AACE 2016

ORLANDO – In the case of transgender youth and adults – those with what is now called gender dysphoria – physicians are faced with treating individuals who generally have no physical disease or abnormalities.

Endocrinologists are the professionals who are often tasked with the medical aspects of treating gender dysphoria. In an effort to help them understand the underpinnings and aspects of the conditions, Dr. Stephen Rosenthal, professor of pediatrics and medical director of the Child and Adolescent Medical Gender Center at the University of California, San Francisco, reviewed current knowledge about the biological basis for gender identity, current treatment models, and barriers to care of patients with gender dysphoria.

Speaking at the annual meeting of the American Association of Clinical Endocrinologists, Dr. Rosenthal said the dysphoria derives from the significant emotional distress that may be associated with a transgender identity, essentially from the social and psychological pressures of being born and living in a body (the “natal sex”) that does not match an individual’s gender identity, defined as one’s fundamental sense of self as male or female. “It’s not always limited to those two choices, and it’s not always binary,” he said, since individuals may identify with aspects of both or, at times, neither gender.

He defined some terms, such as transgender, which refers to a transient or persistent identification with gender different from the one others assume based on physical sex characteristics at birth. That gender becomes the one of rearing, which may not be how the individual feels growing up. Gender identity should not be confused with sexual identity or orientation because people of any gender can have any sexual orientation.

“Gender Identity Disorder,” a term used in the DSM IV (Diagnostic and Statistical Manual of Mental Disorders IV) has been replaced by “Gender Dysphoria in Children” in DSM 5. And even that term may be revised since transgender identity in itself is not a pathology.

In one survey of 28,176 people, 0.5% self-identified as transgender. Another survey showed statistically significant risks associated with being transgender. Comparing 180 transgender youth with 180 non–transgender youth (average age, 19.6 years; range, 12-29 years), researchers found a two- to threefold increased risk of depression, anxiety disorder, suicidal ideation, suicide attempt, and self- harm without lethal intent among the transgender youths. Parental support helped alleviate some of these risks, especially suicide attempts, but did not eliminate them entirely; that support also contributed to better mental and physical health, improved self-esteem, and even adequate food and housing for transgender adolescents.

Clues to biological influences

A complex interplay of biological, environmental, and cultural factors affect the determination of gender identity. Evidence points to the role of biology in gender identity development through studies of genetics, hormones, and the brain, but none of these is a “litmus test” for gender identity, Dr. Rosenthal said.

A study of 23 monozygotic twin pairs, 21 same-sex dizygotic twin pairs, and 7 opposite-sex twin pairs showed a 39.1% concordance for gender dysphoria among the monozygotic twins but none for the other sets.

Most transgender individuals do not have any obvious disorder of sexual development, but that is not to rule out a role of prenatal or postnatal androgens (specifically enzymes of the steroid pathways), androgen insensitivity, or extragonadal sources of androgen, as in congenital adrenal hyperplasia (CAH). Among 250 46XX females with CAH raised as female, 5.2% had male gender identity or gender dysphoria (a 10- to 20-fold increased risk vs. controls), suggesting a possible role for prenatal androgens in gender identity development.

A neurobiological basis for transgender is supported by some studies of sexually dimorphic brain structures but is by no means conclusive. Numerous studies of gray and white matter showed that sexually dimorphic structures are more closely aligned with gender identity than with physical sex (even before cross-sex hormones have been applied). But morphometry on areas of the brain that show the largest sex differences found that variability was more prevalent than was consistency in the 1,400 brains studied.

Tests of “functional sexual dimorphism” used PET or MRI to measure changes in regional blood flow in the anterior hypothalamus when control adolescent girls or boys or those with gender dysphoria were asked to smell substances containing pheromones of the opposite sex (for girls: androstadienone in a mixture of male sweat and semen; for boys: estrogen-like compounds in urine of pregnant women). Both girls and boys with gender dysphoria had responses significantly different from those of their respective controls.

Natural history of gender dysphoria

Dr. Rosenthal said symptoms of gender dysphoria in prepubertal children decrease or disappear in 70%-95% of cases, but if they persist into early puberty, the individual is likely to be transgender as an adult. Children with more intense gender dysphoria and those who believed they “were” the opposite sex were more likely to have persistent gender dysphoria as adults. In a study based on parents’ completed measures, prepubescent transgender boys and girls who have socially transitioned had depression scores no higher than those of matched nontransgender controls. They had much lower anxiety and depression, compared with non–socially transitioned transgender historical control children.

