittee for leadership engagement has been created and furnishes tools and training for advancing quality initiatives. The Institute for Healthcare Improvement (www.ihi.org) also offers a wealth of measures, speaker series, and white papers on improvement in health care.

It’s important to put in time at the start of a project to demonstrate your value, but if you’re constantly staying up late working on a project, consider pitching a compensated role to your boss.

Start small. You can test your ability to work with interdisciplinary departments, often a prerequisite of many quality initiatives, by first joining a committee, Dr. Nagamine advises. “See how effective or persuasive you are in pitching an idea and seeing it through with other departments,” she says.

Brace for a marathon. “Most people,” Dr. Gundersen says, “do not hand you 100% of their cooperation and a budget you can work with.” It takes time to get buy-in, especially if you’re doing interdisciplinary initiatives. If possible, break your projects into achievable units. “Start with some quick wins. Small payoffs here and there can re-energize your team and eventually yield a larger payoff,” she says.

Limit sweat equity. It’s important to put in time at the start of a project to demonstrate your value, but if you’re constantly staying up late working on a project, consider pitching a compensated role to your boss. “Being a good citizen and volunteering for committees is one thing,” Dr. Nagamine cautions, “but taking on leadership roles in too many projects, without dedicated time, is not sustainable and can jeopardize the success of your projects.”

—Gretchen Henkel

A gluten-free diet reduced stool frequency as well as small bowel permeability in irritable bowel syndrome patients without celiac disease.

The findings, published in the May issue of Gastroenterology, "support the need for further clinical intervention studies to evaluate the clinical effects of gluten withdrawal in patients with diarrhea-predominant IBS," reported Dr. Maria I. Vazquez-Roque and her colleagues.

Dr. Vasquez-Roque, of the Mayo Clinic’s Clinical Enteric Neuroscience Translational and Epidemiological Research Program, in Rochester, Minn., and her colleagues recruited 45 subjects (43 women) from a database of more than 800 patients with irritable bowel syndrome who had been evaluated at the Mayo Clinic.

All patients had diarrhea-predominant IBS (IBS-D), were not on a gluten-free diet prior to the study, and did not have celiac disease.

They were randomized to either a gluten-free diet or a gluten-containing diet for 28 days. Patients’ meals and snacks were ingested or prepared in the Mayo Clinical Research Unit, and study participants were asked to eat only the foods provided by the study dietitians during the entire study period, the authors wrote. Dietitians assessed diet compliance using direct questioning of participants.

After 28 days of the study, the investigators looked at several clinical and histologic markers.

First, they tallied stool frequency, and found that patients on the gluten-containing diet had more stools per day than gluten-free patients did (P = .04), with a 95% confidence interval for the absolute difference between number of stools per day at –0.652 to –0.015 (Gastroenterology 2013 Jan. 28 [doi: 10.1053/j.gastro.2013.01.049]).

"While the absolute difference in stool frequency is small, it is important to appreciate that this increased frequency is on a background of the typical increase in stool frequency (average 2.6 bowel movements/day at baseline) and consistency in patients with IBS-D," the authors wrote.

This effect was more pronounced in subjects who were HLA-DQ2 or 8 positive (95% CI, –1.005 to –0.092; P = .019), they added.

Next, the investigators looked at small bowel permeability.

They found increased small bowel permeability with gluten-containing diet patients relative to their gluten-free counterparts, based on both cumulative mannitol excretion levels and lactulose:mannitol ratio. Similarly, this effect was more pronounced in HLA-DQ2 or 8 positive patients.

"While the clinical significance of these changes in permeability is not demonstrated in the current study, the abundant experimental evidence from the published literature is that increased mucosal permeability enhances inflammation and leads to increased sensitivity," they wrote.

Finally, the authors looked at tight-junction mRNA expression.

"Alterations in intestinal permeability and jejunal mucosal tight junction (TJ) signaling have been described in IBS-D, including postinfectious IBS-D," they wrote.

They found that expressions of ZO-1, occludin, and claudin-1 mRNA in colonic mucosa were significantly lower with the gluten-containing diet, compared with the gluten-free patients, particularly in subjects with HLA-DQ2 or 8 positive status.

There were no significant variations in tight junction signaling in the small bowel mucosa.

The authors conceded several limitations to their study. For one, it "did not evaluate effects of gluten on the microbiome, afferent functions, or cytokine expression in the mucosal biopsies from patients before and after the interventions. These would be interesting parameters to include in future studies," they wrote.

Additionally, "our study does not specifically address the effects of gluten protein per se, and it is possible that other proteins in wheat flour may be responsible for the changes observed."

Nevertheless, "our data provide mechanistic explanations for the observation that gluten withdrawal may improve patient symptoms in IBS," they concluded.

The researchers disclosed receiving funding for this study from the National Institutes of Health. One investigator also disclosed having received grants from Alba Therapeutics, maker of the drug larazotide, used in celiac disease.

A gluten-free diet reduced stool frequency as well as small bowel permeability in irritable bowel syndrome patients without celiac disease.

The findings, published in the May issue of Gastroenterology, "support the need for further clinical intervention studies to evaluate the clinical effects of gluten withdrawal in patients with diarrhea-predominant IBS," reported Dr. Maria I. Vazquez-Roque and her colleagues.

Dr. Vasquez-Roque, of the Mayo Clinic’s Clinical Enteric Neuroscience Translational and Epidemiological Research Program, in Rochester, Minn., and her colleagues recruited 45 subjects (43 women) from a database of more than 800 patients with irritable bowel syndrome who had been evaluated at the Mayo Clinic.

All patients had diarrhea-predominant IBS (IBS-D), were not on a gluten-free diet prior to the study, and did not have celiac disease.

They were randomized to either a gluten-free diet or a gluten-containing diet for 28 days. Patients’ meals and snacks were ingested or prepared in the Mayo Clinical Research Unit, and study participants were asked to eat only the foods provided by the study dietitians during the entire study period, the authors wrote. Dietitians assessed diet compliance using direct questioning of participants.

After 28 days of the study, the investigators looked at several clinical and histologic markers.

First, they tallied stool frequency, and found that patients on the gluten-containing diet had more stools per day than gluten-free patients did (P = .04), with a 95% confidence interval for the absolute difference between number of stools per day at –0.652 to –0.015 (Gastroenterology 2013 Jan. 28 [doi: 10.1053/j.gastro.2013.01.049]).

"While the absolute difference in stool frequency is small, it is important to appreciate that this increased frequency is on a background of the typical increase in stool frequency (average 2.6 bowel movements/day at baseline) and consistency in patients with IBS-D," the authors wrote.

This effect was more pronounced in subjects who were HLA-DQ2 or 8 positive (95% CI, –1.005 to –0.092; P = .019), they added.

Next, the investigators looked at small bowel permeability.

They found increased small bowel permeability with gluten-containing diet patients relative to their gluten-free counterparts, based on both cumulative mannitol excretion levels and lactulose:mannitol ratio. Similarly, this effect was more pronounced in HLA-DQ2 or 8 positive patients.

"While the clinical significance of these changes in permeability is not demonstrated in the current study, the abundant experimental evidence from the published literature is that increased mucosal permeability enhances inflammation and leads to increased sensitivity," they wrote.

Finally, the authors looked at tight-junction mRNA expression.

"Alterations in intestinal permeability and jejunal mucosal tight junction (TJ) signaling have been described in IBS-D, including postinfectious IBS-D," they wrote.

They found that expressions of ZO-1, occludin, and claudin-1 mRNA in colonic mucosa were significantly lower with the gluten-containing diet, compared with the gluten-free patients, particularly in subjects with HLA-DQ2 or 8 positive status.

There were no significant variations in tight junction signaling in the small bowel mucosa.

The authors conceded several limitations to their study. For one, it "did not evaluate effects of gluten on the microbiome, afferent functions, or cytokine expression in the mucosal biopsies from patients before and after the interventions. These would be interesting parameters to include in future studies," they wrote.

Additionally, "our study does not specifically address the effects of gluten protein per se, and it is possible that other proteins in wheat flour may be responsible for the changes observed."

Nevertheless, "our data provide mechanistic explanations for the observation that gluten withdrawal may improve patient symptoms in IBS," they concluded.

The researchers disclosed receiving funding for this study from the National Institutes of Health. One investigator also disclosed having received grants from Alba Therapeutics, maker of the drug larazotide, used in celiac disease.

A gluten-free diet reduced stool frequency as well as small bowel permeability in irritable bowel syndrome patients without celiac disease.

The findings, published in the May issue of Gastroenterology, "support the need for further clinical intervention studies to evaluate the clinical effects of gluten withdrawal in patients with diarrhea-predominant IBS," reported Dr. Maria I. Vazquez-Roque and her colleagues.

Dr. Vasquez-Roque, of the Mayo Clinic’s Clinical Enteric Neuroscience Translational and Epidemiological Research Program, in Rochester, Minn., and her colleagues recruited 45 subjects (43 women) from a database of more than 800 patients with irritable bowel syndrome who had been evaluated at the Mayo Clinic.

All patients had diarrhea-predominant IBS (IBS-D), were not on a gluten-free diet prior to the study, and did not have celiac disease.

They were randomized to either a gluten-free diet or a gluten-containing diet for 28 days. Patients’ meals and snacks were ingested or prepared in the Mayo Clinical Research Unit, and study participants were asked to eat only the foods provided by the study dietitians during the entire study period, the authors wrote. Dietitians assessed diet compliance using direct questioning of participants.

After 28 days of the study, the investigators looked at several clinical and histologic markers.

First, they tallied stool frequency, and found that patients on the gluten-containing diet had more stools per day than gluten-free patients did (P = .04), with a 95% confidence interval for the absolute difference between number of stools per day at –0.652 to –0.015 (Gastroenterology 2013 Jan. 28 [doi: 10.1053/j.gastro.2013.01.049]).

"While the absolute difference in stool frequency is small, it is important to appreciate that this increased frequency is on a background of the typical increase in stool frequency (average 2.6 bowel movements/day at baseline) and consistency in patients with IBS-D," the authors wrote.

This effect was more pronounced in subjects who were HLA-DQ2 or 8 positive (95% CI, –1.005 to –0.092; P = .019), they added.

Next, the investigators looked at small bowel permeability.

They found increased small bowel permeability with gluten-containing diet patients relative to their gluten-free counterparts, based on both cumulative mannitol excretion levels and lactulose:mannitol ratio. Similarly, this effect was more pronounced in HLA-DQ2 or 8 positive patients.

"While the clinical significance of these changes in permeability is not demonstrated in the current study, the abundant experimental evidence from the published literature is that increased mucosal permeability enhances inflammation and leads to increased sensitivity," they wrote.

Finally, the authors looked at tight-junction mRNA expression.

"Alterations in intestinal permeability and jejunal mucosal tight junction (TJ) signaling have been described in IBS-D, including postinfectious IBS-D," they wrote.

They found that expressions of ZO-1, occludin, and claudin-1 mRNA in colonic mucosa were significantly lower with the gluten-containing diet, compared with the gluten-free patients, particularly in subjects with HLA-DQ2 or 8 positive status.

There were no significant variations in tight junction signaling in the small bowel mucosa.

The authors conceded several limitations to their study. For one, it "did not evaluate effects of gluten on the microbiome, afferent functions, or cytokine expression in the mucosal biopsies from patients before and after the interventions. These would be interesting parameters to include in future studies," they wrote.

Additionally, "our study does not specifically address the effects of gluten protein per se, and it is possible that other proteins in wheat flour may be responsible for the changes observed."

Nevertheless, "our data provide mechanistic explanations for the observation that gluten withdrawal may improve patient symptoms in IBS," they concluded.

The researchers disclosed receiving funding for this study from the National Institutes of Health. One investigator also disclosed having received grants from Alba Therapeutics, maker of the drug larazotide, used in celiac disease.

Patients with liver injury secondary to anti–tumor necrosis factor–alpha agents often exhibit histological changes similar to those seen in spontaneous autoimmune hepatitis, wrote Dr. Marwan Ghabril and his colleagues. The report was published in the May issue of Clinical Gastroenterology and Hepatology.

The finding comes from a review seeking to characterize the presentation, injury pattern, course of illness, and treatment of anti-TNF agent–induced liver injury, which Dr. Ghabril, of Indiana University in Indianapolis, said "may be severe and prolonged."

To that end, he and his colleagues studied six patients from the U.S. Drug-Induced Liver Injury Network (DILIN) database who had liver damage that was likely secondary to anti-TNFs, according to DILIN criteria.

Additionally, 28 cases were culled from a literature review of the PubMed database using the search terms "hepatotoxicity," "liver injury," "tumor necrosis factor," and the generic names of all TNF-alpha antagonists.

Among all patients, infliximab was most commonly the offending agent, followed by etanercept and adalimumab; no cases were attributed to natalizumab, golimumab, or certolizumab.

Diseases for which the anti-TNFs were prescribed included ankylosing spondylitis, Crohn’s disease, chronic ulcerative colitis, juvenile inflammatory arthritis, psoriatic arthritis, psoriasis, and rheumatoid arthritis.

First, Dr. Ghabril looked at the six patients from the DILIN database. Among these patients, the median duration of drug use before onset of liver injury was 16 weeks (range, 2-52 weeks).

"At presentation, half had jaundice, half had nausea, but only one had fever and none had immuno-allergic features of skin rash or eosinophilia," wrote the authors.

Only one of these patients developed significantly impaired coagulation, with an INR of 3.5, and none of the DILIN patients developed ascites or other signs of hepatic failure, they added.

The peak ALT ranged from 384 to 1,687 U/L, and the peak bilirubin from 1.5 to 27.7 mg/dL.

"Five of the six patients were treated with corticosteroids. One patient had a protracted illness, but all ultimately recovered and could be withdrawn from corticosteroid therapy without recurrence," they wrote.

Next, the authors turned their attention to the PubMed cases.

"Peak serum ALT ranged from 140 to 2,250 U/L and bilirubin from normal to 27.7 mg/dL," the authors reported.

Most patients (n = 22) had autoimmune serological markers and/or histological features at some point during the clinical course, they found.

Twelve patients stopped the drug and initiated corticosteroid therapy, oral or parenteral; all recovered. The rest improved after discontinuation of the anti-TNF, without steroid treatment, except for one patient who had underlying cirrhosis and required liver transplantation.

Notably, several patients were able to continue anti-TNF treatment with another agent without further incident, the authors wrote. Indeed, "three tolerated treatment with etanercept without recurrence of liver injury after cessation of infliximab or adalimumab. Two did well with adalimumab after [drug-induced liver injury] associated with infliximab, and one was successfully switched from adalimumab to abatacept."

Finally, the investigators contrasted patients with serological or histological autoimmune features with patients who lacked any autoimmune characteristics.

The autoimmune patients tended to have a longer latency period. The median period after the drug was initiated but before liver injury was noted was 16 weeks for the autoimmune patients versus 10 weeks for the nonautoimmune patients (P = .17). The autoimmune patients also had a higher peak ALT (median 784 vs. 528; P = .03).

"The mechanism by which the TNF-alpha antagonists lead to drug-induced liver injury is unknown," the authors wrote.

"Because the injury can occur after only one infusion, dose-dependent toxicity is unlikely. Unpredictable, idiosyncratic drug-induced liver injury seems most likely, as in this series no patients had clinical evidence of a rash or eosinophilia, and only one presented with fever."

"Further studies are needed to ascertain whether genetic or other markers of the hepatotoxicity associated with TNF-alpha antagonists can be identified," they said.

The DILIN database is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors reported having no conflicts of interest.

Patients with liver injury secondary to anti–tumor necrosis factor–alpha agents often exhibit histological changes similar to those seen in spontaneous autoimmune hepatitis, wrote Dr. Marwan Ghabril and his colleagues. The report was published in the May issue of Clinical Gastroenterology and Hepatology.

The finding comes from a review seeking to characterize the presentation, injury pattern, course of illness, and treatment of anti-TNF agent–induced liver injury, which Dr. Ghabril, of Indiana University in Indianapolis, said "may be severe and prolonged."

To that end, he and his colleagues studied six patients from the U.S. Drug-Induced Liver Injury Network (DILIN) database who had liver damage that was likely secondary to anti-TNFs, according to DILIN criteria.

Additionally, 28 cases were culled from a literature review of the PubMed database using the search terms "hepatotoxicity," "liver injury," "tumor necrosis factor," and the generic names of all TNF-alpha antagonists.

Among all patients, infliximab was most commonly the offending agent, followed by etanercept and adalimumab; no cases were attributed to natalizumab, golimumab, or certolizumab.

Diseases for which the anti-TNFs were prescribed included ankylosing spondylitis, Crohn’s disease, chronic ulcerative colitis, juvenile inflammatory arthritis, psoriatic arthritis, psoriasis, and rheumatoid arthritis.

First, Dr. Ghabril looked at the six patients from the DILIN database. Among these patients, the median duration of drug use before onset of liver injury was 16 weeks (range, 2-52 weeks).

"At presentation, half had jaundice, half had nausea, but only one had fever and none had immuno-allergic features of skin rash or eosinophilia," wrote the authors.

Only one of these patients developed significantly impaired coagulation, with an INR of 3.5, and none of the DILIN patients developed ascites or other signs of hepatic failure, they added.

The peak ALT ranged from 384 to 1,687 U/L, and the peak bilirubin from 1.5 to 27.7 mg/dL.

"Five of the six patients were treated with corticosteroids. One patient had a protracted illness, but all ultimately recovered and could be withdrawn from corticosteroid therapy without recurrence," they wrote.

Next, the authors turned their attention to the PubMed cases.

"Peak serum ALT ranged from 140 to 2,250 U/L and bilirubin from normal to 27.7 mg/dL," the authors reported.

Most patients (n = 22) had autoimmune serological markers and/or histological features at some point during the clinical course, they found.

Twelve patients stopped the drug and initiated corticosteroid therapy, oral or parenteral; all recovered. The rest improved after discontinuation of the anti-TNF, without steroid treatment, except for one patient who had underlying cirrhosis and required liver transplantation.

Notably, several patients were able to continue anti-TNF treatment with another agent without further incident, the authors wrote. Indeed, "three tolerated treatment with etanercept without recurrence of liver injury after cessation of infliximab or adalimumab. Two did well with adalimumab after [drug-induced liver injury] associated with infliximab, and one was successfully switched from adalimumab to abatacept."

Finally, the investigators contrasted patients with serological or histological autoimmune features with patients who lacked any autoimmune characteristics.

The autoimmune patients tended to have a longer latency period. The median period after the drug was initiated but before liver injury was noted was 16 weeks for the autoimmune patients versus 10 weeks for the nonautoimmune patients (P = .17). The autoimmune patients also had a higher peak ALT (median 784 vs. 528; P = .03).

"The mechanism by which the TNF-alpha antagonists lead to drug-induced liver injury is unknown," the authors wrote.

"Because the injury can occur after only one infusion, dose-dependent toxicity is unlikely. Unpredictable, idiosyncratic drug-induced liver injury seems most likely, as in this series no patients had clinical evidence of a rash or eosinophilia, and only one presented with fever."

"Further studies are needed to ascertain whether genetic or other markers of the hepatotoxicity associated with TNF-alpha antagonists can be identified," they said.

The DILIN database is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors reported having no conflicts of interest.

Patients with liver injury secondary to anti–tumor necrosis factor–alpha agents often exhibit histological changes similar to those seen in spontaneous autoimmune hepatitis, wrote Dr. Marwan Ghabril and his colleagues. The report was published in the May issue of Clinical Gastroenterology and Hepatology.

The finding comes from a review seeking to characterize the presentation, injury pattern, course of illness, and treatment of anti-TNF agent–induced liver injury, which Dr. Ghabril, of Indiana University in Indianapolis, said "may be severe and prolonged."

To that end, he and his colleagues studied six patients from the U.S. Drug-Induced Liver Injury Network (DILIN) database who had liver damage that was likely secondary to anti-TNFs, according to DILIN criteria.

Additionally, 28 cases were culled from a literature review of the PubMed database using the search terms "hepatotoxicity," "liver injury," "tumor necrosis factor," and the generic names of all TNF-alpha antagonists.

Among all patients, infliximab was most commonly the offending agent, followed by etanercept and adalimumab; no cases were attributed to natalizumab, golimumab, or certolizumab.

Diseases for which the anti-TNFs were prescribed included ankylosing spondylitis, Crohn’s disease, chronic ulcerative colitis, juvenile inflammatory arthritis, psoriatic arthritis, psoriasis, and rheumatoid arthritis.

First, Dr. Ghabril looked at the six patients from the DILIN database. Among these patients, the median duration of drug use before onset of liver injury was 16 weeks (range, 2-52 weeks).

"At presentation, half had jaundice, half had nausea, but only one had fever and none had immuno-allergic features of skin rash or eosinophilia," wrote the authors.

Only one of these patients developed significantly impaired coagulation, with an INR of 3.5, and none of the DILIN patients developed ascites or other signs of hepatic failure, they added.

The peak ALT ranged from 384 to 1,687 U/L, and the peak bilirubin from 1.5 to 27.7 mg/dL.

"Five of the six patients were treated with corticosteroids. One patient had a protracted illness, but all ultimately recovered and could be withdrawn from corticosteroid therapy without recurrence," they wrote.

Next, the authors turned their attention to the PubMed cases.

"Peak serum ALT ranged from 140 to 2,250 U/L and bilirubin from normal to 27.7 mg/dL," the authors reported.

Most patients (n = 22) had autoimmune serological markers and/or histological features at some point during the clinical course, they found.

Twelve patients stopped the drug and initiated corticosteroid therapy, oral or parenteral; all recovered. The rest improved after discontinuation of the anti-TNF, without steroid treatment, except for one patient who had underlying cirrhosis and required liver transplantation.

Notably, several patients were able to continue anti-TNF treatment with another agent without further incident, the authors wrote. Indeed, "three tolerated treatment with etanercept without recurrence of liver injury after cessation of infliximab or adalimumab. Two did well with adalimumab after [drug-induced liver injury] associated with infliximab, and one was successfully switched from adalimumab to abatacept."

Finally, the investigators contrasted patients with serological or histological autoimmune features with patients who lacked any autoimmune characteristics.

The autoimmune patients tended to have a longer latency period. The median period after the drug was initiated but before liver injury was noted was 16 weeks for the autoimmune patients versus 10 weeks for the nonautoimmune patients (P = .17). The autoimmune patients also had a higher peak ALT (median 784 vs. 528; P = .03).

"The mechanism by which the TNF-alpha antagonists lead to drug-induced liver injury is unknown," the authors wrote.

"Because the injury can occur after only one infusion, dose-dependent toxicity is unlikely. Unpredictable, idiosyncratic drug-induced liver injury seems most likely, as in this series no patients had clinical evidence of a rash or eosinophilia, and only one presented with fever."

"Further studies are needed to ascertain whether genetic or other markers of the hepatotoxicity associated with TNF-alpha antagonists can be identified," they said.

The DILIN database is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors reported having no conflicts of interest.

Current Psychiatry and the American Academy of Clinical Psychiatrists welcomed more than 550 psychiatric practitioners from across the United States and abroad to this annual conference, which was headed by Meeting Chair Richard Balon, MD, and Co-chairs Donald W. Black, MD, and Nagy Youssef, MD, March 27-29, 2014 at the Hilton Chicago in Chicago, Illinois. Attendees earned as many as 10 AMA PRA Category 1 Credits™.

Thursday, March 27, 2014

MORNING SESSION

Obsessive-compulsive disorder can be misdiagnosed as psychosis, anxiety, or a sexual disorder. In addition to contamination, patients can present with pathologic doubt, somatic obsessions, or obsessions about taboo or symmetry. Among FDA-approved medications, clomipramine might be more effective than selective serotonin reuptake inhibitors (SSRIs). Exposure response prevention therapy shows better response than pharmacotherapy, but best outcomes are seen with combination therapy. Jon E. Grant, JD, MD, MPH, University of Chicago, also discussed obsessive-compulsive personality disorder, body dysmorphic disorder, hoarding, trichotillomania, and excoriation disorder—as well as changes in DSM-5 that cover this group of disorders.

