M. Alexander Otto

BOSTON – More than a third of 419 children treated for brain tumors at Cincinnati Children’s Hospital Medical Center later developed endocrine problems, according to a review presented at the Endocrine Society annual meeting.

Over 60% of the 96 suprasellar tumor patients developed endocrine dysfunction, which isn’t surprising considering the location of the tumor, but wide-ranging endocrine problems were also common in the 145 posterior fossa, 158 supratentorial, and 20 spinal cord cases, ranging from 14% in the spinal cord group to 42% in the posterior fossa group, after some combination of radiation, chemotherapy, and surgery based on tumor location and other factors.

“Even with tumors that aren’t supposed to be high risk, there was a high risk of endocrinopathies. We need yearly screening of these patients” for about 6 years, after which symptom-based screening may be sufficient. The clock should be restarted if there’s a recurrence. “Not everyone does this” at Cincinnati Children’s and probably most other institutions, said investigator and endocrinology fellow Dr. Vincent Horne.

The findings are “changing how our oncology department is thinking about [screening]; there’s a concentrated effort to increase proactive screening and follow these patients long term,” he said.

“Even within our specialized, multidisciplinary center,” endocrinopathy screening referrals were low, about 61% overall and only 80% in the suprasellar group. “Patients at highest risk” – those with craniopharyngioma – “are being seen early by us,” but others aren’t being referred. It’s possible that the extent of endocrine problems after pediatric brain tumor treatment is simply unrecognized, he said.

Endocrine abnormalities were found in 114 (45%) of the 254 patients evaluated, which translated to problems in more than a third of all patients.

More than half of the children had more than one problem, and most of the issues occurred within 6 years of treatment. Central hypothyroidism was found in 53% of the children, probably because Cincinnati Children’s already has thyroid screening in place.

About 40% were growth hormone deficient, and almost a third had precocious puberty. About 30% were gonadotropin-releasing hormone deficient, over 20% had primary hypothyroidism, and about the same had diabetes insipidus. Just over 6% were hyperprolactinemic.

Of the 151 patients who completed adrenocorticotropic hormone (ACTH) testing, 14.6% were deficient. ACTH deficient children were about evenly split between the suprasellar and supratentorial groups, with the remaining in the posterior fossa cohort.

“We are probably not thinking about” the risk of radiation “to locations like the posterior fossa. That group actually had the highest risk of primary hypothyroidism [20%] because of the spinal radiation. The supratentorial group is also receiving radiation; even though we think we are missing the hypothalamus, obviously that’s not necessarily the case,” Dr. Horne said.

His team looked into endocrine screening because previous studies “were limited and done years ago.” People are living longer now after treatment, “so we need to think about how to screen for endocrine disease. This is an attempt to clarify how we should do it,” he said.

Children were a median of 8 years old at diagnosis, and the median radiation dose was 54 Gy.

There was no industry funding for the work, and the investigators had no disclosures.

[email protected]

BOSTON – More than a third of 419 children treated for brain tumors at Cincinnati Children’s Hospital Medical Center later developed endocrine problems, according to a review presented at the Endocrine Society annual meeting.

Over 60% of the 96 suprasellar tumor patients developed endocrine dysfunction, which isn’t surprising considering the location of the tumor, but wide-ranging endocrine problems were also common in the 145 posterior fossa, 158 supratentorial, and 20 spinal cord cases, ranging from 14% in the spinal cord group to 42% in the posterior fossa group, after some combination of radiation, chemotherapy, and surgery based on tumor location and other factors.

“Even with tumors that aren’t supposed to be high risk, there was a high risk of endocrinopathies. We need yearly screening of these patients” for about 6 years, after which symptom-based screening may be sufficient. The clock should be restarted if there’s a recurrence. “Not everyone does this” at Cincinnati Children’s and probably most other institutions, said investigator and endocrinology fellow Dr. Vincent Horne.

The findings are “changing how our oncology department is thinking about [screening]; there’s a concentrated effort to increase proactive screening and follow these patients long term,” he said.

“Even within our specialized, multidisciplinary center,” endocrinopathy screening referrals were low, about 61% overall and only 80% in the suprasellar group. “Patients at highest risk” – those with craniopharyngioma – “are being seen early by us,” but others aren’t being referred. It’s possible that the extent of endocrine problems after pediatric brain tumor treatment is simply unrecognized, he said.

Endocrine abnormalities were found in 114 (45%) of the 254 patients evaluated, which translated to problems in more than a third of all patients.

More than half of the children had more than one problem, and most of the issues occurred within 6 years of treatment. Central hypothyroidism was found in 53% of the children, probably because Cincinnati Children’s already has thyroid screening in place.

About 40% were growth hormone deficient, and almost a third had precocious puberty. About 30% were gonadotropin-releasing hormone deficient, over 20% had primary hypothyroidism, and about the same had diabetes insipidus. Just over 6% were hyperprolactinemic.

Of the 151 patients who completed adrenocorticotropic hormone (ACTH) testing, 14.6% were deficient. ACTH deficient children were about evenly split between the suprasellar and supratentorial groups, with the remaining in the posterior fossa cohort.

“We are probably not thinking about” the risk of radiation “to locations like the posterior fossa. That group actually had the highest risk of primary hypothyroidism [20%] because of the spinal radiation. The supratentorial group is also receiving radiation; even though we think we are missing the hypothalamus, obviously that’s not necessarily the case,” Dr. Horne said.

His team looked into endocrine screening because previous studies “were limited and done years ago.” People are living longer now after treatment, “so we need to think about how to screen for endocrine disease. This is an attempt to clarify how we should do it,” he said.