Medically induced sexual transitioning

For pediatric and adolescent transsexual patients who express a desire to transition to the opposite sex, an Endocrine Society clinical practice guideline on endocrine treatment recommends that a mental health professional make the diagnosis of gender dysphoria. Then the medical provider needs to ensure that the patient understands the consequences of hormone suppression and cross-sex hormone therapy prior to beginning treatments. Only after early puberty has begun should gonadotropin-releasing hormone (GnRH) agonists be used to suppress pubertal hormones. At about age 16 years, cross-sex hormone treatments can begin, with surgery deferred at least until age 18 years if the patient desires full transitioning.

A Dutch study (Pediatrics. 2014 Oct. 134:696-704) showed that after gender reassignment, in young adulthood, gender dysphoria “was alleviated and psychological functioning had steadily improved. Well-being was similar to or better than same-age young adults from the general population.” No patients reported any regret during any stages of the sex-reassignment protocol.

There is some concern about adverse effects of the GnRH agonists, such as on bone mass and health, the brain, and fertility. But no detrimental effects were observed in a study on executive functioning, which undergoes significant development during puberty, in either male-to-female or female-to-male individuals.

Future parenthood may be an option if the patient is old enough. “We always encourage them to either freeze sperm, or we can potentially freeze eggs before embarking on phenotypic transition,” Dr. Rosenthal said. But allowing a patient to get to a stage of spermatogenesis or egg production would allow puberty to proceed to a significant degree. “So one of the exciting areas of research is actually taking prepubertal tissue … [in mice] they took neonatal testicular tissue and they basically showed you could take it all the way through the steps of full maturation and get progeny that were reproductively competent,” he said. Similar studies are being done in humans, mainly because there is interest in preserving fertility of children undergoing cancer treatments.

Barriers to care for transgender youth include limited access to medications, including off-label use, great expense, and insurance company denials of reimbursement. There are also relatively few clinical programs and a lack of training for health care professionals, as well as prejudice and misunderstanding, even among professionals.

ORLANDO – In the case of transgender youth and adults – those with what is now called gender dysphoria – physicians are faced with treating individuals who generally have no physical disease or abnormalities.

Endocrinologists are the professionals who are often tasked with the medical aspects of treating gender dysphoria. In an effort to help them understand the underpinnings and aspects of the conditions, Dr. Stephen Rosenthal, professor of pediatrics and medical director of the Child and Adolescent Medical Gender Center at the University of California, San Francisco, reviewed current knowledge about the biological basis for gender identity, current treatment models, and barriers to care of patients with gender dysphoria.

Speaking at the annual meeting of the American Association of Clinical Endocrinologists, Dr. Rosenthal said the dysphoria derives from the significant emotional distress that may be associated with a transgender identity, essentially from the social and psychological pressures of being born and living in a body (the “natal sex”) that does not match an individual’s gender identity, defined as one’s fundamental sense of self as male or female. “It’s not always limited to those two choices, and it’s not always binary,” he said, since individuals may identify with aspects of both or, at times, neither gender.

He defined some terms, such as transgender, which refers to a transient or persistent identification with gender different from the one others assume based on physical sex characteristics at birth. That gender becomes the one of rearing, which may not be how the individual feels growing up. Gender identity should not be confused with sexual identity or orientation because people of any gender can have any sexual orientation.

“Gender Identity Disorder,” a term used in the DSM IV (Diagnostic and Statistical Manual of Mental Disorders IV) has been replaced by “Gender Dysphoria in Children” in DSM 5. And even that term may be revised since transgender identity in itself is not a pathology.

In one survey of 28,176 people, 0.5% self-identified as transgender. Another survey showed statistically significant risks associated with being transgender. Comparing 180 transgender youth with 180 non–transgender youth (average age, 19.6 years; range, 12-29 years), researchers found a two- to threefold increased risk of depression, anxiety disorder, suicidal ideation, suicide attempt, and self- harm without lethal intent among the transgender youths. Parental support helped alleviate some of these risks, especially suicide attempts, but did not eliminate them entirely; that support also contributed to better mental and physical health, improved self-esteem, and even adequate food and housing for transgender adolescents.

Clues to biological influences

A complex interplay of biological, environmental, and cultural factors affect the determination of gender identity. Evidence points to the role of biology in gender identity development through studies of genetics, hormones, and the brain, but none of these is a “litmus test” for gender identity, Dr. Rosenthal said.

