Caution must be used when prescribing direct oral anticoagulants to older patients, especially those in a frail condition, according to an opinion piece by Anne-Laure Sennesael and her associates.

In the case study, an 86-year-old woman weighing 55 kg was admitted to an emergency department with persistent epistaxis. The patient was taking 20 mg of rivaroxaban and 80 mg of aspirin daily. There was a history of peripheral arterial disease, and the patient had received a bioprosthetic heart implant 4 years prior. Creatinine clearance was 21 mL/min, hemoglobin was 9.4 g/dL, and prothrombin time Quick value was 30%.

Rivaroxaban was discontinued, and the patient was switched to a new anticoagulant, acenocoumarol. Aspirin also was discontinued, and the patient was discharged, reported Ms. Sennesael, of the Université catholique de Louvain in Brussels.

Use of direct oral anticoagulants (DOACs) are increasing rapidly, the authors write, mostly because doctors and patients view them as more convenient to use. However, in some patients, vitamin K antagonists (VKAs) remain the best course of treatment. In this case, the patient was receiving too much rivaroxaban in light of her low creatinine level. In addition, aspirin plus a DOAC is not appropriate, as it increases the risk of major bleeding significantly.

“A conservative strategy may be more valuable,” Ms. Sennesael and her associates wrote. “This kind of ‘less is more’ approach includes avoiding prescribing DOACs rather than VKAs without clear, compelling, evidence-based reasons; regularly reassessing renal function; monitoring for adverse effects; and reappraising aspirin prescription.”

Read the full study at JAMA Internal Medicine (doi:10.1001/jamainternmed.2015.3589).

[email protected]

Caution must be used when prescribing direct oral anticoagulants to older patients, especially those in a frail condition, according to an opinion piece by Anne-Laure Sennesael and her associates.

In the case study, an 86-year-old woman weighing 55 kg was admitted to an emergency department with persistent epistaxis. The patient was taking 20 mg of rivaroxaban and 80 mg of aspirin daily. There was a history of peripheral arterial disease, and the patient had received a bioprosthetic heart implant 4 years prior. Creatinine clearance was 21 mL/min, hemoglobin was 9.4 g/dL, and prothrombin time Quick value was 30%.

Rivaroxaban was discontinued, and the patient was switched to a new anticoagulant, acenocoumarol. Aspirin also was discontinued, and the patient was discharged, reported Ms. Sennesael, of the Université catholique de Louvain in Brussels.

Use of direct oral anticoagulants (DOACs) are increasing rapidly, the authors write, mostly because doctors and patients view them as more convenient to use. However, in some patients, vitamin K antagonists (VKAs) remain the best course of treatment. In this case, the patient was receiving too much rivaroxaban in light of her low creatinine level. In addition, aspirin plus a DOAC is not appropriate, as it increases the risk of major bleeding significantly.

“A conservative strategy may be more valuable,” Ms. Sennesael and her associates wrote. “This kind of ‘less is more’ approach includes avoiding prescribing DOACs rather than VKAs without clear, compelling, evidence-based reasons; regularly reassessing renal function; monitoring for adverse effects; and reappraising aspirin prescription.”

Read the full study at JAMA Internal Medicine (doi:10.1001/jamainternmed.2015.3589).

[email protected]

Caution must be used when prescribing direct oral anticoagulants to older patients, especially those in a frail condition, according to an opinion piece by Anne-Laure Sennesael and her associates.

In the case study, an 86-year-old woman weighing 55 kg was admitted to an emergency department with persistent epistaxis. The patient was taking 20 mg of rivaroxaban and 80 mg of aspirin daily. There was a history of peripheral arterial disease, and the patient had received a bioprosthetic heart implant 4 years prior. Creatinine clearance was 21 mL/min, hemoglobin was 9.4 g/dL, and prothrombin time Quick value was 30%.

Rivaroxaban was discontinued, and the patient was switched to a new anticoagulant, acenocoumarol. Aspirin also was discontinued, and the patient was discharged, reported Ms. Sennesael, of the Université catholique de Louvain in Brussels.

Use of direct oral anticoagulants (DOACs) are increasing rapidly, the authors write, mostly because doctors and patients view them as more convenient to use. However, in some patients, vitamin K antagonists (VKAs) remain the best course of treatment. In this case, the patient was receiving too much rivaroxaban in light of her low creatinine level. In addition, aspirin plus a DOAC is not appropriate, as it increases the risk of major bleeding significantly.

“A conservative strategy may be more valuable,” Ms. Sennesael and her associates wrote. “This kind of ‘less is more’ approach includes avoiding prescribing DOACs rather than VKAs without clear, compelling, evidence-based reasons; regularly reassessing renal function; monitoring for adverse effects; and reappraising aspirin prescription.”

Read the full study at JAMA Internal Medicine (doi:10.1001/jamainternmed.2015.3589).

[email protected]

CHICAGO – For some patients, surveillance of low-risk abdominal aortic aneurysms is so stressful that early repair might be a better option.

Until now, though, it’s been hard to know who those patients are. There hasn’t been a way to quantify the impact of abdominal aortic aneurysm (AAA) surveillance on quality of life.

Dr. Bjoern Suckow, a vascular surgeon at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., and his colleagues at the University of Massachusetts and elsewhere are working to fix that problem. “I do believe that there is a certain subset of patients who we know are” at low risk for rupture “who are so consumed by fear and anxiety during surveillance that the impact on quality of life might make us want to repair them slightly sooner. I hope this will help us weed out who that subgroup might be,” Dr. Suckow said at a meeting hosted by the Society for Vascular Surgery.

Alexander Otto/Frontline Medical News

With the help of patient and physician focus groups and interviews, the team developed AAA-specific quality of life (QOL) surveys and administered them to 351 patients under surveillance for aneurysms below about 5.5 cm, and 657 who had undergone mostly endovascular AAA repair at six United States institutions.

The surveys included nine questions to assess concerns about rupture, surgery, costs, and death. The responses were averaged to give an emotional impact score (EIS) ranging from 0 to 100, with higher scores indicating worse emotional QOL. The survey also included 10 questions to assess changes in heavy lifting, strenuous activity, travel habits, and other behaviors. Those results were averaged to give a behavioral change score (BCS) that also ranged from 0 to 100, with higher scores indicating greater negative impact.

A significant portion of the surveillance patients thought it was “very likely” their aneurysm would rupture within a year; their EIS was 45 and BCS 30; patients who thought rupture was unlikely had an EIS of 12 and BCS of 13 (P less than .001). Overall, patients under surveillance had worse emotional impact sores than did those who had undergone repair.

“We routinely counsel patients with small aneurysms that the rupture risk is low” – less than 5% – “and outweighed by the higher risk of repair. We were surprised that even though we feel we do a great job counseling and educating our patients, some of them do not understand or retain what we mean.” Eventually, surveys could be used in the clinic to identify patients with “less understanding, so [we can] spend more time with them,” Dr. Suckow said.

In general, “the range of impact on QOL by AAA surveillance is broad. For most patients, the impact is minimal, but for some, especially those with a greater perceived rupture risk, it is severe. Overall, surveillance has a persistent negative impact on QOL, particularly emotional QOL. This impact appears to diminish following either open or endovascular repair,” he said.

The respondents were about 76 years old, on average. Most were white men, and about half were high school graduates.

Dr. Suckow has no relevant financial conflicts. The work was funded by the National Institutes of Health and career development awards from the Society for Vascular Surgery and the American College of Surgeons.

[email protected]

CHICAGO – For some patients, surveillance of low-risk abdominal aortic aneurysms is so stressful that early repair might be a better option.

Until now, though, it’s been hard to know who those patients are. There hasn’t been a way to quantify the impact of abdominal aortic aneurysm (AAA) surveillance on quality of life.

Dr. Bjoern Suckow, a vascular surgeon at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., and his colleagues at the University of Massachusetts and elsewhere are working to fix that problem. “I do believe that there is a certain subset of patients who we know are” at low risk for rupture “who are so consumed by fear and anxiety during surveillance that the impact on quality of life might make us want to repair them slightly sooner. I hope this will help us weed out who that subgroup might be,” Dr. Suckow said at a meeting hosted by the Society for Vascular Surgery.

Alexander Otto/Frontline Medical News

With the help of patient and physician focus groups and interviews, the team developed AAA-specific quality of life (QOL) surveys and administered them to 351 patients under surveillance for aneurysms below about 5.5 cm, and 657 who had undergone mostly endovascular AAA repair at six United States institutions.

The surveys included nine questions to assess concerns about rupture, surgery, costs, and death. The responses were averaged to give an emotional impact score (EIS) ranging from 0 to 100, with higher scores indicating worse emotional QOL. The survey also included 10 questions to assess changes in heavy lifting, strenuous activity, travel habits, and other behaviors. Those results were averaged to give a behavioral change score (BCS) that also ranged from 0 to 100, with higher scores indicating greater negative impact.

A significant portion of the surveillance patients thought it was “very likely” their aneurysm would rupture within a year; their EIS was 45 and BCS 30; patients who thought rupture was unlikely had an EIS of 12 and BCS of 13 (P less than .001). Overall, patients under surveillance had worse emotional impact sores than did those who had undergone repair.

“We routinely counsel patients with small aneurysms that the rupture risk is low” – less than 5% – “and outweighed by the higher risk of repair. We were surprised that even though we feel we do a great job counseling and educating our patients, some of them do not understand or retain what we mean.” Eventually, surveys could be used in the clinic to identify patients with “less understanding, so [we can] spend more time with them,” Dr. Suckow said.

In general, “the range of impact on QOL by AAA surveillance is broad. For most patients, the impact is minimal, but for some, especially those with a greater perceived rupture risk, it is severe. Overall, surveillance has a persistent negative impact on QOL, particularly emotional QOL. This impact appears to diminish following either open or endovascular repair,” he said.

The respondents were about 76 years old, on average. Most were white men, and about half were high school graduates.

Dr. Suckow has no relevant financial conflicts. The work was funded by the National Institutes of Health and career development awards from the Society for Vascular Surgery and the American College of Surgeons.

[email protected]

CHICAGO – For some patients, surveillance of low-risk abdominal aortic aneurysms is so stressful that early repair might be a better option.

Until now, though, it’s been hard to know who those patients are. There hasn’t been a way to quantify the impact of abdominal aortic aneurysm (AAA) surveillance on quality of life.

Dr. Bjoern Suckow, a vascular surgeon at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., and his colleagues at the University of Massachusetts and elsewhere are working to fix that problem. “I do believe that there is a certain subset of patients who we know are” at low risk for rupture “who are so consumed by fear and anxiety during surveillance that the impact on quality of life might make us want to repair them slightly sooner. I hope this will help us weed out who that subgroup might be,” Dr. Suckow said at a meeting hosted by the Society for Vascular Surgery.

Alexander Otto/Frontline Medical News

With the help of patient and physician focus groups and interviews, the team developed AAA-specific quality of life (QOL) surveys and administered them to 351 patients under surveillance for aneurysms below about 5.5 cm, and 657 who had undergone mostly endovascular AAA repair at six United States institutions.

The surveys included nine questions to assess concerns about rupture, surgery, costs, and death. The responses were averaged to give an emotional impact score (EIS) ranging from 0 to 100, with higher scores indicating worse emotional QOL. The survey also included 10 questions to assess changes in heavy lifting, strenuous activity, travel habits, and other behaviors. Those results were averaged to give a behavioral change score (BCS) that also ranged from 0 to 100, with higher scores indicating greater negative impact.

A significant portion of the surveillance patients thought it was “very likely” their aneurysm would rupture within a year; their EIS was 45 and BCS 30; patients who thought rupture was unlikely had an EIS of 12 and BCS of 13 (P less than .001). Overall, patients under surveillance had worse emotional impact sores than did those who had undergone repair.

“We routinely counsel patients with small aneurysms that the rupture risk is low” – less than 5% – “and outweighed by the higher risk of repair. We were surprised that even though we feel we do a great job counseling and educating our patients, some of them do not understand or retain what we mean.” Eventually, surveys could be used in the clinic to identify patients with “less understanding, so [we can] spend more time with them,” Dr. Suckow said.

In general, “the range of impact on QOL by AAA surveillance is broad. For most patients, the impact is minimal, but for some, especially those with a greater perceived rupture risk, it is severe. Overall, surveillance has a persistent negative impact on QOL, particularly emotional QOL. This impact appears to diminish following either open or endovascular repair,” he said.

The respondents were about 76 years old, on average. Most were white men, and about half were high school graduates.

Dr. Suckow has no relevant financial conflicts. The work was funded by the National Institutes of Health and career development awards from the Society for Vascular Surgery and the American College of Surgeons.

[email protected]

Venoplasties and stenting carried out in an office-based setting have the same therapeutic results and carry no greater risk as the same procedure done in an inpatient setting, researchers reported.

Dr. Arkady Ganelin and researchers from the Total Vascular Center in Brooklyn, N.Y. evaluated 245 patients who had undergone venography for the correction of suspected iliac vein stenosis at their office-based center. Overall, 90 women and 47 men underwent unilateral intervention and 23 women and 14 men underwent bilateral intervention.

There was a low incidence of complications such as thrombosis (2%), a figure that was similar to an inpatient setting, the researchers reported (J Vasc Surg: Venous and Lym Dis. 2015 doi: 10.1016/j.jvsv.2015.03.007).

One patient had a retroperitoneal hematoma, which occurred more than 30 days after the procedure. The average pain score was 2 out of 10 on the Likert scale.

“Our initial experience with conducting office-based procedures that were formerly only inpatient procedures has demonstrated that an office-based procedure can be safely performed with minimal complications,” the study authors wrote.

The financial burden of U.S. health care has been continuously increasing and the shift of endovascular procedures from the hospital to an office-based setting is the natural next step, they said.

If the results are sustained over the long term, office-based iliac venography and stent placement may replace the need of performing these procedures in the hospital, they concluded.

This conclusion, however, poses the question of which option would be chosen by a patient, they added.

The researchers reported having no financial disclosures.

Venoplasties and stenting carried out in an office-based setting have the same therapeutic results and carry no greater risk as the same procedure done in an inpatient setting, researchers reported.

Dr. Arkady Ganelin and researchers from the Total Vascular Center in Brooklyn, N.Y. evaluated 245 patients who had undergone venography for the correction of suspected iliac vein stenosis at their office-based center. Overall, 90 women and 47 men underwent unilateral intervention and 23 women and 14 men underwent bilateral intervention.

There was a low incidence of complications such as thrombosis (2%), a figure that was similar to an inpatient setting, the researchers reported (J Vasc Surg: Venous and Lym Dis. 2015 doi: 10.1016/j.jvsv.2015.03.007).

One patient had a retroperitoneal hematoma, which occurred more than 30 days after the procedure. The average pain score was 2 out of 10 on the Likert scale.

“Our initial experience with conducting office-based procedures that were formerly only inpatient procedures has demonstrated that an office-based procedure can be safely performed with minimal complications,” the study authors wrote.

The financial burden of U.S. health care has been continuously increasing and the shift of endovascular procedures from the hospital to an office-based setting is the natural next step, they said.

If the results are sustained over the long term, office-based iliac venography and stent placement may replace the need of performing these procedures in the hospital, they concluded.

This conclusion, however, poses the question of which option would be chosen by a patient, they added.

The researchers reported having no financial disclosures.

Venoplasties and stenting carried out in an office-based setting have the same therapeutic results and carry no greater risk as the same procedure done in an inpatient setting, researchers reported.

Dr. Arkady Ganelin and researchers from the Total Vascular Center in Brooklyn, N.Y. evaluated 245 patients who had undergone venography for the correction of suspected iliac vein stenosis at their office-based center. Overall, 90 women and 47 men underwent unilateral intervention and 23 women and 14 men underwent bilateral intervention.

There was a low incidence of complications such as thrombosis (2%), a figure that was similar to an inpatient setting, the researchers reported (J Vasc Surg: Venous and Lym Dis. 2015 doi: 10.1016/j.jvsv.2015.03.007).

One patient had a retroperitoneal hematoma, which occurred more than 30 days after the procedure. The average pain score was 2 out of 10 on the Likert scale.

“Our initial experience with conducting office-based procedures that were formerly only inpatient procedures has demonstrated that an office-based procedure can be safely performed with minimal complications,” the study authors wrote.