Children were a median of 8 years old at diagnosis, and the median radiation dose was 54 Gy.

There was no industry funding for the work, and the investigators had no disclosures.

[email protected]

BOSTON – More than a third of 419 children treated for brain tumors at Cincinnati Children’s Hospital Medical Center later developed endocrine problems, according to a review presented at the Endocrine Society annual meeting.

Over 60% of the 96 suprasellar tumor patients developed endocrine dysfunction, which isn’t surprising considering the location of the tumor, but wide-ranging endocrine problems were also common in the 145 posterior fossa, 158 supratentorial, and 20 spinal cord cases, ranging from 14% in the spinal cord group to 42% in the posterior fossa group, after some combination of radiation, chemotherapy, and surgery based on tumor location and other factors.

“Even with tumors that aren’t supposed to be high risk, there was a high risk of endocrinopathies. We need yearly screening of these patients” for about 6 years, after which symptom-based screening may be sufficient. The clock should be restarted if there’s a recurrence. “Not everyone does this” at Cincinnati Children’s and probably most other institutions, said investigator and endocrinology fellow Dr. Vincent Horne.

The findings are “changing how our oncology department is thinking about [screening]; there’s a concentrated effort to increase proactive screening and follow these patients long term,” he said.

“Even within our specialized, multidisciplinary center,” endocrinopathy screening referrals were low, about 61% overall and only 80% in the suprasellar group. “Patients at highest risk” – those with craniopharyngioma – “are being seen early by us,” but others aren’t being referred. It’s possible that the extent of endocrine problems after pediatric brain tumor treatment is simply unrecognized, he said.

Endocrine abnormalities were found in 114 (45%) of the 254 patients evaluated, which translated to problems in more than a third of all patients.

More than half of the children had more than one problem, and most of the issues occurred within 6 years of treatment. Central hypothyroidism was found in 53% of the children, probably because Cincinnati Children’s already has thyroid screening in place.

About 40% were growth hormone deficient, and almost a third had precocious puberty. About 30% were gonadotropin-releasing hormone deficient, over 20% had primary hypothyroidism, and about the same had diabetes insipidus. Just over 6% were hyperprolactinemic.

Of the 151 patients who completed adrenocorticotropic hormone (ACTH) testing, 14.6% were deficient. ACTH deficient children were about evenly split between the suprasellar and supratentorial groups, with the remaining in the posterior fossa cohort.

“We are probably not thinking about” the risk of radiation “to locations like the posterior fossa. That group actually had the highest risk of primary hypothyroidism [20%] because of the spinal radiation. The supratentorial group is also receiving radiation; even though we think we are missing the hypothalamus, obviously that’s not necessarily the case,” Dr. Horne said.

His team looked into endocrine screening because previous studies “were limited and done years ago.” People are living longer now after treatment, “so we need to think about how to screen for endocrine disease. This is an attempt to clarify how we should do it,” he said.

Children were a median of 8 years old at diagnosis, and the median radiation dose was 54 Gy.

There was no industry funding for the work, and the investigators had no disclosures.

[email protected]

LOS ANGELES – Children who pass oral food challenges to baked egg and milk with wheat flour are at risk for reacting to baked goods made with nonwheat flours, according to a review of more than 200 pediatric food challenges at National Jewish Health in Denver.

The children were already known to be sensitive to egg and milk, and some were being challenged to see if exposure therapy was helping. Unbeknown to the pediatric food allergy team, a kitchen worker at National Jewish had started making muffins with rice flour, thinking it would be safer.

During the month of muffins with rice flour, the failure rate for baked egg challenge muffins rose from 28% (33/120) to 58% (11/19) with rice flour. Failure to baked milk muffins rose from 14% (9/66) to 36% (5/14) (J Allergy Clin Immunol. 2016 Feb. doi: 10.1016/j.jaci.2015.12.579).

Adjusting for age, gender, and atopic dermatitis, children were more than five times more likely to fail baked eggs without wheat (odds ratio, 5.4; P = .002), and more than four times more likely to fail baked milk (OR, 4.06; P = .05).

Given that the phenomenon hasn’t been reported before, “This was very surprising to us,” said study investigator Dr. Bruce Lanser, director of the pediatric food allergy program at National Jewish. “You have to warn parents that if children pass a baked challenge with wheat, they have to continue to eat their baked milk and egg with wheat. Gluten-free products are not going to have the same effect.

“If somebody is avoiding wheat because it causes a bit of redness and itchiness, you have to clear that wheat allergy” before moving to baked egg and milk, Dr. Lanser added.

There’s also concern that “kids will go home after passing a wheat muffin challenge, eat something that’s gluten-free, and have a reaction,” he noted. Wheat-free baked goods might also not build tolerance as well, although that’s not clear from the study, Dr. Lanser said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

Wheat seems to have something unique that alters the allergic properties of egg and milk proteins to help children outgrow their sensitivities. “Rice doesn’t have the same effect,” he observed, and it’s not known if any other grains do. Dr. Lanser said he is interested in looking into rye, barley, oats, and other alternatives.

The mean age of the children in the study was 6 years, and most children had multiple food allergies. Sensitization was confirmed by skin tests and specific IgE.

Meanwhile, there’s a new rule in the National Jewish kitchen: Unless a child has true celiac disease, “always make [challenge] muffins with wheat,” Dr. Lanser said.

There was no industry funding for the work, and the investigators had no disclosures.

[email protected]

LOS ANGELES – Children who pass oral food challenges to baked egg and milk with wheat flour are at risk for reacting to baked goods made with nonwheat flours, according to a review of more than 200 pediatric food challenges at National Jewish Health in Denver.