A study of 23 monozygotic twin pairs, 21 same-sex dizygotic twin pairs, and 7 opposite-sex twin pairs showed a 39.1% concordance for gender dysphoria among the monozygotic twins but none for the other sets.

Most transgender individuals do not have any obvious disorder of sexual development, but that is not to rule out a role of prenatal or postnatal androgens (specifically enzymes of the steroid pathways), androgen insensitivity, or extragonadal sources of androgen, as in congenital adrenal hyperplasia (CAH). Among 250 46XX females with CAH raised as female, 5.2% had male gender identity or gender dysphoria (a 10- to 20-fold increased risk vs. controls), suggesting a possible role for prenatal androgens in gender identity development.

A neurobiological basis for transgender is supported by some studies of sexually dimorphic brain structures but is by no means conclusive. Numerous studies of gray and white matter showed that sexually dimorphic structures are more closely aligned with gender identity than with physical sex (even before cross-sex hormones have been applied). But morphometry on areas of the brain that show the largest sex differences found that variability was more prevalent than was consistency in the 1,400 brains studied.

Tests of “functional sexual dimorphism” used PET or MRI to measure changes in regional blood flow in the anterior hypothalamus when control adolescent girls or boys or those with gender dysphoria were asked to smell substances containing pheromones of the opposite sex (for girls: androstadienone in a mixture of male sweat and semen; for boys: estrogen-like compounds in urine of pregnant women). Both girls and boys with gender dysphoria had responses significantly different from those of their respective controls.

Natural history of gender dysphoria

Dr. Rosenthal said symptoms of gender dysphoria in prepubertal children decrease or disappear in 70%-95% of cases, but if they persist into early puberty, the individual is likely to be transgender as an adult. Children with more intense gender dysphoria and those who believed they “were” the opposite sex were more likely to have persistent gender dysphoria as adults. In a study based on parents’ completed measures, prepubescent transgender boys and girls who have socially transitioned had depression scores no higher than those of matched nontransgender controls. They had much lower anxiety and depression, compared with non–socially transitioned transgender historical control children.

Medically induced sexual transitioning

For pediatric and adolescent transsexual patients who express a desire to transition to the opposite sex, an Endocrine Society clinical practice guideline on endocrine treatment recommends that a mental health professional make the diagnosis of gender dysphoria. Then the medical provider needs to ensure that the patient understands the consequences of hormone suppression and cross-sex hormone therapy prior to beginning treatments. Only after early puberty has begun should gonadotropin-releasing hormone (GnRH) agonists be used to suppress pubertal hormones. At about age 16 years, cross-sex hormone treatments can begin, with surgery deferred at least until age 18 years if the patient desires full transitioning.

A Dutch study (Pediatrics. 2014 Oct. 134:696-704) showed that after gender reassignment, in young adulthood, gender dysphoria “was alleviated and psychological functioning had steadily improved. Well-being was similar to or better than same-age young adults from the general population.” No patients reported any regret during any stages of the sex-reassignment protocol.

There is some concern about adverse effects of the GnRH agonists, such as on bone mass and health, the brain, and fertility. But no detrimental effects were observed in a study on executive functioning, which undergoes significant development during puberty, in either male-to-female or female-to-male individuals.

Future parenthood may be an option if the patient is old enough. “We always encourage them to either freeze sperm, or we can potentially freeze eggs before embarking on phenotypic transition,” Dr. Rosenthal said. But allowing a patient to get to a stage of spermatogenesis or egg production would allow puberty to proceed to a significant degree. “So one of the exciting areas of research is actually taking prepubertal tissue … [in mice] they took neonatal testicular tissue and they basically showed you could take it all the way through the steps of full maturation and get progeny that were reproductively competent,” he said. Similar studies are being done in humans, mainly because there is interest in preserving fertility of children undergoing cancer treatments.

Barriers to care for transgender youth include limited access to medications, including off-label use, great expense, and insurance company denials of reimbursement. There are also relatively few clinical programs and a lack of training for health care professionals, as well as prejudice and misunderstanding, even among professionals.

ORLANDO – In the case of transgender youth and adults – those with what is now called gender dysphoria – physicians are faced with treating individuals who generally have no physical disease or abnormalities.

Endocrinologists are the professionals who are often tasked with the medical aspects of treating gender dysphoria. In an effort to help them understand the underpinnings and aspects of the conditions, Dr. Stephen Rosenthal, professor of pediatrics and medical director of the Child and Adolescent Medical Gender Center at the University of California, San Francisco, reviewed current knowledge about the biological basis for gender identity, current treatment models, and barriers to care of patients with gender dysphoria.