The financial burden of U.S. health care has been continuously increasing and the shift of endovascular procedures from the hospital to an office-based setting is the natural next step, they said.

If the results are sustained over the long term, office-based iliac venography and stent placement may replace the need of performing these procedures in the hospital, they concluded.

This conclusion, however, poses the question of which option would be chosen by a patient, they added.

The researchers reported having no financial disclosures.

(Reuters Health) - Overweight and obese people with type 2 diabetes may feel better after a meal if they start it off with vegetables or proteins and end with the carbs, suggests a new study of 11 people.

Finishing the broccoli and chicken before tucking into bread and fruit juice was tied to a lower rise in blood sugar levels over the next two hours, compared to eating the same foods in the opposite order, researchers report in Diabetes Care.

"When we saw the result, we were really encouraged that this is something that could potentially benefit people," said Dr.Louis Aronne, the study's senior author from Weill Cornell Medical College in New York.

Approximately 29 million Americans - about 9 percent of the U.S. population - have diabetes, according to the Centers for Disease Control and Prevention. About 30 percent of those people are undiagnosed.

Type 2 is the most common form of diabetes and is often linked to obesity. In type 2 diabetes, the body's cells are resistant to the hormone insulin, or the body doesn't make enough of it. Insulin helps the body's cells use glucose in the blood for fuel.

Drinking whey protein shakes before meals has been linked to lower blood sugar levels after eating, but little was known about the influence of foods, and the order in which they're consumed, on blood sugar levels following a meal, the researchers write.

Blood sugar normally rises after eating, but for people with diabetes it can spike dangerously. Diabetics are often told to avoid foods high on the glycemic index - a measure of how rapidly a food gets converted to glucose in the blood - like white breads and sugary drinks.

The new research suggests that people may benefit from timing their consumption of carbohydrates during a meal instead of simply avoiding certain foods.

The researchers recruited 11 people with type 2 diabetes who were all overweight or obese. They were also taking a drug called metformin, which helps to control blood sugar.

The participants all fasted for 12 hours overnight before consuming a 628 calorie meal with protein, carbohydrates and fat.

One week, they consumed the carbohydrates (ciabatta bread and orange juice) first. Then they ate skinless grilled chicken, a small salad and buttered steamed broccoli 15 minutes later.

The participants ate the same meal a week later, but the order of the foods was reversed, with the salad and broccoli first, then the chicken, then the carbs.

The researchers also took blood samples before the meals and 30, 60 and 120 minutes afterward.

When the participants ate vegetables and proteins first, their blood sugar levels were about 29 percent lower 30 minutes after starting the meal, compared to when they ate the carbs first. At 60 and 120 minutes after participants began eating, blood sugar levels were 37 percent and 17 percent lower, respectively, compared to when the carbs came first.

"It's possible what this is doing is delaying or tempering how fast the carbohydrates get absorbed," said Dr. Sethu Reddy, chief of the Adult Diabetes Section at the Joslin Diabetes Center in Boston.

"I think certainly it's an interesting study that says eating a good salad before your meal may help with glucose absorption," said Reddy, who was not involved with the new study.

The new study may not be the full story, Reddy told Reuters Health. For example, he said, it will be important to see what happens beyond two hours, and what's happening to the carbohydrates.

The researchers also say more studies with longer follow-up times are needed.

"We're doing the next study," Aronne told Reuters Health. "We're doing a longer study and we're looking at some of the other key hormones."

As of now, he said, the theory is that the absorption of the carbohydrates is somehow slowed down by eating vegetables, which are low on the glycemic index.

"This shows that the highly desired foods can be a part of a diet if we sneak them in there," Aronne said.

(Reuters Health) - Overweight and obese people with type 2 diabetes may feel better after a meal if they start it off with vegetables or proteins and end with the carbs, suggests a new study of 11 people.

Finishing the broccoli and chicken before tucking into bread and fruit juice was tied to a lower rise in blood sugar levels over the next two hours, compared to eating the same foods in the opposite order, researchers report in Diabetes Care.

"When we saw the result, we were really encouraged that this is something that could potentially benefit people," said Dr.Louis Aronne, the study's senior author from Weill Cornell Medical College in New York.

Approximately 29 million Americans - about 9 percent of the U.S. population - have diabetes, according to the Centers for Disease Control and Prevention. About 30 percent of those people are undiagnosed.

Type 2 is the most common form of diabetes and is often linked to obesity. In type 2 diabetes, the body's cells are resistant to the hormone insulin, or the body doesn't make enough of it. Insulin helps the body's cells use glucose in the blood for fuel.

Drinking whey protein shakes before meals has been linked to lower blood sugar levels after eating, but little was known about the influence of foods, and the order in which they're consumed, on blood sugar levels following a meal, the researchers write.

Blood sugar normally rises after eating, but for people with diabetes it can spike dangerously. Diabetics are often told to avoid foods high on the glycemic index - a measure of how rapidly a food gets converted to glucose in the blood - like white breads and sugary drinks.

The new research suggests that people may benefit from timing their consumption of carbohydrates during a meal instead of simply avoiding certain foods.

The researchers recruited 11 people with type 2 diabetes who were all overweight or obese. They were also taking a drug called metformin, which helps to control blood sugar.

The participants all fasted for 12 hours overnight before consuming a 628 calorie meal with protein, carbohydrates and fat.

One week, they consumed the carbohydrates (ciabatta bread and orange juice) first. Then they ate skinless grilled chicken, a small salad and buttered steamed broccoli 15 minutes later.

The participants ate the same meal a week later, but the order of the foods was reversed, with the salad and broccoli first, then the chicken, then the carbs.

The researchers also took blood samples before the meals and 30, 60 and 120 minutes afterward.

When the participants ate vegetables and proteins first, their blood sugar levels were about 29 percent lower 30 minutes after starting the meal, compared to when they ate the carbs first. At 60 and 120 minutes after participants began eating, blood sugar levels were 37 percent and 17 percent lower, respectively, compared to when the carbs came first.

"It's possible what this is doing is delaying or tempering how fast the carbohydrates get absorbed," said Dr. Sethu Reddy, chief of the Adult Diabetes Section at the Joslin Diabetes Center in Boston.

"I think certainly it's an interesting study that says eating a good salad before your meal may help with glucose absorption," said Reddy, who was not involved with the new study.

The new study may not be the full story, Reddy told Reuters Health. For example, he said, it will be important to see what happens beyond two hours, and what's happening to the carbohydrates.

The researchers also say more studies with longer follow-up times are needed.

"We're doing the next study," Aronne told Reuters Health. "We're doing a longer study and we're looking at some of the other key hormones."

As of now, he said, the theory is that the absorption of the carbohydrates is somehow slowed down by eating vegetables, which are low on the glycemic index.

"This shows that the highly desired foods can be a part of a diet if we sneak them in there," Aronne said.

(Reuters Health) - Overweight and obese people with type 2 diabetes may feel better after a meal if they start it off with vegetables or proteins and end with the carbs, suggests a new study of 11 people.

Finishing the broccoli and chicken before tucking into bread and fruit juice was tied to a lower rise in blood sugar levels over the next two hours, compared to eating the same foods in the opposite order, researchers report in Diabetes Care.

"When we saw the result, we were really encouraged that this is something that could potentially benefit people," said Dr.Louis Aronne, the study's senior author from Weill Cornell Medical College in New York.

Approximately 29 million Americans - about 9 percent of the U.S. population - have diabetes, according to the Centers for Disease Control and Prevention. About 30 percent of those people are undiagnosed.

Type 2 is the most common form of diabetes and is often linked to obesity. In type 2 diabetes, the body's cells are resistant to the hormone insulin, or the body doesn't make enough of it. Insulin helps the body's cells use glucose in the blood for fuel.

Drinking whey protein shakes before meals has been linked to lower blood sugar levels after eating, but little was known about the influence of foods, and the order in which they're consumed, on blood sugar levels following a meal, the researchers write.

Blood sugar normally rises after eating, but for people with diabetes it can spike dangerously. Diabetics are often told to avoid foods high on the glycemic index - a measure of how rapidly a food gets converted to glucose in the blood - like white breads and sugary drinks.

The new research suggests that people may benefit from timing their consumption of carbohydrates during a meal instead of simply avoiding certain foods.

The researchers recruited 11 people with type 2 diabetes who were all overweight or obese. They were also taking a drug called metformin, which helps to control blood sugar.

The participants all fasted for 12 hours overnight before consuming a 628 calorie meal with protein, carbohydrates and fat.

One week, they consumed the carbohydrates (ciabatta bread and orange juice) first. Then they ate skinless grilled chicken, a small salad and buttered steamed broccoli 15 minutes later.

The participants ate the same meal a week later, but the order of the foods was reversed, with the salad and broccoli first, then the chicken, then the carbs.

The researchers also took blood samples before the meals and 30, 60 and 120 minutes afterward.

When the participants ate vegetables and proteins first, their blood sugar levels were about 29 percent lower 30 minutes after starting the meal, compared to when they ate the carbs first. At 60 and 120 minutes after participants began eating, blood sugar levels were 37 percent and 17 percent lower, respectively, compared to when the carbs came first.

"It's possible what this is doing is delaying or tempering how fast the carbohydrates get absorbed," said Dr. Sethu Reddy, chief of the Adult Diabetes Section at the Joslin Diabetes Center in Boston.

"I think certainly it's an interesting study that says eating a good salad before your meal may help with glucose absorption," said Reddy, who was not involved with the new study.

The new study may not be the full story, Reddy told Reuters Health. For example, he said, it will be important to see what happens beyond two hours, and what's happening to the carbohydrates.

The researchers also say more studies with longer follow-up times are needed.

"We're doing the next study," Aronne told Reuters Health. "We're doing a longer study and we're looking at some of the other key hormones."

As of now, he said, the theory is that the absorption of the carbohydrates is somehow slowed down by eating vegetables, which are low on the glycemic index.

"This shows that the highly desired foods can be a part of a diet if we sneak them in there," Aronne said.

A 10-year-old girl is seen in dermatology for evaluation of dry skin. She reports few if any symptoms but expresses frustration at her inability to curb the problem; she’s tried several different moisturizers to no avail.

Additional history-taking reveals that she’s had patches of dry skin since age 4; these have appeared and disappeared on her arms, legs, and neck. None has ever been problematic enough to require medical attention.

But recently, a dry patch manifested on the patient’s forearm that her primary care provider diagnosed as fungal infection. Unfortunately, the prescribed antifungal creams (terbinafine and clotrimazole) had no positive impact on the situation.

The patient and her mother deny any family history of skin disease.

EXAMINATION
The scaly, annular plaque on the patient’s extensor left forearm is distinctly salmon-pink, with a tenacious white scale. Elsewhere, there are scaly areas in both post-auricular sulci. There are no significant changes to the skin on the patient’s knees, elbows, or scalp. Several tiny pits are observed on her fingernails.

What is the diagnosis?

DISCUSSION
It would be difficult to imagine a more clear-cut case of psoriasis: not only manifesting with a classic plaque on the left extensor forearm but also with corroboratory stigmata behind the ears and classic fingernail pits. Then why, you might ask, was the diagnosis missed?

Psoriasis has a classic look: annular borders, salmon-pink color, and thick, tenacious scale. Distribution matters, since the condition tends to manifest in specific areas, particularly the extensor portions of extremities. It’s helpful to know that psoriasis affects almost 3% of the white population in the United States, meaning that you will see it with considerable frequency. It would also help if you knew the diagnosis can be corroborated by identification of other, lesser known features.

But if you’re unaware of these facts, you won’t look for these things—and if you don’t look specifically for them, you won’t see them. Then, to add insult to injury, when you consult your bag of “diseases that present with annular borders and scaly surfaces,” you’ll find one item in your differential: fungal infection. When antifungal medications don’t work, you’ll find yourself stuck, because you simply don’t have any other diagnoses to consider.

I’ve known internists who have practiced for more than 25 years and still make this diagnostic mistake. So it’s not a matter of lack of intelligence. They simply do not invest the time to expand their knowledge of dermatologic conditions.

My job was to break the news to the patient and her mother about the diagnosis and, perhaps more importantly, her prognosis. The only good news is that the patient is living in the golden age of psoriasis treatment; if her condition flares, and even if she eventually develops psoriatic arthritis (as do almost 25% of psoriasis patients), we have terrific treatment for it.

I prescribed topical fluocinonide 0.05% ointment (for bid application) to address her plaque and scheduled a follow-up visit for one month later. Before she left, though, I had to address her most pressing question: “Why did my doctor say this was a fungal infection?” Good question indeed.

TAKE-HOME LEARNING POINTS
• Psoriasis is quite commonly seen in primary care, since it affects almost 3% of the white population.

• Psoriasis is the quintessential papulosquamous disorder, manifesting with salmon-pink scaly patches on extensor extremities, behind ears, and/or in scalp.

• The diagnosis may be corroborated by identification of pits in the fingernails (25% of cases).

• Confirmation of the diagnosis can be made by punch biopsy, which usually shows characteristic changes.

• The overarching learning point: Your differential for “round and scaly” needs more than one item in it.

A 10-year-old girl is seen in dermatology for evaluation of dry skin. She reports few if any symptoms but expresses frustration at her inability to curb the problem; she’s tried several different moisturizers to no avail.

Additional history-taking reveals that she’s had patches of dry skin since age 4; these have appeared and disappeared on her arms, legs, and neck. None has ever been problematic enough to require medical attention.

But recently, a dry patch manifested on the patient’s forearm that her primary care provider diagnosed as fungal infection. Unfortunately, the prescribed antifungal creams (terbinafine and clotrimazole) had no positive impact on the situation.

The patient and her mother deny any family history of skin disease.

EXAMINATION
The scaly, annular plaque on the patient’s extensor left forearm is distinctly salmon-pink, with a tenacious white scale. Elsewhere, there are scaly areas in both post-auricular sulci. There are no significant changes to the skin on the patient’s knees, elbows, or scalp. Several tiny pits are observed on her fingernails.

What is the diagnosis?

DISCUSSION
It would be difficult to imagine a more clear-cut case of psoriasis: not only manifesting with a classic plaque on the left extensor forearm but also with corroboratory stigmata behind the ears and classic fingernail pits. Then why, you might ask, was the diagnosis missed?

Psoriasis has a classic look: annular borders, salmon-pink color, and thick, tenacious scale. Distribution matters, since the condition tends to manifest in specific areas, particularly the extensor portions of extremities. It’s helpful to know that psoriasis affects almost 3% of the white population in the United States, meaning that you will see it with considerable frequency. It would also help if you knew the diagnosis can be corroborated by identification of other, lesser known features.

But if you’re unaware of these facts, you won’t look for these things—and if you don’t look specifically for them, you won’t see them. Then, to add insult to injury, when you consult your bag of “diseases that present with annular borders and scaly surfaces,” you’ll find one item in your differential: fungal infection. When antifungal medications don’t work, you’ll find yourself stuck, because you simply don’t have any other diagnoses to consider.

I’ve known internists who have practiced for more than 25 years and still make this diagnostic mistake. So it’s not a matter of lack of intelligence. They simply do not invest the time to expand their knowledge of dermatologic conditions.

My job was to break the news to the patient and her mother about the diagnosis and, perhaps more importantly, her prognosis. The only good news is that the patient is living in the golden age of psoriasis treatment; if her condition flares, and even if she eventually develops psoriatic arthritis (as do almost 25% of psoriasis patients), we have terrific treatment for it.

I prescribed topical fluocinonide 0.05% ointment (for bid application) to address her plaque and scheduled a follow-up visit for one month later. Before she left, though, I had to address her most pressing question: “Why did my doctor say this was a fungal infection?” Good question indeed.

TAKE-HOME LEARNING POINTS
• Psoriasis is quite commonly seen in primary care, since it affects almost 3% of the white population.

• Psoriasis is the quintessential papulosquamous disorder, manifesting with salmon-pink scaly patches on extensor extremities, behind ears, and/or in scalp.

• The diagnosis may be corroborated by identification of pits in the fingernails (25% of cases).

• Confirmation of the diagnosis can be made by punch biopsy, which usually shows characteristic changes.

• The overarching learning point: Your differential for “round and scaly” needs more than one item in it.

A 10-year-old girl is seen in dermatology for evaluation of dry skin. She reports few if any symptoms but expresses frustration at her inability to curb the problem; she’s tried several different moisturizers to no avail.