Patients with schizophrenia are at higher risk of death from cardiac and pulmonary disease than the general population. The quality of care of patients with psychosis generally is poor, because of lack of recognition, time, and resources, as well as systematic barriers to accessing health care. Questions about weight gain, lethargy, infections, and sexual functioning can help the practitioner assess a patient’s general health. When appropriate, Henry A. Nasrallah, MD, St. Louis University School of Medicine, recommends, consider switching antipsychotics, which might reverse adverse metabolic events.

Nonpharmacologic treatment goals include improving sleep, educating patients, providing them with tools for improving sleep, and creating an opportunity for patient-practitioner discussion. Stimulus control and sleep restriction are primary therapeutic techniques to improve sleep quality and reduce non-sleeping time in bed. Thomas Roth, PhD, Henry Ford Hospital, also discussed how to modify sleep hygiene techniques for pediatric, adolescent, and geriatric patients.

Donald W. Black, MD, University of Iowa, says that work groups for DSM-5 were asked to consider dimensionality and culture and gender issues. New diagnostic categories include obsessive-compulsive and related disorders and trauma and stressor-related disorders. Some diagnoses were reformulated or introduced, including autism spectrum disorder and disruptive mood dysregulation disorder. The multi-axial system was discontinued in DSM-5. He also reviewed coding issues.

In a sponsored symposium, Prakash S. Masand, MD, Global Medical Education, Inc., looked at the clinical challenges of addressing all 3 symptom domains that characterize depression (emotional, physical, and cognitive) as an introduction to reviewing the efficacy, mechanism of action, and side effects of vortioxetine (Brintellix), a new serotonergic agent for treating major depressive disorder (MDD). In all studies submitted to the FDA, vortioxetine was found to be superior to placebo, in at least 1 dosage group, for alleviating depressive symptoms and for reducing the risk of depressive recurrence.

AFTERNOON SESSION

Oppositional defiant disorder is more common in boys (onset at age 6 to 10) and is associated with inconsistent and neglectful parenting. Treatment modalities, including educational training, anticonvulsants, and lithium, do not have a strong evidence base. Intermittent explosive disorder is characterized by short-lived but frequent behavioral outbursts and often begins in adolescence. Dr. Grant also reviewed the evidence on conduct disorder, pyromania, and kleptomania.

Cognitive symptoms of schizophrenia often appear before psychotic symptoms and remain stable across the lifespan. There are no pharmacologic treatments for cognitive deficits in schizophrenia; however, Dr. Nasrallah listed tactics to improve cognitive function, including regular aerobic exercise. These cognitive deficits can be categorized as neurocognitive (memory, learning, executive function) and social (social skills, theory of mind, social cues) and contribute to functional decline and often prevent patients from working and going to school. Dr. Nasrallah described how bipolar disorder (BD) overlaps with schizophrenia in terms of cognitive dysfunction.

^{Henry Nasrallah, MD}

Psychiatric disorders exhibit specific sleep/ wake impairments. Sleep disorders can mimic psychiatric symptoms, such as fatigue, cognitive problems, and depression. Sleep disturbances, including insomnia, obstructive sleep apnea, and decreased need for sleep, often coexist with depression, generalized anxiety disorder, posttraumatic stress disorder, and BD, and insomnia is associated with a greater risk of suicide. With antidepressant treatment, sleep in depressed patients improves but does not normalize. Dr. Roth also reviewed pharmacotherapeutic options and non-drug modalities to improve patients’ sleep.

Antidepressants have no efficacy in treating acute episodes of bipolar depression, and using such agents might yield a poor long-term outcome in BD, according to Robert M. Post, MD, George Washington University School of Medicine, Michael J. Ostacher, MD, MPH, MMSc, Stanford University, and Vivek Singh, MD, University of Texas Health Science Center at San Antonio, in an interactive faculty discussion. For patients with bipolar I disorder, lithium monotherapy or the combination of lithium and valproate is more effective than valproate alone; evidence does not support valproate as a maintenance treatment. When a patient with BD shows partial response, attendees at this sponsored symposium were advised, consider adding psychotherapy and psycho-education. Combining a mood stabilizer and an antipsychotic might be more effective than monotherapy and safer, by allowing lower dosages. The only 3 treatments FDA-approved for bipolar depression are the olanzapine-fluoxetine combination, quetiapine, and lurasidone.

^{Boaz Levy, PhD, (left) receives the 2014 George Winokur Research Award from Carol S. North, MD, for his article on recovery of cognitive function in patients with co-occuring bipolar disorder and alcohol dependence.}

Friday, March 28, 2014

MORNING SESSION

Carmen Pinto, MD, at a sponsored symposium, reviewed the utility and safety of
long-acting injectable (LAI) antipsychotics for treating schizophrenia, with a focus on LAI aripiprazole, a partial HT-receptor agonist/partial HT-receptor antagonist. Four monthly injections (400 mg/injection) of the drug are needed to reach steady state; each injection reaches peak level in 5 to 7 days. LAI aripiprazole has been shown to delay time to relapse due to nonadherence and onset of nonresponse to the drug, and has high patient acceptance—even in those who already stable. Safety and side effects with LAI aripiprazole are the same as seen with the oral formulation.

In multimodal therapy for chronic pain, psychiatrists have a role in assessing
psychiatric comorbidities, coping ability, social functioning, and other life functions, including work and personal relationships. Cognitive-behavioral therapy can be particularly useful for chronic pain by helping patients reframe their pain experiences. Raphael J. Leo, MA, MD, FAPM, University at Buffalo, reviewed non-opioid co-analgesics that can be used for patients with comorbid pain and a substance use disorder. If opioids are necessary, consider “weak” or long-acting opioids. Monitor patients for aberrant, drug-seeking behavior.

In the second part of his overview, Dr. Black highlighted specific changes to DSM-5 of particular concern to clinicians. New chapters were created and disorders were consolidated, he explained, such as autism spectrum disorder, somatic symptom disorder, and major neurocognitive disorder. New diagnoses include hoarding disorder and binge eating disorder. Subtypes of schizophrenia were dropped. Pathologic gambling was renamed gambling disorder and gender dysphoria is now called gender identity disorder. The bereavement exclusion of a major depressive episode was dropped.

Antidepressants are effective in mitigating pain in neuropathy, headache, fibromyalgia, and chronic musculoskeletal pain, and have been advocated for other pain syndromes. Selection of an antidepressant depends on the type of pain condition, comorbid depression or anxiety, tolerability, and medical comorbidities. Dr. Leo presented prescribing strategies for tricyclics, serotoninnorepinephrine
reuptake inhibitors, SSRIs, and other antidepressants.

Treating of BD in geriatric patients becomes complicated because therapeutic choices are narrowed and response to therapy is less successful with age, according to George T. Grossberg, MD, St. Louis University. Rapid cycling tends to be the norm in geriatric BD patients. Look for agitation and irritability, rather than full-blown mania; grandiose delusions; psychiatric comorbidity, especially anxiety disorder; and sexually inappropriate behavior. Pharmacotherapeutic options include: mood stabilizers, atypical antipsychotics, and antidepressants (specifically, bupropion and SSRIs—not TCAs, venlafaxine, or duloxetine—and over the short term only). Consider divalproex for mania and hypomania, used cautiously because of its adverse side-effect potential.

^{George T. Grossberg, MD}

AFTERNOON SESSION

Often, BD is misdiagnosed as unipolar depression, or the correct diagnosis of BD is delayed, according to Gustavo Alva, MD, ATP Clinical Research. Comorbid substance use disorder or an anxiety disorder is common. Comorbid cardiovascular disease brings a greater risk of mortality in patients with BD than suicide. Approximately two-thirds of patients with BD are taking adjunctive medications; however, antidepressants are no more effective than placebo in treating bipolar depression. At this sponsored symposium, Vladimir Maletic, MD, University of South Carolina, described a 6-week trial in which lurasidone plus lithium or divalporex was more effective in reducing depression, as measured by MADRS, than placebo plus lithium or  akathisia, somnolence, and extrapyramidal symptoms.

When assessing an older patient with psychosis, first establish the cause of the symptoms, such as Alzheimer’s disease, affective disorder, substance use, or hallucinations associated with grief. Older patients with schizophrenia who have been taking typical antipsychotics for years might benefit from a switch to an atypical or a dosage reduction. Dr. Grossberg recommends considering antipsychotics for older patients when symptoms cause severe emotional distress that does not respond to other interventions or an acute episode that poses a safety risk for patients or others. Choose an antipsychotic based on side effects, and “start low and go slow,” when possible. The goal is to reduce agitation and distress—not necessarily to resolve psychotic symptoms.

Anita H. Clayton, MD, University of Virginia Health System, provided a review of sexual function from puberty through midlife and older years. Social factors play a role in sexual satisfaction, such as gender expectations, religious beliefs, and the influence of reporting in the media. Sexual dysfunction becomes worse in men after age 29; in women, the rate of sexual dysfunction appears to be consistent across the lifespan. Cardiovascular disease is a significant risk factor for sexual dysfunction in men, but not in women. Sexual function and depression have a bidirectional relationship; sexual dysfunction may be a symptom or cause of depression and antidepressants may affect desire and function. Medications, including psychotropics, oral contraceptives, and opioids, can cause sexual dysfunction.

Providers often are reluctant to bring up sexual issues with their patients, Dr. Clayton says, but patients often want to talk about their sexual problems. In reproductive-age women, look for hypoactive sexual desire disorder and pain. In men, assess for erectile dysfunction or premature ejaculation. Inquire about every phase of the sexual response cycle. When managing sexual dysfunction, aim to minimize contributing factors such as illness or medication, consider FDA-approved medications, encourage a healthy lifestyle, and employ psychological interventions when appropriate. In patients with antidepressant-associated sexual dysfunction, consider switching medications or adding an antidote, such as bupropion, buspirone, or sildenafil.

Saturday, March 29, 2014

MORNING SESSION

Because of the lack of double-blind, placebo-controlled trials, the risks of untreated depression vs the risks of antidepressant use in pregnancy are unclear. Marlene P. Freeman, MD, Massachusetts General Hospital, described the limited, long-term data on tricyclics and fluoxetine. Some studies have shown a small risk of birth defects with SSRIs; others did not find an association. For moderate or severe depression, use antidepressants at the lowest dosage and try non-medication options, such as psychotherapy and complementary and alternative medicine. During the third trimester, women may need a higher dosage to maintain therapeutic drug levels. Data indicates that folic acid use during pregnancy is associated with a decreased risk of autism and schizophrenia.

James W. Jefferson, MD, University of Wisconsin School of Medicine and Public Health, recommends ruling out medical conditions, such as cancer, that might be causing your patients’ fatigue or depression. Many medications, including over-the-counter agents and supplements, can cause fatigue. Bupropion was more effective than placebo and SSRIs in treating depressed patients with sleepiness and fatigue. Adding a psychostimulant to an SSRI does not have a significantly better effect than placebo on depressive symptoms. Adjunctive modafanil may improve depression and fatigue. Data for dopamine agonists are limited.

Lithium should be used with caution in pregnant women because of the risk of congenital malformations. Dr. Freeman also discussed the potential risks to the fetus with the mother’s use of valproate and lamotrigine (with the latter, a small increase in oral clefting). High-potency typical antipsychotics are considered safe; low-potency drugs have a higher risk of major malformations. For atypicals, the risk of malformations appears minimal; newborns might display extrapyramidal effects and withdrawal symptoms. Infants exposed to psychostimulants may have lower birth weight, but are not at increased risk of birth defects.

Dr. Jefferson reviewed the efficacy, pharmacokinetics, and adverse effects of vilazodone, levomilnacipran, and vortioxetine, which are antidepressants new to the market. Dr. Jefferson recommends reading package inserts to become familiar with new drugs. He also described studies of medications that were not FDA-approved, including edivoxetine, quetiapine XR monotherapy for MDD, and agomelatine. Agents under investigation include onabotulinumtoxin A injections, ketamine, and lanicemine.

Katherine E. Burdick, PhD, Mount Sinai School of Medicine, defined cognitive domains. First-episode MDD patients perform worse in psychomotor speed and attention than healthy controls. Late-onset depression (after age 60) is associated with worse performance on processing speed and verbal memory. Cognitive deficits in depressed patients range from mild to moderate and are influenced by symptom status and duration of illness. Treating cognitive deficits begins with prevention. Cholinesterase inhibitors are not effective for improving cognition in MDD. Antidepressants, including SSRIs, do not adequately treat cognitive deficits, Roger S. McIntyre, MD, FRCPC, University of Toronto, explained.

Current Psychiatry and the American Academy of Clinical Psychiatrists welcomed more than 550 psychiatric practitioners from across the United States and abroad to this annual conference, which was headed by Meeting Chair Richard Balon, MD, and Co-chairs Donald W. Black, MD, and Nagy Youssef, MD, March 27-29, 2014 at the Hilton Chicago in Chicago, Illinois. Attendees earned as many as 10 AMA PRA Category 1 Credits™.

Thursday, March 27, 2014

MORNING SESSION

Obsessive-compulsive disorder can be misdiagnosed as psychosis, anxiety, or a sexual disorder. In addition to contamination, patients can present with pathologic doubt, somatic obsessions, or obsessions about taboo or symmetry. Among FDA-approved medications, clomipramine might be more effective than selective serotonin reuptake inhibitors (SSRIs). Exposure response prevention therapy shows better response than pharmacotherapy, but best outcomes are seen with combination therapy. Jon E. Grant, JD, MD, MPH, University of Chicago, also discussed obsessive-compulsive personality disorder, body dysmorphic disorder, hoarding, trichotillomania, and excoriation disorder—as well as changes in DSM-5 that cover this group of disorders.

Patients with schizophrenia are at higher risk of death from cardiac and pulmonary disease than the general population. The quality of care of patients with psychosis generally is poor, because of lack of recognition, time, and resources, as well as systematic barriers to accessing health care. Questions about weight gain, lethargy, infections, and sexual functioning can help the practitioner assess a patient’s general health. When appropriate, Henry A. Nasrallah, MD, St. Louis University School of Medicine, recommends, consider switching antipsychotics, which might reverse adverse metabolic events.

Nonpharmacologic treatment goals include improving sleep, educating patients, providing them with tools for improving sleep, and creating an opportunity for patient-practitioner discussion. Stimulus control and sleep restriction are primary therapeutic techniques to improve sleep quality and reduce non-sleeping time in bed. Thomas Roth, PhD, Henry Ford Hospital, also discussed how to modify sleep hygiene techniques for pediatric, adolescent, and geriatric patients.

Donald W. Black, MD, University of Iowa, says that work groups for DSM-5 were asked to consider dimensionality and culture and gender issues. New diagnostic categories include obsessive-compulsive and related disorders and trauma and stressor-related disorders. Some diagnoses were reformulated or introduced, including autism spectrum disorder and disruptive mood dysregulation disorder. The multi-axial system was discontinued in DSM-5. He also reviewed coding issues.

In a sponsored symposium, Prakash S. Masand, MD, Global Medical Education, Inc., looked at the clinical challenges of addressing all 3 symptom domains that characterize depression (emotional, physical, and cognitive) as an introduction to reviewing the efficacy, mechanism of action, and side effects of vortioxetine (Brintellix), a new serotonergic agent for treating major depressive disorder (MDD). In all studies submitted to the FDA, vortioxetine was found to be superior to placebo, in at least 1 dosage group, for alleviating depressive symptoms and for reducing the risk of depressive recurrence.

AFTERNOON SESSION

Oppositional defiant disorder is more common in boys (onset at age 6 to 10) and is associated with inconsistent and neglectful parenting. Treatment modalities, including educational training, anticonvulsants, and lithium, do not have a strong evidence base. Intermittent explosive disorder is characterized by short-lived but frequent behavioral outbursts and often begins in adolescence. Dr. Grant also reviewed the evidence on conduct disorder, pyromania, and kleptomania.

Cognitive symptoms of schizophrenia often appear before psychotic symptoms and remain stable across the lifespan. There are no pharmacologic treatments for cognitive deficits in schizophrenia; however, Dr. Nasrallah listed tactics to improve cognitive function, including regular aerobic exercise. These cognitive deficits can be categorized as neurocognitive (memory, learning, executive function) and social (social skills, theory of mind, social cues) and contribute to functional decline and often prevent patients from working and going to school. Dr. Nasrallah described how bipolar disorder (BD) overlaps with schizophrenia in terms of cognitive dysfunction.

^{Henry Nasrallah, MD}

Psychiatric disorders exhibit specific sleep/ wake impairments. Sleep disorders can mimic psychiatric symptoms, such as fatigue, cognitive problems, and depression. Sleep disturbances, including insomnia, obstructive sleep apnea, and decreased need for sleep, often coexist with depression, generalized anxiety disorder, posttraumatic stress disorder, and BD, and insomnia is associated with a greater risk of suicide. With antidepressant treatment, sleep in depressed patients improves but does not normalize. Dr. Roth also reviewed pharmacotherapeutic options and non-drug modalities to improve patients’ sleep.

Antidepressants have no efficacy in treating acute episodes of bipolar depression, and using such agents might yield a poor long-term outcome in BD, according to Robert M. Post, MD, George Washington University School of Medicine, Michael J. Ostacher, MD, MPH, MMSc, Stanford University, and Vivek Singh, MD, University of Texas Health Science Center at San Antonio, in an interactive faculty discussion. For patients with bipolar I disorder, lithium monotherapy or the combination of lithium and valproate is more effective than valproate alone; evidence does not support valproate as a maintenance treatment. When a patient with BD shows partial response, attendees at this sponsored symposium were advised, consider adding psychotherapy and psycho-education. Combining a mood stabilizer and an antipsychotic might be more effective than monotherapy and safer, by allowing lower dosages. The only 3 treatments FDA-approved for bipolar depression are the olanzapine-fluoxetine combination, quetiapine, and lurasidone.

^{Boaz Levy, PhD, (left) receives the 2014 George Winokur Research Award from Carol S. North, MD, for his article on recovery of cognitive function in patients with co-occuring bipolar disorder and alcohol dependence.}

Friday, March 28, 2014

MORNING SESSION

Carmen Pinto, MD, at a sponsored symposium, reviewed the utility and safety of
long-acting injectable (LAI) antipsychotics for treating schizophrenia, with a focus on LAI aripiprazole, a partial HT-receptor agonist/partial HT-receptor antagonist. Four monthly injections (400 mg/injection) of the drug are needed to reach steady state; each injection reaches peak level in 5 to 7 days. LAI aripiprazole has been shown to delay time to relapse due to nonadherence and onset of nonresponse to the drug, and has high patient acceptance—even in those who already stable. Safety and side effects with LAI aripiprazole are the same as seen with the oral formulation.

In multimodal therapy for chronic pain, psychiatrists have a role in assessing
psychiatric comorbidities, coping ability, social functioning, and other life functions, including work and personal relationships. Cognitive-behavioral therapy can be particularly useful for chronic pain by helping patients reframe their pain experiences. Raphael J. Leo, MA, MD, FAPM, University at Buffalo, reviewed non-opioid co-analgesics that can be used for patients with comorbid pain and a substance use disorder. If opioids are necessary, consider “weak” or long-acting opioids. Monitor patients for aberrant, drug-seeking behavior.

In the second part of his overview, Dr. Black highlighted specific changes to DSM-5 of particular concern to clinicians. New chapters were created and disorders were consolidated, he explained, such as autism spectrum disorder, somatic symptom disorder, and major neurocognitive disorder. New diagnoses include hoarding disorder and binge eating disorder. Subtypes of schizophrenia were dropped. Pathologic gambling was renamed gambling disorder and gender dysphoria is now called gender identity disorder. The bereavement exclusion of a major depressive episode was dropped.

Antidepressants are effective in mitigating pain in neuropathy, headache, fibromyalgia, and chronic musculoskeletal pain, and have been advocated for other pain syndromes. Selection of an antidepressant depends on the type of pain condition, comorbid depression or anxiety, tolerability, and medical comorbidities. Dr. Leo presented prescribing strategies for tricyclics, serotoninnorepinephrine
reuptake inhibitors, SSRIs, and other antidepressants.

Treating of BD in geriatric patients becomes complicated because therapeutic choices are narrowed and response to therapy is less successful with age, according to George T. Grossberg, MD, St. Louis University. Rapid cycling tends to be the norm in geriatric BD patients. Look for agitation and irritability, rather than full-blown mania; grandiose delusions; psychiatric comorbidity, especially anxiety disorder; and sexually inappropriate behavior. Pharmacotherapeutic options include: mood stabilizers, atypical antipsychotics, and antidepressants (specifically, bupropion and SSRIs—not TCAs, venlafaxine, or duloxetine—and over the short term only). Consider divalproex for mania and hypomania, used cautiously because of its adverse side-effect potential.

^{George T. Grossberg, MD}

AFTERNOON SESSION

Often, BD is misdiagnosed as unipolar depression, or the correct diagnosis of BD is delayed, according to Gustavo Alva, MD, ATP Clinical Research. Comorbid substance use disorder or an anxiety disorder is common. Comorbid cardiovascular disease brings a greater risk of mortality in patients with BD than suicide. Approximately two-thirds of patients with BD are taking adjunctive medications; however, antidepressants are no more effective than placebo in treating bipolar depression. At this sponsored symposium, Vladimir Maletic, MD, University of South Carolina, described a 6-week trial in which lurasidone plus lithium or divalporex was more effective in reducing depression, as measured by MADRS, than placebo plus lithium or  akathisia, somnolence, and extrapyramidal symptoms.

When assessing an older patient with psychosis, first establish the cause of the symptoms, such as Alzheimer’s disease, affective disorder, substance use, or hallucinations associated with grief. Older patients with schizophrenia who have been taking typical antipsychotics for years might benefit from a switch to an atypical or a dosage reduction. Dr. Grossberg recommends considering antipsychotics for older patients when symptoms cause severe emotional distress that does not respond to other interventions or an acute episode that poses a safety risk for patients or others. Choose an antipsychotic based on side effects, and “start low and go slow,” when possible. The goal is to reduce agitation and distress—not necessarily to resolve psychotic symptoms.

Anita H. Clayton, MD, University of Virginia Health System, provided a review of sexual function from puberty through midlife and older years. Social factors play a role in sexual satisfaction, such as gender expectations, religious beliefs, and the influence of reporting in the media. Sexual dysfunction becomes worse in men after age 29; in women, the rate of sexual dysfunction appears to be consistent across the lifespan. Cardiovascular disease is a significant risk factor for sexual dysfunction in men, but not in women. Sexual function and depression have a bidirectional relationship; sexual dysfunction may be a symptom or cause of depression and antidepressants may affect desire and function. Medications, including psychotropics, oral contraceptives, and opioids, can cause sexual dysfunction.

Providers often are reluctant to bring up sexual issues with their patients, Dr. Clayton says, but patients often want to talk about their sexual problems. In reproductive-age women, look for hypoactive sexual desire disorder and pain. In men, assess for erectile dysfunction or premature ejaculation. Inquire about every phase of the sexual response cycle. When managing sexual dysfunction, aim to minimize contributing factors such as illness or medication, consider FDA-approved medications, encourage a healthy lifestyle, and employ psychological interventions when appropriate. In patients with antidepressant-associated sexual dysfunction, consider switching medications or adding an antidote, such as bupropion, buspirone, or sildenafil.

Saturday, March 29, 2014

MORNING SESSION

Because of the lack of double-blind, placebo-controlled trials, the risks of untreated depression vs the risks of antidepressant use in pregnancy are unclear. Marlene P. Freeman, MD, Massachusetts General Hospital, described the limited, long-term data on tricyclics and fluoxetine. Some studies have shown a small risk of birth defects with SSRIs; others did not find an association. For moderate or severe depression, use antidepressants at the lowest dosage and try non-medication options, such as psychotherapy and complementary and alternative medicine. During the third trimester, women may need a higher dosage to maintain therapeutic drug levels. Data indicates that folic acid use during pregnancy is associated with a decreased risk of autism and schizophrenia.

James W. Jefferson, MD, University of Wisconsin School of Medicine and Public Health, recommends ruling out medical conditions, such as cancer, that might be causing your patients’ fatigue or depression. Many medications, including over-the-counter agents and supplements, can cause fatigue. Bupropion was more effective than placebo and SSRIs in treating depressed patients with sleepiness and fatigue. Adding a psychostimulant to an SSRI does not have a significantly better effect than placebo on depressive symptoms. Adjunctive modafanil may improve depression and fatigue. Data for dopamine agonists are limited.