The children were already known to be sensitive to egg and milk, and some were being challenged to see if exposure therapy was helping. Unbeknown to the pediatric food allergy team, a kitchen worker at National Jewish had started making muffins with rice flour, thinking it would be safer.

During the month of muffins with rice flour, the failure rate for baked egg challenge muffins rose from 28% (33/120) to 58% (11/19) with rice flour. Failure to baked milk muffins rose from 14% (9/66) to 36% (5/14) (J Allergy Clin Immunol. 2016 Feb. doi: 10.1016/j.jaci.2015.12.579).

Adjusting for age, gender, and atopic dermatitis, children were more than five times more likely to fail baked eggs without wheat (odds ratio, 5.4; P = .002), and more than four times more likely to fail baked milk (OR, 4.06; P = .05).

Given that the phenomenon hasn’t been reported before, “This was very surprising to us,” said study investigator Dr. Bruce Lanser, director of the pediatric food allergy program at National Jewish. “You have to warn parents that if children pass a baked challenge with wheat, they have to continue to eat their baked milk and egg with wheat. Gluten-free products are not going to have the same effect.

“If somebody is avoiding wheat because it causes a bit of redness and itchiness, you have to clear that wheat allergy” before moving to baked egg and milk, Dr. Lanser added.

There’s also concern that “kids will go home after passing a wheat muffin challenge, eat something that’s gluten-free, and have a reaction,” he noted. Wheat-free baked goods might also not build tolerance as well, although that’s not clear from the study, Dr. Lanser said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

Wheat seems to have something unique that alters the allergic properties of egg and milk proteins to help children outgrow their sensitivities. “Rice doesn’t have the same effect,” he observed, and it’s not known if any other grains do. Dr. Lanser said he is interested in looking into rye, barley, oats, and other alternatives.

The mean age of the children in the study was 6 years, and most children had multiple food allergies. Sensitization was confirmed by skin tests and specific IgE.

Meanwhile, there’s a new rule in the National Jewish kitchen: Unless a child has true celiac disease, “always make [challenge] muffins with wheat,” Dr. Lanser said.

There was no industry funding for the work, and the investigators had no disclosures.

[email protected]

LOS ANGELES – Children who pass oral food challenges to baked egg and milk with wheat flour are at risk for reacting to baked goods made with nonwheat flours, according to a review of more than 200 pediatric food challenges at National Jewish Health in Denver.

The children were already known to be sensitive to egg and milk, and some were being challenged to see if exposure therapy was helping. Unbeknown to the pediatric food allergy team, a kitchen worker at National Jewish had started making muffins with rice flour, thinking it would be safer.

During the month of muffins with rice flour, the failure rate for baked egg challenge muffins rose from 28% (33/120) to 58% (11/19) with rice flour. Failure to baked milk muffins rose from 14% (9/66) to 36% (5/14) (J Allergy Clin Immunol. 2016 Feb. doi: 10.1016/j.jaci.2015.12.579).

Adjusting for age, gender, and atopic dermatitis, children were more than five times more likely to fail baked eggs without wheat (odds ratio, 5.4; P = .002), and more than four times more likely to fail baked milk (OR, 4.06; P = .05).

Given that the phenomenon hasn’t been reported before, “This was very surprising to us,” said study investigator Dr. Bruce Lanser, director of the pediatric food allergy program at National Jewish. “You have to warn parents that if children pass a baked challenge with wheat, they have to continue to eat their baked milk and egg with wheat. Gluten-free products are not going to have the same effect.

“If somebody is avoiding wheat because it causes a bit of redness and itchiness, you have to clear that wheat allergy” before moving to baked egg and milk, Dr. Lanser added.

There’s also concern that “kids will go home after passing a wheat muffin challenge, eat something that’s gluten-free, and have a reaction,” he noted. Wheat-free baked goods might also not build tolerance as well, although that’s not clear from the study, Dr. Lanser said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.

Wheat seems to have something unique that alters the allergic properties of egg and milk proteins to help children outgrow their sensitivities. “Rice doesn’t have the same effect,” he observed, and it’s not known if any other grains do. Dr. Lanser said he is interested in looking into rye, barley, oats, and other alternatives.

The mean age of the children in the study was 6 years, and most children had multiple food allergies. Sensitization was confirmed by skin tests and specific IgE.

Meanwhile, there’s a new rule in the National Jewish kitchen: Unless a child has true celiac disease, “always make [challenge] muffins with wheat,” Dr. Lanser said.

There was no industry funding for the work, and the investigators had no disclosures.

[email protected]

BOSTON – A random morning serum cortisol above 11.1 mcg/dL safely rules out adrenal insufficiency in both inpatients and outpatients, according to a review of 3,300 adrenal insufficiency work-ups at the Edinburgh Centre for Endocrinology and Diabetes.

The finding could help eliminate the cost and hassle of unnecessary adrenocorticotropic hormone (ACTH) stimulation tests; the investigators estimated that the cut point would eliminate almost half of them without any ill effects. “You can be very confident that patients aren’t insufficient if they are above that line,” with more than 99% sensitivity. If they are below it, “they may be normal, and they may be abnormal.” Below 1.8 mcg/dL, adrenal insufficiency is almost certain, but between the cutoffs, ACTH stimulation is necessary, said lead investigator Dr. Scott Mackenzie, a trainee at the center.

In short, “basal serum cortisol as a screening test ... offers a convenient and accessible means of identifying patients who require further assessment,” he said at the annual meeting of the Endocrine Society.

Similar cut points have been suggested by previous studies, but the Scottish investigation is the first to validate its findings both inside and outside of the hospital.