Speaking at the annual meeting of the American Association of Clinical Endocrinologists, Dr. Rosenthal said the dysphoria derives from the significant emotional distress that may be associated with a transgender identity, essentially from the social and psychological pressures of being born and living in a body (the “natal sex”) that does not match an individual’s gender identity, defined as one’s fundamental sense of self as male or female. “It’s not always limited to those two choices, and it’s not always binary,” he said, since individuals may identify with aspects of both or, at times, neither gender.

He defined some terms, such as transgender, which refers to a transient or persistent identification with gender different from the one others assume based on physical sex characteristics at birth. That gender becomes the one of rearing, which may not be how the individual feels growing up. Gender identity should not be confused with sexual identity or orientation because people of any gender can have any sexual orientation.

“Gender Identity Disorder,” a term used in the DSM IV (Diagnostic and Statistical Manual of Mental Disorders IV) has been replaced by “Gender Dysphoria in Children” in DSM 5. And even that term may be revised since transgender identity in itself is not a pathology.

In one survey of 28,176 people, 0.5% self-identified as transgender. Another survey showed statistically significant risks associated with being transgender. Comparing 180 transgender youth with 180 non–transgender youth (average age, 19.6 years; range, 12-29 years), researchers found a two- to threefold increased risk of depression, anxiety disorder, suicidal ideation, suicide attempt, and self- harm without lethal intent among the transgender youths. Parental support helped alleviate some of these risks, especially suicide attempts, but did not eliminate them entirely; that support also contributed to better mental and physical health, improved self-esteem, and even adequate food and housing for transgender adolescents.

Clues to biological influences

A complex interplay of biological, environmental, and cultural factors affect the determination of gender identity. Evidence points to the role of biology in gender identity development through studies of genetics, hormones, and the brain, but none of these is a “litmus test” for gender identity, Dr. Rosenthal said.

A study of 23 monozygotic twin pairs, 21 same-sex dizygotic twin pairs, and 7 opposite-sex twin pairs showed a 39.1% concordance for gender dysphoria among the monozygotic twins but none for the other sets.

Most transgender individuals do not have any obvious disorder of sexual development, but that is not to rule out a role of prenatal or postnatal androgens (specifically enzymes of the steroid pathways), androgen insensitivity, or extragonadal sources of androgen, as in congenital adrenal hyperplasia (CAH). Among 250 46XX females with CAH raised as female, 5.2% had male gender identity or gender dysphoria (a 10- to 20-fold increased risk vs. controls), suggesting a possible role for prenatal androgens in gender identity development.

A neurobiological basis for transgender is supported by some studies of sexually dimorphic brain structures but is by no means conclusive. Numerous studies of gray and white matter showed that sexually dimorphic structures are more closely aligned with gender identity than with physical sex (even before cross-sex hormones have been applied). But morphometry on areas of the brain that show the largest sex differences found that variability was more prevalent than was consistency in the 1,400 brains studied.

Tests of “functional sexual dimorphism” used PET or MRI to measure changes in regional blood flow in the anterior hypothalamus when control adolescent girls or boys or those with gender dysphoria were asked to smell substances containing pheromones of the opposite sex (for girls: androstadienone in a mixture of male sweat and semen; for boys: estrogen-like compounds in urine of pregnant women). Both girls and boys with gender dysphoria had responses significantly different from those of their respective controls.

Natural history of gender dysphoria

Dr. Rosenthal said symptoms of gender dysphoria in prepubertal children decrease or disappear in 70%-95% of cases, but if they persist into early puberty, the individual is likely to be transgender as an adult. Children with more intense gender dysphoria and those who believed they “were” the opposite sex were more likely to have persistent gender dysphoria as adults. In a study based on parents’ completed measures, prepubescent transgender boys and girls who have socially transitioned had depression scores no higher than those of matched nontransgender controls. They had much lower anxiety and depression, compared with non–socially transitioned transgender historical control children.

Medically induced sexual transitioning

For pediatric and adolescent transsexual patients who express a desire to transition to the opposite sex, an Endocrine Society clinical practice guideline on endocrine treatment recommends that a mental health professional make the diagnosis of gender dysphoria. Then the medical provider needs to ensure that the patient understands the consequences of hormone suppression and cross-sex hormone therapy prior to beginning treatments. Only after early puberty has begun should gonadotropin-releasing hormone (GnRH) agonists be used to suppress pubertal hormones. At about age 16 years, cross-sex hormone treatments can begin, with surgery deferred at least until age 18 years if the patient desires full transitioning.