Lithium should be used with caution in pregnant women because of the risk of congenital malformations. Dr. Freeman also discussed the potential risks to the fetus with the mother’s use of valproate and lamotrigine (with the latter, a small increase in oral clefting). High-potency typical antipsychotics are considered safe; low-potency drugs have a higher risk of major malformations. For atypicals, the risk of malformations appears minimal; newborns might display extrapyramidal effects and withdrawal symptoms. Infants exposed to psychostimulants may have lower birth weight, but are not at increased risk of birth defects.

Dr. Jefferson reviewed the efficacy, pharmacokinetics, and adverse effects of vilazodone, levomilnacipran, and vortioxetine, which are antidepressants new to the market. Dr. Jefferson recommends reading package inserts to become familiar with new drugs. He also described studies of medications that were not FDA-approved, including edivoxetine, quetiapine XR monotherapy for MDD, and agomelatine. Agents under investigation include onabotulinumtoxin A injections, ketamine, and lanicemine.

Katherine E. Burdick, PhD, Mount Sinai School of Medicine, defined cognitive domains. First-episode MDD patients perform worse in psychomotor speed and attention than healthy controls. Late-onset depression (after age 60) is associated with worse performance on processing speed and verbal memory. Cognitive deficits in depressed patients range from mild to moderate and are influenced by symptom status and duration of illness. Treating cognitive deficits begins with prevention. Cholinesterase inhibitors are not effective for improving cognition in MDD. Antidepressants, including SSRIs, do not adequately treat cognitive deficits, Roger S. McIntyre, MD, FRCPC, University of Toronto, explained.

Current Psychiatry and the American Academy of Clinical Psychiatrists welcomed more than 550 psychiatric practitioners from across the United States and abroad to this annual conference, which was headed by Meeting Chair Richard Balon, MD, and Co-chairs Donald W. Black, MD, and Nagy Youssef, MD, March 27-29, 2014 at the Hilton Chicago in Chicago, Illinois. Attendees earned as many as 10 AMA PRA Category 1 Credits™.

Thursday, March 27, 2014

MORNING SESSION

Obsessive-compulsive disorder can be misdiagnosed as psychosis, anxiety, or a sexual disorder. In addition to contamination, patients can present with pathologic doubt, somatic obsessions, or obsessions about taboo or symmetry. Among FDA-approved medications, clomipramine might be more effective than selective serotonin reuptake inhibitors (SSRIs). Exposure response prevention therapy shows better response than pharmacotherapy, but best outcomes are seen with combination therapy. Jon E. Grant, JD, MD, MPH, University of Chicago, also discussed obsessive-compulsive personality disorder, body dysmorphic disorder, hoarding, trichotillomania, and excoriation disorder—as well as changes in DSM-5 that cover this group of disorders.

Patients with schizophrenia are at higher risk of death from cardiac and pulmonary disease than the general population. The quality of care of patients with psychosis generally is poor, because of lack of recognition, time, and resources, as well as systematic barriers to accessing health care. Questions about weight gain, lethargy, infections, and sexual functioning can help the practitioner assess a patient’s general health. When appropriate, Henry A. Nasrallah, MD, St. Louis University School of Medicine, recommends, consider switching antipsychotics, which might reverse adverse metabolic events.

Nonpharmacologic treatment goals include improving sleep, educating patients, providing them with tools for improving sleep, and creating an opportunity for patient-practitioner discussion. Stimulus control and sleep restriction are primary therapeutic techniques to improve sleep quality and reduce non-sleeping time in bed. Thomas Roth, PhD, Henry Ford Hospital, also discussed how to modify sleep hygiene techniques for pediatric, adolescent, and geriatric patients.

Donald W. Black, MD, University of Iowa, says that work groups for DSM-5 were asked to consider dimensionality and culture and gender issues. New diagnostic categories include obsessive-compulsive and related disorders and trauma and stressor-related disorders. Some diagnoses were reformulated or introduced, including autism spectrum disorder and disruptive mood dysregulation disorder. The multi-axial system was discontinued in DSM-5. He also reviewed coding issues.

In a sponsored symposium, Prakash S. Masand, MD, Global Medical Education, Inc., looked at the clinical challenges of addressing all 3 symptom domains that characterize depression (emotional, physical, and cognitive) as an introduction to reviewing the efficacy, mechanism of action, and side effects of vortioxetine (Brintellix), a new serotonergic agent for treating major depressive disorder (MDD). In all studies submitted to the FDA, vortioxetine was found to be superior to placebo, in at least 1 dosage group, for alleviating depressive symptoms and for reducing the risk of depressive recurrence.

AFTERNOON SESSION

Oppositional defiant disorder is more common in boys (onset at age 6 to 10) and is associated with inconsistent and neglectful parenting. Treatment modalities, including educational training, anticonvulsants, and lithium, do not have a strong evidence base. Intermittent explosive disorder is characterized by short-lived but frequent behavioral outbursts and often begins in adolescence. Dr. Grant also reviewed the evidence on conduct disorder, pyromania, and kleptomania.

Cognitive symptoms of schizophrenia often appear before psychotic symptoms and remain stable across the lifespan. There are no pharmacologic treatments for cognitive deficits in schizophrenia; however, Dr. Nasrallah listed tactics to improve cognitive function, including regular aerobic exercise. These cognitive deficits can be categorized as neurocognitive (memory, learning, executive function) and social (social skills, theory of mind, social cues) and contribute to functional decline and often prevent patients from working and going to school. Dr. Nasrallah described how bipolar disorder (BD) overlaps with schizophrenia in terms of cognitive dysfunction.

^{Henry Nasrallah, MD}

Psychiatric disorders exhibit specific sleep/ wake impairments. Sleep disorders can mimic psychiatric symptoms, such as fatigue, cognitive problems, and depression. Sleep disturbances, including insomnia, obstructive sleep apnea, and decreased need for sleep, often coexist with depression, generalized anxiety disorder, posttraumatic stress disorder, and BD, and insomnia is associated with a greater risk of suicide. With antidepressant treatment, sleep in depressed patients improves but does not normalize. Dr. Roth also reviewed pharmacotherapeutic options and non-drug modalities to improve patients’ sleep.

Antidepressants have no efficacy in treating acute episodes of bipolar depression, and using such agents might yield a poor long-term outcome in BD, according to Robert M. Post, MD, George Washington University School of Medicine, Michael J. Ostacher, MD, MPH, MMSc, Stanford University, and Vivek Singh, MD, University of Texas Health Science Center at San Antonio, in an interactive faculty discussion. For patients with bipolar I disorder, lithium monotherapy or the combination of lithium and valproate is more effective than valproate alone; evidence does not support valproate as a maintenance treatment. When a patient with BD shows partial response, attendees at this sponsored symposium were advised, consider adding psychotherapy and psycho-education. Combining a mood stabilizer and an antipsychotic might be more effective than monotherapy and safer, by allowing lower dosages. The only 3 treatments FDA-approved for bipolar depression are the olanzapine-fluoxetine combination, quetiapine, and lurasidone.

^{Boaz Levy, PhD, (left) receives the 2014 George Winokur Research Award from Carol S. North, MD, for his article on recovery of cognitive function in patients with co-occuring bipolar disorder and alcohol dependence.}

Friday, March 28, 2014

MORNING SESSION

Carmen Pinto, MD, at a sponsored symposium, reviewed the utility and safety of
long-acting injectable (LAI) antipsychotics for treating schizophrenia, with a focus on LAI aripiprazole, a partial HT-receptor agonist/partial HT-receptor antagonist. Four monthly injections (400 mg/injection) of the drug are needed to reach steady state; each injection reaches peak level in 5 to 7 days. LAI aripiprazole has been shown to delay time to relapse due to nonadherence and onset of nonresponse to the drug, and has high patient acceptance—even in those who already stable. Safety and side effects with LAI aripiprazole are the same as seen with the oral formulation.

In multimodal therapy for chronic pain, psychiatrists have a role in assessing
psychiatric comorbidities, coping ability, social functioning, and other life functions, including work and personal relationships. Cognitive-behavioral therapy can be particularly useful for chronic pain by helping patients reframe their pain experiences. Raphael J. Leo, MA, MD, FAPM, University at Buffalo, reviewed non-opioid co-analgesics that can be used for patients with comorbid pain and a substance use disorder. If opioids are necessary, consider “weak” or long-acting opioids. Monitor patients for aberrant, drug-seeking behavior.

In the second part of his overview, Dr. Black highlighted specific changes to DSM-5 of particular concern to clinicians. New chapters were created and disorders were consolidated, he explained, such as autism spectrum disorder, somatic symptom disorder, and major neurocognitive disorder. New diagnoses include hoarding disorder and binge eating disorder. Subtypes of schizophrenia were dropped. Pathologic gambling was renamed gambling disorder and gender dysphoria is now called gender identity disorder. The bereavement exclusion of a major depressive episode was dropped.

Antidepressants are effective in mitigating pain in neuropathy, headache, fibromyalgia, and chronic musculoskeletal pain, and have been advocated for other pain syndromes. Selection of an antidepressant depends on the type of pain condition, comorbid depression or anxiety, tolerability, and medical comorbidities. Dr. Leo presented prescribing strategies for tricyclics, serotoninnorepinephrine
reuptake inhibitors, SSRIs, and other antidepressants.

Treating of BD in geriatric patients becomes complicated because therapeutic choices are narrowed and response to therapy is less successful with age, according to George T. Grossberg, MD, St. Louis University. Rapid cycling tends to be the norm in geriatric BD patients. Look for agitation and irritability, rather than full-blown mania; grandiose delusions; psychiatric comorbidity, especially anxiety disorder; and sexually inappropriate behavior. Pharmacotherapeutic options include: mood stabilizers, atypical antipsychotics, and antidepressants (specifically, bupropion and SSRIs—not TCAs, venlafaxine, or duloxetine—and over the short term only). Consider divalproex for mania and hypomania, used cautiously because of its adverse side-effect potential.

^{George T. Grossberg, MD}

AFTERNOON SESSION

Often, BD is misdiagnosed as unipolar depression, or the correct diagnosis of BD is delayed, according to Gustavo Alva, MD, ATP Clinical Research. Comorbid substance use disorder or an anxiety disorder is common. Comorbid cardiovascular disease brings a greater risk of mortality in patients with BD than suicide. Approximately two-thirds of patients with BD are taking adjunctive medications; however, antidepressants are no more effective than placebo in treating bipolar depression. At this sponsored symposium, Vladimir Maletic, MD, University of South Carolina, described a 6-week trial in which lurasidone plus lithium or divalporex was more effective in reducing depression, as measured by MADRS, than placebo plus lithium or  akathisia, somnolence, and extrapyramidal symptoms.

When assessing an older patient with psychosis, first establish the cause of the symptoms, such as Alzheimer’s disease, affective disorder, substance use, or hallucinations associated with grief. Older patients with schizophrenia who have been taking typical antipsychotics for years might benefit from a switch to an atypical or a dosage reduction. Dr. Grossberg recommends considering antipsychotics for older patients when symptoms cause severe emotional distress that does not respond to other interventions or an acute episode that poses a safety risk for patients or others. Choose an antipsychotic based on side effects, and “start low and go slow,” when possible. The goal is to reduce agitation and distress—not necessarily to resolve psychotic symptoms.

Anita H. Clayton, MD, University of Virginia Health System, provided a review of sexual function from puberty through midlife and older years. Social factors play a role in sexual satisfaction, such as gender expectations, religious beliefs, and the influence of reporting in the media. Sexual dysfunction becomes worse in men after age 29; in women, the rate of sexual dysfunction appears to be consistent across the lifespan. Cardiovascular disease is a significant risk factor for sexual dysfunction in men, but not in women. Sexual function and depression have a bidirectional relationship; sexual dysfunction may be a symptom or cause of depression and antidepressants may affect desire and function. Medications, including psychotropics, oral contraceptives, and opioids, can cause sexual dysfunction.

Providers often are reluctant to bring up sexual issues with their patients, Dr. Clayton says, but patients often want to talk about their sexual problems. In reproductive-age women, look for hypoactive sexual desire disorder and pain. In men, assess for erectile dysfunction or premature ejaculation. Inquire about every phase of the sexual response cycle. When managing sexual dysfunction, aim to minimize contributing factors such as illness or medication, consider FDA-approved medications, encourage a healthy lifestyle, and employ psychological interventions when appropriate. In patients with antidepressant-associated sexual dysfunction, consider switching medications or adding an antidote, such as bupropion, buspirone, or sildenafil.

Saturday, March 29, 2014

MORNING SESSION

Because of the lack of double-blind, placebo-controlled trials, the risks of untreated depression vs the risks of antidepressant use in pregnancy are unclear. Marlene P. Freeman, MD, Massachusetts General Hospital, described the limited, long-term data on tricyclics and fluoxetine. Some studies have shown a small risk of birth defects with SSRIs; others did not find an association. For moderate or severe depression, use antidepressants at the lowest dosage and try non-medication options, such as psychotherapy and complementary and alternative medicine. During the third trimester, women may need a higher dosage to maintain therapeutic drug levels. Data indicates that folic acid use during pregnancy is associated with a decreased risk of autism and schizophrenia.

James W. Jefferson, MD, University of Wisconsin School of Medicine and Public Health, recommends ruling out medical conditions, such as cancer, that might be causing your patients’ fatigue or depression. Many medications, including over-the-counter agents and supplements, can cause fatigue. Bupropion was more effective than placebo and SSRIs in treating depressed patients with sleepiness and fatigue. Adding a psychostimulant to an SSRI does not have a significantly better effect than placebo on depressive symptoms. Adjunctive modafanil may improve depression and fatigue. Data for dopamine agonists are limited.

Lithium should be used with caution in pregnant women because of the risk of congenital malformations. Dr. Freeman also discussed the potential risks to the fetus with the mother’s use of valproate and lamotrigine (with the latter, a small increase in oral clefting). High-potency typical antipsychotics are considered safe; low-potency drugs have a higher risk of major malformations. For atypicals, the risk of malformations appears minimal; newborns might display extrapyramidal effects and withdrawal symptoms. Infants exposed to psychostimulants may have lower birth weight, but are not at increased risk of birth defects.

Dr. Jefferson reviewed the efficacy, pharmacokinetics, and adverse effects of vilazodone, levomilnacipran, and vortioxetine, which are antidepressants new to the market. Dr. Jefferson recommends reading package inserts to become familiar with new drugs. He also described studies of medications that were not FDA-approved, including edivoxetine, quetiapine XR monotherapy for MDD, and agomelatine. Agents under investigation include onabotulinumtoxin A injections, ketamine, and lanicemine.

Katherine E. Burdick, PhD, Mount Sinai School of Medicine, defined cognitive domains. First-episode MDD patients perform worse in psychomotor speed and attention than healthy controls. Late-onset depression (after age 60) is associated with worse performance on processing speed and verbal memory. Cognitive deficits in depressed patients range from mild to moderate and are influenced by symptom status and duration of illness. Treating cognitive deficits begins with prevention. Cholinesterase inhibitors are not effective for improving cognition in MDD. Antidepressants, including SSRIs, do not adequately treat cognitive deficits, Roger S. McIntyre, MD, FRCPC, University of Toronto, explained.

A 57-year-old woman with no history of cardiovascular disease comes to the clinic for her annual evaluation. She does not have diabetes mellitus, but she does have hypertension and chronic osteoarthritis, currently treated with acetaminophen. Additionally, she admits to active tobacco use. Her systolic blood pressure is 130 mm Hg on therapy with hydrochlorothiazide. Her electrocardiogram demonstrates left ventricular hypertrophy. Her low-density lipoprotein (LDL) cholesterol level is 140 mg/dL, and her high-density lipoprotein (HDL) cholesterol level is 50 mg/dL. Should this patient be started on aspirin therapy?

Acetylsalicylic acid (aspirin) is an analgesic, antipyretic, and anti-inflammatory agent, but its more prominent use today is as an antithrombotic agent to treat or prevent cardiovascular events. Its antithrombotic properties are due to its effects on the enzyme cyclooxygenase. However, cyclooxygenase is also involved in regulation of the gastric mucosa, and so aspirin increases the risk of gastrointestinal bleeding.

Approximately 50 million people take aspirin on a daily basis to treat or prevent cardiovascular disease.¹ Of these, at least half are taking more than 100 mg per day,² reflecting the general belief that, for aspirin dosage, “more is better”—which is not true.

Additionally, recommendations about the use of aspirin were based on studies that included relatively few members of several important subgroups, such as people with diabetes without known cardiovascular disease, women, and the elderly, and thus may not reflect appropriate indications and dosages for these groups.

Here, we examine the literature, outline an individualized approach to aspirin therapy, and highlight areas for future study.

HISTORY OF ASPIRIN USE IN CARDIOVASCULAR DISEASE

• 1700s—Willow bark is used as an analgesic.
• 1897—Synthetic aspirin is developed as an antipyretic and anti-inflammatory agent.
• 1974—First landmark trial of aspirin for secondary prevention of myocardial infarction.³
• 1982—Nobel Prize awarded for discovery of aspirin mechanism.
• 1985—US Food and Drug Administration approves aspirin for the treatment and secondary prevention of acute myocardial infarction.
• 1998—The Second International Study of Infarct Survival (ISIS-2) finds that giving aspirin to patients with myocardial infarction within 24 hours of presentation leads to a significant reduction in vascular deaths.⁴

Ongoing uncertainties

Aspirin now carries a class I indication for all patients with suspected myocardial infarction. Since there are an estimated 600,000 new coronary events and 325,000 recurrent ischemic events per year in the United States,⁵ the need for aspirin will continue to remain great. It is also approved to prevent and treat stroke and in patients with unstable angina.

However, questions continue to emerge about aspirin’s dosing and appropriate use in specific populations. The initial prevention trials used a wide range of doses and, as mentioned, included few women, few people with diabetes, and few elderly people. The uncertainties are especially pertinent for patients without known vascular disease, in whom the absolute risk reduction is much less, making the assessment of bleeding risk particularly important. Furthermore, the absolute risk-to-benefit assessment may be different in certain populations.

Guidelines on the use of aspirin to prevent cardiovascular disease (Table 1)^6–10 have evolved to take into account these possible disparities, and studies are taking place to further investigate aspirin use in these groups.

ASPIRIN AND GASTROINTESTINAL BLEEDING

Aspirin’s association with bleeding, particularly gastrointestinal bleeding, was recognized early as a use-limiting side effect. With or without aspirin, gastrointestinal bleeding is a common cause of morbidity and death, with an incidence of approximately 100 per 100,000 bleeding episodes in adults per year for upper gastrointestinal bleeding and 20 to 30 per 100,000 per year for lower gastrointestinal bleeding.^11,12

The standard dosage (ie, 325 mg/day) is associated with a significantly higher risk of gastrointestinal bleeding (including fatal bleeds) than is 75 mg.¹³ However, even with lower doses, the risk of gastrointestinal bleeding is estimated to be twice as high as with no aspirin.¹⁴

And here is the irony: studies have shown that higher doses of aspirin offer no advantage in preventing thrombotic events compared with lower doses.¹⁵ For example, the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Organization to Assess Strategies for Ischemic Stroke Syndromes study reported a higher rate of gastrointestinal bleeding with standard-dose aspirin therapy than with low-dose aspirin, with no additional cardiovascular benefit with the higher dose.¹⁶

Furthermore, several other risk factors increase the risk of gastrointestinal bleeding with aspirin use (Table 2). These risk factors are common in the general population but were not necessarily represented in participants in clinical trials. Thus, estimates of risk based on trial data most likely underestimate actual risk in the general population, and therefore, the individual patient’s risk of gastrointestinal bleeding, based on these and other factors, needs to be taken into consideration.

ASPIRIN IN PATIENTS WITH CORONARY ARTERY DISEASE

Randomized clinical trials have validated the benefits of aspirin in secondary prevention of cardiovascular events in patients who have had a myocardial infarction. Patients with coronary disease who withdraw from aspirin therapy or otherwise do not adhere to it have a risk of cardiovascular events three times higher than those who stay with it.¹⁷

Despite the strong data, however, several issues and questions remain about the use of aspirin for secondary prevention.

Bleeding risk must be considered, since gastrointestinal bleeding is associated with a higher risk of death and myocardial infarction in patients with cardiovascular disease.¹⁸ Many patients with coronary disease are on more than one antiplatelet or anticoagulant therapy for concomitant conditions such as atrial fibrillation or because they underwent a percutaneous intervention, which further increases the risk of bleeding.

This bleeding risk is reflected in changes in the most recent recommendations for aspirin dosing after percutaneous coronary intervention. Earlier guidelines advocated use of either 162 or 325 mg after the procedure. However, the most recent update (in 2011) now supports 81 mg for maintenance dosing after intervention.⁷

Patients with coronary disease but without prior myocardial infarction or intervention. Current guidelines recommend 75 to 162 mg of aspirin in all patients with coronary artery disease.⁶ However, this group is diverse and includes patients who have undergone percutaneous coronary intervention, patients with chronic stable angina, and patients with asymptomatic coronary artery disease found on imaging studies. The magnitude of benefit is not clear for those who have no symptoms or who have stable angina.

Most of the evidence supporting aspirin use in chronic angina came from a single trial in Sweden, in which 2,000 patients with chronic stable angina were given either 75 mg daily or placebo. Those who received aspirin had a 34% lower rate of myocardial infarction and sudden death.¹⁹

A substudy of the Physicians’ Health Study, with fewer patients, also noted a significant reduction in the rate of first myocardial infarction. The dose of aspirin in this study was 325 mg every other day.²⁰

In the Women’s Health Initiative Observational Study, 70% of women with stable cardiovascular disease taking aspirin were taking 325 mg daily.²¹ This study demonstrated a significant reduction in the cardiovascular mortality rate, which supports current guidelines, and found no difference in outcomes with doses of 81 mg compared with 325 mg.²¹ This again corroborates that low-dose aspirin is preferential to standard-dose aspirin in women with cardiovascular disease.

These findings have not been validated in larger prospective trials. Thus, current guidelines for aspirin use may reflect extrapolation of aspirin benefit from higher-risk patients to lower-risk patients.

Nevertheless, although the debate continues, it has generally been accepted that in patients who are at high risk of vascular disease or who have had a myocardial infarction, the benefits of aspirin—a 20% relative reduction in vascular events²²—clearly outweigh the risks.

ASPIRIN FOR PRIMARY PREVENTION

Assessing risk vs benefit is more complex when considering populations without known cardiovascular disease.

Only a few studies have specifically evaluated the use of aspirin for primary prevention (Table 3).^23–31 The initial trials were in male physicians in the United Kingdom and the United States in the late 1980s and had somewhat conflicting results. A British study did not find a significant reduction in myocardial infarction,²³ but the US Physician’s Health Study study did: the relative risk was 0.56 (95% confidence interval 0.45–0.70, P < .00001).²⁴ The US study had more than four times the number of participants, used different dosing (325 mg every other day compared with 500 or 300 mg daily in the British study), and had a higher rate of compliance.

Several studies over the next decade demonstrated variable but significant reductions in cardiovascular events as well.^25–27

A meta-analysis of primary prevention trials of aspirin was published in 2009.²² Although the relative risk reduction was similar in primary and secondary prevention, the absolute risk reduction in primary prevention was not nearly as great as in secondary prevention.

These findings are somewhat difficult to interpret, as the component trials included a wide spectrum of patients, ranging from healthy people with no symptoms and no known risk factors to those with limited risk factors. The trials were also performed over several decades during which primary prevention strategies were evolving. Additionally, most of the participants were middle-aged, nondiabetic men, so the results may not necessarily apply to people with diabetes, to women, or to the elderly. Thus, the pooled data in favor of aspirin for primary prevention may not be as broadly applicable to the general population as was once thought.

Aspirin for primary prevention in women

Guidelines for aspirin use in primary prevention were initially thought to be equally applicable to both sexes. However, concerns about the relatively low number of women participating in the studies and the possible mechanistic differences in aspirin efficacy in men vs women prompted further study.