Additional history-taking reveals that she’s had patches of dry skin since age 4; these have appeared and disappeared on her arms, legs, and neck. None has ever been problematic enough to require medical attention.

But recently, a dry patch manifested on the patient’s forearm that her primary care provider diagnosed as fungal infection. Unfortunately, the prescribed antifungal creams (terbinafine and clotrimazole) had no positive impact on the situation.

The patient and her mother deny any family history of skin disease.

EXAMINATION
The scaly, annular plaque on the patient’s extensor left forearm is distinctly salmon-pink, with a tenacious white scale. Elsewhere, there are scaly areas in both post-auricular sulci. There are no significant changes to the skin on the patient’s knees, elbows, or scalp. Several tiny pits are observed on her fingernails.

What is the diagnosis?

DISCUSSION
It would be difficult to imagine a more clear-cut case of psoriasis: not only manifesting with a classic plaque on the left extensor forearm but also with corroboratory stigmata behind the ears and classic fingernail pits. Then why, you might ask, was the diagnosis missed?

Psoriasis has a classic look: annular borders, salmon-pink color, and thick, tenacious scale. Distribution matters, since the condition tends to manifest in specific areas, particularly the extensor portions of extremities. It’s helpful to know that psoriasis affects almost 3% of the white population in the United States, meaning that you will see it with considerable frequency. It would also help if you knew the diagnosis can be corroborated by identification of other, lesser known features.

But if you’re unaware of these facts, you won’t look for these things—and if you don’t look specifically for them, you won’t see them. Then, to add insult to injury, when you consult your bag of “diseases that present with annular borders and scaly surfaces,” you’ll find one item in your differential: fungal infection. When antifungal medications don’t work, you’ll find yourself stuck, because you simply don’t have any other diagnoses to consider.

I’ve known internists who have practiced for more than 25 years and still make this diagnostic mistake. So it’s not a matter of lack of intelligence. They simply do not invest the time to expand their knowledge of dermatologic conditions.

My job was to break the news to the patient and her mother about the diagnosis and, perhaps more importantly, her prognosis. The only good news is that the patient is living in the golden age of psoriasis treatment; if her condition flares, and even if she eventually develops psoriatic arthritis (as do almost 25% of psoriasis patients), we have terrific treatment for it.

I prescribed topical fluocinonide 0.05% ointment (for bid application) to address her plaque and scheduled a follow-up visit for one month later. Before she left, though, I had to address her most pressing question: “Why did my doctor say this was a fungal infection?” Good question indeed.

TAKE-HOME LEARNING POINTS
• Psoriasis is quite commonly seen in primary care, since it affects almost 3% of the white population.

• Psoriasis is the quintessential papulosquamous disorder, manifesting with salmon-pink scaly patches on extensor extremities, behind ears, and/or in scalp.

• The diagnosis may be corroborated by identification of pits in the fingernails (25% of cases).

• Confirmation of the diagnosis can be made by punch biopsy, which usually shows characteristic changes.

• The overarching learning point: Your differential for “round and scaly” needs more than one item in it.

A macrophage stretching its

pseudopodia to engulf particles

The transcription factor C/EBPα reprograms B cells into macrophages by “short-circuiting” the cells so they re-express genes reserved for embryonic development, according to research published in Stem Cell Reports.

Over the past 28 years, researchers have shown that a number of specialized cell types can be forcibly converted into other cell types, but the science of how this change takes place is still emerging.

“For a long time, it was unclear whether forcing cell fate decisions by expressing transcription factors in the wrong cell type could teach us something about what happens normally during physiological differentiation,” said Thomas Graf, PhD, of the Center for Genomic Regulation in Barcelona, Spain.

“What we have now found is that the two processes are actually surprisingly similar.”

The researchers found that B-cell transdifferentiation takes place when C/EBPα binds to two regions of DNA that act as gene expression enhancers. One of these regions is normally active in immune cells, and the other is only turned on when macrophage precursors are ready to differentiate.

This indicates that the convergence of these two enhancer pathways can cause the B cell to act like a macrophage precursor, thus triggering the unnatural transdifferentiation.

“This has taught us a great deal about how a transcription factor can activate a new gene expression program (in our case, that of macrophages) but has left us in the dark about the other part of the equation; namely, how the factor silences the B-cell program, something that must happen if transdifferentiation is to work,” Dr Graf said. “This is one of the questions we are focusing on now.”

Dr Graf is interested in this pathway because C/EBPα-induced, B cell-to-macrophage transdifferentiation can convert both human B-cell lymphoma and leukemia cells into functional, non-cancerous macrophages.

He believes that induced transdifferentiation could become therapeutically relevant if a drug could be found that can replace the transcription factor. And understanding the mechanisms of the process could help labs that use this transdifferentiation approach to generate cells for regenerative purposes.

A macrophage stretching its

pseudopodia to engulf particles

The transcription factor C/EBPα reprograms B cells into macrophages by “short-circuiting” the cells so they re-express genes reserved for embryonic development, according to research published in Stem Cell Reports.

Over the past 28 years, researchers have shown that a number of specialized cell types can be forcibly converted into other cell types, but the science of how this change takes place is still emerging.

“For a long time, it was unclear whether forcing cell fate decisions by expressing transcription factors in the wrong cell type could teach us something about what happens normally during physiological differentiation,” said Thomas Graf, PhD, of the Center for Genomic Regulation in Barcelona, Spain.

“What we have now found is that the two processes are actually surprisingly similar.”

The researchers found that B-cell transdifferentiation takes place when C/EBPα binds to two regions of DNA that act as gene expression enhancers. One of these regions is normally active in immune cells, and the other is only turned on when macrophage precursors are ready to differentiate.

This indicates that the convergence of these two enhancer pathways can cause the B cell to act like a macrophage precursor, thus triggering the unnatural transdifferentiation.

“This has taught us a great deal about how a transcription factor can activate a new gene expression program (in our case, that of macrophages) but has left us in the dark about the other part of the equation; namely, how the factor silences the B-cell program, something that must happen if transdifferentiation is to work,” Dr Graf said. “This is one of the questions we are focusing on now.”

Dr Graf is interested in this pathway because C/EBPα-induced, B cell-to-macrophage transdifferentiation can convert both human B-cell lymphoma and leukemia cells into functional, non-cancerous macrophages.

He believes that induced transdifferentiation could become therapeutically relevant if a drug could be found that can replace the transcription factor. And understanding the mechanisms of the process could help labs that use this transdifferentiation approach to generate cells for regenerative purposes.

A macrophage stretching its

pseudopodia to engulf particles

The transcription factor C/EBPα reprograms B cells into macrophages by “short-circuiting” the cells so they re-express genes reserved for embryonic development, according to research published in Stem Cell Reports.

Over the past 28 years, researchers have shown that a number of specialized cell types can be forcibly converted into other cell types, but the science of how this change takes place is still emerging.

“For a long time, it was unclear whether forcing cell fate decisions by expressing transcription factors in the wrong cell type could teach us something about what happens normally during physiological differentiation,” said Thomas Graf, PhD, of the Center for Genomic Regulation in Barcelona, Spain.

“What we have now found is that the two processes are actually surprisingly similar.”

The researchers found that B-cell transdifferentiation takes place when C/EBPα binds to two regions of DNA that act as gene expression enhancers. One of these regions is normally active in immune cells, and the other is only turned on when macrophage precursors are ready to differentiate.

This indicates that the convergence of these two enhancer pathways can cause the B cell to act like a macrophage precursor, thus triggering the unnatural transdifferentiation.

“This has taught us a great deal about how a transcription factor can activate a new gene expression program (in our case, that of macrophages) but has left us in the dark about the other part of the equation; namely, how the factor silences the B-cell program, something that must happen if transdifferentiation is to work,” Dr Graf said. “This is one of the questions we are focusing on now.”

Dr Graf is interested in this pathway because C/EBPα-induced, B cell-to-macrophage transdifferentiation can convert both human B-cell lymphoma and leukemia cells into functional, non-cancerous macrophages.

He believes that induced transdifferentiation could become therapeutically relevant if a drug could be found that can replace the transcription factor. And understanding the mechanisms of the process could help labs that use this transdifferentiation approach to generate cells for regenerative purposes.

Chang Lu, PhD, (left) and

his student, Zhenning Cao.

Dr Lu is holding the chip

used in the study.

Photo from Virginia Tech

A new technique enables epigenomic analysis using fewer cells than other methods involving chromatin immunoprecipitation and deep sequencing (ChIP-seq), according to researchers.

The technique, microfluidic oscillatory washing-based ChIP-seq (MOWChIP-seq), allows for genome-wide analysis of histone modifications using as few as 100

cells.

Using MOWChIP-seq, researchers uncovered new information regarding early hematopoiesis.

The team described this work in Nature Methods.

They used multilayer soft lithography to create a poly (dimethylsiloxane) device with a microfluidic chamber for ChIP. The researchers flowed magnetic beads coated with a ChIP antibody into the chamber, which formed a packed bed.

They then flowed sonicated chromatin fragments through the chamber, which were adsorbed onto the bead surface. The team said the gaps between the immunoprecipitation beads are smaller than 2 μm and facilitate rapid, high-efficiency adsorption of target chromatin fragments under the small diffusion length.

The researchers washed the beads by oscillatory washing in two different buffers to remove nonspecifically adsorbed chromatin fragments. Then, they flowed the beads out of the chamber and collected them for off-chip processing.

“The use of a packed bed of beads for ChIP allowed us to collect the chromatin fragments with a very high efficiency,” said study author Chang Lu, PhD, of Virginia Tech in Blacksburg.

“At the same time, effective washing for removing undesired molecules and debris guarantees the purity of the collected molecules. These two factors constitute a successful strategy for epigenomic analysis with extremely high sensitivity.”

In addition, the entire MOWChIP-seq process takes about 90 minutes.

To test MOWChIP-seq, Dr Lu and his colleagues used the technique to study the epigenomes of hematopoietic stem and progenitor cells (HSPCs) isolated from the fetal liver of a mouse.

“Little is known about the dynamics of the epigenome during embryonic hematopoiesis, largely due to the difficulty in isolating sufficient quantities of these cells from developing embryos,” said study author Kai Tan, PhD, of the University of Iowa in Iowa City. “This technology is the perfect tool for tackling this problem.”

MOWChIP-seq revealed new enhancers and super enhancers in the HSPCs.

By comparing all of the enhancers they identified to an enhancer catalog covering 16 blood cell types, the researchers found that 2561 (58%) of the enhancers they found were unique to fetal liver HSPCs. They said this suggests enhancer activity is highly dynamic during early hematopoiesis.

Now, the researchers plan to use MOWChIP-seq to study other epigenomic changes involved in inflammation and cancer.

“Our technology paves the way for studies of epigenomes with extremely low numbers of cells from animals and from patients,” Dr Lu said.

Virginia Tech Intellectual Properties has filed a utility patent on MOWChIP-seq on behalf of Dr Lu.

Chang Lu, PhD, (left) and

his student, Zhenning Cao.

Dr Lu is holding the chip

used in the study.

Photo from Virginia Tech

A new technique enables epigenomic analysis using fewer cells than other methods involving chromatin immunoprecipitation and deep sequencing (ChIP-seq), according to researchers.

The technique, microfluidic oscillatory washing-based ChIP-seq (MOWChIP-seq), allows for genome-wide analysis of histone modifications using as few as 100

cells.

Using MOWChIP-seq, researchers uncovered new information regarding early hematopoiesis.

The team described this work in Nature Methods.

They used multilayer soft lithography to create a poly (dimethylsiloxane) device with a microfluidic chamber for ChIP. The researchers flowed magnetic beads coated with a ChIP antibody into the chamber, which formed a packed bed.

They then flowed sonicated chromatin fragments through the chamber, which were adsorbed onto the bead surface. The team said the gaps between the immunoprecipitation beads are smaller than 2 μm and facilitate rapid, high-efficiency adsorption of target chromatin fragments under the small diffusion length.

The researchers washed the beads by oscillatory washing in two different buffers to remove nonspecifically adsorbed chromatin fragments. Then, they flowed the beads out of the chamber and collected them for off-chip processing.

“The use of a packed bed of beads for ChIP allowed us to collect the chromatin fragments with a very high efficiency,” said study author Chang Lu, PhD, of Virginia Tech in Blacksburg.

“At the same time, effective washing for removing undesired molecules and debris guarantees the purity of the collected molecules. These two factors constitute a successful strategy for epigenomic analysis with extremely high sensitivity.”

In addition, the entire MOWChIP-seq process takes about 90 minutes.

To test MOWChIP-seq, Dr Lu and his colleagues used the technique to study the epigenomes of hematopoietic stem and progenitor cells (HSPCs) isolated from the fetal liver of a mouse.

“Little is known about the dynamics of the epigenome during embryonic hematopoiesis, largely due to the difficulty in isolating sufficient quantities of these cells from developing embryos,” said study author Kai Tan, PhD, of the University of Iowa in Iowa City. “This technology is the perfect tool for tackling this problem.”

MOWChIP-seq revealed new enhancers and super enhancers in the HSPCs.

By comparing all of the enhancers they identified to an enhancer catalog covering 16 blood cell types, the researchers found that 2561 (58%) of the enhancers they found were unique to fetal liver HSPCs. They said this suggests enhancer activity is highly dynamic during early hematopoiesis.

Now, the researchers plan to use MOWChIP-seq to study other epigenomic changes involved in inflammation and cancer.

“Our technology paves the way for studies of epigenomes with extremely low numbers of cells from animals and from patients,” Dr Lu said.

Virginia Tech Intellectual Properties has filed a utility patent on MOWChIP-seq on behalf of Dr Lu.

Chang Lu, PhD, (left) and

his student, Zhenning Cao.

Dr Lu is holding the chip

used in the study.

Photo from Virginia Tech

A new technique enables epigenomic analysis using fewer cells than other methods involving chromatin immunoprecipitation and deep sequencing (ChIP-seq), according to researchers.

The technique, microfluidic oscillatory washing-based ChIP-seq (MOWChIP-seq), allows for genome-wide analysis of histone modifications using as few as 100

cells.

Using MOWChIP-seq, researchers uncovered new information regarding early hematopoiesis.

The team described this work in Nature Methods.

They used multilayer soft lithography to create a poly (dimethylsiloxane) device with a microfluidic chamber for ChIP. The researchers flowed magnetic beads coated with a ChIP antibody into the chamber, which formed a packed bed.

They then flowed sonicated chromatin fragments through the chamber, which were adsorbed onto the bead surface. The team said the gaps between the immunoprecipitation beads are smaller than 2 μm and facilitate rapid, high-efficiency adsorption of target chromatin fragments under the small diffusion length.

The researchers washed the beads by oscillatory washing in two different buffers to remove nonspecifically adsorbed chromatin fragments. Then, they flowed the beads out of the chamber and collected them for off-chip processing.

“The use of a packed bed of beads for ChIP allowed us to collect the chromatin fragments with a very high efficiency,” said study author Chang Lu, PhD, of Virginia Tech in Blacksburg.

“At the same time, effective washing for removing undesired molecules and debris guarantees the purity of the collected molecules. These two factors constitute a successful strategy for epigenomic analysis with extremely high sensitivity.”

In addition, the entire MOWChIP-seq process takes about 90 minutes.

To test MOWChIP-seq, Dr Lu and his colleagues used the technique to study the epigenomes of hematopoietic stem and progenitor cells (HSPCs) isolated from the fetal liver of a mouse.

“Little is known about the dynamics of the epigenome during embryonic hematopoiesis, largely due to the difficulty in isolating sufficient quantities of these cells from developing embryos,” said study author Kai Tan, PhD, of the University of Iowa in Iowa City. “This technology is the perfect tool for tackling this problem.”

MOWChIP-seq revealed new enhancers and super enhancers in the HSPCs.

By comparing all of the enhancers they identified to an enhancer catalog covering 16 blood cell types, the researchers found that 2561 (58%) of the enhancers they found were unique to fetal liver HSPCs. They said this suggests enhancer activity is highly dynamic during early hematopoiesis.

Now, the researchers plan to use MOWChIP-seq to study other epigenomic changes involved in inflammation and cancer.

“Our technology paves the way for studies of epigenomes with extremely low numbers of cells from animals and from patients,” Dr Lu said.