The team arrived at the 11.1 mcg/dL morning cortisol cut point by comparing basal cortisol levels and synacthen results in 1,628 outpatients. They predefined a sensitivity of more than 99% for adrenal sufficiency to avoid missing anyone with true disease. The cut point’s predictive power was then validated in 875 outpatients and 797 inpatients. Morning basal cortisol levels proved superior to afternoon levels.

The investigators were thinking about cost-effectiveness, but they also wanted to increase screening. “We may be able to reduce the number of adrenal insufficiency cases we are missing because [primary care is] reluctant to send people to the clinic for synacthen tests” due to the cost and inconvenience. As with many locations in the United States, “our practice is to do [ACTH on] everyone.” If there was “a quick and easy 9 a.m. blood test” instead, it would help, Dr. Mackenzie said.

Adrenal insufficiency was on the differential for a wide variety of reasons, including hypogonadism, pituitary issues, prolactinemia, fatigue, hypoglycemia, postural hypotension, and hyponatremia. Most of the patients were middle aged, and they were about evenly split between men and women.

There was no outside funding for the work, and the investigators had no disclosures.

[email protected]

BOSTON – A random morning serum cortisol above 11.1 mcg/dL safely rules out adrenal insufficiency in both inpatients and outpatients, according to a review of 3,300 adrenal insufficiency work-ups at the Edinburgh Centre for Endocrinology and Diabetes.

The finding could help eliminate the cost and hassle of unnecessary adrenocorticotropic hormone (ACTH) stimulation tests; the investigators estimated that the cut point would eliminate almost half of them without any ill effects. “You can be very confident that patients aren’t insufficient if they are above that line,” with more than 99% sensitivity. If they are below it, “they may be normal, and they may be abnormal.” Below 1.8 mcg/dL, adrenal insufficiency is almost certain, but between the cutoffs, ACTH stimulation is necessary, said lead investigator Dr. Scott Mackenzie, a trainee at the center.

In short, “basal serum cortisol as a screening test ... offers a convenient and accessible means of identifying patients who require further assessment,” he said at the annual meeting of the Endocrine Society.

Similar cut points have been suggested by previous studies, but the Scottish investigation is the first to validate its findings both inside and outside of the hospital.

The team arrived at the 11.1 mcg/dL morning cortisol cut point by comparing basal cortisol levels and synacthen results in 1,628 outpatients. They predefined a sensitivity of more than 99% for adrenal sufficiency to avoid missing anyone with true disease. The cut point’s predictive power was then validated in 875 outpatients and 797 inpatients. Morning basal cortisol levels proved superior to afternoon levels.

The investigators were thinking about cost-effectiveness, but they also wanted to increase screening. “We may be able to reduce the number of adrenal insufficiency cases we are missing because [primary care is] reluctant to send people to the clinic for synacthen tests” due to the cost and inconvenience. As with many locations in the United States, “our practice is to do [ACTH on] everyone.” If there was “a quick and easy 9 a.m. blood test” instead, it would help, Dr. Mackenzie said.

Adrenal insufficiency was on the differential for a wide variety of reasons, including hypogonadism, pituitary issues, prolactinemia, fatigue, hypoglycemia, postural hypotension, and hyponatremia. Most of the patients were middle aged, and they were about evenly split between men and women.

There was no outside funding for the work, and the investigators had no disclosures.

[email protected]

BOSTON – A random morning serum cortisol above 11.1 mcg/dL safely rules out adrenal insufficiency in both inpatients and outpatients, according to a review of 3,300 adrenal insufficiency work-ups at the Edinburgh Centre for Endocrinology and Diabetes.

The finding could help eliminate the cost and hassle of unnecessary adrenocorticotropic hormone (ACTH) stimulation tests; the investigators estimated that the cut point would eliminate almost half of them without any ill effects. “You can be very confident that patients aren’t insufficient if they are above that line,” with more than 99% sensitivity. If they are below it, “they may be normal, and they may be abnormal.” Below 1.8 mcg/dL, adrenal insufficiency is almost certain, but between the cutoffs, ACTH stimulation is necessary, said lead investigator Dr. Scott Mackenzie, a trainee at the center.

In short, “basal serum cortisol as a screening test ... offers a convenient and accessible means of identifying patients who require further assessment,” he said at the annual meeting of the Endocrine Society.

Similar cut points have been suggested by previous studies, but the Scottish investigation is the first to validate its findings both inside and outside of the hospital.

The team arrived at the 11.1 mcg/dL morning cortisol cut point by comparing basal cortisol levels and synacthen results in 1,628 outpatients. They predefined a sensitivity of more than 99% for adrenal sufficiency to avoid missing anyone with true disease. The cut point’s predictive power was then validated in 875 outpatients and 797 inpatients. Morning basal cortisol levels proved superior to afternoon levels.

The investigators were thinking about cost-effectiveness, but they also wanted to increase screening. “We may be able to reduce the number of adrenal insufficiency cases we are missing because [primary care is] reluctant to send people to the clinic for synacthen tests” due to the cost and inconvenience. As with many locations in the United States, “our practice is to do [ACTH on] everyone.” If there was “a quick and easy 9 a.m. blood test” instead, it would help, Dr. Mackenzie said.

Adrenal insufficiency was on the differential for a wide variety of reasons, including hypogonadism, pituitary issues, prolactinemia, fatigue, hypoglycemia, postural hypotension, and hyponatremia. Most of the patients were middle aged, and they were about evenly split between men and women.

There was no outside funding for the work, and the investigators had no disclosures.

[email protected]

BOSTON – The longer that estrogen therapy is delayed in girls with Turner syndrome, the lower their bone density will be in subsequent years, based on results of a retrospective, cross-sectional study from Monash University, in Melbourne, Australia.