A meta-analysis of randomized controlled trials found that aspirin was associated with a 12% relative reduction in the incidence of cardiovascular events in women and 14% in men. On the other hand, for stroke, the relative risk reduction was 17% in women, while men had no benefit.³²

Most of the women in this meta-analysis were participants in the Women’s Health Study, and they were at low baseline risk.²⁸ Although only about 10% of patients in this study were over age 65, this older group accounted for most of the benefit: these older women had a 26% risk reduction in major adverse cardiovascular events and 30% reduction in stroke.

Thus, for women, aspirin seems to become effective for primary prevention at an older age than in men, and the guidelines have been changed accordingly (Figure 1).

More women should be taking aspirin than actually are. For example, Rivera et al³³ found that only 41% of eligible women were receiving aspirin for primary prevention and 48% of eligible women were receiving it for secondary prevention.

People with diabetes

People with diabetes without overt cardiovascular disease are at higher risk of cardiovascular events than age- and sex-matched controls.³⁴ On the other hand, people with diabetes may be more prone to aspirin resistance and may not derive as much cardiovascular benefit from aspirin.

Early primary prevention studies included few people with diabetes. Subsequent meta-analyses of trials that used a wide range of aspirin doses found a relative risk reduction of 9%, which was not statistically significant.^9,35,36

But there is some evidence that people with diabetes, with³⁷ and without²² coronary disease, may be at higher inherent risk of bleeding than people without diabetes. Although aspirin may not necessarily increase the risk of bleeding in diabetic patients, recent data suggest no benefit in terms of a reduction in vascular events.³⁸

The balance of risk vs benefit for aspirin in this special population is not clear, although some argue that these patients should be treated somewhere on the spectrum of risk between primary and secondary prevention.

The US Preventive Services Task Force did not differentiate between people with or without diabetes in its 2009 guidelines for aspirin for primary prevention.⁸ However, the debate is reflected in a change in 2010 American College of Cardiology/American Diabetes Association guidelines regarding aspirin use in people with diabetes without known cardiovascular disease.³⁹ As opposed to earlier recommendations from these organizations in favor of aspirin for all people with diabetes regardless of 10-year risk, current recommendations advise low-dose aspirin (81–162 mg) for diabetic patients without known vascular disease who have a greater than 10% risk of a cardiovascular event and are not at increased risk of bleeding.

These changes were based on the findings of two trials: the Prevention and Progression of Arterial Disease and Diabetes Trial (POPADAD) and the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) study. These did not show a statistically significant benefit in prevention of cardiovascular events with aspirin.^29,30

After the new guidelines came out, a meta-analysis further bolstered its recommendations. ⁴⁰ In seven randomized clinical trials in 11,000 patients, the relative risk reduction was 9% with aspirin, which did not reach statistical significance.

 

 

Statins may dilute the benefit of aspirin

The use of statins has been increasing, and this trend may have played a role in the marginal benefit of aspirin therapy in these recent studies. In the Japanese trial, approximately 25% of the patients were known to be using a statin; the percentage of statin use was not reported specifically in POPADAD, but both of these studies were published in 2008, when the proportion of diabetic patients taking a statin would be expected to be higher than in earlier primary prevention trials, which were performed primarily in the 1990s. Thus, the beneficial effects of statins may have somewhat diluted the risk reduction attributable to aspirin.

Trials under way in patients with diabetes

The evolving and somewhat conflicting guidelines highlight the need for further study in patients with diabetes. To address this area, two trials are in progress: the Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D) and A Study of Cardiovascular Events in Diabetes (ASCEND).^41,42

ACCEPT-D is testing low-dose aspirin (100 mg daily) in diabetic patients who are also on simvastatin. This study also includes prespecified subgroups stratified by sex, age, and baseline lipid levels.

The ASCEND trial will use the same aspirin dose as ACCEPT-D, with a target enrollment of 10,000 patients with diabetes without known vascular disease.

More frequent dosing for people with diabetes?

Although not supported by current guidelines, recent work has suggested that people with diabetes may need more-frequent dosing of aspirin.⁴³ This topic warrants further investigation.

Aspirin as primary prevention in elderly patients

The incidence of cardiovascular events increases with age³⁷—but so does the incidence of gastrointestinal bleeding.⁴⁴ Upper gastrointestinal bleeding is especially worrisome in the elderly, in whom the estimated case-fatality rate is high.¹² Assessment of risk and benefit is particularly important in patients over age 65 without known coronary disease.

Uncertainty about aspirin use in this population is reflected in the most recent US Preventive Services Task Force guidelines, which do not advocate either for or against regular aspirin use for primary prevention in those over the age of 80.

Data on this topic from clinical trials are limited. The Antithrombotic Trialists’ Collaboration (2009) found that although age is associated with a risk of major coronary events similar to that of other traditional risk factors such as diabetes, hypertension, and tobacco use, older age is also associated with the highest risk of major extracranial bleeding.²²

Because of the lack of data in this population, several studies are currently under way. The Aspirin in Reducing Events in the Elderly (ASPREE) trial is studying 100 mg daily in nondiabetic patients without known cardiovascular disease who are age 70 and older.⁴⁵ An additional trial will study patients age 60 to 85 with concurrent diagnoses of hypertension, hyperlipidemia, or diabetes and will test the same aspirin dose as in ASPREE.⁴⁶ These trials should provide further insight into the safety and efficacy of aspirin for primary prevention in the elderly.

FUTURE DIRECTIONS

Aspirin remains a cornerstone of therapy in patients with cardiovascular disease and in secondary prevention of adverse cardiovascular events, but its role in primary prevention remains under scrutiny. Recommendations have evolved to reflect emerging data in special populations, and an algorithm based on Framingham risk assessment in men for myocardial infarction and ischemic stroke assessment in women for assessing appropriateness of aspirin therapy based on currently available guidelines is presented in Figure 1.^6,8,47–49 Targeted studies have advanced our understanding of aspirin use in women, and future studies in people with diabetes and in the elderly should provide further insight into the role of aspirin for primary prevention in these specific groups as well.

Additionally, the range of doses used in clinical studies has propagated the general misperception that higher doses of aspirin are more efficacious. Future studies should continue to use lower doses of aspirin to minimize bleeding risk with an added focus on re-examining its net benefit in the modern era of increasing statin use, which may reduce the absolute risk reduction attributable to aspirin.

One particular area of debate is whether enteric coating can result in functional aspirin resistance. Grosser et al⁵⁰ found that sustained aspirin resistance was rare, and “pseudoresistance” was related to the use of a single enteric-coated aspirin instead of immediate-release aspirin in people who had not been taking aspirin up to then. This complements an earlier study, which found that enteric-coated aspirin had an appropriate effect when given for 7 days.⁵¹ Therefore, for patients who have not been taking aspirin, the first dose should always be immediate-release, not enteric coated.

SHOULD OUR PATIENT RECEIVE ASPIRIN?

The patient we described at the beginning of this article has several risk factors—hypertension, dyslipidemia, left ventricular hypertrophy, and smoking—but no known cardiovascular disease as yet. Her risk of an adverse cardiovascular event appears moderate. However, her 10-year risk of stroke by the Framingham risk calculation is 10%, which would qualify her for aspirin for primary prevention. Of particular note is that the significance of left ventricular hypertrophy as a risk factor for stroke in women is higher than in men and in our case accounts for half of this patient’s risk.

We should explain to the patient that the anticipated benefits of aspirin for stroke prevention outweigh bleeding risks, and thus aspirin therapy would be recommended. However, with her elevated LDL-cholesterol, she may benefit from a statin, which could lessen the relative risk reduction from additional aspirin use.

A 57-year-old woman with no history of cardiovascular disease comes to the clinic for her annual evaluation. She does not have diabetes mellitus, but she does have hypertension and chronic osteoarthritis, currently treated with acetaminophen. Additionally, she admits to active tobacco use. Her systolic blood pressure is 130 mm Hg on therapy with hydrochlorothiazide. Her electrocardiogram demonstrates left ventricular hypertrophy. Her low-density lipoprotein (LDL) cholesterol level is 140 mg/dL, and her high-density lipoprotein (HDL) cholesterol level is 50 mg/dL. Should this patient be started on aspirin therapy?

Acetylsalicylic acid (aspirin) is an analgesic, antipyretic, and anti-inflammatory agent, but its more prominent use today is as an antithrombotic agent to treat or prevent cardiovascular events. Its antithrombotic properties are due to its effects on the enzyme cyclooxygenase. However, cyclooxygenase is also involved in regulation of the gastric mucosa, and so aspirin increases the risk of gastrointestinal bleeding.

Approximately 50 million people take aspirin on a daily basis to treat or prevent cardiovascular disease.¹ Of these, at least half are taking more than 100 mg per day,² reflecting the general belief that, for aspirin dosage, “more is better”—which is not true.

Additionally, recommendations about the use of aspirin were based on studies that included relatively few members of several important subgroups, such as people with diabetes without known cardiovascular disease, women, and the elderly, and thus may not reflect appropriate indications and dosages for these groups.

Here, we examine the literature, outline an individualized approach to aspirin therapy, and highlight areas for future study.

HISTORY OF ASPIRIN USE IN CARDIOVASCULAR DISEASE

• 1700s—Willow bark is used as an analgesic.
• 1897—Synthetic aspirin is developed as an antipyretic and anti-inflammatory agent.
• 1974—First landmark trial of aspirin for secondary prevention of myocardial infarction.³
• 1982—Nobel Prize awarded for discovery of aspirin mechanism.
• 1985—US Food and Drug Administration approves aspirin for the treatment and secondary prevention of acute myocardial infarction.
• 1998—The Second International Study of Infarct Survival (ISIS-2) finds that giving aspirin to patients with myocardial infarction within 24 hours of presentation leads to a significant reduction in vascular deaths.⁴

Ongoing uncertainties

Aspirin now carries a class I indication for all patients with suspected myocardial infarction. Since there are an estimated 600,000 new coronary events and 325,000 recurrent ischemic events per year in the United States,⁵ the need for aspirin will continue to remain great. It is also approved to prevent and treat stroke and in patients with unstable angina.

However, questions continue to emerge about aspirin’s dosing and appropriate use in specific populations. The initial prevention trials used a wide range of doses and, as mentioned, included few women, few people with diabetes, and few elderly people. The uncertainties are especially pertinent for patients without known vascular disease, in whom the absolute risk reduction is much less, making the assessment of bleeding risk particularly important. Furthermore, the absolute risk-to-benefit assessment may be different in certain populations.

Guidelines on the use of aspirin to prevent cardiovascular disease (Table 1)^6–10 have evolved to take into account these possible disparities, and studies are taking place to further investigate aspirin use in these groups.

ASPIRIN AND GASTROINTESTINAL BLEEDING

Aspirin’s association with bleeding, particularly gastrointestinal bleeding, was recognized early as a use-limiting side effect. With or without aspirin, gastrointestinal bleeding is a common cause of morbidity and death, with an incidence of approximately 100 per 100,000 bleeding episodes in adults per year for upper gastrointestinal bleeding and 20 to 30 per 100,000 per year for lower gastrointestinal bleeding.^11,12

The standard dosage (ie, 325 mg/day) is associated with a significantly higher risk of gastrointestinal bleeding (including fatal bleeds) than is 75 mg.¹³ However, even with lower doses, the risk of gastrointestinal bleeding is estimated to be twice as high as with no aspirin.¹⁴

And here is the irony: studies have shown that higher doses of aspirin offer no advantage in preventing thrombotic events compared with lower doses.¹⁵ For example, the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Organization to Assess Strategies for Ischemic Stroke Syndromes study reported a higher rate of gastrointestinal bleeding with standard-dose aspirin therapy than with low-dose aspirin, with no additional cardiovascular benefit with the higher dose.¹⁶

Furthermore, several other risk factors increase the risk of gastrointestinal bleeding with aspirin use (Table 2). These risk factors are common in the general population but were not necessarily represented in participants in clinical trials. Thus, estimates of risk based on trial data most likely underestimate actual risk in the general population, and therefore, the individual patient’s risk of gastrointestinal bleeding, based on these and other factors, needs to be taken into consideration.

ASPIRIN IN PATIENTS WITH CORONARY ARTERY DISEASE

Randomized clinical trials have validated the benefits of aspirin in secondary prevention of cardiovascular events in patients who have had a myocardial infarction. Patients with coronary disease who withdraw from aspirin therapy or otherwise do not adhere to it have a risk of cardiovascular events three times higher than those who stay with it.¹⁷

Despite the strong data, however, several issues and questions remain about the use of aspirin for secondary prevention.

Bleeding risk must be considered, since gastrointestinal bleeding is associated with a higher risk of death and myocardial infarction in patients with cardiovascular disease.¹⁸ Many patients with coronary disease are on more than one antiplatelet or anticoagulant therapy for concomitant conditions such as atrial fibrillation or because they underwent a percutaneous intervention, which further increases the risk of bleeding.

This bleeding risk is reflected in changes in the most recent recommendations for aspirin dosing after percutaneous coronary intervention. Earlier guidelines advocated use of either 162 or 325 mg after the procedure. However, the most recent update (in 2011) now supports 81 mg for maintenance dosing after intervention.⁷

Patients with coronary disease but without prior myocardial infarction or intervention. Current guidelines recommend 75 to 162 mg of aspirin in all patients with coronary artery disease.⁶ However, this group is diverse and includes patients who have undergone percutaneous coronary intervention, patients with chronic stable angina, and patients with asymptomatic coronary artery disease found on imaging studies. The magnitude of benefit is not clear for those who have no symptoms or who have stable angina.

Most of the evidence supporting aspirin use in chronic angina came from a single trial in Sweden, in which 2,000 patients with chronic stable angina were given either 75 mg daily or placebo. Those who received aspirin had a 34% lower rate of myocardial infarction and sudden death.¹⁹

A substudy of the Physicians’ Health Study, with fewer patients, also noted a significant reduction in the rate of first myocardial infarction. The dose of aspirin in this study was 325 mg every other day.²⁰

In the Women’s Health Initiative Observational Study, 70% of women with stable cardiovascular disease taking aspirin were taking 325 mg daily.²¹ This study demonstrated a significant reduction in the cardiovascular mortality rate, which supports current guidelines, and found no difference in outcomes with doses of 81 mg compared with 325 mg.²¹ This again corroborates that low-dose aspirin is preferential to standard-dose aspirin in women with cardiovascular disease.

These findings have not been validated in larger prospective trials. Thus, current guidelines for aspirin use may reflect extrapolation of aspirin benefit from higher-risk patients to lower-risk patients.

Nevertheless, although the debate continues, it has generally been accepted that in patients who are at high risk of vascular disease or who have had a myocardial infarction, the benefits of aspirin—a 20% relative reduction in vascular events²²—clearly outweigh the risks.

ASPIRIN FOR PRIMARY PREVENTION

Assessing risk vs benefit is more complex when considering populations without known cardiovascular disease.

Only a few studies have specifically evaluated the use of aspirin for primary prevention (Table 3).^23–31 The initial trials were in male physicians in the United Kingdom and the United States in the late 1980s and had somewhat conflicting results. A British study did not find a significant reduction in myocardial infarction,²³ but the US Physician’s Health Study study did: the relative risk was 0.56 (95% confidence interval 0.45–0.70, P < .00001).²⁴ The US study had more than four times the number of participants, used different dosing (325 mg every other day compared with 500 or 300 mg daily in the British study), and had a higher rate of compliance.

Several studies over the next decade demonstrated variable but significant reductions in cardiovascular events as well.^25–27

A meta-analysis of primary prevention trials of aspirin was published in 2009.²² Although the relative risk reduction was similar in primary and secondary prevention, the absolute risk reduction in primary prevention was not nearly as great as in secondary prevention.

These findings are somewhat difficult to interpret, as the component trials included a wide spectrum of patients, ranging from healthy people with no symptoms and no known risk factors to those with limited risk factors. The trials were also performed over several decades during which primary prevention strategies were evolving. Additionally, most of the participants were middle-aged, nondiabetic men, so the results may not necessarily apply to people with diabetes, to women, or to the elderly. Thus, the pooled data in favor of aspirin for primary prevention may not be as broadly applicable to the general population as was once thought.

Aspirin for primary prevention in women

Guidelines for aspirin use in primary prevention were initially thought to be equally applicable to both sexes. However, concerns about the relatively low number of women participating in the studies and the possible mechanistic differences in aspirin efficacy in men vs women prompted further study.

A meta-analysis of randomized controlled trials found that aspirin was associated with a 12% relative reduction in the incidence of cardiovascular events in women and 14% in men. On the other hand, for stroke, the relative risk reduction was 17% in women, while men had no benefit.³²

Most of the women in this meta-analysis were participants in the Women’s Health Study, and they were at low baseline risk.²⁸ Although only about 10% of patients in this study were over age 65, this older group accounted for most of the benefit: these older women had a 26% risk reduction in major adverse cardiovascular events and 30% reduction in stroke.

Thus, for women, aspirin seems to become effective for primary prevention at an older age than in men, and the guidelines have been changed accordingly (Figure 1).

More women should be taking aspirin than actually are. For example, Rivera et al³³ found that only 41% of eligible women were receiving aspirin for primary prevention and 48% of eligible women were receiving it for secondary prevention.

People with diabetes

People with diabetes without overt cardiovascular disease are at higher risk of cardiovascular events than age- and sex-matched controls.³⁴ On the other hand, people with diabetes may be more prone to aspirin resistance and may not derive as much cardiovascular benefit from aspirin.

Early primary prevention studies included few people with diabetes. Subsequent meta-analyses of trials that used a wide range of aspirin doses found a relative risk reduction of 9%, which was not statistically significant.^9,35,36

But there is some evidence that people with diabetes, with³⁷ and without²² coronary disease, may be at higher inherent risk of bleeding than people without diabetes. Although aspirin may not necessarily increase the risk of bleeding in diabetic patients, recent data suggest no benefit in terms of a reduction in vascular events.³⁸

The balance of risk vs benefit for aspirin in this special population is not clear, although some argue that these patients should be treated somewhere on the spectrum of risk between primary and secondary prevention.

The US Preventive Services Task Force did not differentiate between people with or without diabetes in its 2009 guidelines for aspirin for primary prevention.⁸ However, the debate is reflected in a change in 2010 American College of Cardiology/American Diabetes Association guidelines regarding aspirin use in people with diabetes without known cardiovascular disease.³⁹ As opposed to earlier recommendations from these organizations in favor of aspirin for all people with diabetes regardless of 10-year risk, current recommendations advise low-dose aspirin (81–162 mg) for diabetic patients without known vascular disease who have a greater than 10% risk of a cardiovascular event and are not at increased risk of bleeding.

These changes were based on the findings of two trials: the Prevention and Progression of Arterial Disease and Diabetes Trial (POPADAD) and the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) study. These did not show a statistically significant benefit in prevention of cardiovascular events with aspirin.^29,30

After the new guidelines came out, a meta-analysis further bolstered its recommendations. ⁴⁰ In seven randomized clinical trials in 11,000 patients, the relative risk reduction was 9% with aspirin, which did not reach statistical significance.

 

 

Statins may dilute the benefit of aspirin

The use of statins has been increasing, and this trend may have played a role in the marginal benefit of aspirin therapy in these recent studies. In the Japanese trial, approximately 25% of the patients were known to be using a statin; the percentage of statin use was not reported specifically in POPADAD, but both of these studies were published in 2008, when the proportion of diabetic patients taking a statin would be expected to be higher than in earlier primary prevention trials, which were performed primarily in the 1990s. Thus, the beneficial effects of statins may have somewhat diluted the risk reduction attributable to aspirin.

Trials under way in patients with diabetes

The evolving and somewhat conflicting guidelines highlight the need for further study in patients with diabetes. To address this area, two trials are in progress: the Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D) and A Study of Cardiovascular Events in Diabetes (ASCEND).^41,42

ACCEPT-D is testing low-dose aspirin (100 mg daily) in diabetic patients who are also on simvastatin. This study also includes prespecified subgroups stratified by sex, age, and baseline lipid levels.

The ASCEND trial will use the same aspirin dose as ACCEPT-D, with a target enrollment of 10,000 patients with diabetes without known vascular disease.

More frequent dosing for people with diabetes?

Although not supported by current guidelines, recent work has suggested that people with diabetes may need more-frequent dosing of aspirin.⁴³ This topic warrants further investigation.

Aspirin as primary prevention in elderly patients

The incidence of cardiovascular events increases with age³⁷—but so does the incidence of gastrointestinal bleeding.⁴⁴ Upper gastrointestinal bleeding is especially worrisome in the elderly, in whom the estimated case-fatality rate is high.¹² Assessment of risk and benefit is particularly important in patients over age 65 without known coronary disease.

Uncertainty about aspirin use in this population is reflected in the most recent US Preventive Services Task Force guidelines, which do not advocate either for or against regular aspirin use for primary prevention in those over the age of 80.

Data on this topic from clinical trials are limited. The Antithrombotic Trialists’ Collaboration (2009) found that although age is associated with a risk of major coronary events similar to that of other traditional risk factors such as diabetes, hypertension, and tobacco use, older age is also associated with the highest risk of major extracranial bleeding.²²

Because of the lack of data in this population, several studies are currently under way. The Aspirin in Reducing Events in the Elderly (ASPREE) trial is studying 100 mg daily in nondiabetic patients without known cardiovascular disease who are age 70 and older.⁴⁵ An additional trial will study patients age 60 to 85 with concurrent diagnoses of hypertension, hyperlipidemia, or diabetes and will test the same aspirin dose as in ASPREE.⁴⁶ These trials should provide further insight into the safety and efficacy of aspirin for primary prevention in the elderly.

FUTURE DIRECTIONS

Aspirin remains a cornerstone of therapy in patients with cardiovascular disease and in secondary prevention of adverse cardiovascular events, but its role in primary prevention remains under scrutiny. Recommendations have evolved to reflect emerging data in special populations, and an algorithm based on Framingham risk assessment in men for myocardial infarction and ischemic stroke assessment in women for assessing appropriateness of aspirin therapy based on currently available guidelines is presented in Figure 1.^6,8,47–49 Targeted studies have advanced our understanding of aspirin use in women, and future studies in people with diabetes and in the elderly should provide further insight into the role of aspirin for primary prevention in these specific groups as well.

Additionally, the range of doses used in clinical studies has propagated the general misperception that higher doses of aspirin are more efficacious. Future studies should continue to use lower doses of aspirin to minimize bleeding risk with an added focus on re-examining its net benefit in the modern era of increasing statin use, which may reduce the absolute risk reduction attributable to aspirin.

One particular area of debate is whether enteric coating can result in functional aspirin resistance. Grosser et al⁵⁰ found that sustained aspirin resistance was rare, and “pseudoresistance” was related to the use of a single enteric-coated aspirin instead of immediate-release aspirin in people who had not been taking aspirin up to then. This complements an earlier study, which found that enteric-coated aspirin had an appropriate effect when given for 7 days.⁵¹ Therefore, for patients who have not been taking aspirin, the first dose should always be immediate-release, not enteric coated.

SHOULD OUR PATIENT RECEIVE ASPIRIN?

The patient we described at the beginning of this article has several risk factors—hypertension, dyslipidemia, left ventricular hypertrophy, and smoking—but no known cardiovascular disease as yet. Her risk of an adverse cardiovascular event appears moderate. However, her 10-year risk of stroke by the Framingham risk calculation is 10%, which would qualify her for aspirin for primary prevention. Of particular note is that the significance of left ventricular hypertrophy as a risk factor for stroke in women is higher than in men and in our case accounts for half of this patient’s risk.

We should explain to the patient that the anticipated benefits of aspirin for stroke prevention outweigh bleeding risks, and thus aspirin therapy would be recommended. However, with her elevated LDL-cholesterol, she may benefit from a statin, which could lessen the relative risk reduction from additional aspirin use.

A 57-year-old woman with no history of cardiovascular disease comes to the clinic for her annual evaluation. She does not have diabetes mellitus, but she does have hypertension and chronic osteoarthritis, currently treated with acetaminophen. Additionally, she admits to active tobacco use. Her systolic blood pressure is 130 mm Hg on therapy with hydrochlorothiazide. Her electrocardiogram demonstrates left ventricular hypertrophy. Her low-density lipoprotein (LDL) cholesterol level is 140 mg/dL, and her high-density lipoprotein (HDL) cholesterol level is 50 mg/dL. Should this patient be started on aspirin therapy?