Virginia Tech Intellectual Properties has filed a utility patent on MOWChIP-seq on behalf of Dr Lu.

Time-lapse images of

apoptosis in cancer cells

Researchers say they have identified a new mechanism by which the tumor suppressor protein p53 triggers apoptosis, and they believe this process could be harnessed to kill cancer cells.

The team discovered how p53 acts in the cytoplasm to trigger cell death by binding to and activating the BAX protein.

The process involves a shape change in one of p53’s amino acids that serves as the “switch” to activate BAX and trigger the apoptotic pathway.

The team also identified the enzyme in the cytoplasm that promotes the change that controls the “switch.”

Richard Kriwacki, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described these findings in Molecular Cell.

Like up to half of all proteins, p53 includes both structured and disordered regions. A disordered region is a segment that does not adopt a single shape but

remains flexible and constantly switches between different shapes until

it encounters a partner.

Dr Kriwacki and his colleagues showed that both structured and disordered regions of p53 play a role in BAX activation in the cytoplasm.

The process starts when a structured region of p53 known as the DNA-binding domain binds to BAX. That sets the stage for the unstructured region of p53 to form a second bond, which activates BAX and triggers apoptosis.

“There were no previous reports of this disordered region of p53 binding to BAX, so the finding that this region was the key to BAX activation was a total surprise,” Dr Kriwacki said.

The disordered p53 segment included the amino acid proline, which can change between two shapes, particularly in the presence of the enzyme Pin1.

Using NMR spectroscopy, the researchers showed that the proline shape change promotes p53 binding and activation of BAX.

“These results expand our understanding of the different ways p53 modulates cell behavior,” Dr Kriwacki said. “The findings also raise the possibility of killing tumor cells using small molecules to trigger BAX-dependent apoptosis.”

Time-lapse images of

apoptosis in cancer cells

Researchers say they have identified a new mechanism by which the tumor suppressor protein p53 triggers apoptosis, and they believe this process could be harnessed to kill cancer cells.

The team discovered how p53 acts in the cytoplasm to trigger cell death by binding to and activating the BAX protein.

The process involves a shape change in one of p53’s amino acids that serves as the “switch” to activate BAX and trigger the apoptotic pathway.

The team also identified the enzyme in the cytoplasm that promotes the change that controls the “switch.”

Richard Kriwacki, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described these findings in Molecular Cell.

Like up to half of all proteins, p53 includes both structured and disordered regions. A disordered region is a segment that does not adopt a single shape but

remains flexible and constantly switches between different shapes until

it encounters a partner.

Dr Kriwacki and his colleagues showed that both structured and disordered regions of p53 play a role in BAX activation in the cytoplasm.

The process starts when a structured region of p53 known as the DNA-binding domain binds to BAX. That sets the stage for the unstructured region of p53 to form a second bond, which activates BAX and triggers apoptosis.

“There were no previous reports of this disordered region of p53 binding to BAX, so the finding that this region was the key to BAX activation was a total surprise,” Dr Kriwacki said.

The disordered p53 segment included the amino acid proline, which can change between two shapes, particularly in the presence of the enzyme Pin1.

Using NMR spectroscopy, the researchers showed that the proline shape change promotes p53 binding and activation of BAX.

“These results expand our understanding of the different ways p53 modulates cell behavior,” Dr Kriwacki said. “The findings also raise the possibility of killing tumor cells using small molecules to trigger BAX-dependent apoptosis.”

Time-lapse images of

apoptosis in cancer cells

Researchers say they have identified a new mechanism by which the tumor suppressor protein p53 triggers apoptosis, and they believe this process could be harnessed to kill cancer cells.

The team discovered how p53 acts in the cytoplasm to trigger cell death by binding to and activating the BAX protein.

The process involves a shape change in one of p53’s amino acids that serves as the “switch” to activate BAX and trigger the apoptotic pathway.

The team also identified the enzyme in the cytoplasm that promotes the change that controls the “switch.”

Richard Kriwacki, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues described these findings in Molecular Cell.

Like up to half of all proteins, p53 includes both structured and disordered regions. A disordered region is a segment that does not adopt a single shape but

remains flexible and constantly switches between different shapes until

it encounters a partner.

Dr Kriwacki and his colleagues showed that both structured and disordered regions of p53 play a role in BAX activation in the cytoplasm.

The process starts when a structured region of p53 known as the DNA-binding domain binds to BAX. That sets the stage for the unstructured region of p53 to form a second bond, which activates BAX and triggers apoptosis.

“There were no previous reports of this disordered region of p53 binding to BAX, so the finding that this region was the key to BAX activation was a total surprise,” Dr Kriwacki said.

The disordered p53 segment included the amino acid proline, which can change between two shapes, particularly in the presence of the enzyme Pin1.

Using NMR spectroscopy, the researchers showed that the proline shape change promotes p53 binding and activation of BAX.

“These results expand our understanding of the different ways p53 modulates cell behavior,” Dr Kriwacki said. “The findings also raise the possibility of killing tumor cells using small molecules to trigger BAX-dependent apoptosis.”

Biofeedback gets results without adverse effects

A 2008 meta-analysis of 53 trials (32 RCTs, 21 pre-post; 1532 patients, 72% female, average age 36 years) examined the effectiveness of biofeedback for tension-type headaches (TTH) with a mean duration of headache symptoms of 14 years.¹ The mean duration of treatment was fewer than 10 hours over 11 sessions. Control groups included placebo, relaxation, pharmacotherapy, cognitive therapy, and physical therapy.

Biofeedback reduced headache pain (measured in structured headache diaries by frequency, duration, and intensity) more than controls (weighted mean difference [WMD]=0.73; 95% confidence interval [CI], 0.61-0.84; WMD effect sizes >0.8 are considered large, 0.6-0.8 are moderate, and 0.2-0.6 are small).

Eighteen trials (15 RCTs, 3 pre-post; 736 patients) included follow-up analysis ranging from 3 to 60 months (mean 15 months), during which biofeedback showed a moderate effect size compared with controls (WMD=0.62; 95% CI, 0.53-0.72). Biofeedback plus relaxation produced a larger effect than controls (6 RCTs, 3 pre-post; 124 patients; WMD=0.98; 95% CI, 0.69-1.3). No adverse effects were reported.

Tricyclics help, too, but have adverse effects

A 2010 meta-analysis of 37 RCTs examined the effectiveness of tricyclic antidepressants as prophylactic treatment for headaches in 3176 patients.² Seventeen RCTs (1275 patients, 73% women, average age 40 years) evaluated tension headaches, and 15 of them included only patients who had headaches for more than 14 days per month (the other 20 RCTs, with 1901 patients, studied migraine headaches).

Control groups included placebo, selective serotonin reuptake inhibitors (SSRIs), tetracyclics, topiramate, dihydroergotamine, spinal manipulation, and cognitive behavioral therapy, but only placebo (8 RCTs included) and SSRIs (4 RCTs included) had more than 2 RCTs evaluated. Variables included headache days per month, headache intensity (measured by scales that varied among trials), and headache index (calculated by multiplying intensity by frequency).

In 8 trials with 574 patients, the standard mean difference (SMD) headache index improved for tricyclics compared with placebo over a treatment duration averaging 10 weeks (WMD=−0.99; 95% CI, −1.7 to −0.32). However, the tricyclic arm reported more adverse effects such as drowsiness, dizziness, dry mouth, and abdominal complaints (relative risk [RR]=1.9; 95% CI, 1.2-3.0).

Tricyclics and SSRIs reduced the frequency of TTH equally (4 trials; N=479; standardized mean difference=−0.80; 95% CI, −1.63 to 0.02) but tricyclics were more likely to reduce intensity by 50% (RR=1.7; 95% CI, 1.3-2.2).

Headaches decline after acupuncture, not during

A 2008 meta-analysis of 5 RCTs (838 patients, 68% female) evaluated the effectiveness of acupuncture compared with sham acupuncture for treating episodic and chronic TTH.³ Separate data on efficacy for each subtype was not provided. Selection of acupuncture points varied among the trials, and treatment durations ranged from 3 to 8 weeks.

Headache days per month didn’t decline during treatment (WMD=−2.9; 95% CI, −7.5 to 1.6), but were significantly decreased on follow-up at 20 to 25 weeks (WMD=−1.8; 95% CI, −3.0 to −0.64).

Biofeedback gets results without adverse effects

A 2008 meta-analysis of 53 trials (32 RCTs, 21 pre-post; 1532 patients, 72% female, average age 36 years) examined the effectiveness of biofeedback for tension-type headaches (TTH) with a mean duration of headache symptoms of 14 years.¹ The mean duration of treatment was fewer than 10 hours over 11 sessions. Control groups included placebo, relaxation, pharmacotherapy, cognitive therapy, and physical therapy.

Biofeedback reduced headache pain (measured in structured headache diaries by frequency, duration, and intensity) more than controls (weighted mean difference [WMD]=0.73; 95% confidence interval [CI], 0.61-0.84; WMD effect sizes >0.8 are considered large, 0.6-0.8 are moderate, and 0.2-0.6 are small).

Eighteen trials (15 RCTs, 3 pre-post; 736 patients) included follow-up analysis ranging from 3 to 60 months (mean 15 months), during which biofeedback showed a moderate effect size compared with controls (WMD=0.62; 95% CI, 0.53-0.72). Biofeedback plus relaxation produced a larger effect than controls (6 RCTs, 3 pre-post; 124 patients; WMD=0.98; 95% CI, 0.69-1.3). No adverse effects were reported.

Tricyclics help, too, but have adverse effects

A 2010 meta-analysis of 37 RCTs examined the effectiveness of tricyclic antidepressants as prophylactic treatment for headaches in 3176 patients.² Seventeen RCTs (1275 patients, 73% women, average age 40 years) evaluated tension headaches, and 15 of them included only patients who had headaches for more than 14 days per month (the other 20 RCTs, with 1901 patients, studied migraine headaches).

Control groups included placebo, selective serotonin reuptake inhibitors (SSRIs), tetracyclics, topiramate, dihydroergotamine, spinal manipulation, and cognitive behavioral therapy, but only placebo (8 RCTs included) and SSRIs (4 RCTs included) had more than 2 RCTs evaluated. Variables included headache days per month, headache intensity (measured by scales that varied among trials), and headache index (calculated by multiplying intensity by frequency).

In 8 trials with 574 patients, the standard mean difference (SMD) headache index improved for tricyclics compared with placebo over a treatment duration averaging 10 weeks (WMD=−0.99; 95% CI, −1.7 to −0.32). However, the tricyclic arm reported more adverse effects such as drowsiness, dizziness, dry mouth, and abdominal complaints (relative risk [RR]=1.9; 95% CI, 1.2-3.0).

Tricyclics and SSRIs reduced the frequency of TTH equally (4 trials; N=479; standardized mean difference=−0.80; 95% CI, −1.63 to 0.02) but tricyclics were more likely to reduce intensity by 50% (RR=1.7; 95% CI, 1.3-2.2).

Headaches decline after acupuncture, not during

A 2008 meta-analysis of 5 RCTs (838 patients, 68% female) evaluated the effectiveness of acupuncture compared with sham acupuncture for treating episodic and chronic TTH.³ Separate data on efficacy for each subtype was not provided. Selection of acupuncture points varied among the trials, and treatment durations ranged from 3 to 8 weeks.

Headache days per month didn’t decline during treatment (WMD=−2.9; 95% CI, −7.5 to 1.6), but were significantly decreased on follow-up at 20 to 25 weeks (WMD=−1.8; 95% CI, −3.0 to −0.64).

Biofeedback gets results without adverse effects

A 2008 meta-analysis of 53 trials (32 RCTs, 21 pre-post; 1532 patients, 72% female, average age 36 years) examined the effectiveness of biofeedback for tension-type headaches (TTH) with a mean duration of headache symptoms of 14 years.¹ The mean duration of treatment was fewer than 10 hours over 11 sessions. Control groups included placebo, relaxation, pharmacotherapy, cognitive therapy, and physical therapy.

Biofeedback reduced headache pain (measured in structured headache diaries by frequency, duration, and intensity) more than controls (weighted mean difference [WMD]=0.73; 95% confidence interval [CI], 0.61-0.84; WMD effect sizes >0.8 are considered large, 0.6-0.8 are moderate, and 0.2-0.6 are small).

Eighteen trials (15 RCTs, 3 pre-post; 736 patients) included follow-up analysis ranging from 3 to 60 months (mean 15 months), during which biofeedback showed a moderate effect size compared with controls (WMD=0.62; 95% CI, 0.53-0.72). Biofeedback plus relaxation produced a larger effect than controls (6 RCTs, 3 pre-post; 124 patients; WMD=0.98; 95% CI, 0.69-1.3). No adverse effects were reported.

Tricyclics help, too, but have adverse effects

A 2010 meta-analysis of 37 RCTs examined the effectiveness of tricyclic antidepressants as prophylactic treatment for headaches in 3176 patients.² Seventeen RCTs (1275 patients, 73% women, average age 40 years) evaluated tension headaches, and 15 of them included only patients who had headaches for more than 14 days per month (the other 20 RCTs, with 1901 patients, studied migraine headaches).

Control groups included placebo, selective serotonin reuptake inhibitors (SSRIs), tetracyclics, topiramate, dihydroergotamine, spinal manipulation, and cognitive behavioral therapy, but only placebo (8 RCTs included) and SSRIs (4 RCTs included) had more than 2 RCTs evaluated. Variables included headache days per month, headache intensity (measured by scales that varied among trials), and headache index (calculated by multiplying intensity by frequency).

In 8 trials with 574 patients, the standard mean difference (SMD) headache index improved for tricyclics compared with placebo over a treatment duration averaging 10 weeks (WMD=−0.99; 95% CI, −1.7 to −0.32). However, the tricyclic arm reported more adverse effects such as drowsiness, dizziness, dry mouth, and abdominal complaints (relative risk [RR]=1.9; 95% CI, 1.2-3.0).

Tricyclics and SSRIs reduced the frequency of TTH equally (4 trials; N=479; standardized mean difference=−0.80; 95% CI, −1.63 to 0.02) but tricyclics were more likely to reduce intensity by 50% (RR=1.7; 95% CI, 1.3-2.2).

Headaches decline after acupuncture, not during

A 2008 meta-analysis of 5 RCTs (838 patients, 68% female) evaluated the effectiveness of acupuncture compared with sham acupuncture for treating episodic and chronic TTH.³ Separate data on efficacy for each subtype was not provided. Selection of acupuncture points varied among the trials, and treatment durations ranged from 3 to 8 weeks.

Headache days per month didn’t decline during treatment (WMD=−2.9; 95% CI, −7.5 to 1.6), but were significantly decreased on follow-up at 20 to 25 weeks (WMD=−1.8; 95% CI, −3.0 to −0.64).

From the Yale School of Medicine, New Haven, CT.

Abstract

• Objective: To review the sexual health concerns of women with gynecologic cancer and provide guidance for primary care physicians.
• Methods: Review of the literature.
• Results: Issues of sexuality and intimacy are known to significantly impact the quality of life of patients following diagnosis and treatment of gynecologic cancers. At the time of diagnosis, women should be informed of the potential physiologic, hormonal, and psychosocial effects of gynecologic cancer on sexuality. Many providers fail to address these issues given time constraints and patients’ trepidation in alerting their providers to their concerns. While systemic hormone therapy directly addresses these symptoms, its use remains controversial due to potential cancer recurrence risks. Thus, treatment centers around therapeutic alternatives. For vasomotor symptoms, selective serotonin reuptake inhibitors have shown effectiveness and are typically well tolerated, and antiepileptics such as gabapentin have shown promise. There is promising but limited data employing pelvic floor physical therapy as a tool to aid in addressing pelvic floor symptoms. Psychological care and the involvement of the partner are also part of managing the sexual health concerns of these patients.
• Conclusion: Sexual morbidity is a distressing and undertreated problem among gynecologic cancer survivors. Successful treatment requires the provider’s appreciation of the problem and willingness to address it.