For every year after age 11 that Turner patients went without estrogen – generally due to delayed initiation, but sometimes noncompliance – there was a significant reduction in bone mineral density in both the lumbar spine (Beta -0.582, P less than 0.001) and femoral neck (Beta -0.383, P = 0.008).

Estrogen deficiency and subsequent suboptimal bone mass accrual are known to contribute to the increased risk of osteoporosis in women with Turner syndrome, and about a doubling of the risk of fragility fractures, mostly of the forearm. About a third of the 76 women in the study had at least one fracture, explained investigator Dr. Amanda Vincent, head of the Midlife Health and Menopause Program at Monash.

“Avoiding estrogen deficiency is important to optimize bone health in Turner syndrome.” It “depends on early diagnosis, age-appropriate pubertal induction, and optimization of compliance,” Dr. Vincent said at the Endocrine Society annual meeting.

The median age of Turner syndrome diagnosis was 11 years, but estrogen treatments didn’t begin until a median age of 15. The women in the study were a median of about 30 years old, which means that they were adolescents at the time when estrogen treatment was often delayed in the mistaken belief that growth hormone therapy would be more effective before puberty was induced.

It’s now known that estrogen replacement works synergistically with, and even potentiates, the effects of growth hormone. Current guidelines recommend pubertal induction by age 13 (J Clin Endocrinol Metab. 2007 Jan;92(1):10-25).

The women had at least one dual-energy x-ray absorptiometry scan at Monash since 1998. Z-scores below - 2, indicating low bone density, were found in the lumbar spines of about a quarter the subjects, and in the femoral necks of about 8%. Primary amenorrhea and premature menopause, followed by vitamin D deficiency, were the most common risk factors for low bone mass. Almost 40% of the women reported non-continuous use of estrogen. About half had undergone growth hormone therapy.

At a median height of 149 cm, the subjects were about 15 cm shorter than age-matched, healthy controls, and also had a slightly higher median body mass index of 25.6 kg/m². Lumbar spine bone area, bone mineral content, areal bone mineral density, and bone mineral apparent density were significantly lower in Turner syndrome patients. In the femoral neck, areal bone mineral density was significantly lower.

There was no relationship between bone markers and growth hormone use or Turner syndrome karyotype; the predominant karyotype was 45XO, but the study also included mosaic karyotypes.

The investigators had no disclosures.

[email protected]

BOSTON – The longer that estrogen therapy is delayed in girls with Turner syndrome, the lower their bone density will be in subsequent years, based on results of a retrospective, cross-sectional study from Monash University, in Melbourne, Australia.

For every year after age 11 that Turner patients went without estrogen – generally due to delayed initiation, but sometimes noncompliance – there was a significant reduction in bone mineral density in both the lumbar spine (Beta -0.582, P less than 0.001) and femoral neck (Beta -0.383, P = 0.008).

Estrogen deficiency and subsequent suboptimal bone mass accrual are known to contribute to the increased risk of osteoporosis in women with Turner syndrome, and about a doubling of the risk of fragility fractures, mostly of the forearm. About a third of the 76 women in the study had at least one fracture, explained investigator Dr. Amanda Vincent, head of the Midlife Health and Menopause Program at Monash.

“Avoiding estrogen deficiency is important to optimize bone health in Turner syndrome.” It “depends on early diagnosis, age-appropriate pubertal induction, and optimization of compliance,” Dr. Vincent said at the Endocrine Society annual meeting.

The median age of Turner syndrome diagnosis was 11 years, but estrogen treatments didn’t begin until a median age of 15. The women in the study were a median of about 30 years old, which means that they were adolescents at the time when estrogen treatment was often delayed in the mistaken belief that growth hormone therapy would be more effective before puberty was induced.

It’s now known that estrogen replacement works synergistically with, and even potentiates, the effects of growth hormone. Current guidelines recommend pubertal induction by age 13 (J Clin Endocrinol Metab. 2007 Jan;92(1):10-25).

The women had at least one dual-energy x-ray absorptiometry scan at Monash since 1998. Z-scores below - 2, indicating low bone density, were found in the lumbar spines of about a quarter the subjects, and in the femoral necks of about 8%. Primary amenorrhea and premature menopause, followed by vitamin D deficiency, were the most common risk factors for low bone mass. Almost 40% of the women reported non-continuous use of estrogen. About half had undergone growth hormone therapy.

At a median height of 149 cm, the subjects were about 15 cm shorter than age-matched, healthy controls, and also had a slightly higher median body mass index of 25.6 kg/m². Lumbar spine bone area, bone mineral content, areal bone mineral density, and bone mineral apparent density were significantly lower in Turner syndrome patients. In the femoral neck, areal bone mineral density was significantly lower.

There was no relationship between bone markers and growth hormone use or Turner syndrome karyotype; the predominant karyotype was 45XO, but the study also included mosaic karyotypes.

The investigators had no disclosures.

[email protected]

BOSTON – The longer that estrogen therapy is delayed in girls with Turner syndrome, the lower their bone density will be in subsequent years, based on results of a retrospective, cross-sectional study from Monash University, in Melbourne, Australia.

For every year after age 11 that Turner patients went without estrogen – generally due to delayed initiation, but sometimes noncompliance – there was a significant reduction in bone mineral density in both the lumbar spine (Beta -0.582, P less than 0.001) and femoral neck (Beta -0.383, P = 0.008).

Estrogen deficiency and subsequent suboptimal bone mass accrual are known to contribute to the increased risk of osteoporosis in women with Turner syndrome, and about a doubling of the risk of fragility fractures, mostly of the forearm. About a third of the 76 women in the study had at least one fracture, explained investigator Dr. Amanda Vincent, head of the Midlife Health and Menopause Program at Monash.