Acetylsalicylic acid (aspirin) is an analgesic, antipyretic, and anti-inflammatory agent, but its more prominent use today is as an antithrombotic agent to treat or prevent cardiovascular events. Its antithrombotic properties are due to its effects on the enzyme cyclooxygenase. However, cyclooxygenase is also involved in regulation of the gastric mucosa, and so aspirin increases the risk of gastrointestinal bleeding.

Approximately 50 million people take aspirin on a daily basis to treat or prevent cardiovascular disease.¹ Of these, at least half are taking more than 100 mg per day,² reflecting the general belief that, for aspirin dosage, “more is better”—which is not true.

Additionally, recommendations about the use of aspirin were based on studies that included relatively few members of several important subgroups, such as people with diabetes without known cardiovascular disease, women, and the elderly, and thus may not reflect appropriate indications and dosages for these groups.

Here, we examine the literature, outline an individualized approach to aspirin therapy, and highlight areas for future study.

HISTORY OF ASPIRIN USE IN CARDIOVASCULAR DISEASE

• 1700s—Willow bark is used as an analgesic.
• 1897—Synthetic aspirin is developed as an antipyretic and anti-inflammatory agent.
• 1974—First landmark trial of aspirin for secondary prevention of myocardial infarction.³
• 1982—Nobel Prize awarded for discovery of aspirin mechanism.
• 1985—US Food and Drug Administration approves aspirin for the treatment and secondary prevention of acute myocardial infarction.
• 1998—The Second International Study of Infarct Survival (ISIS-2) finds that giving aspirin to patients with myocardial infarction within 24 hours of presentation leads to a significant reduction in vascular deaths.⁴

Ongoing uncertainties

Aspirin now carries a class I indication for all patients with suspected myocardial infarction. Since there are an estimated 600,000 new coronary events and 325,000 recurrent ischemic events per year in the United States,⁵ the need for aspirin will continue to remain great. It is also approved to prevent and treat stroke and in patients with unstable angina.

However, questions continue to emerge about aspirin’s dosing and appropriate use in specific populations. The initial prevention trials used a wide range of doses and, as mentioned, included few women, few people with diabetes, and few elderly people. The uncertainties are especially pertinent for patients without known vascular disease, in whom the absolute risk reduction is much less, making the assessment of bleeding risk particularly important. Furthermore, the absolute risk-to-benefit assessment may be different in certain populations.

Guidelines on the use of aspirin to prevent cardiovascular disease (Table 1)^6–10 have evolved to take into account these possible disparities, and studies are taking place to further investigate aspirin use in these groups.

ASPIRIN AND GASTROINTESTINAL BLEEDING

Aspirin’s association with bleeding, particularly gastrointestinal bleeding, was recognized early as a use-limiting side effect. With or without aspirin, gastrointestinal bleeding is a common cause of morbidity and death, with an incidence of approximately 100 per 100,000 bleeding episodes in adults per year for upper gastrointestinal bleeding and 20 to 30 per 100,000 per year for lower gastrointestinal bleeding.^11,12

The standard dosage (ie, 325 mg/day) is associated with a significantly higher risk of gastrointestinal bleeding (including fatal bleeds) than is 75 mg.¹³ However, even with lower doses, the risk of gastrointestinal bleeding is estimated to be twice as high as with no aspirin.¹⁴

And here is the irony: studies have shown that higher doses of aspirin offer no advantage in preventing thrombotic events compared with lower doses.¹⁵ For example, the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Organization to Assess Strategies for Ischemic Stroke Syndromes study reported a higher rate of gastrointestinal bleeding with standard-dose aspirin therapy than with low-dose aspirin, with no additional cardiovascular benefit with the higher dose.¹⁶

Furthermore, several other risk factors increase the risk of gastrointestinal bleeding with aspirin use (Table 2). These risk factors are common in the general population but were not necessarily represented in participants in clinical trials. Thus, estimates of risk based on trial data most likely underestimate actual risk in the general population, and therefore, the individual patient’s risk of gastrointestinal bleeding, based on these and other factors, needs to be taken into consideration.

ASPIRIN IN PATIENTS WITH CORONARY ARTERY DISEASE

Randomized clinical trials have validated the benefits of aspirin in secondary prevention of cardiovascular events in patients who have had a myocardial infarction. Patients with coronary disease who withdraw from aspirin therapy or otherwise do not adhere to it have a risk of cardiovascular events three times higher than those who stay with it.¹⁷

Despite the strong data, however, several issues and questions remain about the use of aspirin for secondary prevention.

Bleeding risk must be considered, since gastrointestinal bleeding is associated with a higher risk of death and myocardial infarction in patients with cardiovascular disease.¹⁸ Many patients with coronary disease are on more than one antiplatelet or anticoagulant therapy for concomitant conditions such as atrial fibrillation or because they underwent a percutaneous intervention, which further increases the risk of bleeding.

This bleeding risk is reflected in changes in the most recent recommendations for aspirin dosing after percutaneous coronary intervention. Earlier guidelines advocated use of either 162 or 325 mg after the procedure. However, the most recent update (in 2011) now supports 81 mg for maintenance dosing after intervention.⁷

Patients with coronary disease but without prior myocardial infarction or intervention. Current guidelines recommend 75 to 162 mg of aspirin in all patients with coronary artery disease.⁶ However, this group is diverse and includes patients who have undergone percutaneous coronary intervention, patients with chronic stable angina, and patients with asymptomatic coronary artery disease found on imaging studies. The magnitude of benefit is not clear for those who have no symptoms or who have stable angina.

Most of the evidence supporting aspirin use in chronic angina came from a single trial in Sweden, in which 2,000 patients with chronic stable angina were given either 75 mg daily or placebo. Those who received aspirin had a 34% lower rate of myocardial infarction and sudden death.¹⁹

A substudy of the Physicians’ Health Study, with fewer patients, also noted a significant reduction in the rate of first myocardial infarction. The dose of aspirin in this study was 325 mg every other day.²⁰

In the Women’s Health Initiative Observational Study, 70% of women with stable cardiovascular disease taking aspirin were taking 325 mg daily.²¹ This study demonstrated a significant reduction in the cardiovascular mortality rate, which supports current guidelines, and found no difference in outcomes with doses of 81 mg compared with 325 mg.²¹ This again corroborates that low-dose aspirin is preferential to standard-dose aspirin in women with cardiovascular disease.

These findings have not been validated in larger prospective trials. Thus, current guidelines for aspirin use may reflect extrapolation of aspirin benefit from higher-risk patients to lower-risk patients.

Nevertheless, although the debate continues, it has generally been accepted that in patients who are at high risk of vascular disease or who have had a myocardial infarction, the benefits of aspirin—a 20% relative reduction in vascular events²²—clearly outweigh the risks.

ASPIRIN FOR PRIMARY PREVENTION

Assessing risk vs benefit is more complex when considering populations without known cardiovascular disease.

Only a few studies have specifically evaluated the use of aspirin for primary prevention (Table 3).^23–31 The initial trials were in male physicians in the United Kingdom and the United States in the late 1980s and had somewhat conflicting results. A British study did not find a significant reduction in myocardial infarction,²³ but the US Physician’s Health Study study did: the relative risk was 0.56 (95% confidence interval 0.45–0.70, P < .00001).²⁴ The US study had more than four times the number of participants, used different dosing (325 mg every other day compared with 500 or 300 mg daily in the British study), and had a higher rate of compliance.

Several studies over the next decade demonstrated variable but significant reductions in cardiovascular events as well.^25–27

A meta-analysis of primary prevention trials of aspirin was published in 2009.²² Although the relative risk reduction was similar in primary and secondary prevention, the absolute risk reduction in primary prevention was not nearly as great as in secondary prevention.

These findings are somewhat difficult to interpret, as the component trials included a wide spectrum of patients, ranging from healthy people with no symptoms and no known risk factors to those with limited risk factors. The trials were also performed over several decades during which primary prevention strategies were evolving. Additionally, most of the participants were middle-aged, nondiabetic men, so the results may not necessarily apply to people with diabetes, to women, or to the elderly. Thus, the pooled data in favor of aspirin for primary prevention may not be as broadly applicable to the general population as was once thought.

Aspirin for primary prevention in women

Guidelines for aspirin use in primary prevention were initially thought to be equally applicable to both sexes. However, concerns about the relatively low number of women participating in the studies and the possible mechanistic differences in aspirin efficacy in men vs women prompted further study.

A meta-analysis of randomized controlled trials found that aspirin was associated with a 12% relative reduction in the incidence of cardiovascular events in women and 14% in men. On the other hand, for stroke, the relative risk reduction was 17% in women, while men had no benefit.³²

Most of the women in this meta-analysis were participants in the Women’s Health Study, and they were at low baseline risk.²⁸ Although only about 10% of patients in this study were over age 65, this older group accounted for most of the benefit: these older women had a 26% risk reduction in major adverse cardiovascular events and 30% reduction in stroke.

Thus, for women, aspirin seems to become effective for primary prevention at an older age than in men, and the guidelines have been changed accordingly (Figure 1).

More women should be taking aspirin than actually are. For example, Rivera et al³³ found that only 41% of eligible women were receiving aspirin for primary prevention and 48% of eligible women were receiving it for secondary prevention.

People with diabetes

People with diabetes without overt cardiovascular disease are at higher risk of cardiovascular events than age- and sex-matched controls.³⁴ On the other hand, people with diabetes may be more prone to aspirin resistance and may not derive as much cardiovascular benefit from aspirin.

Early primary prevention studies included few people with diabetes. Subsequent meta-analyses of trials that used a wide range of aspirin doses found a relative risk reduction of 9%, which was not statistically significant.^9,35,36

But there is some evidence that people with diabetes, with³⁷ and without²² coronary disease, may be at higher inherent risk of bleeding than people without diabetes. Although aspirin may not necessarily increase the risk of bleeding in diabetic patients, recent data suggest no benefit in terms of a reduction in vascular events.³⁸

The balance of risk vs benefit for aspirin in this special population is not clear, although some argue that these patients should be treated somewhere on the spectrum of risk between primary and secondary prevention.

The US Preventive Services Task Force did not differentiate between people with or without diabetes in its 2009 guidelines for aspirin for primary prevention.⁸ However, the debate is reflected in a change in 2010 American College of Cardiology/American Diabetes Association guidelines regarding aspirin use in people with diabetes without known cardiovascular disease.³⁹ As opposed to earlier recommendations from these organizations in favor of aspirin for all people with diabetes regardless of 10-year risk, current recommendations advise low-dose aspirin (81–162 mg) for diabetic patients without known vascular disease who have a greater than 10% risk of a cardiovascular event and are not at increased risk of bleeding.

These changes were based on the findings of two trials: the Prevention and Progression of Arterial Disease and Diabetes Trial (POPADAD) and the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) study. These did not show a statistically significant benefit in prevention of cardiovascular events with aspirin.^29,30

After the new guidelines came out, a meta-analysis further bolstered its recommendations. ⁴⁰ In seven randomized clinical trials in 11,000 patients, the relative risk reduction was 9% with aspirin, which did not reach statistical significance.

 

 

Statins may dilute the benefit of aspirin

The use of statins has been increasing, and this trend may have played a role in the marginal benefit of aspirin therapy in these recent studies. In the Japanese trial, approximately 25% of the patients were known to be using a statin; the percentage of statin use was not reported specifically in POPADAD, but both of these studies were published in 2008, when the proportion of diabetic patients taking a statin would be expected to be higher than in earlier primary prevention trials, which were performed primarily in the 1990s. Thus, the beneficial effects of statins may have somewhat diluted the risk reduction attributable to aspirin.

Trials under way in patients with diabetes

The evolving and somewhat conflicting guidelines highlight the need for further study in patients with diabetes. To address this area, two trials are in progress: the Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D) and A Study of Cardiovascular Events in Diabetes (ASCEND).^41,42

ACCEPT-D is testing low-dose aspirin (100 mg daily) in diabetic patients who are also on simvastatin. This study also includes prespecified subgroups stratified by sex, age, and baseline lipid levels.

The ASCEND trial will use the same aspirin dose as ACCEPT-D, with a target enrollment of 10,000 patients with diabetes without known vascular disease.

More frequent dosing for people with diabetes?

Although not supported by current guidelines, recent work has suggested that people with diabetes may need more-frequent dosing of aspirin.⁴³ This topic warrants further investigation.

Aspirin as primary prevention in elderly patients

The incidence of cardiovascular events increases with age³⁷—but so does the incidence of gastrointestinal bleeding.⁴⁴ Upper gastrointestinal bleeding is especially worrisome in the elderly, in whom the estimated case-fatality rate is high.¹² Assessment of risk and benefit is particularly important in patients over age 65 without known coronary disease.

Uncertainty about aspirin use in this population is reflected in the most recent US Preventive Services Task Force guidelines, which do not advocate either for or against regular aspirin use for primary prevention in those over the age of 80.

Data on this topic from clinical trials are limited. The Antithrombotic Trialists’ Collaboration (2009) found that although age is associated with a risk of major coronary events similar to that of other traditional risk factors such as diabetes, hypertension, and tobacco use, older age is also associated with the highest risk of major extracranial bleeding.²²

Because of the lack of data in this population, several studies are currently under way. The Aspirin in Reducing Events in the Elderly (ASPREE) trial is studying 100 mg daily in nondiabetic patients without known cardiovascular disease who are age 70 and older.⁴⁵ An additional trial will study patients age 60 to 85 with concurrent diagnoses of hypertension, hyperlipidemia, or diabetes and will test the same aspirin dose as in ASPREE.⁴⁶ These trials should provide further insight into the safety and efficacy of aspirin for primary prevention in the elderly.

FUTURE DIRECTIONS

Aspirin remains a cornerstone of therapy in patients with cardiovascular disease and in secondary prevention of adverse cardiovascular events, but its role in primary prevention remains under scrutiny. Recommendations have evolved to reflect emerging data in special populations, and an algorithm based on Framingham risk assessment in men for myocardial infarction and ischemic stroke assessment in women for assessing appropriateness of aspirin therapy based on currently available guidelines is presented in Figure 1.^6,8,47–49 Targeted studies have advanced our understanding of aspirin use in women, and future studies in people with diabetes and in the elderly should provide further insight into the role of aspirin for primary prevention in these specific groups as well.

Additionally, the range of doses used in clinical studies has propagated the general misperception that higher doses of aspirin are more efficacious. Future studies should continue to use lower doses of aspirin to minimize bleeding risk with an added focus on re-examining its net benefit in the modern era of increasing statin use, which may reduce the absolute risk reduction attributable to aspirin.

One particular area of debate is whether enteric coating can result in functional aspirin resistance. Grosser et al⁵⁰ found that sustained aspirin resistance was rare, and “pseudoresistance” was related to the use of a single enteric-coated aspirin instead of immediate-release aspirin in people who had not been taking aspirin up to then. This complements an earlier study, which found that enteric-coated aspirin had an appropriate effect when given for 7 days.⁵¹ Therefore, for patients who have not been taking aspirin, the first dose should always be immediate-release, not enteric coated.

SHOULD OUR PATIENT RECEIVE ASPIRIN?

The patient we described at the beginning of this article has several risk factors—hypertension, dyslipidemia, left ventricular hypertrophy, and smoking—but no known cardiovascular disease as yet. Her risk of an adverse cardiovascular event appears moderate. However, her 10-year risk of stroke by the Framingham risk calculation is 10%, which would qualify her for aspirin for primary prevention. Of particular note is that the significance of left ventricular hypertrophy as a risk factor for stroke in women is higher than in men and in our case accounts for half of this patient’s risk.

We should explain to the patient that the anticipated benefits of aspirin for stroke prevention outweigh bleeding risks, and thus aspirin therapy would be recommended. However, with her elevated LDL-cholesterol, she may benefit from a statin, which could lessen the relative risk reduction from additional aspirin use.

In the last few decades, the survival rates have improved in many of the malignancies that affect young adults. This progress has made fertility preservation and quality of life after cancer treatment important, most of all in survivors of childhood cancers.

Men who are about to undergo cancer treatment can bank their sperm, but as yet no analogous noninvasive option is available for women. The most studied methods are often invasive and require the woman to take large doses of hormones. They may also necessitate a delay in starting cancer treatment.

Which method of fertility preservation a woman should choose depends on several factors, including the type of disease, the treatment required, the age of the patient, whether she has a long-term partner, and whether treatment can be delayed.

Chemotherapy and radiotherapy have well-known deleterious effects on female reproductive function. Many studies have shown that acute loss of growing follicles within the ovary and resultant premature ovarian failure often follow chemotherapy. This ovarian damage has long-term consequences, such as shortened reproductive life span and hormone deficiency.¹

Fertility preservation requires a team effort. It should be managed by an oncology center that has built a close collaboration between oncologists, fertility specialists, psychologists, and primary care physicians to allow early discussion and to offer a full range of options to these patients.

The aim of this paper is to discuss the current options for preserving fertility in female cancer patients who have to undergo gonadotoxic cancer treatment.

FEMALE FERTILITY AND ASSESSMENT OF OVARIAN RESERVE

At birth, baby girls have about 1 million primordial ovarian follicles, which is the most they will ever have. By the time they reach menarche, this number has declined to 180,000, and at menopause only about 1,000 remain.²

Throughout a woman’s reproductive life, the number of oocytes remaining—both primordial follicles and the relatively small number of maturing, growing follicles—is called her ovarian reserve. When cancer is diagnosed, we need to assess the patient’s ovarian reserve to direct the discussion about the need for fertility preservation.

In search of markers of ovarian reserve

Fertility experts have been looking for clinical biomarkers that could give us an estimate of the number of nongrowing follicles and, consequently, of the ovarian reserve.

All methods used for the assessment of ovarian reserve actually provide an indirect determination of the remaining pool of oocytes. In clinical practice, a high blood level of follicle-stimulating hormone (FSH) on cycle day 3 (>15 mU/mL) or a low level of anti-Müllerian hormone (AMH) (<1 ng/mL) is generally associated with a low ovarian reserve.

The serum FSH level is the marker most commonly used, but it varies widely at different times in the menstrual cycle.

The FSH test is usually performed on day 3 of the menstrual cycle, when the estrogen level is expected to be low due to negative feedback. The FSH result needs to be combined with the estradiol level, especially in those patients with irregular menstruation or in cases of amenorrhea. A random FSH test is considered valid if the detected estrogen level is low. Women undergoing in vitro fertilization with a day 3 FSH lower than 15 mIU/mL are more likely to conceive than women with a higher FSH level.

AMH and antral follicles. Recently, two other variables have been introduced in clinical practice: the AMH concentration and the antral follicle count (the number of small antral follicles within the ovary) as assessed by transvaginal ultrasonography.

AMH is released by the granulosa cells of small, growing follicles. Because its level is much more stable over the menstrual cycle than the FSH level, it can be measured on any day of the cycle.³ In cancer survivors, AMH is particularly useful in demonstrating the degree of ovarian tissue damage induced by radiotherapy and chemotherapy and in evaluating the ovarian reserve.⁴

A reduced number of antral follicles causes a diminished AMH production, which becomes undetectable with menopause. The AMH level is strongly associated with the basal antral follicle count. Various threshold values (0.2–1.26 ng/mL) have been used to identify women with low ovarian reserve.

HOW CANCER TREATMENT DAMAGES THE OVARIES

Advances in surgery, radiotherapy, and chemotherapy have significantly improved the prognosis for young cancer patients. However, cancer treatments often result in ovarian dysfunction, and premature menopause and irreversible sterility are the most dramatic outcomes. The resulting low estrogen levels, in addition to their physiologic consequences, also worsen quality of life through psychological effects, which can as well influence the patient’s compliance with treatment.

Chemotherapy: Alkylating agents are the most gonadotoxic

The mechanism by which chemotherapy affects ovarian function is poorly understood. Histologically, chemotherapeutic drugs could lead to ovarian atrophy and stromal fibrosis, to depletion of the primordial follicle stockpile, and to reduced ovarian weight, resulting in ovarian dysfunction.⁵

The patient's age correlates with the probability of ovarian damage or, inversely, ovarian resistance to chemotherapy. Young women have more primordial oocytes, and after chemotherapy they face a sharp reduction of their ovarian reserve. Still, younger patients show a lower rate of ovarian toxicity than older women.⁶

The type and the cumulative dose of cytotoxic agents used are other important variables.⁷ There are six main classes of chemotherapeutic drugs: alkylating agents, platinum derivatives, antibiotics, antimetabolites, plant alkaloids, and taxanes. They all affect ovarian function, but alkylating agents are the most gonadotoxic.

Alkylating agents covalently bind an alkyl group to the DNA molecule and inhibit it from replicating. In the ovaries they directly injure primordial oocytes and deplete follicles. ⁸ They also seriously damage the ovarian vasculature so that the follicles cannot grow.⁹ Their destructive effect on the primordial follicles is dose-dependent and varies with the age and developmental maturity of the patient at the time of the therapy, with older women more likely to be left infertile afterward.¹⁰

Cyclophosphamide is an alkylating agent often used to treat severe manifestations of autoimmune diseases such as systemic lupus erythematosus, BehÇet disease, steroid-resistant glomerulonephritis, inflammatory bowel disease, pemphigus vulgaris, and others. Because it can lead to premature ovarian failure and infertility, women receiving cyclophosphamide for autoimmune conditions may also need treatment to preserve fertility.¹¹

Radiotherapy

Ovarian follicles are remarkably vulnerable to damage from ionizing radiation, which results in ovarian atrophy and reduced follicle stores.¹

The risk of radiotherapy-induced infertility is closely related to the patient’s age and developmental maturity at the time of therapy and to dose fractionation and the extent of the irradiation field. Every patient has a different sensitivity to radiation damage that is probably genetically predetermined, but age seems to be the most important variable. Wo and Viswanathan¹² used a mathematical model devised by Wallace et al¹³ to show that the older the patient, the lower the radiation dose necessary to impair ovarian function.

The irradiation field is another aspect to consider. Pelvic radiation can be necessary in rectal cancer, cervical cancer, and lymphoma. In these cases, surgically moving the ovaries to a region outside the radiation field could be an option to minimize radiotherapy-induced ovarian damage.¹⁴

Radiotherapy can also damage the uterus. Pelvic irradiation can reduce uterine volume, alter uterine elasticity through myometrial fibrosis, and modify vascularization and endometrial thickness.^15,16 These alterations are closely correlated with the total radiation dose, the site of irradiation, and the patient’s age at the time of the treatment, the prepubertal uterus being more susceptible to damage. ^15,17 Larsen et al¹⁵ found that girls who received uterine irradiation before puberty had lower uterine volumes in adulthood than girls who received chemotherapy alone or radiation to other parts of the body, and that the younger the patient at the time of radiotherapy, the smaller the uterus later. These effects could result in adverse pregnancy outcomes.

Furthermore, radiation could also damage the uterine vasculature. Holm et al¹⁶ used ultrasonography to evaluate the effect of total-body irradiation and found that uterine volume and uterine blood flow were both impaired.¹⁵

All these possible alterations could lead to a reduced uterine response to cytotrophoblast invasion and to decreased fetoplacental blood flow, which could impair embryonic and fetal growth. In that case, a surrogate pregnancy would be the only method to achieve parenthood using the couple’s gametes.

OPTIONS FOR FERTILITY PRESERVATION

Assisted reproductive technology

Young women diagnosed with an oncologic disease may wish to use assisted reproductive technology (Table 1) to keep open the possibility of having children at a later date. One approach is to harvest oocytes, fertilize them in vitro, and deep-freeze (cryopreserve) the resulting embryos to be thawed and implanted later. Alternatively, oocytes can be frozen directly, although success rates are lower with this method. And another approach is to obtain and cryopreserve ovarian tissue. If none of these is possible, oocytes may be obtained from a donor.

Controlled ovarian stimulation

If oocytes are to be harvested, a number of them should be harvested at one time.

There is not an optimal number of oocytes that should be retrieved, but cryopreservation of a large number of oocytes allows us to perform multiple attempts at in vitro fertilization, improving the chances of pregnancy. The fertilization rate (defined as the total number of zygotes at the 2-pronucleus stage divided by the number of fertilized oocytes) with intracytoplasmic sperm injection is 70% to 80%. On average, for every 10 eggs, 7 to 8 eggs will normally be fertilized. The implantation rate (defined as the total number of pregnancies divided by the total number of embryo transferred) with intracytoplasmic sperm injection is 40% to 50%—ie, only half of the transferred embryos will successfully implant and result in a pregnancy.