Issues of sexuality and intimacy are known to significantly impact the lives of patients following diagnosis and treatment of gynecologic cancers. [1,2] Treatment of gynecologic malignancy is highly dependent on pathology and stage, with some patients receiving small excisional procedures while others subject to extensive surgeries, chemotherapy, and radiation treatment, and it is difficult to predict how each individual’s sexual health will be impacted. However, the evidence suggests that at least half of women treated for gynecologic cancer will experience sexual dysfunction [3]. Although the impact of gynecologic cancer and treatment can be profound, providers often do not address their patients’ sexual concerns [4,5], yet most patients have indicated that they would like these issues to be addressed [6].

Female Sexual Dysfunction

Sexual dysfunction is multifactorial and involves physical, social, and psychological dimensions. It is common in the general population, with rates ranging from 25-63% [7]. The DSM-IV [8] defines female sexual dysfunction as a disturbance in or pain during the sexual response, which can be further classified as hypoactive sexual disorder, orgasmic disorder, sexual pain disorder, or sexual arousal disorder [9]. It should be noted that women who have been treated for gynecologic cancers may have a premorbid history of sexual dysfunction. Assessment of a woman’s sexual function prior to her cancer diagnosis can help establish which sexuality changes are due to the cancer treatment and may allow the provider to tailor interventions accordingly.

Sexual Dysfunction and Quality of Life

As treatments for gynecologic cancers improve, toxicity of treatment decreases, and survival increases, quality of life for survivors has become as become an increasingly important health issue. Several studies have examined patient-reported quality of life in short- and long-term cancer survivors and report overall significant alteration in quality of life over many aspects of health and psychological well-being [10]. It is well established that health-related quality of life and sexual functioning are closely associated [11].

In gynecologic cancer patients, sexual and quality of life outcomes can vary. For example, Kim el al recently compared quality of life and sexual functioning in ovarian cancer survivors with no evidence of disease after primary treatment and a cohort of health women. Sexuality, both in terms of desire, arousal, lubrication, orgasm, satisfaction, and pain and in terms of interest in sex, sexual activity, and enjoyment of sex were similar between the groups; however social functioning deteriorated in cancer patients [12]. Other women report different experiences. Women with a history of vulvar, vaginal, or cervical cancer who may have had extensive pelvic surgery, lymphadenectomy, and radiation treatment to the pelvis typically report greater alterations in quality of life and sexual activity depending on the extent of their treatment [13].

Patients undergoing chemotherapy often report significant changes in quality of life due to the physical symptoms of fatigue, nausea, hair loss, diarrhea, etc. as well the psychological effects of cancer diagnosis, changes in body image, and poor coping [14]. Sexual side effects are common due to alterations in the HPA axis, direct gonadal toxicity and neuropathies [15].

Impact of Gynecologic Cancer on Sexuality

Gynecologic cancer and treatment can alter sexuality through a variety of effects. The impact of anatomical changes may alter a women’s self-esteem, body image, and sense of femininity, resulting in a reluctance to engage in intimate behaviors. Furthermore, if the partnership is disrupted by changes in roles in the household or within the relationship, relationships dynamics may be tested and result in mental distress for the patient, thus effecting sexuality and intimacy.

Surgical or chemical withdrawal of sex hormones, new medications, and postoperative sequelae can contribute to sexual arousal problems. The emotional and psychological components of a cancer diagnosis also can hinder the sexual response [16]. Depression and anxiety, the rates of which increase with cancer diagnosis, can also significantly affect sexual function [17].

Sexual pain is common in this population due to hormonal considerations as well as post-treatment side effects and a frequent cause of sexual dysfunction for these patients. Pelvic radiation may result in adverse physical changes to the vagina including vaginal stenosis, thinning of vaginal mucosa, loss of lubrication, and loss of elasticity [18,19]. A recent review of 20 studies of cervical cancer survivors found that patients were at risk for lack of lubrication and had high rates of dyspareunia [20]. Psychosocial factors have been found to be important predictors of sexual desire and more important than hormones in predicting low sexual desire in middle age [21]. These factors include emotional and physical closeness to the partner, satisfactory communication, and a positive relation to one’s own body [16].

Effects on Relationships and Partners

Women whose sexual capacity is compromised may be worried about their partners’ quality of life and overall well-being. Indeed, the partners of women with gynecologic cancer are also impacted by the changes to sexual function and loss of sexuality and intimacy. Hawkins et al found that cessation or decreased frequency of sex and intimacy was reported in 79% of male partners of women affected by cancer. Among partners of the persons with cancer in this study, changes to sexuality were associated with feelings of self-blame, reflection, sadness, anger and lack of sexual fulfillment [22]. Further, male partners of women diagnosed with gynecological cancer often express conflicting emotional states including feeling worried about their significant other’s health, having the desire to engage in sexual activity, and feeling guilty about wanting to increase sexual intimacy. These feelings, in turn, can lead to resentment and withdrawal from their partner and overall relationship discord [23].

Evidence suggests partners of cancer patients greatly benefit from increased social support even years after an apparent cure [24]. Specifically, male partners who take on a new role as caregiver in the relationship experience difficulties with emotional changes, challenges to their masculinity, and new stressors [25]. These new roles and feelings also contribute to changes in sexuality and intimacy in relationships, making support for partners all the more necessary.

Menopausal Symptoms Following Cancer Treatment

Gynecologic cancer treatment invariably affects the female hormonal balance, sometimes suddenly with surgical excision of the gonads or via radiation treatment or chemotherapy. It is well known that the sudden withdrawal of estrogen and testosterone, especially in the premenopausal postoperative population, can lead to significant acute menopausal symptoms. Given the many emotional and physical issues affecting patients during treatment, it can be difficult to delineate what proportion of sexual problems are caused by or enhanced by vasomotor symptoms, sleep disorders, and vaginal atrophy.

In general, premenopausal women who experience abrupt surgical menopause may often have immediate severe symptoms. Many agree that the younger a woman is when going through this process, the more severe her symptoms may be. Although the average age of endometrial cancer diagnosis is 67, approximately 25% of women who are diagnosed are premenopausal, and 5% of cases occur in women under 40. As the obesity epidemic worsens and more women are exposed to higher levels of estrogen at younger ages, it is expected that the number of premenopausal women who are diagnosed will continue to rise. The average age of diagnosis for ovarian cancer is 63, however, there is a large cohort of women diagnosed with borderline and malignant tumors in the premenopausal period [26]. These patients often experience vasomotor symptoms in the hours to days following surgery.

Interventions for Survivors of Gynecologic Cancer with Sexual Dysfunction

Systemic Hormone Therapy

Systemic hormonal therapy to treat menopausal symptoms remains controversial following the release of findings from the Women’s Health Initiative, which showed a number of adverse effects, including an increased risk of breast cancer in healthy postmenopausal women who received systemic hormonal therapy for menopausal symptoms. While views have changed since that time, providers are often reluctant to prescribe hormonal therapy, and patients are reticent to take it, due to fears of cancer recurrence. However, there is no evidence showing hormones negatively influence survival after treatment for epithelial ovarian, squamous cervical, or vulvar cancer [27]. With the exception of endometrial cancer, there is no biological evidence that HRT may increase recurrence risk [28]. Approach to clinical decision making should be individualized, taking into consideration the patients’ symptoms, quality of life, tumor histology, and overall prognosis.

Cervical cancer, vulvar cancer, and vaginal cancer are not considered hormonally responsive tumors. While the data are limited, a study published in 1987 of cervical cancer survivors treated with systemic hormone replacement therapy showed no increase in relapse rates and showed an increase in quality of life [29]. There are no studies regarding systemic HRT in patients with vulvar or vaginal cancer though it is generally accepted they can be treated with HRT. No significant data exists for cervical adenocarcinoma patients, and most oncologists suggest treating these patients the same as those with endometrial cancer primary.

There is limited data on the use of HRT in women with ovarian cancer but available studies do not show any difference in overall or disease-free survival between HRT groups and controls [27,30–32]. Many studies report a significant increase in quality of life with HRT. A 2013 retrospective chart review of 77 patients with epithelial ovarian cancer who received postoperative HRT showed no significant difference in progression-free survival [33].

The most controversy surrounds the use of HRT in patients with endometrial cancer [34]. The only major data available come from the Gynecologic Oncology Group’s truncated study, which was a large prospective randomized controlled trial. Over 1200 women treated for stage I and II endometrial cancer were enrolled between 1997 and 2003, and before the study was terminated these patients were followed for a median of 3 years following initiation of therapy. The recurrence rate of malignancy was low, 2.1, and an insignificant risk of recurrence of 1.27 was noted between with HRT and placebo groups (80% CI, 0.916-1.77) [35]. Women included in this study were between the ages of 26 and 91, and their indications for therapy included vasomotor symptoms, vaginal atrophy, as well as osteoporosis risk and cardiovascular disease risk. Gynecologist oncologists often use estrogen therapy to treat symptomatic women with early stage endometrial cancer given the very low risk of recurrence.

Tibolone is a synthetic steroid with activity on estrogen and progesterone receptors, and mainly acts as an agonist at estrogen receptors. It is prescribed outside the United States for osteoporosis and is being investigated as treatment for female sexual dysfunction. Efficacy on vasomotor symptoms has been positive thus far. One case-control study confirmed tibolone’s safety for endometrial cancer survivors, with no adverse effects on disease-free or overall survival [36]. One group recently examined tibolone in the setting of breast cancer patients in a prospective randomized controlled trial and reported an increased risk of breast cancer recurrences in women receiving tibolone for HT [37]. That study reported no increase in risk of gynecologic cancers and did report favorable outcomes for patients in terms of osteoporosis and vasomotor symptoms.

Topical Therapy

Women who are concerned about systemic HRT but who have been treated with radiation in addition to their surgery may be interested in topical estrogen therapy. These women may have vaginal stenosis and atrophic symptoms, and for them topical estrogen therapy can be helpful [38]. Many formulations of topical estrogen are available, including creams, tablets, and rings. Using vaginal estrogens and dilators can be useful to help with eventual resumption of sexual activity once healing has taken place and can help to avoid dyspareunia. Combination topical and systemic therapy can also be useful to relieve symptoms. Women concerned about absorption with topical therapy can be advised that while there is some absorption initially, absorption is reduced as atrophy is improved with treatment.

One recent study examined the use of alpha-tocopherol to reduce acute vaginal complications in women with endometrial and cervical cancer undergoing radiation treatment. The treatment group experienced reduced vaginal toxicity and pain, although vaginal secretion was not significantly different in the 2 groups studied [39]. No adverse effects were noted. This compound has not been studied further but may be beneficial in the future.

Some women may prefer to avoid hormones altogether. Over-the-counter vaginal moisturizers and lubricants can be recommended to women to help with intercourse and atrophic symptoms, with or without estrogen therapy.

Physical Therapy

Pelvic floor physical therapy has become an increasingly popular modality for treatment of many aspects pelvic floor dysfunction, the symptoms of which include defecatory dysfunction, constipation, bladder dysfunction, painful urination, dyspareunia, pelvic pain, and low back pain [40]. Pelvic floor physical therapy is well studied and utilized frequently for urinary incontinence and pelvic organ prolapse, but is understudied for sexual dysfunction [41,42].

Promising areas of study include educational sessions, cognitive behavioral therapy, vaginal dilator therapy, pelvic floor muscle strengthening and relaxation techniques with biofeedback, stretching and massage [40]. Biofeedback specifically has been studied in controlled studies for treatment of sexual dysfunction specifically in the setting of vulvar pain syndromes [43]. A small randomized control trial evaluated the use of pelvic floor muscle training in gynecologic cancer survivors and found that the intervention group reported improved sexual function and improved quality of life [44]. Given the few side effects of this therapy, it may be a helpful addition to a multidisciplinary approach to treating pelvic floor dysfunction in gynecologic cancer patients.

For cervical and endometrial cancer patients, vaginal dilators are often prescribed following radiation therapy to minimize vaginal stenosis. Literature suggests that after radiotherapy dilation therapy is effective when used as directed, typically 3 times per week for 10 minutes to mechanically separate the vaginal walls and increase elasticity [45]. Adherence to recommendations for vaginal dilator use is low in this population due to factors such as aversion to the practice and intrusiveness of the mechanism [46,47]. Acknowledgment of apprehension regarding dilator use should be part of the counseling prior to initiation of treatment; interventions designed to educate women about dilator use benefit may increase adherence [48].

Psychological Therapies

Survivors of gynecological cancer with sexual dysfunction may experience the psychological symptoms in the context of the other emotional challenges of a cancer diagnosis [49]. Changes in body image, physical appearance, and feelings of well-being can significantly affect sexuality and intimacy, while anxiety and negative feelings about a diagnosis can cause further sexual dysfunction. Conversely, sexual morbidity in these patients predicts worsening of general psychological symptoms, including depressive symptoms and overall quality of life [13–15].

While there are limited studies directly assessing the effect of psychological therapies for the treatment of sexual dysfunction in this population, the existing literature shows enduring symptomatic improvement following brief interventions. In women for whom emotional distress, depression, and anxiety appear to be a significant aspect of their concern regarding intimacy and sexuality, these interventions can be particularly helpful.

Cognitive behavioral therapy (CBT), which focuses on mindfulness and the relationships between maladaptive thoughts and how they impact behavior, has been shown to have efficacy in treating the broader psycho-social concerns of gynecological cancer patients [50,51]. In a recent study Brotto and colleagues randomized 31 survivors of gynecological cancer with self-reported sexual dysfunction to either three 90-minute CBT sessions or a waitlist control. Patients who underwent the intervention reported significant improvements in sexual arousal and desire both immediately post-therapy and at 6-month follow-up while patients in the waitlist arm experienced no significant changes in symptomatology [52].

Psychoeducational interventions are another promising avenue for addressing sexual dysfunction in this population [53]. In a 2008 therapeutic trial, Brotto and colleagues combined elements of CBT with education in 3 one-hour sessions featuring written materials on sexuality and relationships. The intervention enrolled 22 women with early stage gynecologic cancer who met criteria for female sexual arousal disorder. The psychoeducational intervention was associated with positive effect on sexual desire, arousal, orgasm, satisfaction, sexual distress, depression, and overall well-being [16]. Psychoeducation can also be used to augment other therapeutic modalities. Robinson and colleagues used such an intervention to improve adherence to vaginal dilator use in 32 women with early stage endometrial cancer who were being treated with radiotherapy [48].

Some gynecologic cancer patients may have significant alterations in their anatomy and thus penetrative intercourse may not be possible. In patients even without these physical changes, some may prefer to avoid intercourse due to pain or anxiety. Thus patients can have significant benefits from discussing their concerns with a therapist specializing in these issues as many patients are concerned about their ability to engage in intimate behavior. Therapy can assist with the changing sexual relationship and assist the partners in different ways of engaging in intimate acts. It is important to avoid stressing penetrative intercourse as the goal for sexual function with these or any patients with anxiety relating to their disease as there are many ways to engage in mutually pleasurable experiences for both partners, thus removing anxiety about inability to resume vaginal intercourse post-treatment. Discussing this with patients can be challenging but can often reduce anxiety surrounding body image issues following treatment.

Studies have shown that cancer care providers often do not adequately address sexual concerns [54] but that when these concerns are appropriately managed, patient satisfaction and quality of life significantly improve [55]. Several studies have focused on how providers can incorporate the approaches of CBT and psychoeducation to better address the sexual concerns of patients without requiring external psychiatric care [56,57]. Barbera et al have described a successful model in which multidisciplinary care teams provide education and counseling for gynecological cancer patients in a sexuality clinic [58]. patients had a significant symptom burden, including menopausal symptoms, the effects of radiation therapy, chemotherapy, and surgical operation as well as psychological responses to cancer, and reported high levels of satisfaction with their experience at the clinic.

Involvement of the partner in interventions has not been well studied; however, involving the partner in in psychological therapies to address sexual dysfunction should be beneficial.

Alternative Therapies for Vasomotor Symptoms

Gynecologic cancer patients suffering prominent vasomotor symptoms have limited alternatives to hormone therapy. Clinicians must balance potential medication benefit with potential exacerbation of other medical and psychological issues, including sexual dysfunction.