A Dutch study (Pediatrics. 2014 Oct. 134:696-704) showed that after gender reassignment, in young adulthood, gender dysphoria “was alleviated and psychological functioning had steadily improved. Well-being was similar to or better than same-age young adults from the general population.” No patients reported any regret during any stages of the sex-reassignment protocol.

There is some concern about adverse effects of the GnRH agonists, such as on bone mass and health, the brain, and fertility. But no detrimental effects were observed in a study on executive functioning, which undergoes significant development during puberty, in either male-to-female or female-to-male individuals.

Future parenthood may be an option if the patient is old enough. “We always encourage them to either freeze sperm, or we can potentially freeze eggs before embarking on phenotypic transition,” Dr. Rosenthal said. But allowing a patient to get to a stage of spermatogenesis or egg production would allow puberty to proceed to a significant degree. “So one of the exciting areas of research is actually taking prepubertal tissue … [in mice] they took neonatal testicular tissue and they basically showed you could take it all the way through the steps of full maturation and get progeny that were reproductively competent,” he said. Similar studies are being done in humans, mainly because there is interest in preserving fertility of children undergoing cancer treatments.

Barriers to care for transgender youth include limited access to medications, including off-label use, great expense, and insurance company denials of reimbursement. There are also relatively few clinical programs and a lack of training for health care professionals, as well as prejudice and misunderstanding, even among professionals.

ORLANDO – Old notions about transgender and transsexual individuals are changing, driven by the emergence of transgender identity, scientific evidence, political activism in those communities, and the gay and lesbian rights movement, as well as patients demanding to be part of the decision-making process.

The terminology has evolved as well. What was called transsexualism in the DSM-III in 1980 became gender identity disorder in the DSM-IV (1994; 2000), and in the current DSM-5 is gender dysphoria. Terminology is still in flux with the possibility that terminology may evolve to “gender incongruence.”

The umbrella term “transgender” now covers transsexual, crossdressing, bigender, drag queen/king, female/male impersonator, and gender queer, and probably more, according to Eli Coleman, Ph.D., professor and director of the program in human sexuality at the University of Minnesota, Minneapolis. “Probably the most proper term you hear now is ‘trans,’ ” he said during a session on transgender medicine at the annual meeting of the American Association of Clinical Endocrinologists.

The DSM-5 criteria for gender dysphoria include a marked incongruence between one’s experienced/expressed gender and the assigned gender for at least 6 months with at least two of the following: an incongruence between one’s felt gender identity and one’s primary and secondary sex characteristics, a strong desire to be rid of one’s gender, a strong desire for the primary and/or secondary sex characteristics of the other gender, a strong desire to be of the other gender (or an alternative gender from the assigned one), a strong desire to be treated as such, and a strong conviction that one has the typical feeling and reactions of the other gender. Dr. Coleman said a further criterion of the DSM-5 is that “the condition is associated with clinically significant distress or impairment in social, occupational, or other areas of functioning.”

A new view of trans

There is now an awareness of a spectrum of gender identity and an affirmation of the right of individuals to express that identity as they would like. Many treatment options exist, and it is up to the individual to decide which way and how far they want to go. Dr. Coleman quoted the late Virginia Prince, a transvestite and a pioneering transgender activist: “If you get on a train in Los Angeles bound for New York, you don’t have to go all the way to New York. If you want, you can get off in Chicago.” So even if a person wants to undergo medical transitioning, hormone therapy does not necessarily have to be followed by sex-reassignment surgery.

Dr. Coleman is past president of the World Professional Association for Transgender Health (WPATH, www.wpath.org), which has published “Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People,” Version 7, a set of guidelines for health care providers. The guidelines are designed help patients achieve comfort with their gendered selves, maximize their overall health and psychological well-being, and achieve self-fulfillment. If untreated or undertreated, gender dysphoria is associated with increased morbidity and mortality, according to WPATH. Hormone treatment may reduce gender dysphoria symptoms by reducing the characteristics of the original sex and inducing ones of the opposite sex. Hormones can be used before or after sex-reassignment surgery, or on their own for patients not seeking surgery who “want [to] … get off in Chicago,” Dr. Coleman said.