So that more than one ripe egg can be obtained at a time, the patient must undergo a regimen of controlled ovarian stimulation to achieve multifollicular growth. Stimulation protocols are based on giving pituitary hormones, ie, analogues of gonadotropin-releasing hormone (GnRH) (both agonists and antagonists), followed by recombinant FSH or human menopausal gonadotropin to promote follicular development. A single dose of human chorionic gonadotropin (hCG) is given to induce ovulation when the lead follicles have reached 18 to 20 mm in size.¹⁸

Many oncologists consider controlled ovarian stimulation dangerous for cancer patients because it takes time and thus delays cancer treatment. Furthermore, the regimen boosts the levels of circulating estrogens, which could be harmful in patients with hormone-dependent tumors.¹⁹

Oocytes can also be retrieved during unstimulated cycles. This avoids increasing estrogen concentrations above the physiologic level, but no more than a single oocyte is collected per cycle. The patient could undergo multiple oocyte harvestings, one per cycle, but this would delay her cancer treatment even more—by months—which is not recommended.

Serious efforts to minimize estrogen production during controlled ovarian stimulation have been made, although further studies are needed. Research is under way to develop appropriate ovarian stimulation protocols based on drugs with antiestrogenic effects.

Tamoxifen, an antagonist of the estrogen receptor, is widely used in breast cancer treatment. ²⁰ It can also be given during controlled ovarian stimulation because it promotes follicular growth and induces ovulation.²¹ Oktay et al²² found that the embryo yield was 2.5 times higher in women with breast cancer treated with tamoxifen than in a retrospective control group consisting of breast cancer patients attempting natural-cycle oocyte retrieval.

Letrozole, an aromatase inhibitor, is also commonly used in treating breast and ovarian cancer. Aromatase is an enzyme that catalyzes the conversion of androgenic precursors to estrogens, and it is found in many tissues, including granulosa cells. Several studies report the use of letrozole, alone or in combination with low doses of recombinant FSH, in ovarian stimulation protocols in cancer patients, with positive clinical outcomes.²³

Tamoxifen or letrozole, combined with recombinant FSH, is an attractive option in a controlled ovarian stimulation protocol for cancer patients,²⁴ although further investigation is needed.

 

 

Cryopreservation methods

Two main protocols are currently used to freeze oocytes, embryos, and ovarian tissue: slow freezing and vitrification.

In the slow-freezing method, cryoprotectant agents are used to draw water out of the cells, raising intracellular viscosity without (or with minimal) intracellular ice crystal formation, while the sample is cooled slowly in a controlled manner. These cryoprotectant chemicals lower the freezing point of the solution, allowing greater cellular dehydration during the slow freezing. They also protect the plasmatic cell membrane by changing its physical state from liquid to partially dry. To avoid excessive deformation that could damage the cytoplasmic structures, cryoprotectant agents are added in successive stages.²⁵

Vitrification is a newer method that uses higher concentrations of cryoprotectants and flash freezing. The instant drop in temperature converts this highly concentrated solution from an aqueous state to a semisolid, amorphous state that does not contain ice crystals, which are the main cause of damage during the freezing process.²⁶ Since most cryoprotectant agents are extremely toxic, it is necessary to minimize the time that oocytes, embryos, and ovarian tissue are exposed to them.

Cryopreservation of embryos

According to the American Society of Clinical Oncology and the American Society of Reproductive Medicine, embryo freezing is the most established method for fertility preservation, with tangible and widely reported success.²⁷ In normal practice, oocytes are retrieved after a controlled ovarian stimulation and then fertilized in vitro. Then they are treated with cryoprotectant agents, frozen, and stored. Upon demand, embryos can be thawed and implanted.

The Society for Assisted Reproductive Technology reports that the current live birth rate per transfer using thawed embryos from nondonor oocytes in US women under age 35 is 38.7%; at age 35 to 37 it is 35.1%.²⁸ In women with cancer, storing as many embryos as possible could help improve embryo survival and the implantation rate. The optimal time to perform embryo cryopreservation is still being discussed,²⁹ but, as in women without cancer, it is commonly done 3 to 5 days after fertilization.

In the past few years, the use of vitrification has greatly increased, as the post-thawing survival rates and pregnancy rates are higher with this method than with slow freezing.³⁰

Despite its success, embryo cryopreservation has important drawbacks. First, the patient must be of reproductive age and have a partner or accept the use of donor sperm. Second, most patients undergo controlled ovarian stimulation before oocyte retrieval, causing a delay in starting cancer treatment, which is not acceptable in many cases. Moreover, the high serum estrogen levels caused by ovarian stimulation may be contraindicated in women with estrogen-sensitive malignancies.¹⁹

Oocyte cryopreservation

Cryopreservation of oocytes avoids the need for sperm and, thus, may be offered to more patients than embryo cryopreservation. In addition, it may circumvent ethical or legal considerations associated with embryo freezing, such as ownership of reproductive material.

However, oocytes are more difficult to cryopreserve than embryos. Indeed, ice crystals frequently form inside and outside the cells, damaging the cell membrane and the meiotic spindle. In routine practice, mature oocytes in metaphase II are used for cryopreservation. Metaphase II oocytes are large cells that contain a delicate meiotic spindle. Moreover, their cytoplasm contains a higher proportion of water than other cells, which could affect their viability after freezing and thawing due to ice crystal formation. In addition, cryopreservation could be responsible for hardening of the zona pellucida (through diffuse thickening of the cell membrane), adversely affecting fertilization rates.³¹

Significant improvements were achieved in fertilization of cryopreserved oocytes with intracytoplasmic sperm injection. Nevertheless, there are still concerns regarding oocyte cryopreservation. Further studies are needed to determine the risk of aneuploidy caused by damage to the meiotic spindle after oocyte cryopreservation. The potentially detrimental effects of high cryopreservant concentrations used in vitrification also need to be investigated.

In vitro maturation

A novel fertility preservation strategy involves collecting immature oocytes from primordial follicles in unstimulated cycles and then letting them mature in vitro.

To date, immature oocytes retrieved at the germinal vesicle stage can be cryopreserved with vitrification followed by in vitro maturation after thawing, but several studies have demonstrated that better results are obtained when vitrification follows the in vitro maturation process.³²

Compared with mature oocytes, immature oocytes are less susceptible to damage during cryopreservation and thus have a better chance of surviving freezing and thawing, thanks to some peculiar characteristics: they are small, have few organelles, lack a zona pellucida, have low metabolic activity, and are in a state of relative quiescence.³³ Controlled ovarian stimulation is not necessary, so this procedure preserves fertility without delaying the start of cancer treatment.

Patients are usually evaluated with transvaginal ultrasonography in the early follicular phase of the menstrual cycle (between day 2 and day 4) to count and measure the antral follicles. Immature oocytes are collected when the leading follicle has reached 10 to 12 mm in size and 36 hours after a subcutaneous injection of hCG.³⁴ The retrieved oocytes are then incubated for 24 to 48 hours in a special medium supplemented with FSH and luteinizing hormone (LH). Immature oocytes can also be collected in the luteal phase.

This option could be considered when cancer treatment cannot be delayed for conventional follicular-phase retrieval³⁵ or in case of a premature LH surge during ovarian stimulation. ³⁶ It should be offered to patients facing infertility related to cancer treatment only after appropriate counseling and as a part of a clinical study.

Ovarian tissue cryopreservation

Cryopreservation of ovarian tissue is an experimental but highly promising technique for preserving fertility. Like oocyte cryopreservation, it avoids the need for hormonal stimulation and the need to delay cancer treatment. It may also be the only possible option for prepubertal girls, as well as for women who cannot postpone their cancer treatment. Although it is still experimental, it has obtained progressively better results: after having ovarian tissue preserved, thawed, and subsequently reimplanted in the same position or in a different part of the body, some patients transiently resumed having menstrual cycles and endocrine activity and in a very few cases achieved pregnancy.³⁷

Ovarian tissue for cryopreservation is usually taken via laparoscopic surgery, unless the patient has to undergo open laparotomy for another indication. Laparoscopic surgery offers significant advantages, such as the possibility of performing it on short notice without delaying oncologic therapy. Considering that women at age 30 have about 35 primordial follicles per square millimeter of ovarian tissue, 5 cubic fragments 5 mm wide may be sufficient to obtain more than 4,000 primordial follicles.³⁸ In cases in which complete ovariectomy is necessary, it is possible to remove and cryopreserve fragments of normal ovarian tissue located at the margins of the surgical specimen. Ovarian tissue withdrawal can also be performed in pediatric patients and during other surgical procedures.

The most studied method of cryopreserving ovarian tissue is slow freezing, but the use of vitrification is increasing. This technique was initially carried out in order to preserve the largest number of primordial follicles, but in recent years the possibility of cryopreserving the whole ovary with or without its vascular pedicle has also been studied. Martinez-Madrid et al³⁹ described a protocol of cryopreserving the entire ovary with its stem and found it possible to reach a follicular survival rate of 75%, preserving vessels and stromal structure.³⁹

Currently, the most promising approach seems to be the transplantation of the ovarian tissue back into the donor, ie, autotransplantation. This avoids the need for immunosuppression.

The location can be either orthotopic or heterotopic. In orthotopic transplantation the tissue is placed back in its original location. In theory, the patient could then become pregnant in the usual way if the rest of the reproductive system is not damaged.

In heterotopic transplantation the tissue is placed in a different location, usually easily accessible, like the forearm or the subcutaneous abdominal area. Heterotopic transplants have been shown to be able to restore ovarian function, but not to give pregnancies after oocyte collection.⁴⁰ Indeed, the pregnancies obtained after transplantation came from autografts of ovarian cortex in orthotopic sites like the fossa ovarica or the remnant ovary.

With autotransplantation, there is a high risk of transmission of metastatic cancer cells. Blood-bone cancers such as leukemia and lymphomas are likely to be associated with the highest risk of ovarian metastasis through transplantation of thawed cryopreserved ovarian tissue. Neuroblastoma and breast cancer are associated with a moderate risk of metastasis to the ovaries. Ovarian involvement is extremely rare in Wilms tumor, lymphomas (except for Burkitt lymphoma), osteosarcomas, Ewing sarcoma, and extragenital rhabdomyosarcoma. Squamous cell cervical cancer metastasizes to the ovaries in fewer than 0.2% of cases, even in the most advanced stages. Histologic evaluation of ovarian samples before transplantation has been proposed to prevent cancer transmission, although it is not possible to completely abolish this risk.^41,42 This jeopardy could potentially be eliminated by in vitro maturation of immature oocytes collected from cryopreserved ovarian tissue.

Despite significant advances, to date there have been fewer than 20 babies born worldwide through this method.⁴³

Oocyte donation

Assisted reproduction techniques also include in vitro fertilization using a sperm sample from the partner and oocytes from a donor. The embryos obtained are then transferred, saving the woman from ovarian stimulation without any delay in starting the cancer treatment. Although this method has a high success rate, it inevitably raises personal considerations.

OVARIAN TRANSPOSITION

When a woman of childbearing age needs radiation treatment for a pelvic malignancy, transposition of the ovaries above the pelvic brim outside the radiation field (oophoropexy) should be considered before starting therapy. It is indicated in patients diagnosed with malignancies that require pelvic radiation but not the removal of the ovaries. It can be performed during surgical treatment of the tumor or as a separate laparoscopic procedure. The radiation dose that the transposed ovaries receive is considerably less than that in ovaries left in place.

Laparoscopic ovarian transposition is highly effective. However, the risk involved in the surgical procedure should not be underestimated. The most important complications are vascular injury, infarction of the fallopian tube, and ovarian cyst formation.⁴⁴

PHARMACOLOGIC PROTECTION

Some drugs induce a state of ovarian quiescence similar to menopause. Can they be used during chemotherapy to protect the ovaries, allowing restoration of normal ovarian function and natural fertility after cancer treatment and preventing premature ovarian failure?

GnRH analogues slow the cellular activity of the gonads, in theory making them less sensitive to damage by cytotoxic agents. Initially, the release of gonadotropins is stimulated (flare-up effect), but after 10 to 15 days pituitary GnRH receptors are down-regulated by internalization of receptors. Since chemotherapy affects mainly actively dividing cells such as mature ovarian follicles, the use of the analogues is based on the assumption that by reducing FSH levels, follicles will remain quiescent, decreasing their sensitivity to the gonadotoxic effect of chemotherapy.

In a randomized study of 281 patients with early breast cancer, Del Mastro et al⁴⁵ reported a reduction in the occurrence of early menopause in those treated with a GnRH analogue during chemotherapy after 1 year of follow-up. However, the debate regarding the effect of GnRH analogues on the fertility of cancer patients is still open and needs further investigation.

In recent years, research has focused on imatinib, a new, potentially protective drug,⁴⁶ but a lot of work still needs to be done. To date, the use of GnRH analogues is not recommended outside of clinical studies, and it should be offered only after careful counseling about other options to preserve fertility.

In the last few decades, the survival rates have improved in many of the malignancies that affect young adults. This progress has made fertility preservation and quality of life after cancer treatment important, most of all in survivors of childhood cancers.

Men who are about to undergo cancer treatment can bank their sperm, but as yet no analogous noninvasive option is available for women. The most studied methods are often invasive and require the woman to take large doses of hormones. They may also necessitate a delay in starting cancer treatment.

Which method of fertility preservation a woman should choose depends on several factors, including the type of disease, the treatment required, the age of the patient, whether she has a long-term partner, and whether treatment can be delayed.

Chemotherapy and radiotherapy have well-known deleterious effects on female reproductive function. Many studies have shown that acute loss of growing follicles within the ovary and resultant premature ovarian failure often follow chemotherapy. This ovarian damage has long-term consequences, such as shortened reproductive life span and hormone deficiency.¹

Fertility preservation requires a team effort. It should be managed by an oncology center that has built a close collaboration between oncologists, fertility specialists, psychologists, and primary care physicians to allow early discussion and to offer a full range of options to these patients.

The aim of this paper is to discuss the current options for preserving fertility in female cancer patients who have to undergo gonadotoxic cancer treatment.

FEMALE FERTILITY AND ASSESSMENT OF OVARIAN RESERVE

At birth, baby girls have about 1 million primordial ovarian follicles, which is the most they will ever have. By the time they reach menarche, this number has declined to 180,000, and at menopause only about 1,000 remain.²

Throughout a woman’s reproductive life, the number of oocytes remaining—both primordial follicles and the relatively small number of maturing, growing follicles—is called her ovarian reserve. When cancer is diagnosed, we need to assess the patient’s ovarian reserve to direct the discussion about the need for fertility preservation.

In search of markers of ovarian reserve

Fertility experts have been looking for clinical biomarkers that could give us an estimate of the number of nongrowing follicles and, consequently, of the ovarian reserve.

All methods used for the assessment of ovarian reserve actually provide an indirect determination of the remaining pool of oocytes. In clinical practice, a high blood level of follicle-stimulating hormone (FSH) on cycle day 3 (>15 mU/mL) or a low level of anti-Müllerian hormone (AMH) (<1 ng/mL) is generally associated with a low ovarian reserve.

The serum FSH level is the marker most commonly used, but it varies widely at different times in the menstrual cycle.

The FSH test is usually performed on day 3 of the menstrual cycle, when the estrogen level is expected to be low due to negative feedback. The FSH result needs to be combined with the estradiol level, especially in those patients with irregular menstruation or in cases of amenorrhea. A random FSH test is considered valid if the detected estrogen level is low. Women undergoing in vitro fertilization with a day 3 FSH lower than 15 mIU/mL are more likely to conceive than women with a higher FSH level.

AMH and antral follicles. Recently, two other variables have been introduced in clinical practice: the AMH concentration and the antral follicle count (the number of small antral follicles within the ovary) as assessed by transvaginal ultrasonography.

AMH is released by the granulosa cells of small, growing follicles. Because its level is much more stable over the menstrual cycle than the FSH level, it can be measured on any day of the cycle.³ In cancer survivors, AMH is particularly useful in demonstrating the degree of ovarian tissue damage induced by radiotherapy and chemotherapy and in evaluating the ovarian reserve.⁴

A reduced number of antral follicles causes a diminished AMH production, which becomes undetectable with menopause. The AMH level is strongly associated with the basal antral follicle count. Various threshold values (0.2–1.26 ng/mL) have been used to identify women with low ovarian reserve.

HOW CANCER TREATMENT DAMAGES THE OVARIES

Advances in surgery, radiotherapy, and chemotherapy have significantly improved the prognosis for young cancer patients. However, cancer treatments often result in ovarian dysfunction, and premature menopause and irreversible sterility are the most dramatic outcomes. The resulting low estrogen levels, in addition to their physiologic consequences, also worsen quality of life through psychological effects, which can as well influence the patient’s compliance with treatment.

Chemotherapy: Alkylating agents are the most gonadotoxic

The mechanism by which chemotherapy affects ovarian function is poorly understood. Histologically, chemotherapeutic drugs could lead to ovarian atrophy and stromal fibrosis, to depletion of the primordial follicle stockpile, and to reduced ovarian weight, resulting in ovarian dysfunction.⁵

The patient's age correlates with the probability of ovarian damage or, inversely, ovarian resistance to chemotherapy. Young women have more primordial oocytes, and after chemotherapy they face a sharp reduction of their ovarian reserve. Still, younger patients show a lower rate of ovarian toxicity than older women.⁶

The type and the cumulative dose of cytotoxic agents used are other important variables.⁷ There are six main classes of chemotherapeutic drugs: alkylating agents, platinum derivatives, antibiotics, antimetabolites, plant alkaloids, and taxanes. They all affect ovarian function, but alkylating agents are the most gonadotoxic.

Alkylating agents covalently bind an alkyl group to the DNA molecule and inhibit it from replicating. In the ovaries they directly injure primordial oocytes and deplete follicles. ⁸ They also seriously damage the ovarian vasculature so that the follicles cannot grow.⁹ Their destructive effect on the primordial follicles is dose-dependent and varies with the age and developmental maturity of the patient at the time of the therapy, with older women more likely to be left infertile afterward.¹⁰

Cyclophosphamide is an alkylating agent often used to treat severe manifestations of autoimmune diseases such as systemic lupus erythematosus, BehÇet disease, steroid-resistant glomerulonephritis, inflammatory bowel disease, pemphigus vulgaris, and others. Because it can lead to premature ovarian failure and infertility, women receiving cyclophosphamide for autoimmune conditions may also need treatment to preserve fertility.¹¹

Radiotherapy

Ovarian follicles are remarkably vulnerable to damage from ionizing radiation, which results in ovarian atrophy and reduced follicle stores.¹

The risk of radiotherapy-induced infertility is closely related to the patient’s age and developmental maturity at the time of therapy and to dose fractionation and the extent of the irradiation field. Every patient has a different sensitivity to radiation damage that is probably genetically predetermined, but age seems to be the most important variable. Wo and Viswanathan¹² used a mathematical model devised by Wallace et al¹³ to show that the older the patient, the lower the radiation dose necessary to impair ovarian function.

The irradiation field is another aspect to consider. Pelvic radiation can be necessary in rectal cancer, cervical cancer, and lymphoma. In these cases, surgically moving the ovaries to a region outside the radiation field could be an option to minimize radiotherapy-induced ovarian damage.¹⁴

Radiotherapy can also damage the uterus. Pelvic irradiation can reduce uterine volume, alter uterine elasticity through myometrial fibrosis, and modify vascularization and endometrial thickness.^15,16 These alterations are closely correlated with the total radiation dose, the site of irradiation, and the patient’s age at the time of the treatment, the prepubertal uterus being more susceptible to damage. ^15,17 Larsen et al¹⁵ found that girls who received uterine irradiation before puberty had lower uterine volumes in adulthood than girls who received chemotherapy alone or radiation to other parts of the body, and that the younger the patient at the time of radiotherapy, the smaller the uterus later. These effects could result in adverse pregnancy outcomes.

Furthermore, radiation could also damage the uterine vasculature. Holm et al¹⁶ used ultrasonography to evaluate the effect of total-body irradiation and found that uterine volume and uterine blood flow were both impaired.¹⁵

All these possible alterations could lead to a reduced uterine response to cytotrophoblast invasion and to decreased fetoplacental blood flow, which could impair embryonic and fetal growth. In that case, a surrogate pregnancy would be the only method to achieve parenthood using the couple’s gametes.

OPTIONS FOR FERTILITY PRESERVATION

Assisted reproductive technology

Young women diagnosed with an oncologic disease may wish to use assisted reproductive technology (Table 1) to keep open the possibility of having children at a later date. One approach is to harvest oocytes, fertilize them in vitro, and deep-freeze (cryopreserve) the resulting embryos to be thawed and implanted later. Alternatively, oocytes can be frozen directly, although success rates are lower with this method. And another approach is to obtain and cryopreserve ovarian tissue. If none of these is possible, oocytes may be obtained from a donor.

Controlled ovarian stimulation

If oocytes are to be harvested, a number of them should be harvested at one time.

There is not an optimal number of oocytes that should be retrieved, but cryopreservation of a large number of oocytes allows us to perform multiple attempts at in vitro fertilization, improving the chances of pregnancy. The fertilization rate (defined as the total number of zygotes at the 2-pronucleus stage divided by the number of fertilized oocytes) with intracytoplasmic sperm injection is 70% to 80%. On average, for every 10 eggs, 7 to 8 eggs will normally be fertilized. The implantation rate (defined as the total number of pregnancies divided by the total number of embryo transferred) with intracytoplasmic sperm injection is 40% to 50%—ie, only half of the transferred embryos will successfully implant and result in a pregnancy.

So that more than one ripe egg can be obtained at a time, the patient must undergo a regimen of controlled ovarian stimulation to achieve multifollicular growth. Stimulation protocols are based on giving pituitary hormones, ie, analogues of gonadotropin-releasing hormone (GnRH) (both agonists and antagonists), followed by recombinant FSH or human menopausal gonadotropin to promote follicular development. A single dose of human chorionic gonadotropin (hCG) is given to induce ovulation when the lead follicles have reached 18 to 20 mm in size.¹⁸

Many oncologists consider controlled ovarian stimulation dangerous for cancer patients because it takes time and thus delays cancer treatment. Furthermore, the regimen boosts the levels of circulating estrogens, which could be harmful in patients with hormone-dependent tumors.¹⁹

Oocytes can also be retrieved during unstimulated cycles. This avoids increasing estrogen concentrations above the physiologic level, but no more than a single oocyte is collected per cycle. The patient could undergo multiple oocyte harvestings, one per cycle, but this would delay her cancer treatment even more—by months—which is not recommended.

Serious efforts to minimize estrogen production during controlled ovarian stimulation have been made, although further studies are needed. Research is under way to develop appropriate ovarian stimulation protocols based on drugs with antiestrogenic effects.

Tamoxifen, an antagonist of the estrogen receptor, is widely used in breast cancer treatment. ²⁰ It can also be given during controlled ovarian stimulation because it promotes follicular growth and induces ovulation.²¹ Oktay et al²² found that the embryo yield was 2.5 times higher in women with breast cancer treated with tamoxifen than in a retrospective control group consisting of breast cancer patients attempting natural-cycle oocyte retrieval.

Letrozole, an aromatase inhibitor, is also commonly used in treating breast and ovarian cancer. Aromatase is an enzyme that catalyzes the conversion of androgenic precursors to estrogens, and it is found in many tissues, including granulosa cells. Several studies report the use of letrozole, alone or in combination with low doses of recombinant FSH, in ovarian stimulation protocols in cancer patients, with positive clinical outcomes.²³

Tamoxifen or letrozole, combined with recombinant FSH, is an attractive option in a controlled ovarian stimulation protocol for cancer patients,²⁴ although further investigation is needed.

 

 

Cryopreservation methods

Two main protocols are currently used to freeze oocytes, embryos, and ovarian tissue: slow freezing and vitrification.