Antidepressants

The use of SSRIs and SNRIs for vasomotor symptoms was pioneered by medical oncologists for men with hot flashes secondary to GnRH agonist therapy for prostate cancer and women with breast cancer [59,60]. Limited studies have shown that antidepressant medications do not increase cancer recurrence risk in ovarian cancer patients and are relatively well tolerated [61]. However, these medications are known to have partial efficacy in improving vasomotor symptoms and may worsen sexual symptoms, a well-known side effect of antidepressants. There is variation of the reported rates of sexual dysfunction associated with various antidepressants and clinicians may take the likelihood of sexual side effects into account when prescribing SSRIs or SNRIS [62]. More recently developed SSRIS, such as citalopram and its enantiomer escitalopram, have shown significant improvements in vasomotor symptoms and were better tolerated than venlafaxine and fluoxetine [63,64]. Additionally, limited uncontrolled studies of mirtazipine, a structurally unique SSRI, and bupropion, which acts on dopamine and norepinephrine, have shown significant decreases in hot flash symptoms and are less associated with sexual side effects than SSRIS/SNRIS [65,66].

Other Agents

Other pharmaceutical options for menopausal vasomotor symptoms include gabapentin and adrenergic agonists. Gabapentin can yield impressive reductions in vasomotor symptoms. A recent double-blind randomized trial in 50 patients revealed a 60% reduction in hot flashes as 12 weeks and an 80% reduction in self-reported composite symptom scores [67]. However, side effects such as palpitations, edema, and fatigue, lead to high study withdrawal rates and limit its widespread clinical use for this indication [68]. Clonidine has been assessed versus venlafaxine in several clinical trials with breast cancer patients. These trials have shown mixed results, with findings of both inferiority and superiority to venlafaxine, but with consistent significant improvement in symptoms over placebo. Side effects, such insomnia, constipation and dry mouth, occurred but did not lead to higher dropout rates than venlafaxine [69,70].

Long-Term Sexual Outcomes

For women treated for gynecological cancers, alterations in sexual function may persist in the long term. A study following cervical cancer patients managed with radical hysterectomy up to 2 years post treatment showed they had more sexual dysfunction compared with healthy controls, although at rates similar to those who underwent radical hysterectomy for benign disease [71]. A 2007 review of quality of life studies revealed that although ovarian cancer survivors 5 years past diagnosis had excellent overall quality of life, sexual symptoms persisted, with as many as 57% of patients reporting a decline in sexual function due to their cancer [72].

Studies show some differences in outcomes based on treatment modality. A recent review of cervical cancer outcomes revealed that women who received radiotherapy as a component of their treatment have a higher risk of long-term sexual side effects [73]. In contrast, a study assessing endometrial cancer patients 5 years after initial diagnosis between those patients who had received surgery alone and those who had received surgery and vaginal brachytherapy. There was no significant difference in any measures of quality of life and sexual function between these 2 groups [74].

Age appears to play a role in long-term sexual outcomes regardless of diagnosis. Bifulco and colleagues assessed quality of life in survivors of gynecological cancer, comparing women under age 45 to those over 45 after nearly 3 years of survival. After controlling for age and other factors, younger patients were found to have worse sexual activity, including significantly higher rates of poor body image, perceived worse sexual vaginal function, and more severe menopausal symptoms, probably related to the effects of surgical menopause [75].

Despite enduring sexual dysfunction, symptoms tend to improve over time. A cohort study of 103 gynecological cancer patients undergoing radiation therapy were followed for 3 years. Patients were offered standard interventions for sexual dysfunction, including vaginal lubricants, dilators, and menopausal symptomatic therapy, although adherence to these measures was not assessed. Three years after initial therapy, the percentage of sexually active women increased from 21.5% to 44.2% [76]. In the subset of patients who successfully return to sexual activity, outcomes can be comparable to healthy peers. Kim and colleagues compared disease-free sexually active ovarian cancer patients with demographically matched healthy controls on standardized self-report measures. Sexual functioning did not differ between the 2 groups, despite lower social functioning in cancer survivors [12].

Conclusion

Sexuality and intimacy can be greatly affected by the diagnosis and treatment of gynecologic malignancies. It is important to routinely discuss sexuality and sexual functioning with patients from diagnosis onward. Reassuring patients, acknowledging the importance of their concerns, and validating their desire to enjoy improved intimacy should be considered part of the clinician’s role. Valuable information sources that may aid discussions are available on the internet. Oncolink (www.oncolink.org), a large cancer information website maintained by University of Pennsylvania Cancer Center, offers a plethora of information for patients and health care professionals. In addition, the American Cancer Society offers a detailed guide, “Sexuality for the Woman with Cancer” [77]. Treatment is available, and improvement in outcomes is possible. Further prospective studies are needed to clearly delineate risks and benefits of hormone replacement therapy in patients with gynecologic cancers.

Corresponding author: Elena S. Ratner, MD, PO Box 208063, New Haven, CT 06520, [email protected].

From the Yale School of Medicine, New Haven, CT.

Abstract

• Objective: To review the sexual health concerns of women with gynecologic cancer and provide guidance for primary care physicians.
• Methods: Review of the literature.
• Results: Issues of sexuality and intimacy are known to significantly impact the quality of life of patients following diagnosis and treatment of gynecologic cancers. At the time of diagnosis, women should be informed of the potential physiologic, hormonal, and psychosocial effects of gynecologic cancer on sexuality. Many providers fail to address these issues given time constraints and patients’ trepidation in alerting their providers to their concerns. While systemic hormone therapy directly addresses these symptoms, its use remains controversial due to potential cancer recurrence risks. Thus, treatment centers around therapeutic alternatives. For vasomotor symptoms, selective serotonin reuptake inhibitors have shown effectiveness and are typically well tolerated, and antiepileptics such as gabapentin have shown promise. There is promising but limited data employing pelvic floor physical therapy as a tool to aid in addressing pelvic floor symptoms. Psychological care and the involvement of the partner are also part of managing the sexual health concerns of these patients.
• Conclusion: Sexual morbidity is a distressing and undertreated problem among gynecologic cancer survivors. Successful treatment requires the provider’s appreciation of the problem and willingness to address it.

Issues of sexuality and intimacy are known to significantly impact the lives of patients following diagnosis and treatment of gynecologic cancers. [1,2] Treatment of gynecologic malignancy is highly dependent on pathology and stage, with some patients receiving small excisional procedures while others subject to extensive surgeries, chemotherapy, and radiation treatment, and it is difficult to predict how each individual’s sexual health will be impacted. However, the evidence suggests that at least half of women treated for gynecologic cancer will experience sexual dysfunction [3]. Although the impact of gynecologic cancer and treatment can be profound, providers often do not address their patients’ sexual concerns [4,5], yet most patients have indicated that they would like these issues to be addressed [6].

Female Sexual Dysfunction

Sexual dysfunction is multifactorial and involves physical, social, and psychological dimensions. It is common in the general population, with rates ranging from 25-63% [7]. The DSM-IV [8] defines female sexual dysfunction as a disturbance in or pain during the sexual response, which can be further classified as hypoactive sexual disorder, orgasmic disorder, sexual pain disorder, or sexual arousal disorder [9]. It should be noted that women who have been treated for gynecologic cancers may have a premorbid history of sexual dysfunction. Assessment of a woman’s sexual function prior to her cancer diagnosis can help establish which sexuality changes are due to the cancer treatment and may allow the provider to tailor interventions accordingly.

Sexual Dysfunction and Quality of Life

As treatments for gynecologic cancers improve, toxicity of treatment decreases, and survival increases, quality of life for survivors has become as become an increasingly important health issue. Several studies have examined patient-reported quality of life in short- and long-term cancer survivors and report overall significant alteration in quality of life over many aspects of health and psychological well-being [10]. It is well established that health-related quality of life and sexual functioning are closely associated [11].

In gynecologic cancer patients, sexual and quality of life outcomes can vary. For example, Kim el al recently compared quality of life and sexual functioning in ovarian cancer survivors with no evidence of disease after primary treatment and a cohort of health women. Sexuality, both in terms of desire, arousal, lubrication, orgasm, satisfaction, and pain and in terms of interest in sex, sexual activity, and enjoyment of sex were similar between the groups; however social functioning deteriorated in cancer patients [12]. Other women report different experiences. Women with a history of vulvar, vaginal, or cervical cancer who may have had extensive pelvic surgery, lymphadenectomy, and radiation treatment to the pelvis typically report greater alterations in quality of life and sexual activity depending on the extent of their treatment [13].

Patients undergoing chemotherapy often report significant changes in quality of life due to the physical symptoms of fatigue, nausea, hair loss, diarrhea, etc. as well the psychological effects of cancer diagnosis, changes in body image, and poor coping [14]. Sexual side effects are common due to alterations in the HPA axis, direct gonadal toxicity and neuropathies [15].

Impact of Gynecologic Cancer on Sexuality

Gynecologic cancer and treatment can alter sexuality through a variety of effects. The impact of anatomical changes may alter a women’s self-esteem, body image, and sense of femininity, resulting in a reluctance to engage in intimate behaviors. Furthermore, if the partnership is disrupted by changes in roles in the household or within the relationship, relationships dynamics may be tested and result in mental distress for the patient, thus effecting sexuality and intimacy.

Surgical or chemical withdrawal of sex hormones, new medications, and postoperative sequelae can contribute to sexual arousal problems. The emotional and psychological components of a cancer diagnosis also can hinder the sexual response [16]. Depression and anxiety, the rates of which increase with cancer diagnosis, can also significantly affect sexual function [17].

Sexual pain is common in this population due to hormonal considerations as well as post-treatment side effects and a frequent cause of sexual dysfunction for these patients. Pelvic radiation may result in adverse physical changes to the vagina including vaginal stenosis, thinning of vaginal mucosa, loss of lubrication, and loss of elasticity [18,19]. A recent review of 20 studies of cervical cancer survivors found that patients were at risk for lack of lubrication and had high rates of dyspareunia [20]. Psychosocial factors have been found to be important predictors of sexual desire and more important than hormones in predicting low sexual desire in middle age [21]. These factors include emotional and physical closeness to the partner, satisfactory communication, and a positive relation to one’s own body [16].

Effects on Relationships and Partners

Women whose sexual capacity is compromised may be worried about their partners’ quality of life and overall well-being. Indeed, the partners of women with gynecologic cancer are also impacted by the changes to sexual function and loss of sexuality and intimacy. Hawkins et al found that cessation or decreased frequency of sex and intimacy was reported in 79% of male partners of women affected by cancer. Among partners of the persons with cancer in this study, changes to sexuality were associated with feelings of self-blame, reflection, sadness, anger and lack of sexual fulfillment [22]. Further, male partners of women diagnosed with gynecological cancer often express conflicting emotional states including feeling worried about their significant other’s health, having the desire to engage in sexual activity, and feeling guilty about wanting to increase sexual intimacy. These feelings, in turn, can lead to resentment and withdrawal from their partner and overall relationship discord [23].

Evidence suggests partners of cancer patients greatly benefit from increased social support even years after an apparent cure [24]. Specifically, male partners who take on a new role as caregiver in the relationship experience difficulties with emotional changes, challenges to their masculinity, and new stressors [25]. These new roles and feelings also contribute to changes in sexuality and intimacy in relationships, making support for partners all the more necessary.

Menopausal Symptoms Following Cancer Treatment

Gynecologic cancer treatment invariably affects the female hormonal balance, sometimes suddenly with surgical excision of the gonads or via radiation treatment or chemotherapy. It is well known that the sudden withdrawal of estrogen and testosterone, especially in the premenopausal postoperative population, can lead to significant acute menopausal symptoms. Given the many emotional and physical issues affecting patients during treatment, it can be difficult to delineate what proportion of sexual problems are caused by or enhanced by vasomotor symptoms, sleep disorders, and vaginal atrophy.

In general, premenopausal women who experience abrupt surgical menopause may often have immediate severe symptoms. Many agree that the younger a woman is when going through this process, the more severe her symptoms may be. Although the average age of endometrial cancer diagnosis is 67, approximately 25% of women who are diagnosed are premenopausal, and 5% of cases occur in women under 40. As the obesity epidemic worsens and more women are exposed to higher levels of estrogen at younger ages, it is expected that the number of premenopausal women who are diagnosed will continue to rise. The average age of diagnosis for ovarian cancer is 63, however, there is a large cohort of women diagnosed with borderline and malignant tumors in the premenopausal period [26]. These patients often experience vasomotor symptoms in the hours to days following surgery.

Interventions for Survivors of Gynecologic Cancer with Sexual Dysfunction

Systemic Hormone Therapy

Systemic hormonal therapy to treat menopausal symptoms remains controversial following the release of findings from the Women’s Health Initiative, which showed a number of adverse effects, including an increased risk of breast cancer in healthy postmenopausal women who received systemic hormonal therapy for menopausal symptoms. While views have changed since that time, providers are often reluctant to prescribe hormonal therapy, and patients are reticent to take it, due to fears of cancer recurrence. However, there is no evidence showing hormones negatively influence survival after treatment for epithelial ovarian, squamous cervical, or vulvar cancer [27]. With the exception of endometrial cancer, there is no biological evidence that HRT may increase recurrence risk [28]. Approach to clinical decision making should be individualized, taking into consideration the patients’ symptoms, quality of life, tumor histology, and overall prognosis.

Cervical cancer, vulvar cancer, and vaginal cancer are not considered hormonally responsive tumors. While the data are limited, a study published in 1987 of cervical cancer survivors treated with systemic hormone replacement therapy showed no increase in relapse rates and showed an increase in quality of life [29]. There are no studies regarding systemic HRT in patients with vulvar or vaginal cancer though it is generally accepted they can be treated with HRT. No significant data exists for cervical adenocarcinoma patients, and most oncologists suggest treating these patients the same as those with endometrial cancer primary.

There is limited data on the use of HRT in women with ovarian cancer but available studies do not show any difference in overall or disease-free survival between HRT groups and controls [27,30–32]. Many studies report a significant increase in quality of life with HRT. A 2013 retrospective chart review of 77 patients with epithelial ovarian cancer who received postoperative HRT showed no significant difference in progression-free survival [33].

The most controversy surrounds the use of HRT in patients with endometrial cancer [34]. The only major data available come from the Gynecologic Oncology Group’s truncated study, which was a large prospective randomized controlled trial. Over 1200 women treated for stage I and II endometrial cancer were enrolled between 1997 and 2003, and before the study was terminated these patients were followed for a median of 3 years following initiation of therapy. The recurrence rate of malignancy was low, 2.1, and an insignificant risk of recurrence of 1.27 was noted between with HRT and placebo groups (80% CI, 0.916-1.77) [35]. Women included in this study were between the ages of 26 and 91, and their indications for therapy included vasomotor symptoms, vaginal atrophy, as well as osteoporosis risk and cardiovascular disease risk. Gynecologist oncologists often use estrogen therapy to treat symptomatic women with early stage endometrial cancer given the very low risk of recurrence.

Tibolone is a synthetic steroid with activity on estrogen and progesterone receptors, and mainly acts as an agonist at estrogen receptors. It is prescribed outside the United States for osteoporosis and is being investigated as treatment for female sexual dysfunction. Efficacy on vasomotor symptoms has been positive thus far. One case-control study confirmed tibolone’s safety for endometrial cancer survivors, with no adverse effects on disease-free or overall survival [36]. One group recently examined tibolone in the setting of breast cancer patients in a prospective randomized controlled trial and reported an increased risk of breast cancer recurrences in women receiving tibolone for HT [37]. That study reported no increase in risk of gynecologic cancers and did report favorable outcomes for patients in terms of osteoporosis and vasomotor symptoms.

Topical Therapy

Women who are concerned about systemic HRT but who have been treated with radiation in addition to their surgery may be interested in topical estrogen therapy. These women may have vaginal stenosis and atrophic symptoms, and for them topical estrogen therapy can be helpful [38]. Many formulations of topical estrogen are available, including creams, tablets, and rings. Using vaginal estrogens and dilators can be useful to help with eventual resumption of sexual activity once healing has taken place and can help to avoid dyspareunia. Combination topical and systemic therapy can also be useful to relieve symptoms. Women concerned about absorption with topical therapy can be advised that while there is some absorption initially, absorption is reduced as atrophy is improved with treatment.

One recent study examined the use of alpha-tocopherol to reduce acute vaginal complications in women with endometrial and cervical cancer undergoing radiation treatment. The treatment group experienced reduced vaginal toxicity and pain, although vaginal secretion was not significantly different in the 2 groups studied [39]. No adverse effects were noted. This compound has not been studied further but may be beneficial in the future.

Some women may prefer to avoid hormones altogether. Over-the-counter vaginal moisturizers and lubricants can be recommended to women to help with intercourse and atrophic symptoms, with or without estrogen therapy.