Gender nonconformity is not pathological

“Gender nonconformity is not pathological, yet gender dysphoria is a specific distress that can be alleviated through medically necessary treatment,” Dr. Coleman said. “Gender dysphoria may be classified as a mental disorder [but] not necessarily a lifetime diagnosis.” It is the stress of the dysphoria that may be diagnosable and treated, but being gender nonconforming in itself is not the target of treatment. He said mental health professionals therefore have an important role in addressing the negative effects of stigma and helping the individuals become comfortable with a form of gender expression that suits them. This role requires a mental health professional who is skilled in this area.

Treatments to try to change gender identity and expression to become congruent with the sex assigned at birth have failed in the past and are no longer considered ethical, he said. Dr. Coleman suggested that intervening with medical treatments early to suppress puberty and then offering feminizing or masculinizing hormone therapy at the appropriate time may be the best course of action to avoid or alleviate gender dysphoria. He said studies have shown that sex-reassignment surgery can provide “an undeniable effect” on outcomes such as “subjective well-being, cosmesis, and sexual function.”

He recommended that health care professionals become familiar with transgender health care issues, examine their own attitudes and beliefs about these issues, seek out educational opportunities, and get to know and consult with experts in transgender health care. But that is not enough.

“You’ll never understand the condition if you just listen to your patients in the office,” he said. “You’ve got to get into a car and talk to somebody or have coffee with them and really get to know them outside of the office.” That includes meeting with transgender people several years after they have transitioned, who can give insights into the process that are not apparent from just seeing patients in the office in the midst of their gender dysphoria.

The knowledge gained must also be imbued in the health care professional’s staff as well. “You’ve got to have the right attitudes, but you’ve got to train your whole staff about this … that [patients] cannot be treated badly at all,” he said.

ORLANDO – Old notions about transgender and transsexual individuals are changing, driven by the emergence of transgender identity, scientific evidence, political activism in those communities, and the gay and lesbian rights movement, as well as patients demanding to be part of the decision-making process.

The terminology has evolved as well. What was called transsexualism in the DSM-III in 1980 became gender identity disorder in the DSM-IV (1994; 2000), and in the current DSM-5 is gender dysphoria. Terminology is still in flux with the possibility that terminology may evolve to “gender incongruence.”

The umbrella term “transgender” now covers transsexual, crossdressing, bigender, drag queen/king, female/male impersonator, and gender queer, and probably more, according to Eli Coleman, Ph.D., professor and director of the program in human sexuality at the University of Minnesota, Minneapolis. “Probably the most proper term you hear now is ‘trans,’ ” he said during a session on transgender medicine at the annual meeting of the American Association of Clinical Endocrinologists.

The DSM-5 criteria for gender dysphoria include a marked incongruence between one’s experienced/expressed gender and the assigned gender for at least 6 months with at least two of the following: an incongruence between one’s felt gender identity and one’s primary and secondary sex characteristics, a strong desire to be rid of one’s gender, a strong desire for the primary and/or secondary sex characteristics of the other gender, a strong desire to be of the other gender (or an alternative gender from the assigned one), a strong desire to be treated as such, and a strong conviction that one has the typical feeling and reactions of the other gender. Dr. Coleman said a further criterion of the DSM-5 is that “the condition is associated with clinically significant distress or impairment in social, occupational, or other areas of functioning.”

A new view of trans

There is now an awareness of a spectrum of gender identity and an affirmation of the right of individuals to express that identity as they would like. Many treatment options exist, and it is up to the individual to decide which way and how far they want to go. Dr. Coleman quoted the late Virginia Prince, a transvestite and a pioneering transgender activist: “If you get on a train in Los Angeles bound for New York, you don’t have to go all the way to New York. If you want, you can get off in Chicago.” So even if a person wants to undergo medical transitioning, hormone therapy does not necessarily have to be followed by sex-reassignment surgery.

Dr. Coleman is past president of the World Professional Association for Transgender Health (WPATH, www.wpath.org), which has published “Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People,” Version 7, a set of guidelines for health care providers. The guidelines are designed help patients achieve comfort with their gendered selves, maximize their overall health and psychological well-being, and achieve self-fulfillment. If untreated or undertreated, gender dysphoria is associated with increased morbidity and mortality, according to WPATH. Hormone treatment may reduce gender dysphoria symptoms by reducing the characteristics of the original sex and inducing ones of the opposite sex. Hormones can be used before or after sex-reassignment surgery, or on their own for patients not seeking surgery who “want [to] … get off in Chicago,” Dr. Coleman said.