In the slow-freezing method, cryoprotectant agents are used to draw water out of the cells, raising intracellular viscosity without (or with minimal) intracellular ice crystal formation, while the sample is cooled slowly in a controlled manner. These cryoprotectant chemicals lower the freezing point of the solution, allowing greater cellular dehydration during the slow freezing. They also protect the plasmatic cell membrane by changing its physical state from liquid to partially dry. To avoid excessive deformation that could damage the cytoplasmic structures, cryoprotectant agents are added in successive stages.²⁵

Vitrification is a newer method that uses higher concentrations of cryoprotectants and flash freezing. The instant drop in temperature converts this highly concentrated solution from an aqueous state to a semisolid, amorphous state that does not contain ice crystals, which are the main cause of damage during the freezing process.²⁶ Since most cryoprotectant agents are extremely toxic, it is necessary to minimize the time that oocytes, embryos, and ovarian tissue are exposed to them.

Cryopreservation of embryos

According to the American Society of Clinical Oncology and the American Society of Reproductive Medicine, embryo freezing is the most established method for fertility preservation, with tangible and widely reported success.²⁷ In normal practice, oocytes are retrieved after a controlled ovarian stimulation and then fertilized in vitro. Then they are treated with cryoprotectant agents, frozen, and stored. Upon demand, embryos can be thawed and implanted.

The Society for Assisted Reproductive Technology reports that the current live birth rate per transfer using thawed embryos from nondonor oocytes in US women under age 35 is 38.7%; at age 35 to 37 it is 35.1%.²⁸ In women with cancer, storing as many embryos as possible could help improve embryo survival and the implantation rate. The optimal time to perform embryo cryopreservation is still being discussed,²⁹ but, as in women without cancer, it is commonly done 3 to 5 days after fertilization.

In the past few years, the use of vitrification has greatly increased, as the post-thawing survival rates and pregnancy rates are higher with this method than with slow freezing.³⁰

Despite its success, embryo cryopreservation has important drawbacks. First, the patient must be of reproductive age and have a partner or accept the use of donor sperm. Second, most patients undergo controlled ovarian stimulation before oocyte retrieval, causing a delay in starting cancer treatment, which is not acceptable in many cases. Moreover, the high serum estrogen levels caused by ovarian stimulation may be contraindicated in women with estrogen-sensitive malignancies.¹⁹

Oocyte cryopreservation

Cryopreservation of oocytes avoids the need for sperm and, thus, may be offered to more patients than embryo cryopreservation. In addition, it may circumvent ethical or legal considerations associated with embryo freezing, such as ownership of reproductive material.

However, oocytes are more difficult to cryopreserve than embryos. Indeed, ice crystals frequently form inside and outside the cells, damaging the cell membrane and the meiotic spindle. In routine practice, mature oocytes in metaphase II are used for cryopreservation. Metaphase II oocytes are large cells that contain a delicate meiotic spindle. Moreover, their cytoplasm contains a higher proportion of water than other cells, which could affect their viability after freezing and thawing due to ice crystal formation. In addition, cryopreservation could be responsible for hardening of the zona pellucida (through diffuse thickening of the cell membrane), adversely affecting fertilization rates.³¹

Significant improvements were achieved in fertilization of cryopreserved oocytes with intracytoplasmic sperm injection. Nevertheless, there are still concerns regarding oocyte cryopreservation. Further studies are needed to determine the risk of aneuploidy caused by damage to the meiotic spindle after oocyte cryopreservation. The potentially detrimental effects of high cryopreservant concentrations used in vitrification also need to be investigated.

In vitro maturation

A novel fertility preservation strategy involves collecting immature oocytes from primordial follicles in unstimulated cycles and then letting them mature in vitro.

To date, immature oocytes retrieved at the germinal vesicle stage can be cryopreserved with vitrification followed by in vitro maturation after thawing, but several studies have demonstrated that better results are obtained when vitrification follows the in vitro maturation process.³²

Compared with mature oocytes, immature oocytes are less susceptible to damage during cryopreservation and thus have a better chance of surviving freezing and thawing, thanks to some peculiar characteristics: they are small, have few organelles, lack a zona pellucida, have low metabolic activity, and are in a state of relative quiescence.³³ Controlled ovarian stimulation is not necessary, so this procedure preserves fertility without delaying the start of cancer treatment.

Patients are usually evaluated with transvaginal ultrasonography in the early follicular phase of the menstrual cycle (between day 2 and day 4) to count and measure the antral follicles. Immature oocytes are collected when the leading follicle has reached 10 to 12 mm in size and 36 hours after a subcutaneous injection of hCG.³⁴ The retrieved oocytes are then incubated for 24 to 48 hours in a special medium supplemented with FSH and luteinizing hormone (LH). Immature oocytes can also be collected in the luteal phase.

This option could be considered when cancer treatment cannot be delayed for conventional follicular-phase retrieval³⁵ or in case of a premature LH surge during ovarian stimulation. ³⁶ It should be offered to patients facing infertility related to cancer treatment only after appropriate counseling and as a part of a clinical study.

Ovarian tissue cryopreservation

Cryopreservation of ovarian tissue is an experimental but highly promising technique for preserving fertility. Like oocyte cryopreservation, it avoids the need for hormonal stimulation and the need to delay cancer treatment. It may also be the only possible option for prepubertal girls, as well as for women who cannot postpone their cancer treatment. Although it is still experimental, it has obtained progressively better results: after having ovarian tissue preserved, thawed, and subsequently reimplanted in the same position or in a different part of the body, some patients transiently resumed having menstrual cycles and endocrine activity and in a very few cases achieved pregnancy.³⁷

Ovarian tissue for cryopreservation is usually taken via laparoscopic surgery, unless the patient has to undergo open laparotomy for another indication. Laparoscopic surgery offers significant advantages, such as the possibility of performing it on short notice without delaying oncologic therapy. Considering that women at age 30 have about 35 primordial follicles per square millimeter of ovarian tissue, 5 cubic fragments 5 mm wide may be sufficient to obtain more than 4,000 primordial follicles.³⁸ In cases in which complete ovariectomy is necessary, it is possible to remove and cryopreserve fragments of normal ovarian tissue located at the margins of the surgical specimen. Ovarian tissue withdrawal can also be performed in pediatric patients and during other surgical procedures.

The most studied method of cryopreserving ovarian tissue is slow freezing, but the use of vitrification is increasing. This technique was initially carried out in order to preserve the largest number of primordial follicles, but in recent years the possibility of cryopreserving the whole ovary with or without its vascular pedicle has also been studied. Martinez-Madrid et al³⁹ described a protocol of cryopreserving the entire ovary with its stem and found it possible to reach a follicular survival rate of 75%, preserving vessels and stromal structure.³⁹

Currently, the most promising approach seems to be the transplantation of the ovarian tissue back into the donor, ie, autotransplantation. This avoids the need for immunosuppression.

The location can be either orthotopic or heterotopic. In orthotopic transplantation the tissue is placed back in its original location. In theory, the patient could then become pregnant in the usual way if the rest of the reproductive system is not damaged.

In heterotopic transplantation the tissue is placed in a different location, usually easily accessible, like the forearm or the subcutaneous abdominal area. Heterotopic transplants have been shown to be able to restore ovarian function, but not to give pregnancies after oocyte collection.⁴⁰ Indeed, the pregnancies obtained after transplantation came from autografts of ovarian cortex in orthotopic sites like the fossa ovarica or the remnant ovary.

With autotransplantation, there is a high risk of transmission of metastatic cancer cells. Blood-bone cancers such as leukemia and lymphomas are likely to be associated with the highest risk of ovarian metastasis through transplantation of thawed cryopreserved ovarian tissue. Neuroblastoma and breast cancer are associated with a moderate risk of metastasis to the ovaries. Ovarian involvement is extremely rare in Wilms tumor, lymphomas (except for Burkitt lymphoma), osteosarcomas, Ewing sarcoma, and extragenital rhabdomyosarcoma. Squamous cell cervical cancer metastasizes to the ovaries in fewer than 0.2% of cases, even in the most advanced stages. Histologic evaluation of ovarian samples before transplantation has been proposed to prevent cancer transmission, although it is not possible to completely abolish this risk.^41,42 This jeopardy could potentially be eliminated by in vitro maturation of immature oocytes collected from cryopreserved ovarian tissue.

Despite significant advances, to date there have been fewer than 20 babies born worldwide through this method.⁴³

Oocyte donation

Assisted reproduction techniques also include in vitro fertilization using a sperm sample from the partner and oocytes from a donor. The embryos obtained are then transferred, saving the woman from ovarian stimulation without any delay in starting the cancer treatment. Although this method has a high success rate, it inevitably raises personal considerations.

OVARIAN TRANSPOSITION

When a woman of childbearing age needs radiation treatment for a pelvic malignancy, transposition of the ovaries above the pelvic brim outside the radiation field (oophoropexy) should be considered before starting therapy. It is indicated in patients diagnosed with malignancies that require pelvic radiation but not the removal of the ovaries. It can be performed during surgical treatment of the tumor or as a separate laparoscopic procedure. The radiation dose that the transposed ovaries receive is considerably less than that in ovaries left in place.

Laparoscopic ovarian transposition is highly effective. However, the risk involved in the surgical procedure should not be underestimated. The most important complications are vascular injury, infarction of the fallopian tube, and ovarian cyst formation.⁴⁴

PHARMACOLOGIC PROTECTION

Some drugs induce a state of ovarian quiescence similar to menopause. Can they be used during chemotherapy to protect the ovaries, allowing restoration of normal ovarian function and natural fertility after cancer treatment and preventing premature ovarian failure?

GnRH analogues slow the cellular activity of the gonads, in theory making them less sensitive to damage by cytotoxic agents. Initially, the release of gonadotropins is stimulated (flare-up effect), but after 10 to 15 days pituitary GnRH receptors are down-regulated by internalization of receptors. Since chemotherapy affects mainly actively dividing cells such as mature ovarian follicles, the use of the analogues is based on the assumption that by reducing FSH levels, follicles will remain quiescent, decreasing their sensitivity to the gonadotoxic effect of chemotherapy.

In a randomized study of 281 patients with early breast cancer, Del Mastro et al⁴⁵ reported a reduction in the occurrence of early menopause in those treated with a GnRH analogue during chemotherapy after 1 year of follow-up. However, the debate regarding the effect of GnRH analogues on the fertility of cancer patients is still open and needs further investigation.

In recent years, research has focused on imatinib, a new, potentially protective drug,⁴⁶ but a lot of work still needs to be done. To date, the use of GnRH analogues is not recommended outside of clinical studies, and it should be offered only after careful counseling about other options to preserve fertility.

In the last few decades, the survival rates have improved in many of the malignancies that affect young adults. This progress has made fertility preservation and quality of life after cancer treatment important, most of all in survivors of childhood cancers.

Men who are about to undergo cancer treatment can bank their sperm, but as yet no analogous noninvasive option is available for women. The most studied methods are often invasive and require the woman to take large doses of hormones. They may also necessitate a delay in starting cancer treatment.

Which method of fertility preservation a woman should choose depends on several factors, including the type of disease, the treatment required, the age of the patient, whether she has a long-term partner, and whether treatment can be delayed.

Chemotherapy and radiotherapy have well-known deleterious effects on female reproductive function. Many studies have shown that acute loss of growing follicles within the ovary and resultant premature ovarian failure often follow chemotherapy. This ovarian damage has long-term consequences, such as shortened reproductive life span and hormone deficiency.¹

Fertility preservation requires a team effort. It should be managed by an oncology center that has built a close collaboration between oncologists, fertility specialists, psychologists, and primary care physicians to allow early discussion and to offer a full range of options to these patients.

The aim of this paper is to discuss the current options for preserving fertility in female cancer patients who have to undergo gonadotoxic cancer treatment.

FEMALE FERTILITY AND ASSESSMENT OF OVARIAN RESERVE

At birth, baby girls have about 1 million primordial ovarian follicles, which is the most they will ever have. By the time they reach menarche, this number has declined to 180,000, and at menopause only about 1,000 remain.²

Throughout a woman’s reproductive life, the number of oocytes remaining—both primordial follicles and the relatively small number of maturing, growing follicles—is called her ovarian reserve. When cancer is diagnosed, we need to assess the patient’s ovarian reserve to direct the discussion about the need for fertility preservation.

In search of markers of ovarian reserve

Fertility experts have been looking for clinical biomarkers that could give us an estimate of the number of nongrowing follicles and, consequently, of the ovarian reserve.

All methods used for the assessment of ovarian reserve actually provide an indirect determination of the remaining pool of oocytes. In clinical practice, a high blood level of follicle-stimulating hormone (FSH) on cycle day 3 (>15 mU/mL) or a low level of anti-Müllerian hormone (AMH) (<1 ng/mL) is generally associated with a low ovarian reserve.

The serum FSH level is the marker most commonly used, but it varies widely at different times in the menstrual cycle.

The FSH test is usually performed on day 3 of the menstrual cycle, when the estrogen level is expected to be low due to negative feedback. The FSH result needs to be combined with the estradiol level, especially in those patients with irregular menstruation or in cases of amenorrhea. A random FSH test is considered valid if the detected estrogen level is low. Women undergoing in vitro fertilization with a day 3 FSH lower than 15 mIU/mL are more likely to conceive than women with a higher FSH level.

AMH and antral follicles. Recently, two other variables have been introduced in clinical practice: the AMH concentration and the antral follicle count (the number of small antral follicles within the ovary) as assessed by transvaginal ultrasonography.

AMH is released by the granulosa cells of small, growing follicles. Because its level is much more stable over the menstrual cycle than the FSH level, it can be measured on any day of the cycle.³ In cancer survivors, AMH is particularly useful in demonstrating the degree of ovarian tissue damage induced by radiotherapy and chemotherapy and in evaluating the ovarian reserve.⁴

A reduced number of antral follicles causes a diminished AMH production, which becomes undetectable with menopause. The AMH level is strongly associated with the basal antral follicle count. Various threshold values (0.2–1.26 ng/mL) have been used to identify women with low ovarian reserve.

HOW CANCER TREATMENT DAMAGES THE OVARIES

Advances in surgery, radiotherapy, and chemotherapy have significantly improved the prognosis for young cancer patients. However, cancer treatments often result in ovarian dysfunction, and premature menopause and irreversible sterility are the most dramatic outcomes. The resulting low estrogen levels, in addition to their physiologic consequences, also worsen quality of life through psychological effects, which can as well influence the patient’s compliance with treatment.

Chemotherapy: Alkylating agents are the most gonadotoxic

The mechanism by which chemotherapy affects ovarian function is poorly understood. Histologically, chemotherapeutic drugs could lead to ovarian atrophy and stromal fibrosis, to depletion of the primordial follicle stockpile, and to reduced ovarian weight, resulting in ovarian dysfunction.⁵

The patient's age correlates with the probability of ovarian damage or, inversely, ovarian resistance to chemotherapy. Young women have more primordial oocytes, and after chemotherapy they face a sharp reduction of their ovarian reserve. Still, younger patients show a lower rate of ovarian toxicity than older women.⁶

The type and the cumulative dose of cytotoxic agents used are other important variables.⁷ There are six main classes of chemotherapeutic drugs: alkylating agents, platinum derivatives, antibiotics, antimetabolites, plant alkaloids, and taxanes. They all affect ovarian function, but alkylating agents are the most gonadotoxic.

Alkylating agents covalently bind an alkyl group to the DNA molecule and inhibit it from replicating. In the ovaries they directly injure primordial oocytes and deplete follicles. ⁸ They also seriously damage the ovarian vasculature so that the follicles cannot grow.⁹ Their destructive effect on the primordial follicles is dose-dependent and varies with the age and developmental maturity of the patient at the time of the therapy, with older women more likely to be left infertile afterward.¹⁰

Cyclophosphamide is an alkylating agent often used to treat severe manifestations of autoimmune diseases such as systemic lupus erythematosus, BehÇet disease, steroid-resistant glomerulonephritis, inflammatory bowel disease, pemphigus vulgaris, and others. Because it can lead to premature ovarian failure and infertility, women receiving cyclophosphamide for autoimmune conditions may also need treatment to preserve fertility.¹¹

Radiotherapy

Ovarian follicles are remarkably vulnerable to damage from ionizing radiation, which results in ovarian atrophy and reduced follicle stores.¹

The risk of radiotherapy-induced infertility is closely related to the patient’s age and developmental maturity at the time of therapy and to dose fractionation and the extent of the irradiation field. Every patient has a different sensitivity to radiation damage that is probably genetically predetermined, but age seems to be the most important variable. Wo and Viswanathan¹² used a mathematical model devised by Wallace et al¹³ to show that the older the patient, the lower the radiation dose necessary to impair ovarian function.

The irradiation field is another aspect to consider. Pelvic radiation can be necessary in rectal cancer, cervical cancer, and lymphoma. In these cases, surgically moving the ovaries to a region outside the radiation field could be an option to minimize radiotherapy-induced ovarian damage.¹⁴

Radiotherapy can also damage the uterus. Pelvic irradiation can reduce uterine volume, alter uterine elasticity through myometrial fibrosis, and modify vascularization and endometrial thickness.^15,16 These alterations are closely correlated with the total radiation dose, the site of irradiation, and the patient’s age at the time of the treatment, the prepubertal uterus being more susceptible to damage. ^15,17 Larsen et al¹⁵ found that girls who received uterine irradiation before puberty had lower uterine volumes in adulthood than girls who received chemotherapy alone or radiation to other parts of the body, and that the younger the patient at the time of radiotherapy, the smaller the uterus later. These effects could result in adverse pregnancy outcomes.

Furthermore, radiation could also damage the uterine vasculature. Holm et al¹⁶ used ultrasonography to evaluate the effect of total-body irradiation and found that uterine volume and uterine blood flow were both impaired.¹⁵

All these possible alterations could lead to a reduced uterine response to cytotrophoblast invasion and to decreased fetoplacental blood flow, which could impair embryonic and fetal growth. In that case, a surrogate pregnancy would be the only method to achieve parenthood using the couple’s gametes.

OPTIONS FOR FERTILITY PRESERVATION

Assisted reproductive technology

Young women diagnosed with an oncologic disease may wish to use assisted reproductive technology (Table 1) to keep open the possibility of having children at a later date. One approach is to harvest oocytes, fertilize them in vitro, and deep-freeze (cryopreserve) the resulting embryos to be thawed and implanted later. Alternatively, oocytes can be frozen directly, although success rates are lower with this method. And another approach is to obtain and cryopreserve ovarian tissue. If none of these is possible, oocytes may be obtained from a donor.

Controlled ovarian stimulation

If oocytes are to be harvested, a number of them should be harvested at one time.

There is not an optimal number of oocytes that should be retrieved, but cryopreservation of a large number of oocytes allows us to perform multiple attempts at in vitro fertilization, improving the chances of pregnancy. The fertilization rate (defined as the total number of zygotes at the 2-pronucleus stage divided by the number of fertilized oocytes) with intracytoplasmic sperm injection is 70% to 80%. On average, for every 10 eggs, 7 to 8 eggs will normally be fertilized. The implantation rate (defined as the total number of pregnancies divided by the total number of embryo transferred) with intracytoplasmic sperm injection is 40% to 50%—ie, only half of the transferred embryos will successfully implant and result in a pregnancy.

So that more than one ripe egg can be obtained at a time, the patient must undergo a regimen of controlled ovarian stimulation to achieve multifollicular growth. Stimulation protocols are based on giving pituitary hormones, ie, analogues of gonadotropin-releasing hormone (GnRH) (both agonists and antagonists), followed by recombinant FSH or human menopausal gonadotropin to promote follicular development. A single dose of human chorionic gonadotropin (hCG) is given to induce ovulation when the lead follicles have reached 18 to 20 mm in size.¹⁸

Many oncologists consider controlled ovarian stimulation dangerous for cancer patients because it takes time and thus delays cancer treatment. Furthermore, the regimen boosts the levels of circulating estrogens, which could be harmful in patients with hormone-dependent tumors.¹⁹

Oocytes can also be retrieved during unstimulated cycles. This avoids increasing estrogen concentrations above the physiologic level, but no more than a single oocyte is collected per cycle. The patient could undergo multiple oocyte harvestings, one per cycle, but this would delay her cancer treatment even more—by months—which is not recommended.

Serious efforts to minimize estrogen production during controlled ovarian stimulation have been made, although further studies are needed. Research is under way to develop appropriate ovarian stimulation protocols based on drugs with antiestrogenic effects.

Tamoxifen, an antagonist of the estrogen receptor, is widely used in breast cancer treatment. ²⁰ It can also be given during controlled ovarian stimulation because it promotes follicular growth and induces ovulation.²¹ Oktay et al²² found that the embryo yield was 2.5 times higher in women with breast cancer treated with tamoxifen than in a retrospective control group consisting of breast cancer patients attempting natural-cycle oocyte retrieval.

Letrozole, an aromatase inhibitor, is also commonly used in treating breast and ovarian cancer. Aromatase is an enzyme that catalyzes the conversion of androgenic precursors to estrogens, and it is found in many tissues, including granulosa cells. Several studies report the use of letrozole, alone or in combination with low doses of recombinant FSH, in ovarian stimulation protocols in cancer patients, with positive clinical outcomes.²³

Tamoxifen or letrozole, combined with recombinant FSH, is an attractive option in a controlled ovarian stimulation protocol for cancer patients,²⁴ although further investigation is needed.

 

 

Cryopreservation methods

Two main protocols are currently used to freeze oocytes, embryos, and ovarian tissue: slow freezing and vitrification.

In the slow-freezing method, cryoprotectant agents are used to draw water out of the cells, raising intracellular viscosity without (or with minimal) intracellular ice crystal formation, while the sample is cooled slowly in a controlled manner. These cryoprotectant chemicals lower the freezing point of the solution, allowing greater cellular dehydration during the slow freezing. They also protect the plasmatic cell membrane by changing its physical state from liquid to partially dry. To avoid excessive deformation that could damage the cytoplasmic structures, cryoprotectant agents are added in successive stages.²⁵

Vitrification is a newer method that uses higher concentrations of cryoprotectants and flash freezing. The instant drop in temperature converts this highly concentrated solution from an aqueous state to a semisolid, amorphous state that does not contain ice crystals, which are the main cause of damage during the freezing process.²⁶ Since most cryoprotectant agents are extremely toxic, it is necessary to minimize the time that oocytes, embryos, and ovarian tissue are exposed to them.

Cryopreservation of embryos

According to the American Society of Clinical Oncology and the American Society of Reproductive Medicine, embryo freezing is the most established method for fertility preservation, with tangible and widely reported success.²⁷ In normal practice, oocytes are retrieved after a controlled ovarian stimulation and then fertilized in vitro. Then they are treated with cryoprotectant agents, frozen, and stored. Upon demand, embryos can be thawed and implanted.

The Society for Assisted Reproductive Technology reports that the current live birth rate per transfer using thawed embryos from nondonor oocytes in US women under age 35 is 38.7%; at age 35 to 37 it is 35.1%.²⁸ In women with cancer, storing as many embryos as possible could help improve embryo survival and the implantation rate. The optimal time to perform embryo cryopreservation is still being discussed,²⁹ but, as in women without cancer, it is commonly done 3 to 5 days after fertilization.

In the past few years, the use of vitrification has greatly increased, as the post-thawing survival rates and pregnancy rates are higher with this method than with slow freezing.³⁰

Despite its success, embryo cryopreservation has important drawbacks. First, the patient must be of reproductive age and have a partner or accept the use of donor sperm. Second, most patients undergo controlled ovarian stimulation before oocyte retrieval, causing a delay in starting cancer treatment, which is not acceptable in many cases. Moreover, the high serum estrogen levels caused by ovarian stimulation may be contraindicated in women with estrogen-sensitive malignancies.¹⁹

Oocyte cryopreservation

Cryopreservation of oocytes avoids the need for sperm and, thus, may be offered to more patients than embryo cryopreservation. In addition, it may circumvent ethical or legal considerations associated with embryo freezing, such as ownership of reproductive material.

However, oocytes are more difficult to cryopreserve than embryos. Indeed, ice crystals frequently form inside and outside the cells, damaging the cell membrane and the meiotic spindle. In routine practice, mature oocytes in metaphase II are used for cryopreservation. Metaphase II oocytes are large cells that contain a delicate meiotic spindle. Moreover, their cytoplasm contains a higher proportion of water than other cells, which could affect their viability after freezing and thawing due to ice crystal formation. In addition, cryopreservation could be responsible for hardening of the zona pellucida (through diffuse thickening of the cell membrane), adversely affecting fertilization rates.³¹

Significant improvements were achieved in fertilization of cryopreserved oocytes with intracytoplasmic sperm injection. Nevertheless, there are still concerns regarding oocyte cryopreservation. Further studies are needed to determine the risk of aneuploidy caused by damage to the meiotic spindle after oocyte cryopreservation. The potentially detrimental effects of high cryopreservant concentrations used in vitrification also need to be investigated.