“Avoiding estrogen deficiency is important to optimize bone health in Turner syndrome.” It “depends on early diagnosis, age-appropriate pubertal induction, and optimization of compliance,” Dr. Vincent said at the Endocrine Society annual meeting.

The median age of Turner syndrome diagnosis was 11 years, but estrogen treatments didn’t begin until a median age of 15. The women in the study were a median of about 30 years old, which means that they were adolescents at the time when estrogen treatment was often delayed in the mistaken belief that growth hormone therapy would be more effective before puberty was induced.

It’s now known that estrogen replacement works synergistically with, and even potentiates, the effects of growth hormone. Current guidelines recommend pubertal induction by age 13 (J Clin Endocrinol Metab. 2007 Jan;92(1):10-25).

The women had at least one dual-energy x-ray absorptiometry scan at Monash since 1998. Z-scores below - 2, indicating low bone density, were found in the lumbar spines of about a quarter the subjects, and in the femoral necks of about 8%. Primary amenorrhea and premature menopause, followed by vitamin D deficiency, were the most common risk factors for low bone mass. Almost 40% of the women reported non-continuous use of estrogen. About half had undergone growth hormone therapy.

At a median height of 149 cm, the subjects were about 15 cm shorter than age-matched, healthy controls, and also had a slightly higher median body mass index of 25.6 kg/m². Lumbar spine bone area, bone mineral content, areal bone mineral density, and bone mineral apparent density were significantly lower in Turner syndrome patients. In the femoral neck, areal bone mineral density was significantly lower.

There was no relationship between bone markers and growth hormone use or Turner syndrome karyotype; the predominant karyotype was 45XO, but the study also included mosaic karyotypes.

The investigators had no disclosures.

[email protected]

SAN DIEGO – Endometrial pathology findings at 3 months predicted response to levonorgestrel-releasing IUD treatment for complex atypical hyperplasia or grade 1 endometrial cancer at the MD Anderson Cancer Center in Houston.

Twenty-nine of 32 women (91%) who responded by 12 months showed stromal, glandular, or other endometrial changes indicating an effect at 3 months, vs. only 3 of 9 nonresponders (33%) (P less than .001). There were no differences in responders versus nonresponders in median age (47 vs. 56 years, P = .2) or body mass index (45 vs. 55 kg/m², P = .16).

The finding addresses an “unmet need” for markers of response to levonorgestrel-releasing IUD therapy. “You can look at [early] pathology” and have an idea how patients will do, Dr. Shannon Westin, a study investigator who is with the department of gynecologic oncology at MD Anderson, said at the annual meeting of the Society of Gynecologic Oncology.

Twenty-seven of 29 women (93%) with complex atypical hyperplasia (CAH) responded completely to the IUD, meaning they had normal endometrium or hyperplasia without atypia at 12 months. The response rate for endometrial cancer was 67%; 7 of 12 women had a complete response, and an 8th was diagnosed at 12 months with CAH, indicating a partial response. The rest of the patients remained stable or progressed.

Endometrial biopsies were performed every 3 months; the team also did molecular testing on tumors from 20 patients. Baseline protein Ki67 – a marker of proliferation – was significantly higher in nonresponders. Expression of several estrogen-induced genes was higher in responders.

Patients opted for the IUD to retain fertility or because obesity or comorbidities precluded surgery. Exclusion criteria included prior treatment for CAH or endometrial cancer, evidence of extrauterine spread, or levonorgestrel IUD contraindications, such as uterine infection.

Adverse events – primarily irregular bleeding and cramping – were mild and tended to resolve by 12 months. Treatment had little effect on measures of social, mental, and physical function. About half of the patients were white, a third were Hispanic, and most of the remaining patients were black.

There was no external funding for the work. Dr. Westin is a consultant for AstraZeneca, Medivation, Roche, Ovation, and Vermillion, and reported receiving research funding from AstraZeneca, Critical Outcomes Technologies, and Novartis.

[email protected]

SAN DIEGO – Endometrial pathology findings at 3 months predicted response to levonorgestrel-releasing IUD treatment for complex atypical hyperplasia or grade 1 endometrial cancer at the MD Anderson Cancer Center in Houston.

Twenty-nine of 32 women (91%) who responded by 12 months showed stromal, glandular, or other endometrial changes indicating an effect at 3 months, vs. only 3 of 9 nonresponders (33%) (P less than .001). There were no differences in responders versus nonresponders in median age (47 vs. 56 years, P = .2) or body mass index (45 vs. 55 kg/m², P = .16).

The finding addresses an “unmet need” for markers of response to levonorgestrel-releasing IUD therapy. “You can look at [early] pathology” and have an idea how patients will do, Dr. Shannon Westin, a study investigator who is with the department of gynecologic oncology at MD Anderson, said at the annual meeting of the Society of Gynecologic Oncology.

Twenty-seven of 29 women (93%) with complex atypical hyperplasia (CAH) responded completely to the IUD, meaning they had normal endometrium or hyperplasia without atypia at 12 months. The response rate for endometrial cancer was 67%; 7 of 12 women had a complete response, and an 8th was diagnosed at 12 months with CAH, indicating a partial response. The rest of the patients remained stable or progressed.

Endometrial biopsies were performed every 3 months; the team also did molecular testing on tumors from 20 patients. Baseline protein Ki67 – a marker of proliferation – was significantly higher in nonresponders. Expression of several estrogen-induced genes was higher in responders.