Gender nonconformity is not pathological

“Gender nonconformity is not pathological, yet gender dysphoria is a specific distress that can be alleviated through medically necessary treatment,” Dr. Coleman said. “Gender dysphoria may be classified as a mental disorder [but] not necessarily a lifetime diagnosis.” It is the stress of the dysphoria that may be diagnosable and treated, but being gender nonconforming in itself is not the target of treatment. He said mental health professionals therefore have an important role in addressing the negative effects of stigma and helping the individuals become comfortable with a form of gender expression that suits them. This role requires a mental health professional who is skilled in this area.

Treatments to try to change gender identity and expression to become congruent with the sex assigned at birth have failed in the past and are no longer considered ethical, he said. Dr. Coleman suggested that intervening with medical treatments early to suppress puberty and then offering feminizing or masculinizing hormone therapy at the appropriate time may be the best course of action to avoid or alleviate gender dysphoria. He said studies have shown that sex-reassignment surgery can provide “an undeniable effect” on outcomes such as “subjective well-being, cosmesis, and sexual function.”

He recommended that health care professionals become familiar with transgender health care issues, examine their own attitudes and beliefs about these issues, seek out educational opportunities, and get to know and consult with experts in transgender health care. But that is not enough.

“You’ll never understand the condition if you just listen to your patients in the office,” he said. “You’ve got to get into a car and talk to somebody or have coffee with them and really get to know them outside of the office.” That includes meeting with transgender people several years after they have transitioned, who can give insights into the process that are not apparent from just seeing patients in the office in the midst of their gender dysphoria.

The knowledge gained must also be imbued in the health care professional’s staff as well. “You’ve got to have the right attitudes, but you’ve got to train your whole staff about this … that [patients] cannot be treated badly at all,” he said.

ORLANDO – Old notions about transgender and transsexual individuals are changing, driven by the emergence of transgender identity, scientific evidence, political activism in those communities, and the gay and lesbian rights movement, as well as patients demanding to be part of the decision-making process.

The terminology has evolved as well. What was called transsexualism in the DSM-III in 1980 became gender identity disorder in the DSM-IV (1994; 2000), and in the current DSM-5 is gender dysphoria. Terminology is still in flux with the possibility that terminology may evolve to “gender incongruence.”

The umbrella term “transgender” now covers transsexual, crossdressing, bigender, drag queen/king, female/male impersonator, and gender queer, and probably more, according to Eli Coleman, Ph.D., professor and director of the program in human sexuality at the University of Minnesota, Minneapolis. “Probably the most proper term you hear now is ‘trans,’ ” he said during a session on transgender medicine at the annual meeting of the American Association of Clinical Endocrinologists.

The DSM-5 criteria for gender dysphoria include a marked incongruence between one’s experienced/expressed gender and the assigned gender for at least 6 months with at least two of the following: an incongruence between one’s felt gender identity and one’s primary and secondary sex characteristics, a strong desire to be rid of one’s gender, a strong desire for the primary and/or secondary sex characteristics of the other gender, a strong desire to be of the other gender (or an alternative gender from the assigned one), a strong desire to be treated as such, and a strong conviction that one has the typical feeling and reactions of the other gender. Dr. Coleman said a further criterion of the DSM-5 is that “the condition is associated with clinically significant distress or impairment in social, occupational, or other areas of functioning.”

A new view of trans

There is now an awareness of a spectrum of gender identity and an affirmation of the right of individuals to express that identity as they would like. Many treatment options exist, and it is up to the individual to decide which way and how far they want to go. Dr. Coleman quoted the late Virginia Prince, a transvestite and a pioneering transgender activist: “If you get on a train in Los Angeles bound for New York, you don’t have to go all the way to New York. If you want, you can get off in Chicago.” So even if a person wants to undergo medical transitioning, hormone therapy does not necessarily have to be followed by sex-reassignment surgery.

Dr. Coleman is past president of the World Professional Association for Transgender Health (WPATH, www.wpath.org), which has published “Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People,” Version 7, a set of guidelines for health care providers. The guidelines are designed help patients achieve comfort with their gendered selves, maximize their overall health and psychological well-being, and achieve self-fulfillment. If untreated or undertreated, gender dysphoria is associated with increased morbidity and mortality, according to WPATH. Hormone treatment may reduce gender dysphoria symptoms by reducing the characteristics of the original sex and inducing ones of the opposite sex. Hormones can be used before or after sex-reassignment surgery, or on their own for patients not seeking surgery who “want [to] … get off in Chicago,” Dr. Coleman said.