In vitro maturation

A novel fertility preservation strategy involves collecting immature oocytes from primordial follicles in unstimulated cycles and then letting them mature in vitro.

To date, immature oocytes retrieved at the germinal vesicle stage can be cryopreserved with vitrification followed by in vitro maturation after thawing, but several studies have demonstrated that better results are obtained when vitrification follows the in vitro maturation process.³²

Compared with mature oocytes, immature oocytes are less susceptible to damage during cryopreservation and thus have a better chance of surviving freezing and thawing, thanks to some peculiar characteristics: they are small, have few organelles, lack a zona pellucida, have low metabolic activity, and are in a state of relative quiescence.³³ Controlled ovarian stimulation is not necessary, so this procedure preserves fertility without delaying the start of cancer treatment.

Patients are usually evaluated with transvaginal ultrasonography in the early follicular phase of the menstrual cycle (between day 2 and day 4) to count and measure the antral follicles. Immature oocytes are collected when the leading follicle has reached 10 to 12 mm in size and 36 hours after a subcutaneous injection of hCG.³⁴ The retrieved oocytes are then incubated for 24 to 48 hours in a special medium supplemented with FSH and luteinizing hormone (LH). Immature oocytes can also be collected in the luteal phase.

This option could be considered when cancer treatment cannot be delayed for conventional follicular-phase retrieval³⁵ or in case of a premature LH surge during ovarian stimulation. ³⁶ It should be offered to patients facing infertility related to cancer treatment only after appropriate counseling and as a part of a clinical study.

Ovarian tissue cryopreservation

Cryopreservation of ovarian tissue is an experimental but highly promising technique for preserving fertility. Like oocyte cryopreservation, it avoids the need for hormonal stimulation and the need to delay cancer treatment. It may also be the only possible option for prepubertal girls, as well as for women who cannot postpone their cancer treatment. Although it is still experimental, it has obtained progressively better results: after having ovarian tissue preserved, thawed, and subsequently reimplanted in the same position or in a different part of the body, some patients transiently resumed having menstrual cycles and endocrine activity and in a very few cases achieved pregnancy.³⁷

Ovarian tissue for cryopreservation is usually taken via laparoscopic surgery, unless the patient has to undergo open laparotomy for another indication. Laparoscopic surgery offers significant advantages, such as the possibility of performing it on short notice without delaying oncologic therapy. Considering that women at age 30 have about 35 primordial follicles per square millimeter of ovarian tissue, 5 cubic fragments 5 mm wide may be sufficient to obtain more than 4,000 primordial follicles.³⁸ In cases in which complete ovariectomy is necessary, it is possible to remove and cryopreserve fragments of normal ovarian tissue located at the margins of the surgical specimen. Ovarian tissue withdrawal can also be performed in pediatric patients and during other surgical procedures.

The most studied method of cryopreserving ovarian tissue is slow freezing, but the use of vitrification is increasing. This technique was initially carried out in order to preserve the largest number of primordial follicles, but in recent years the possibility of cryopreserving the whole ovary with or without its vascular pedicle has also been studied. Martinez-Madrid et al³⁹ described a protocol of cryopreserving the entire ovary with its stem and found it possible to reach a follicular survival rate of 75%, preserving vessels and stromal structure.³⁹

Currently, the most promising approach seems to be the transplantation of the ovarian tissue back into the donor, ie, autotransplantation. This avoids the need for immunosuppression.

The location can be either orthotopic or heterotopic. In orthotopic transplantation the tissue is placed back in its original location. In theory, the patient could then become pregnant in the usual way if the rest of the reproductive system is not damaged.

In heterotopic transplantation the tissue is placed in a different location, usually easily accessible, like the forearm or the subcutaneous abdominal area. Heterotopic transplants have been shown to be able to restore ovarian function, but not to give pregnancies after oocyte collection.⁴⁰ Indeed, the pregnancies obtained after transplantation came from autografts of ovarian cortex in orthotopic sites like the fossa ovarica or the remnant ovary.

With autotransplantation, there is a high risk of transmission of metastatic cancer cells. Blood-bone cancers such as leukemia and lymphomas are likely to be associated with the highest risk of ovarian metastasis through transplantation of thawed cryopreserved ovarian tissue. Neuroblastoma and breast cancer are associated with a moderate risk of metastasis to the ovaries. Ovarian involvement is extremely rare in Wilms tumor, lymphomas (except for Burkitt lymphoma), osteosarcomas, Ewing sarcoma, and extragenital rhabdomyosarcoma. Squamous cell cervical cancer metastasizes to the ovaries in fewer than 0.2% of cases, even in the most advanced stages. Histologic evaluation of ovarian samples before transplantation has been proposed to prevent cancer transmission, although it is not possible to completely abolish this risk.^41,42 This jeopardy could potentially be eliminated by in vitro maturation of immature oocytes collected from cryopreserved ovarian tissue.

Despite significant advances, to date there have been fewer than 20 babies born worldwide through this method.⁴³

Oocyte donation

Assisted reproduction techniques also include in vitro fertilization using a sperm sample from the partner and oocytes from a donor. The embryos obtained are then transferred, saving the woman from ovarian stimulation without any delay in starting the cancer treatment. Although this method has a high success rate, it inevitably raises personal considerations.

OVARIAN TRANSPOSITION

When a woman of childbearing age needs radiation treatment for a pelvic malignancy, transposition of the ovaries above the pelvic brim outside the radiation field (oophoropexy) should be considered before starting therapy. It is indicated in patients diagnosed with malignancies that require pelvic radiation but not the removal of the ovaries. It can be performed during surgical treatment of the tumor or as a separate laparoscopic procedure. The radiation dose that the transposed ovaries receive is considerably less than that in ovaries left in place.

Laparoscopic ovarian transposition is highly effective. However, the risk involved in the surgical procedure should not be underestimated. The most important complications are vascular injury, infarction of the fallopian tube, and ovarian cyst formation.⁴⁴

PHARMACOLOGIC PROTECTION

Some drugs induce a state of ovarian quiescence similar to menopause. Can they be used during chemotherapy to protect the ovaries, allowing restoration of normal ovarian function and natural fertility after cancer treatment and preventing premature ovarian failure?

GnRH analogues slow the cellular activity of the gonads, in theory making them less sensitive to damage by cytotoxic agents. Initially, the release of gonadotropins is stimulated (flare-up effect), but after 10 to 15 days pituitary GnRH receptors are down-regulated by internalization of receptors. Since chemotherapy affects mainly actively dividing cells such as mature ovarian follicles, the use of the analogues is based on the assumption that by reducing FSH levels, follicles will remain quiescent, decreasing their sensitivity to the gonadotoxic effect of chemotherapy.

In a randomized study of 281 patients with early breast cancer, Del Mastro et al⁴⁵ reported a reduction in the occurrence of early menopause in those treated with a GnRH analogue during chemotherapy after 1 year of follow-up. However, the debate regarding the effect of GnRH analogues on the fertility of cancer patients is still open and needs further investigation.

In recent years, research has focused on imatinib, a new, potentially protective drug,⁴⁶ but a lot of work still needs to be done. To date, the use of GnRH analogues is not recommended outside of clinical studies, and it should be offered only after careful counseling about other options to preserve fertility.

During a routine examination, a 17-year-old boy was noted to have unilateral hyperpigmented patches on his left neck, shoulder, and back. The lesions had been present since birth, had not changed in size or color, and were asymptomatic. His mother had noted an increase in the size of his left jaw starting at age 1.

The hyperpigmented patches had irregular borders (Figure 1). The skin was otherwise clear. Laboratory testing from 5 years earlier showed normal levels of dehydroepiandrosterone, prolactin, parathyroid hormone, thyroxine, and thyroid-stimulating hormone. Computed tomography showed a “ground-glass” appearance of the bones at the base of the skull, consistent with polyostotic fibrous dysplasia (Figure 2).

Q: Which is the most likely diagnosis?

• Neurofibromatosis
• Congenital melanocytic nevus
• McCune-Albright syndrome
• Tuberous sclerosis

A: This patient had typical features of McCune-Albright syndrome (or Albright syndrome), the classic triad of fibrous dysplasia of bone, large unilateral café-au-lait macules or patches, and precocious puberty or other endocrinopathy.¹ The syndrome is rare, with an estimated prevalence of 1/100,000 to 1/1,000,000.² It results from somatic mutation of the GNAS gene (chromosome 20q13) during embryonic development, which causes constitutive activation of intracellular cyclic adenosine monophosphate (cAMP) signaling and cellular dysplasia.³

THE DIAGNOSIS IS CLINICAL

McCune-Albright syndrome is a clinical diagnosis based on the presence of at least two features of the classic triad.^1,4

Other conditions, such as neurofibromatosis, also cause café-au-lait macules in children; but the lesions of McCune-Albright syndrome are fewer in number, larger, and darker and may follow Blaschko lines, with a linear or segmental configuration.⁵ McCune-Albright lesions tend to have jagged, “coast-of-Maine” borders, as opposed to the smoother “coast-of-California” borders of the lesions of neurofibromatosis.¹

Nevertheless, because café-au-lait macules of McCune-Albright syndrome are sometimes indistinguishable from those of neurofibromatosis, the endocrine and skeletal manifestations are essential to making the diagnosis.⁵

SIGNS OF GENETIC MOSAICISM

The somatic (postzygotic) nature of the GNAS mutation means that patients have normal and abnormal cell lines, ie, mosaicism. Therefore, the extent of disease depends on the precise stage in development during which the mutation occurred. This determines which tissues contain mutated cells and the proportion and distribution of affected cells at these loci.^1,4

In addition, differential sensitivity to cAMP signaling between cell types and tissue-specific imprinting of GNAS may contribute to the phenotypic variation seen in McCune-Albright syndrome.⁴ This means that the clinical features often vary, and the classic clinical triad is not always present.⁶

The most common clinical features are fibrous dysplasia, which occurs in 46% to 98% of patients, and café-au-lait macules, which occur in 53.1% to 92.5% of patients.^1,2 Fibrous dysplasia is typically polyostotic, ie, it involves multiple skeletal sites, with the proximal femur and skull base being the most common.⁶ It presents as bone pain, asymmetry, or pathologic fracture (or a combination of these) and shows a characteristic “ground-glass” appearance on computed tomography (Figure 2).¹ Café-au-lait lesions present at birth or shortly thereafter are often unappreciated as a potential presenting sign.¹ These hyperpigmented lesions are typically large and unilateral, often favoring the forehead, nuchal area, sacrum, and buttocks.^5.6

Precocious puberty is the most common endocrinopathy in McCune-Albright syndrome, seen in 64% to 79% of cases, and is more common in girls than in boys.² Other associated endocrinopathies include hyperthyroidism (20% to 30%), excess growth hormone, renal phosphate wasting, and Cushing syndrome.^1,6

SCREEN FOR OTHER MANIFESTATIONS

McCune-Albright syndrome can involve a broad spectrum of tissues. Therefore, once the diagnosis is made, the patient should be thoroughly evaluated for other manifestations.¹ The evaluation may include imaging studies and biochemical testing and may necessitate referral to an endocrinologist, a radiologist, and an orthopedic surgeon.

Young girls with premature vaginal bleeding or recurrent follicular cysts should always be evaluated for McCune-Albright syndrome, since ovarian enlargement can be mistaken for an ovarian tumor.⁷ Likewise, adults with isolated fibrous dysplasia or large unilateral café-au-lait macules should also be evaluated, since patients with McCune-Albright syndrome have a normal life span and so may present later in life.^4,6

TREATMENT

Drug treatment of this syndrome aims to block the effects of prolonged exposure of end-organs to sex steroids. Since precocious puberty of McCune-Alright syndrome is typically peripheral in origin, it is unresponsive to gonadotropin-releasing hormone agonist drugs; instead, aromatase inhibitors (testolactone) with antiestrogens (tamoxifen) may be used in girls, or antiandrogens (spironolactone) in boys.⁸

Unfortunately, despite our advanced mechanistic understanding of this disease, medical management remains challenging, with poor long-term efficacy and few studies on long-term outcomes, such as skeletal growth.

GENETIC TESTING HAS LIMITED VALUE

Although genetic testing for GNAS mutations is available, the mosaic nature of McCune-Albright syndrome makes the detection of mutant alleles in affected tissues and circulating cells exceedingly difficult.^1,4 These constraints, coupled with high costs, have limited the clinical utility of genetic testing at present. In addition, the lack of a known genotype-phenotype correlation in this syndrome limits the value of genetic testing.¹ In the future, improvements in molecular techniques may make genetic testing more useful in the diagnosis and management of McCune-Albright syndrome, especially if clinically relevant genotype-phenotype correlates are identified.⁴ At this time, although genetic testing is not a standard of care, genetic counseling should be offered to all patients with this syndrome.

During a routine examination, a 17-year-old boy was noted to have unilateral hyperpigmented patches on his left neck, shoulder, and back. The lesions had been present since birth, had not changed in size or color, and were asymptomatic. His mother had noted an increase in the size of his left jaw starting at age 1.

The hyperpigmented patches had irregular borders (Figure 1). The skin was otherwise clear. Laboratory testing from 5 years earlier showed normal levels of dehydroepiandrosterone, prolactin, parathyroid hormone, thyroxine, and thyroid-stimulating hormone. Computed tomography showed a “ground-glass” appearance of the bones at the base of the skull, consistent with polyostotic fibrous dysplasia (Figure 2).

Q: Which is the most likely diagnosis?

• Neurofibromatosis
• Congenital melanocytic nevus
• McCune-Albright syndrome
• Tuberous sclerosis

A: This patient had typical features of McCune-Albright syndrome (or Albright syndrome), the classic triad of fibrous dysplasia of bone, large unilateral café-au-lait macules or patches, and precocious puberty or other endocrinopathy.¹ The syndrome is rare, with an estimated prevalence of 1/100,000 to 1/1,000,000.² It results from somatic mutation of the GNAS gene (chromosome 20q13) during embryonic development, which causes constitutive activation of intracellular cyclic adenosine monophosphate (cAMP) signaling and cellular dysplasia.³

THE DIAGNOSIS IS CLINICAL

McCune-Albright syndrome is a clinical diagnosis based on the presence of at least two features of the classic triad.^1,4

Other conditions, such as neurofibromatosis, also cause café-au-lait macules in children; but the lesions of McCune-Albright syndrome are fewer in number, larger, and darker and may follow Blaschko lines, with a linear or segmental configuration.⁵ McCune-Albright lesions tend to have jagged, “coast-of-Maine” borders, as opposed to the smoother “coast-of-California” borders of the lesions of neurofibromatosis.¹

Nevertheless, because café-au-lait macules of McCune-Albright syndrome are sometimes indistinguishable from those of neurofibromatosis, the endocrine and skeletal manifestations are essential to making the diagnosis.⁵

SIGNS OF GENETIC MOSAICISM

The somatic (postzygotic) nature of the GNAS mutation means that patients have normal and abnormal cell lines, ie, mosaicism. Therefore, the extent of disease depends on the precise stage in development during which the mutation occurred. This determines which tissues contain mutated cells and the proportion and distribution of affected cells at these loci.^1,4

In addition, differential sensitivity to cAMP signaling between cell types and tissue-specific imprinting of GNAS may contribute to the phenotypic variation seen in McCune-Albright syndrome.⁴ This means that the clinical features often vary, and the classic clinical triad is not always present.⁶

The most common clinical features are fibrous dysplasia, which occurs in 46% to 98% of patients, and café-au-lait macules, which occur in 53.1% to 92.5% of patients.^1,2 Fibrous dysplasia is typically polyostotic, ie, it involves multiple skeletal sites, with the proximal femur and skull base being the most common.⁶ It presents as bone pain, asymmetry, or pathologic fracture (or a combination of these) and shows a characteristic “ground-glass” appearance on computed tomography (Figure 2).¹ Café-au-lait lesions present at birth or shortly thereafter are often unappreciated as a potential presenting sign.¹ These hyperpigmented lesions are typically large and unilateral, often favoring the forehead, nuchal area, sacrum, and buttocks.^5.6

Precocious puberty is the most common endocrinopathy in McCune-Albright syndrome, seen in 64% to 79% of cases, and is more common in girls than in boys.² Other associated endocrinopathies include hyperthyroidism (20% to 30%), excess growth hormone, renal phosphate wasting, and Cushing syndrome.^1,6

SCREEN FOR OTHER MANIFESTATIONS

McCune-Albright syndrome can involve a broad spectrum of tissues. Therefore, once the diagnosis is made, the patient should be thoroughly evaluated for other manifestations.¹ The evaluation may include imaging studies and biochemical testing and may necessitate referral to an endocrinologist, a radiologist, and an orthopedic surgeon.

Young girls with premature vaginal bleeding or recurrent follicular cysts should always be evaluated for McCune-Albright syndrome, since ovarian enlargement can be mistaken for an ovarian tumor.⁷ Likewise, adults with isolated fibrous dysplasia or large unilateral café-au-lait macules should also be evaluated, since patients with McCune-Albright syndrome have a normal life span and so may present later in life.^4,6

TREATMENT

Drug treatment of this syndrome aims to block the effects of prolonged exposure of end-organs to sex steroids. Since precocious puberty of McCune-Alright syndrome is typically peripheral in origin, it is unresponsive to gonadotropin-releasing hormone agonist drugs; instead, aromatase inhibitors (testolactone) with antiestrogens (tamoxifen) may be used in girls, or antiandrogens (spironolactone) in boys.⁸

Unfortunately, despite our advanced mechanistic understanding of this disease, medical management remains challenging, with poor long-term efficacy and few studies on long-term outcomes, such as skeletal growth.

GENETIC TESTING HAS LIMITED VALUE

Although genetic testing for GNAS mutations is available, the mosaic nature of McCune-Albright syndrome makes the detection of mutant alleles in affected tissues and circulating cells exceedingly difficult.^1,4 These constraints, coupled with high costs, have limited the clinical utility of genetic testing at present. In addition, the lack of a known genotype-phenotype correlation in this syndrome limits the value of genetic testing.¹ In the future, improvements in molecular techniques may make genetic testing more useful in the diagnosis and management of McCune-Albright syndrome, especially if clinically relevant genotype-phenotype correlates are identified.⁴ At this time, although genetic testing is not a standard of care, genetic counseling should be offered to all patients with this syndrome.

During a routine examination, a 17-year-old boy was noted to have unilateral hyperpigmented patches on his left neck, shoulder, and back. The lesions had been present since birth, had not changed in size or color, and were asymptomatic. His mother had noted an increase in the size of his left jaw starting at age 1.

The hyperpigmented patches had irregular borders (Figure 1). The skin was otherwise clear. Laboratory testing from 5 years earlier showed normal levels of dehydroepiandrosterone, prolactin, parathyroid hormone, thyroxine, and thyroid-stimulating hormone. Computed tomography showed a “ground-glass” appearance of the bones at the base of the skull, consistent with polyostotic fibrous dysplasia (Figure 2).

Q: Which is the most likely diagnosis?

• Neurofibromatosis
• Congenital melanocytic nevus
• McCune-Albright syndrome
• Tuberous sclerosis

A: This patient had typical features of McCune-Albright syndrome (or Albright syndrome), the classic triad of fibrous dysplasia of bone, large unilateral café-au-lait macules or patches, and precocious puberty or other endocrinopathy.¹ The syndrome is rare, with an estimated prevalence of 1/100,000 to 1/1,000,000.² It results from somatic mutation of the GNAS gene (chromosome 20q13) during embryonic development, which causes constitutive activation of intracellular cyclic adenosine monophosphate (cAMP) signaling and cellular dysplasia.³

THE DIAGNOSIS IS CLINICAL

McCune-Albright syndrome is a clinical diagnosis based on the presence of at least two features of the classic triad.^1,4

Other conditions, such as neurofibromatosis, also cause café-au-lait macules in children; but the lesions of McCune-Albright syndrome are fewer in number, larger, and darker and may follow Blaschko lines, with a linear or segmental configuration.⁵ McCune-Albright lesions tend to have jagged, “coast-of-Maine” borders, as opposed to the smoother “coast-of-California” borders of the lesions of neurofibromatosis.¹

Nevertheless, because café-au-lait macules of McCune-Albright syndrome are sometimes indistinguishable from those of neurofibromatosis, the endocrine and skeletal manifestations are essential to making the diagnosis.⁵

SIGNS OF GENETIC MOSAICISM

The somatic (postzygotic) nature of the GNAS mutation means that patients have normal and abnormal cell lines, ie, mosaicism. Therefore, the extent of disease depends on the precise stage in development during which the mutation occurred. This determines which tissues contain mutated cells and the proportion and distribution of affected cells at these loci.^1,4

In addition, differential sensitivity to cAMP signaling between cell types and tissue-specific imprinting of GNAS may contribute to the phenotypic variation seen in McCune-Albright syndrome.⁴ This means that the clinical features often vary, and the classic clinical triad is not always present.⁶

The most common clinical features are fibrous dysplasia, which occurs in 46% to 98% of patients, and café-au-lait macules, which occur in 53.1% to 92.5% of patients.^1,2 Fibrous dysplasia is typically polyostotic, ie, it involves multiple skeletal sites, with the proximal femur and skull base being the most common.⁶ It presents as bone pain, asymmetry, or pathologic fracture (or a combination of these) and shows a characteristic “ground-glass” appearance on computed tomography (Figure 2).¹ Café-au-lait lesions present at birth or shortly thereafter are often unappreciated as a potential presenting sign.¹ These hyperpigmented lesions are typically large and unilateral, often favoring the forehead, nuchal area, sacrum, and buttocks.^5.6

Precocious puberty is the most common endocrinopathy in McCune-Albright syndrome, seen in 64% to 79% of cases, and is more common in girls than in boys.² Other associated endocrinopathies include hyperthyroidism (20% to 30%), excess growth hormone, renal phosphate wasting, and Cushing syndrome.^1,6

SCREEN FOR OTHER MANIFESTATIONS

McCune-Albright syndrome can involve a broad spectrum of tissues. Therefore, once the diagnosis is made, the patient should be thoroughly evaluated for other manifestations.¹ The evaluation may include imaging studies and biochemical testing and may necessitate referral to an endocrinologist, a radiologist, and an orthopedic surgeon.

Young girls with premature vaginal bleeding or recurrent follicular cysts should always be evaluated for McCune-Albright syndrome, since ovarian enlargement can be mistaken for an ovarian tumor.⁷ Likewise, adults with isolated fibrous dysplasia or large unilateral café-au-lait macules should also be evaluated, since patients with McCune-Albright syndrome have a normal life span and so may present later in life.^4,6

TREATMENT

Drug treatment of this syndrome aims to block the effects of prolonged exposure of end-organs to sex steroids. Since precocious puberty of McCune-Alright syndrome is typically peripheral in origin, it is unresponsive to gonadotropin-releasing hormone agonist drugs; instead, aromatase inhibitors (testolactone) with antiestrogens (tamoxifen) may be used in girls, or antiandrogens (spironolactone) in boys.⁸

Unfortunately, despite our advanced mechanistic understanding of this disease, medical management remains challenging, with poor long-term efficacy and few studies on long-term outcomes, such as skeletal growth.

GENETIC TESTING HAS LIMITED VALUE

Although genetic testing for GNAS mutations is available, the mosaic nature of McCune-Albright syndrome makes the detection of mutant alleles in affected tissues and circulating cells exceedingly difficult.^1,4 These constraints, coupled with high costs, have limited the clinical utility of genetic testing at present. In addition, the lack of a known genotype-phenotype correlation in this syndrome limits the value of genetic testing.¹ In the future, improvements in molecular techniques may make genetic testing more useful in the diagnosis and management of McCune-Albright syndrome, especially if clinically relevant genotype-phenotype correlates are identified.⁴ At this time, although genetic testing is not a standard of care, genetic counseling should be offered to all patients with this syndrome.