Patients opted for the IUD to retain fertility or because obesity or comorbidities precluded surgery. Exclusion criteria included prior treatment for CAH or endometrial cancer, evidence of extrauterine spread, or levonorgestrel IUD contraindications, such as uterine infection.

Adverse events – primarily irregular bleeding and cramping – were mild and tended to resolve by 12 months. Treatment had little effect on measures of social, mental, and physical function. About half of the patients were white, a third were Hispanic, and most of the remaining patients were black.

There was no external funding for the work. Dr. Westin is a consultant for AstraZeneca, Medivation, Roche, Ovation, and Vermillion, and reported receiving research funding from AstraZeneca, Critical Outcomes Technologies, and Novartis.

[email protected]

SAN DIEGO – Endometrial pathology findings at 3 months predicted response to levonorgestrel-releasing IUD treatment for complex atypical hyperplasia or grade 1 endometrial cancer at the MD Anderson Cancer Center in Houston.

Twenty-nine of 32 women (91%) who responded by 12 months showed stromal, glandular, or other endometrial changes indicating an effect at 3 months, vs. only 3 of 9 nonresponders (33%) (P less than .001). There were no differences in responders versus nonresponders in median age (47 vs. 56 years, P = .2) or body mass index (45 vs. 55 kg/m², P = .16).

The finding addresses an “unmet need” for markers of response to levonorgestrel-releasing IUD therapy. “You can look at [early] pathology” and have an idea how patients will do, Dr. Shannon Westin, a study investigator who is with the department of gynecologic oncology at MD Anderson, said at the annual meeting of the Society of Gynecologic Oncology.

Twenty-seven of 29 women (93%) with complex atypical hyperplasia (CAH) responded completely to the IUD, meaning they had normal endometrium or hyperplasia without atypia at 12 months. The response rate for endometrial cancer was 67%; 7 of 12 women had a complete response, and an 8th was diagnosed at 12 months with CAH, indicating a partial response. The rest of the patients remained stable or progressed.

Endometrial biopsies were performed every 3 months; the team also did molecular testing on tumors from 20 patients. Baseline protein Ki67 – a marker of proliferation – was significantly higher in nonresponders. Expression of several estrogen-induced genes was higher in responders.

Patients opted for the IUD to retain fertility or because obesity or comorbidities precluded surgery. Exclusion criteria included prior treatment for CAH or endometrial cancer, evidence of extrauterine spread, or levonorgestrel IUD contraindications, such as uterine infection.

Adverse events – primarily irregular bleeding and cramping – were mild and tended to resolve by 12 months. Treatment had little effect on measures of social, mental, and physical function. About half of the patients were white, a third were Hispanic, and most of the remaining patients were black.

There was no external funding for the work. Dr. Westin is a consultant for AstraZeneca, Medivation, Roche, Ovation, and Vermillion, and reported receiving research funding from AstraZeneca, Critical Outcomes Technologies, and Novartis.

[email protected]

LOS ANGELES – It only took a few minutes for idarucizumab to normalize blood-clotting parameters in 18 patients with dabigatran-associated intracranial hemorrhages, according to interim results from an ongoing phase III trial presented at the International Stroke Conference.

“When I put patients on [dabigatran], they always ask me what happens if they bleed or need surgery. … Until now, I haven’t been able to tell them with any confidence that I have a way of reversing it. Now I think I can. ... It makes a big difference” in their comfort, said lead investigator Dr. Richard Bernstein, a Northwestern University neurology professor and director of the stroke program at Northwestern Memorial Hospital, in Chicago.

“We would love to know if hematoma expansion was limited [and outcomes improved] by giving this reversal agent,” but the study so far is too small. “We hope to have a larger cohort of brain hemorrhage patients to answer these questions,” he said.

Approved in October 2015, idarucizumab (Praxbind) was fast tracked by the Food and Drug Administration to reverse the blockbuster atrial fibrillation anticoagulant dabigatran (Pradaxa); the labeling for idarucizumab doesn’t mention intracranial hemorrhage patients specifically. Boehringer Ingelheim makes both drugs, and funded Dr. Bernstein’s work.

Eleven of the 18 patients were men, and the average age in the study was about 80 years. The patients had either subdural hematomas or bleeding into the brain itself. They were culled from the 90 subjects analyzed so far in the idarucizumab trial, dubbed RE-VERSE AD (Reversal Effects of Idarucizumab in Patients on Active Dabigatran).

The team followed label dosing: 5 g total given as two separate 2.5-g infusions. Blood samples were taken in between to check how well idarucizumab worked. The whole process took no more than 15 minutes.

The first 2.5 g completely reversed dabigatran in all 18 patients, based on their dilute thrombin or ecarin clotting times. Patients “remained reversed out to 12 hours, and all but one out to 24 hours,” Dr. Bernstein said at the conference, sponsored by the American Heart Association.

Idarucizumab is a monoclonal antibody fragment that binds dabigatran more powerfully than dabigatran binds thrombin. In vitro studies have found no prothrombotic effects. “It has no endogenous target, so the drug has no effect on any other clotting factors that we can tell. We did have, I think, five thrombotic events in our cohort, most of them many days after the dabigatran was reversed. It may have just been a reversion to [patient] clotting risks,” he said.

When – or if – to restart dabigatran “is a clinical question.” If bleeding is controlled or patients are stable after surgery, you can go back on the next day,” he said.

Idarucizumab’s labeling notes that 5% or more of patients developed hypokalemia, delirium, constipation, pyrexia, and pneumonia. It wasn’t clear these events were drug related. Patients had dabigatran reversed either for serious bleeding or emergency surgery.

Dr. Bernstein is a speaker and adviser for Boehringer Ingelheim, and reported honoraria from the company.