Physical Therapy

Pelvic floor physical therapy has become an increasingly popular modality for treatment of many aspects pelvic floor dysfunction, the symptoms of which include defecatory dysfunction, constipation, bladder dysfunction, painful urination, dyspareunia, pelvic pain, and low back pain [40]. Pelvic floor physical therapy is well studied and utilized frequently for urinary incontinence and pelvic organ prolapse, but is understudied for sexual dysfunction [41,42].

Promising areas of study include educational sessions, cognitive behavioral therapy, vaginal dilator therapy, pelvic floor muscle strengthening and relaxation techniques with biofeedback, stretching and massage [40]. Biofeedback specifically has been studied in controlled studies for treatment of sexual dysfunction specifically in the setting of vulvar pain syndromes [43]. A small randomized control trial evaluated the use of pelvic floor muscle training in gynecologic cancer survivors and found that the intervention group reported improved sexual function and improved quality of life [44]. Given the few side effects of this therapy, it may be a helpful addition to a multidisciplinary approach to treating pelvic floor dysfunction in gynecologic cancer patients.

For cervical and endometrial cancer patients, vaginal dilators are often prescribed following radiation therapy to minimize vaginal stenosis. Literature suggests that after radiotherapy dilation therapy is effective when used as directed, typically 3 times per week for 10 minutes to mechanically separate the vaginal walls and increase elasticity [45]. Adherence to recommendations for vaginal dilator use is low in this population due to factors such as aversion to the practice and intrusiveness of the mechanism [46,47]. Acknowledgment of apprehension regarding dilator use should be part of the counseling prior to initiation of treatment; interventions designed to educate women about dilator use benefit may increase adherence [48].

Psychological Therapies

Survivors of gynecological cancer with sexual dysfunction may experience the psychological symptoms in the context of the other emotional challenges of a cancer diagnosis [49]. Changes in body image, physical appearance, and feelings of well-being can significantly affect sexuality and intimacy, while anxiety and negative feelings about a diagnosis can cause further sexual dysfunction. Conversely, sexual morbidity in these patients predicts worsening of general psychological symptoms, including depressive symptoms and overall quality of life [13–15].

While there are limited studies directly assessing the effect of psychological therapies for the treatment of sexual dysfunction in this population, the existing literature shows enduring symptomatic improvement following brief interventions. In women for whom emotional distress, depression, and anxiety appear to be a significant aspect of their concern regarding intimacy and sexuality, these interventions can be particularly helpful.

Cognitive behavioral therapy (CBT), which focuses on mindfulness and the relationships between maladaptive thoughts and how they impact behavior, has been shown to have efficacy in treating the broader psycho-social concerns of gynecological cancer patients [50,51]. In a recent study Brotto and colleagues randomized 31 survivors of gynecological cancer with self-reported sexual dysfunction to either three 90-minute CBT sessions or a waitlist control. Patients who underwent the intervention reported significant improvements in sexual arousal and desire both immediately post-therapy and at 6-month follow-up while patients in the waitlist arm experienced no significant changes in symptomatology [52].

Psychoeducational interventions are another promising avenue for addressing sexual dysfunction in this population [53]. In a 2008 therapeutic trial, Brotto and colleagues combined elements of CBT with education in 3 one-hour sessions featuring written materials on sexuality and relationships. The intervention enrolled 22 women with early stage gynecologic cancer who met criteria for female sexual arousal disorder. The psychoeducational intervention was associated with positive effect on sexual desire, arousal, orgasm, satisfaction, sexual distress, depression, and overall well-being [16]. Psychoeducation can also be used to augment other therapeutic modalities. Robinson and colleagues used such an intervention to improve adherence to vaginal dilator use in 32 women with early stage endometrial cancer who were being treated with radiotherapy [48].

Some gynecologic cancer patients may have significant alterations in their anatomy and thus penetrative intercourse may not be possible. In patients even without these physical changes, some may prefer to avoid intercourse due to pain or anxiety. Thus patients can have significant benefits from discussing their concerns with a therapist specializing in these issues as many patients are concerned about their ability to engage in intimate behavior. Therapy can assist with the changing sexual relationship and assist the partners in different ways of engaging in intimate acts. It is important to avoid stressing penetrative intercourse as the goal for sexual function with these or any patients with anxiety relating to their disease as there are many ways to engage in mutually pleasurable experiences for both partners, thus removing anxiety about inability to resume vaginal intercourse post-treatment. Discussing this with patients can be challenging but can often reduce anxiety surrounding body image issues following treatment.

Studies have shown that cancer care providers often do not adequately address sexual concerns [54] but that when these concerns are appropriately managed, patient satisfaction and quality of life significantly improve [55]. Several studies have focused on how providers can incorporate the approaches of CBT and psychoeducation to better address the sexual concerns of patients without requiring external psychiatric care [56,57]. Barbera et al have described a successful model in which multidisciplinary care teams provide education and counseling for gynecological cancer patients in a sexuality clinic [58]. patients had a significant symptom burden, including menopausal symptoms, the effects of radiation therapy, chemotherapy, and surgical operation as well as psychological responses to cancer, and reported high levels of satisfaction with their experience at the clinic.

Involvement of the partner in interventions has not been well studied; however, involving the partner in in psychological therapies to address sexual dysfunction should be beneficial.

Alternative Therapies for Vasomotor Symptoms

Gynecologic cancer patients suffering prominent vasomotor symptoms have limited alternatives to hormone therapy. Clinicians must balance potential medication benefit with potential exacerbation of other medical and psychological issues, including sexual dysfunction.

Antidepressants

The use of SSRIs and SNRIs for vasomotor symptoms was pioneered by medical oncologists for men with hot flashes secondary to GnRH agonist therapy for prostate cancer and women with breast cancer [59,60]. Limited studies have shown that antidepressant medications do not increase cancer recurrence risk in ovarian cancer patients and are relatively well tolerated [61]. However, these medications are known to have partial efficacy in improving vasomotor symptoms and may worsen sexual symptoms, a well-known side effect of antidepressants. There is variation of the reported rates of sexual dysfunction associated with various antidepressants and clinicians may take the likelihood of sexual side effects into account when prescribing SSRIs or SNRIS [62]. More recently developed SSRIS, such as citalopram and its enantiomer escitalopram, have shown significant improvements in vasomotor symptoms and were better tolerated than venlafaxine and fluoxetine [63,64]. Additionally, limited uncontrolled studies of mirtazipine, a structurally unique SSRI, and bupropion, which acts on dopamine and norepinephrine, have shown significant decreases in hot flash symptoms and are less associated with sexual side effects than SSRIS/SNRIS [65,66].

Other Agents

Other pharmaceutical options for menopausal vasomotor symptoms include gabapentin and adrenergic agonists. Gabapentin can yield impressive reductions in vasomotor symptoms. A recent double-blind randomized trial in 50 patients revealed a 60% reduction in hot flashes as 12 weeks and an 80% reduction in self-reported composite symptom scores [67]. However, side effects such as palpitations, edema, and fatigue, lead to high study withdrawal rates and limit its widespread clinical use for this indication [68]. Clonidine has been assessed versus venlafaxine in several clinical trials with breast cancer patients. These trials have shown mixed results, with findings of both inferiority and superiority to venlafaxine, but with consistent significant improvement in symptoms over placebo. Side effects, such insomnia, constipation and dry mouth, occurred but did not lead to higher dropout rates than venlafaxine [69,70].

Long-Term Sexual Outcomes

For women treated for gynecological cancers, alterations in sexual function may persist in the long term. A study following cervical cancer patients managed with radical hysterectomy up to 2 years post treatment showed they had more sexual dysfunction compared with healthy controls, although at rates similar to those who underwent radical hysterectomy for benign disease [71]. A 2007 review of quality of life studies revealed that although ovarian cancer survivors 5 years past diagnosis had excellent overall quality of life, sexual symptoms persisted, with as many as 57% of patients reporting a decline in sexual function due to their cancer [72].

Studies show some differences in outcomes based on treatment modality. A recent review of cervical cancer outcomes revealed that women who received radiotherapy as a component of their treatment have a higher risk of long-term sexual side effects [73]. In contrast, a study assessing endometrial cancer patients 5 years after initial diagnosis between those patients who had received surgery alone and those who had received surgery and vaginal brachytherapy. There was no significant difference in any measures of quality of life and sexual function between these 2 groups [74].

Age appears to play a role in long-term sexual outcomes regardless of diagnosis. Bifulco and colleagues assessed quality of life in survivors of gynecological cancer, comparing women under age 45 to those over 45 after nearly 3 years of survival. After controlling for age and other factors, younger patients were found to have worse sexual activity, including significantly higher rates of poor body image, perceived worse sexual vaginal function, and more severe menopausal symptoms, probably related to the effects of surgical menopause [75].

Despite enduring sexual dysfunction, symptoms tend to improve over time. A cohort study of 103 gynecological cancer patients undergoing radiation therapy were followed for 3 years. Patients were offered standard interventions for sexual dysfunction, including vaginal lubricants, dilators, and menopausal symptomatic therapy, although adherence to these measures was not assessed. Three years after initial therapy, the percentage of sexually active women increased from 21.5% to 44.2% [76]. In the subset of patients who successfully return to sexual activity, outcomes can be comparable to healthy peers. Kim and colleagues compared disease-free sexually active ovarian cancer patients with demographically matched healthy controls on standardized self-report measures. Sexual functioning did not differ between the 2 groups, despite lower social functioning in cancer survivors [12].

Conclusion

Sexuality and intimacy can be greatly affected by the diagnosis and treatment of gynecologic malignancies. It is important to routinely discuss sexuality and sexual functioning with patients from diagnosis onward. Reassuring patients, acknowledging the importance of their concerns, and validating their desire to enjoy improved intimacy should be considered part of the clinician’s role. Valuable information sources that may aid discussions are available on the internet. Oncolink (www.oncolink.org), a large cancer information website maintained by University of Pennsylvania Cancer Center, offers a plethora of information for patients and health care professionals. In addition, the American Cancer Society offers a detailed guide, “Sexuality for the Woman with Cancer” [77]. Treatment is available, and improvement in outcomes is possible. Further prospective studies are needed to clearly delineate risks and benefits of hormone replacement therapy in patients with gynecologic cancers.

Corresponding author: Elena S. Ratner, MD, PO Box 208063, New Haven, CT 06520, [email protected].

From the Yale School of Medicine, New Haven, CT.

Abstract

• Objective: To review the sexual health concerns of women with gynecologic cancer and provide guidance for primary care physicians.
• Methods: Review of the literature.
• Results: Issues of sexuality and intimacy are known to significantly impact the quality of life of patients following diagnosis and treatment of gynecologic cancers. At the time of diagnosis, women should be informed of the potential physiologic, hormonal, and psychosocial effects of gynecologic cancer on sexuality. Many providers fail to address these issues given time constraints and patients’ trepidation in alerting their providers to their concerns. While systemic hormone therapy directly addresses these symptoms, its use remains controversial due to potential cancer recurrence risks. Thus, treatment centers around therapeutic alternatives. For vasomotor symptoms, selective serotonin reuptake inhibitors have shown effectiveness and are typically well tolerated, and antiepileptics such as gabapentin have shown promise. There is promising but limited data employing pelvic floor physical therapy as a tool to aid in addressing pelvic floor symptoms. Psychological care and the involvement of the partner are also part of managing the sexual health concerns of these patients.
• Conclusion: Sexual morbidity is a distressing and undertreated problem among gynecologic cancer survivors. Successful treatment requires the provider’s appreciation of the problem and willingness to address it.

Issues of sexuality and intimacy are known to significantly impact the lives of patients following diagnosis and treatment of gynecologic cancers. [1,2] Treatment of gynecologic malignancy is highly dependent on pathology and stage, with some patients receiving small excisional procedures while others subject to extensive surgeries, chemotherapy, and radiation treatment, and it is difficult to predict how each individual’s sexual health will be impacted. However, the evidence suggests that at least half of women treated for gynecologic cancer will experience sexual dysfunction [3]. Although the impact of gynecologic cancer and treatment can be profound, providers often do not address their patients’ sexual concerns [4,5], yet most patients have indicated that they would like these issues to be addressed [6].

Female Sexual Dysfunction

Sexual dysfunction is multifactorial and involves physical, social, and psychological dimensions. It is common in the general population, with rates ranging from 25-63% [7]. The DSM-IV [8] defines female sexual dysfunction as a disturbance in or pain during the sexual response, which can be further classified as hypoactive sexual disorder, orgasmic disorder, sexual pain disorder, or sexual arousal disorder [9]. It should be noted that women who have been treated for gynecologic cancers may have a premorbid history of sexual dysfunction. Assessment of a woman’s sexual function prior to her cancer diagnosis can help establish which sexuality changes are due to the cancer treatment and may allow the provider to tailor interventions accordingly.

Sexual Dysfunction and Quality of Life

As treatments for gynecologic cancers improve, toxicity of treatment decreases, and survival increases, quality of life for survivors has become as become an increasingly important health issue. Several studies have examined patient-reported quality of life in short- and long-term cancer survivors and report overall significant alteration in quality of life over many aspects of health and psychological well-being [10]. It is well established that health-related quality of life and sexual functioning are closely associated [11].

In gynecologic cancer patients, sexual and quality of life outcomes can vary. For example, Kim el al recently compared quality of life and sexual functioning in ovarian cancer survivors with no evidence of disease after primary treatment and a cohort of health women. Sexuality, both in terms of desire, arousal, lubrication, orgasm, satisfaction, and pain and in terms of interest in sex, sexual activity, and enjoyment of sex were similar between the groups; however social functioning deteriorated in cancer patients [12]. Other women report different experiences. Women with a history of vulvar, vaginal, or cervical cancer who may have had extensive pelvic surgery, lymphadenectomy, and radiation treatment to the pelvis typically report greater alterations in quality of life and sexual activity depending on the extent of their treatment [13].

Patients undergoing chemotherapy often report significant changes in quality of life due to the physical symptoms of fatigue, nausea, hair loss, diarrhea, etc. as well the psychological effects of cancer diagnosis, changes in body image, and poor coping [14]. Sexual side effects are common due to alterations in the HPA axis, direct gonadal toxicity and neuropathies [15].

Impact of Gynecologic Cancer on Sexuality

Gynecologic cancer and treatment can alter sexuality through a variety of effects. The impact of anatomical changes may alter a women’s self-esteem, body image, and sense of femininity, resulting in a reluctance to engage in intimate behaviors. Furthermore, if the partnership is disrupted by changes in roles in the household or within the relationship, relationships dynamics may be tested and result in mental distress for the patient, thus effecting sexuality and intimacy.

Surgical or chemical withdrawal of sex hormones, new medications, and postoperative sequelae can contribute to sexual arousal problems. The emotional and psychological components of a cancer diagnosis also can hinder the sexual response [16]. Depression and anxiety, the rates of which increase with cancer diagnosis, can also significantly affect sexual function [17].

Sexual pain is common in this population due to hormonal considerations as well as post-treatment side effects and a frequent cause of sexual dysfunction for these patients. Pelvic radiation may result in adverse physical changes to the vagina including vaginal stenosis, thinning of vaginal mucosa, loss of lubrication, and loss of elasticity [18,19]. A recent review of 20 studies of cervical cancer survivors found that patients were at risk for lack of lubrication and had high rates of dyspareunia [20]. Psychosocial factors have been found to be important predictors of sexual desire and more important than hormones in predicting low sexual desire in middle age [21]. These factors include emotional and physical closeness to the partner, satisfactory communication, and a positive relation to one’s own body [16].

Effects on Relationships and Partners

Women whose sexual capacity is compromised may be worried about their partners’ quality of life and overall well-being. Indeed, the partners of women with gynecologic cancer are also impacted by the changes to sexual function and loss of sexuality and intimacy. Hawkins et al found that cessation or decreased frequency of sex and intimacy was reported in 79% of male partners of women affected by cancer. Among partners of the persons with cancer in this study, changes to sexuality were associated with feelings of self-blame, reflection, sadness, anger and lack of sexual fulfillment [22]. Further, male partners of women diagnosed with gynecological cancer often express conflicting emotional states including feeling worried about their significant other’s health, having the desire to engage in sexual activity, and feeling guilty about wanting to increase sexual intimacy. These feelings, in turn, can lead to resentment and withdrawal from their partner and overall relationship discord [23].