[email protected]

LOS ANGELES – It only took a few minutes for idarucizumab to normalize blood-clotting parameters in 18 patients with dabigatran-associated intracranial hemorrhages, according to interim results from an ongoing phase III trial presented at the International Stroke Conference.

“When I put patients on [dabigatran], they always ask me what happens if they bleed or need surgery. … Until now, I haven’t been able to tell them with any confidence that I have a way of reversing it. Now I think I can. ... It makes a big difference” in their comfort, said lead investigator Dr. Richard Bernstein, a Northwestern University neurology professor and director of the stroke program at Northwestern Memorial Hospital, in Chicago.

“We would love to know if hematoma expansion was limited [and outcomes improved] by giving this reversal agent,” but the study so far is too small. “We hope to have a larger cohort of brain hemorrhage patients to answer these questions,” he said.

Approved in October 2015, idarucizumab (Praxbind) was fast tracked by the Food and Drug Administration to reverse the blockbuster atrial fibrillation anticoagulant dabigatran (Pradaxa); the labeling for idarucizumab doesn’t mention intracranial hemorrhage patients specifically. Boehringer Ingelheim makes both drugs, and funded Dr. Bernstein’s work.

Eleven of the 18 patients were men, and the average age in the study was about 80 years. The patients had either subdural hematomas or bleeding into the brain itself. They were culled from the 90 subjects analyzed so far in the idarucizumab trial, dubbed RE-VERSE AD (Reversal Effects of Idarucizumab in Patients on Active Dabigatran).

The team followed label dosing: 5 g total given as two separate 2.5-g infusions. Blood samples were taken in between to check how well idarucizumab worked. The whole process took no more than 15 minutes.

The first 2.5 g completely reversed dabigatran in all 18 patients, based on their dilute thrombin or ecarin clotting times. Patients “remained reversed out to 12 hours, and all but one out to 24 hours,” Dr. Bernstein said at the conference, sponsored by the American Heart Association.

Idarucizumab is a monoclonal antibody fragment that binds dabigatran more powerfully than dabigatran binds thrombin. In vitro studies have found no prothrombotic effects. “It has no endogenous target, so the drug has no effect on any other clotting factors that we can tell. We did have, I think, five thrombotic events in our cohort, most of them many days after the dabigatran was reversed. It may have just been a reversion to [patient] clotting risks,” he said.

When – or if – to restart dabigatran “is a clinical question.” If bleeding is controlled or patients are stable after surgery, you can go back on the next day,” he said.

Idarucizumab’s labeling notes that 5% or more of patients developed hypokalemia, delirium, constipation, pyrexia, and pneumonia. It wasn’t clear these events were drug related. Patients had dabigatran reversed either for serious bleeding or emergency surgery.

Dr. Bernstein is a speaker and adviser for Boehringer Ingelheim, and reported honoraria from the company.

[email protected]

LOS ANGELES – It only took a few minutes for idarucizumab to normalize blood-clotting parameters in 18 patients with dabigatran-associated intracranial hemorrhages, according to interim results from an ongoing phase III trial presented at the International Stroke Conference.

“When I put patients on [dabigatran], they always ask me what happens if they bleed or need surgery. … Until now, I haven’t been able to tell them with any confidence that I have a way of reversing it. Now I think I can. ... It makes a big difference” in their comfort, said lead investigator Dr. Richard Bernstein, a Northwestern University neurology professor and director of the stroke program at Northwestern Memorial Hospital, in Chicago.

“We would love to know if hematoma expansion was limited [and outcomes improved] by giving this reversal agent,” but the study so far is too small. “We hope to have a larger cohort of brain hemorrhage patients to answer these questions,” he said.

Approved in October 2015, idarucizumab (Praxbind) was fast tracked by the Food and Drug Administration to reverse the blockbuster atrial fibrillation anticoagulant dabigatran (Pradaxa); the labeling for idarucizumab doesn’t mention intracranial hemorrhage patients specifically. Boehringer Ingelheim makes both drugs, and funded Dr. Bernstein’s work.

Eleven of the 18 patients were men, and the average age in the study was about 80 years. The patients had either subdural hematomas or bleeding into the brain itself. They were culled from the 90 subjects analyzed so far in the idarucizumab trial, dubbed RE-VERSE AD (Reversal Effects of Idarucizumab in Patients on Active Dabigatran).

The team followed label dosing: 5 g total given as two separate 2.5-g infusions. Blood samples were taken in between to check how well idarucizumab worked. The whole process took no more than 15 minutes.

The first 2.5 g completely reversed dabigatran in all 18 patients, based on their dilute thrombin or ecarin clotting times. Patients “remained reversed out to 12 hours, and all but one out to 24 hours,” Dr. Bernstein said at the conference, sponsored by the American Heart Association.

Idarucizumab is a monoclonal antibody fragment that binds dabigatran more powerfully than dabigatran binds thrombin. In vitro studies have found no prothrombotic effects. “It has no endogenous target, so the drug has no effect on any other clotting factors that we can tell. We did have, I think, five thrombotic events in our cohort, most of them many days after the dabigatran was reversed. It may have just been a reversion to [patient] clotting risks,” he said.

When – or if – to restart dabigatran “is a clinical question.” If bleeding is controlled or patients are stable after surgery, you can go back on the next day,” he said.

Idarucizumab’s labeling notes that 5% or more of patients developed hypokalemia, delirium, constipation, pyrexia, and pneumonia. It wasn’t clear these events were drug related. Patients had dabigatran reversed either for serious bleeding or emergency surgery.

Dr. Bernstein is a speaker and adviser for Boehringer Ingelheim, and reported honoraria from the company.

[email protected]