Evidence suggests partners of cancer patients greatly benefit from increased social support even years after an apparent cure [24]. Specifically, male partners who take on a new role as caregiver in the relationship experience difficulties with emotional changes, challenges to their masculinity, and new stressors [25]. These new roles and feelings also contribute to changes in sexuality and intimacy in relationships, making support for partners all the more necessary.

Menopausal Symptoms Following Cancer Treatment

Gynecologic cancer treatment invariably affects the female hormonal balance, sometimes suddenly with surgical excision of the gonads or via radiation treatment or chemotherapy. It is well known that the sudden withdrawal of estrogen and testosterone, especially in the premenopausal postoperative population, can lead to significant acute menopausal symptoms. Given the many emotional and physical issues affecting patients during treatment, it can be difficult to delineate what proportion of sexual problems are caused by or enhanced by vasomotor symptoms, sleep disorders, and vaginal atrophy.

In general, premenopausal women who experience abrupt surgical menopause may often have immediate severe symptoms. Many agree that the younger a woman is when going through this process, the more severe her symptoms may be. Although the average age of endometrial cancer diagnosis is 67, approximately 25% of women who are diagnosed are premenopausal, and 5% of cases occur in women under 40. As the obesity epidemic worsens and more women are exposed to higher levels of estrogen at younger ages, it is expected that the number of premenopausal women who are diagnosed will continue to rise. The average age of diagnosis for ovarian cancer is 63, however, there is a large cohort of women diagnosed with borderline and malignant tumors in the premenopausal period [26]. These patients often experience vasomotor symptoms in the hours to days following surgery.

Interventions for Survivors of Gynecologic Cancer with Sexual Dysfunction

Systemic Hormone Therapy

Systemic hormonal therapy to treat menopausal symptoms remains controversial following the release of findings from the Women’s Health Initiative, which showed a number of adverse effects, including an increased risk of breast cancer in healthy postmenopausal women who received systemic hormonal therapy for menopausal symptoms. While views have changed since that time, providers are often reluctant to prescribe hormonal therapy, and patients are reticent to take it, due to fears of cancer recurrence. However, there is no evidence showing hormones negatively influence survival after treatment for epithelial ovarian, squamous cervical, or vulvar cancer [27]. With the exception of endometrial cancer, there is no biological evidence that HRT may increase recurrence risk [28]. Approach to clinical decision making should be individualized, taking into consideration the patients’ symptoms, quality of life, tumor histology, and overall prognosis.

Cervical cancer, vulvar cancer, and vaginal cancer are not considered hormonally responsive tumors. While the data are limited, a study published in 1987 of cervical cancer survivors treated with systemic hormone replacement therapy showed no increase in relapse rates and showed an increase in quality of life [29]. There are no studies regarding systemic HRT in patients with vulvar or vaginal cancer though it is generally accepted they can be treated with HRT. No significant data exists for cervical adenocarcinoma patients, and most oncologists suggest treating these patients the same as those with endometrial cancer primary.

There is limited data on the use of HRT in women with ovarian cancer but available studies do not show any difference in overall or disease-free survival between HRT groups and controls [27,30–32]. Many studies report a significant increase in quality of life with HRT. A 2013 retrospective chart review of 77 patients with epithelial ovarian cancer who received postoperative HRT showed no significant difference in progression-free survival [33].

The most controversy surrounds the use of HRT in patients with endometrial cancer [34]. The only major data available come from the Gynecologic Oncology Group’s truncated study, which was a large prospective randomized controlled trial. Over 1200 women treated for stage I and II endometrial cancer were enrolled between 1997 and 2003, and before the study was terminated these patients were followed for a median of 3 years following initiation of therapy. The recurrence rate of malignancy was low, 2.1, and an insignificant risk of recurrence of 1.27 was noted between with HRT and placebo groups (80% CI, 0.916-1.77) [35]. Women included in this study were between the ages of 26 and 91, and their indications for therapy included vasomotor symptoms, vaginal atrophy, as well as osteoporosis risk and cardiovascular disease risk. Gynecologist oncologists often use estrogen therapy to treat symptomatic women with early stage endometrial cancer given the very low risk of recurrence.

Tibolone is a synthetic steroid with activity on estrogen and progesterone receptors, and mainly acts as an agonist at estrogen receptors. It is prescribed outside the United States for osteoporosis and is being investigated as treatment for female sexual dysfunction. Efficacy on vasomotor symptoms has been positive thus far. One case-control study confirmed tibolone’s safety for endometrial cancer survivors, with no adverse effects on disease-free or overall survival [36]. One group recently examined tibolone in the setting of breast cancer patients in a prospective randomized controlled trial and reported an increased risk of breast cancer recurrences in women receiving tibolone for HT [37]. That study reported no increase in risk of gynecologic cancers and did report favorable outcomes for patients in terms of osteoporosis and vasomotor symptoms.

Topical Therapy

Women who are concerned about systemic HRT but who have been treated with radiation in addition to their surgery may be interested in topical estrogen therapy. These women may have vaginal stenosis and atrophic symptoms, and for them topical estrogen therapy can be helpful [38]. Many formulations of topical estrogen are available, including creams, tablets, and rings. Using vaginal estrogens and dilators can be useful to help with eventual resumption of sexual activity once healing has taken place and can help to avoid dyspareunia. Combination topical and systemic therapy can also be useful to relieve symptoms. Women concerned about absorption with topical therapy can be advised that while there is some absorption initially, absorption is reduced as atrophy is improved with treatment.

One recent study examined the use of alpha-tocopherol to reduce acute vaginal complications in women with endometrial and cervical cancer undergoing radiation treatment. The treatment group experienced reduced vaginal toxicity and pain, although vaginal secretion was not significantly different in the 2 groups studied [39]. No adverse effects were noted. This compound has not been studied further but may be beneficial in the future.

Some women may prefer to avoid hormones altogether. Over-the-counter vaginal moisturizers and lubricants can be recommended to women to help with intercourse and atrophic symptoms, with or without estrogen therapy.

Physical Therapy

Pelvic floor physical therapy has become an increasingly popular modality for treatment of many aspects pelvic floor dysfunction, the symptoms of which include defecatory dysfunction, constipation, bladder dysfunction, painful urination, dyspareunia, pelvic pain, and low back pain [40]. Pelvic floor physical therapy is well studied and utilized frequently for urinary incontinence and pelvic organ prolapse, but is understudied for sexual dysfunction [41,42].

Promising areas of study include educational sessions, cognitive behavioral therapy, vaginal dilator therapy, pelvic floor muscle strengthening and relaxation techniques with biofeedback, stretching and massage [40]. Biofeedback specifically has been studied in controlled studies for treatment of sexual dysfunction specifically in the setting of vulvar pain syndromes [43]. A small randomized control trial evaluated the use of pelvic floor muscle training in gynecologic cancer survivors and found that the intervention group reported improved sexual function and improved quality of life [44]. Given the few side effects of this therapy, it may be a helpful addition to a multidisciplinary approach to treating pelvic floor dysfunction in gynecologic cancer patients.

For cervical and endometrial cancer patients, vaginal dilators are often prescribed following radiation therapy to minimize vaginal stenosis. Literature suggests that after radiotherapy dilation therapy is effective when used as directed, typically 3 times per week for 10 minutes to mechanically separate the vaginal walls and increase elasticity [45]. Adherence to recommendations for vaginal dilator use is low in this population due to factors such as aversion to the practice and intrusiveness of the mechanism [46,47]. Acknowledgment of apprehension regarding dilator use should be part of the counseling prior to initiation of treatment; interventions designed to educate women about dilator use benefit may increase adherence [48].

Psychological Therapies

Survivors of gynecological cancer with sexual dysfunction may experience the psychological symptoms in the context of the other emotional challenges of a cancer diagnosis [49]. Changes in body image, physical appearance, and feelings of well-being can significantly affect sexuality and intimacy, while anxiety and negative feelings about a diagnosis can cause further sexual dysfunction. Conversely, sexual morbidity in these patients predicts worsening of general psychological symptoms, including depressive symptoms and overall quality of life [13–15].

While there are limited studies directly assessing the effect of psychological therapies for the treatment of sexual dysfunction in this population, the existing literature shows enduring symptomatic improvement following brief interventions. In women for whom emotional distress, depression, and anxiety appear to be a significant aspect of their concern regarding intimacy and sexuality, these interventions can be particularly helpful.

Cognitive behavioral therapy (CBT), which focuses on mindfulness and the relationships between maladaptive thoughts and how they impact behavior, has been shown to have efficacy in treating the broader psycho-social concerns of gynecological cancer patients [50,51]. In a recent study Brotto and colleagues randomized 31 survivors of gynecological cancer with self-reported sexual dysfunction to either three 90-minute CBT sessions or a waitlist control. Patients who underwent the intervention reported significant improvements in sexual arousal and desire both immediately post-therapy and at 6-month follow-up while patients in the waitlist arm experienced no significant changes in symptomatology [52].

Psychoeducational interventions are another promising avenue for addressing sexual dysfunction in this population [53]. In a 2008 therapeutic trial, Brotto and colleagues combined elements of CBT with education in 3 one-hour sessions featuring written materials on sexuality and relationships. The intervention enrolled 22 women with early stage gynecologic cancer who met criteria for female sexual arousal disorder. The psychoeducational intervention was associated with positive effect on sexual desire, arousal, orgasm, satisfaction, sexual distress, depression, and overall well-being [16]. Psychoeducation can also be used to augment other therapeutic modalities. Robinson and colleagues used such an intervention to improve adherence to vaginal dilator use in 32 women with early stage endometrial cancer who were being treated with radiotherapy [48].

Some gynecologic cancer patients may have significant alterations in their anatomy and thus penetrative intercourse may not be possible. In patients even without these physical changes, some may prefer to avoid intercourse due to pain or anxiety. Thus patients can have significant benefits from discussing their concerns with a therapist specializing in these issues as many patients are concerned about their ability to engage in intimate behavior. Therapy can assist with the changing sexual relationship and assist the partners in different ways of engaging in intimate acts. It is important to avoid stressing penetrative intercourse as the goal for sexual function with these or any patients with anxiety relating to their disease as there are many ways to engage in mutually pleasurable experiences for both partners, thus removing anxiety about inability to resume vaginal intercourse post-treatment. Discussing this with patients can be challenging but can often reduce anxiety surrounding body image issues following treatment.

Studies have shown that cancer care providers often do not adequately address sexual concerns [54] but that when these concerns are appropriately managed, patient satisfaction and quality of life significantly improve [55]. Several studies have focused on how providers can incorporate the approaches of CBT and psychoeducation to better address the sexual concerns of patients without requiring external psychiatric care [56,57]. Barbera et al have described a successful model in which multidisciplinary care teams provide education and counseling for gynecological cancer patients in a sexuality clinic [58]. patients had a significant symptom burden, including menopausal symptoms, the effects of radiation therapy, chemotherapy, and surgical operation as well as psychological responses to cancer, and reported high levels of satisfaction with their experience at the clinic.

Involvement of the partner in interventions has not been well studied; however, involving the partner in in psychological therapies to address sexual dysfunction should be beneficial.

Alternative Therapies for Vasomotor Symptoms

Gynecologic cancer patients suffering prominent vasomotor symptoms have limited alternatives to hormone therapy. Clinicians must balance potential medication benefit with potential exacerbation of other medical and psychological issues, including sexual dysfunction.

Antidepressants

The use of SSRIs and SNRIs for vasomotor symptoms was pioneered by medical oncologists for men with hot flashes secondary to GnRH agonist therapy for prostate cancer and women with breast cancer [59,60]. Limited studies have shown that antidepressant medications do not increase cancer recurrence risk in ovarian cancer patients and are relatively well tolerated [61]. However, these medications are known to have partial efficacy in improving vasomotor symptoms and may worsen sexual symptoms, a well-known side effect of antidepressants. There is variation of the reported rates of sexual dysfunction associated with various antidepressants and clinicians may take the likelihood of sexual side effects into account when prescribing SSRIs or SNRIS [62]. More recently developed SSRIS, such as citalopram and its enantiomer escitalopram, have shown significant improvements in vasomotor symptoms and were better tolerated than venlafaxine and fluoxetine [63,64]. Additionally, limited uncontrolled studies of mirtazipine, a structurally unique SSRI, and bupropion, which acts on dopamine and norepinephrine, have shown significant decreases in hot flash symptoms and are less associated with sexual side effects than SSRIS/SNRIS [65,66].

Other Agents

Other pharmaceutical options for menopausal vasomotor symptoms include gabapentin and adrenergic agonists. Gabapentin can yield impressive reductions in vasomotor symptoms. A recent double-blind randomized trial in 50 patients revealed a 60% reduction in hot flashes as 12 weeks and an 80% reduction in self-reported composite symptom scores [67]. However, side effects such as palpitations, edema, and fatigue, lead to high study withdrawal rates and limit its widespread clinical use for this indication [68]. Clonidine has been assessed versus venlafaxine in several clinical trials with breast cancer patients. These trials have shown mixed results, with findings of both inferiority and superiority to venlafaxine, but with consistent significant improvement in symptoms over placebo. Side effects, such insomnia, constipation and dry mouth, occurred but did not lead to higher dropout rates than venlafaxine [69,70].

Long-Term Sexual Outcomes

For women treated for gynecological cancers, alterations in sexual function may persist in the long term. A study following cervical cancer patients managed with radical hysterectomy up to 2 years post treatment showed they had more sexual dysfunction compared with healthy controls, although at rates similar to those who underwent radical hysterectomy for benign disease [71]. A 2007 review of quality of life studies revealed that although ovarian cancer survivors 5 years past diagnosis had excellent overall quality of life, sexual symptoms persisted, with as many as 57% of patients reporting a decline in sexual function due to their cancer [72].

Studies show some differences in outcomes based on treatment modality. A recent review of cervical cancer outcomes revealed that women who received radiotherapy as a component of their treatment have a higher risk of long-term sexual side effects [73]. In contrast, a study assessing endometrial cancer patients 5 years after initial diagnosis between those patients who had received surgery alone and those who had received surgery and vaginal brachytherapy. There was no significant difference in any measures of quality of life and sexual function between these 2 groups [74].

Age appears to play a role in long-term sexual outcomes regardless of diagnosis. Bifulco and colleagues assessed quality of life in survivors of gynecological cancer, comparing women under age 45 to those over 45 after nearly 3 years of survival. After controlling for age and other factors, younger patients were found to have worse sexual activity, including significantly higher rates of poor body image, perceived worse sexual vaginal function, and more severe menopausal symptoms, probably related to the effects of surgical menopause [75].

Despite enduring sexual dysfunction, symptoms tend to improve over time. A cohort study of 103 gynecological cancer patients undergoing radiation therapy were followed for 3 years. Patients were offered standard interventions for sexual dysfunction, including vaginal lubricants, dilators, and menopausal symptomatic therapy, although adherence to these measures was not assessed. Three years after initial therapy, the percentage of sexually active women increased from 21.5% to 44.2% [76]. In the subset of patients who successfully return to sexual activity, outcomes can be comparable to healthy peers. Kim and colleagues compared disease-free sexually active ovarian cancer patients with demographically matched healthy controls on standardized self-report measures. Sexual functioning did not differ between the 2 groups, despite lower social functioning in cancer survivors [12].

Conclusion

Sexuality and intimacy can be greatly affected by the diagnosis and treatment of gynecologic malignancies. It is important to routinely discuss sexuality and sexual functioning with patients from diagnosis onward. Reassuring patients, acknowledging the importance of their concerns, and validating their desire to enjoy improved intimacy should be considered part of the clinician’s role. Valuable information sources that may aid discussions are available on the internet. Oncolink (www.oncolink.org), a large cancer information website maintained by University of Pennsylvania Cancer Center, offers a plethora of information for patients and health care professionals. In addition, the American Cancer Society offers a detailed guide, “Sexuality for the Woman with Cancer” [77]. Treatment is available, and improvement in outcomes is possible. Further prospective studies are needed to clearly delineate risks and benefits of hormone replacement therapy in patients with gynecologic cancers.

Corresponding author: Elena S. Ratner, MD, PO Box 208063, New Haven, CT 06520, [email protected].