Gender nonconformity is not pathological

“Gender nonconformity is not pathological, yet gender dysphoria is a specific distress that can be alleviated through medically necessary treatment,” Dr. Coleman said. “Gender dysphoria may be classified as a mental disorder [but] not necessarily a lifetime diagnosis.” It is the stress of the dysphoria that may be diagnosable and treated, but being gender nonconforming in itself is not the target of treatment. He said mental health professionals therefore have an important role in addressing the negative effects of stigma and helping the individuals become comfortable with a form of gender expression that suits them. This role requires a mental health professional who is skilled in this area.

Treatments to try to change gender identity and expression to become congruent with the sex assigned at birth have failed in the past and are no longer considered ethical, he said. Dr. Coleman suggested that intervening with medical treatments early to suppress puberty and then offering feminizing or masculinizing hormone therapy at the appropriate time may be the best course of action to avoid or alleviate gender dysphoria. He said studies have shown that sex-reassignment surgery can provide “an undeniable effect” on outcomes such as “subjective well-being, cosmesis, and sexual function.”

He recommended that health care professionals become familiar with transgender health care issues, examine their own attitudes and beliefs about these issues, seek out educational opportunities, and get to know and consult with experts in transgender health care. But that is not enough.

“You’ll never understand the condition if you just listen to your patients in the office,” he said. “You’ve got to get into a car and talk to somebody or have coffee with them and really get to know them outside of the office.” That includes meeting with transgender people several years after they have transitioned, who can give insights into the process that are not apparent from just seeing patients in the office in the midst of their gender dysphoria.

The knowledge gained must also be imbued in the health care professional’s staff as well. “You’ve got to have the right attitudes, but you’ve got to train your whole staff about this … that [patients] cannot be treated badly at all,” he said.

ORLANDO – Gender reassignment surgery is the most extreme step for those transgender individuals who wish to complete the transformation to the opposite sex. While many transgender people do not opt to take this step, it may be an option for people who still have gender dysphoria after a thorough diagnostic work-up by a mental health professional, hormonal treatment, and having lived in the desired gender role as a “real-life test.”

Dr. Stan Monstrey, of Ghent University Hospital, Belgium, is an experienced gender reassignment surgeon and reported at the annual meeting of the American Academy of Clinical Endocrinology that between 1995 and 2005, he saw about 20-30 new patients a year. But now, he said, “We operate on a weekly basis between a minimum of three and sometimes six or seven transsexuals, so ... in our practice, probably between 90% and 95% are still going the whole way, still want what was called initially binary surgery.”

Transwomen: Male to female

The transformation procedure for male to female begins with feminizing aesthetic procedures, such as reducing the Adam’s apple (laryngeal prominence of the thyroid cartilage) and chin, frontal boss of the forehead, and possibly other facial work such as rhinoplasty. “Sometimes minor changes can have a huge effect on the face of the patient,” Dr. Monstrey said. “This is becoming, in our opinion, increasingly important for transwomen.”

Then, in about 75% of cases, Dr. Monstrey performs at least two surgeries under the same anesthesia – breast augmentation and perineal transformation. He said even after years of hormone therapy, most such patients have only a limited amount of breast tissue but want more prominent breasts. Implants can be placed behind or in front of the pectoralis muscle via inframammary, transaxillary, or occasionally periareolar approaches. Results are immediate, and complications are rare.

Another technique, which has become very popular over the past 5-10 years, is lipofilling to fill defects and depressions in the breasts. Stem cells contained in the fat may help soften scars. But when faced with a patient who had a BRCA1 mutation, the surgeons would not use lipofilling, fearing the potential for breast cancer, and would use prostheses instead (J Sex Med. 2014 Oct;11:2496-9). Still, questions remain about even using hormone treatments in such a patient.

Dr. Monstrey mentioned that in Belgium, breast augmentation for transwomen is considered reconstructive surgery and is always reimbursed whereas it is considered aesthetic surgery and never reimbursed for non-transwomen who want larger breasts. (For transmen, breast amputation is similarly reimbursed.)

The second operation is genital transformation. Basically, the interior of the penis is removed and the skin is invaginated to form a vagina of 8-18.5 cm and a scrotal flap, along with castration and removal of the penile bulb erectile tissue (corpus spongiosum) posteriorly. It is important to protect the rectal wall, which is not very strong. The foreskin becomes the new clitoral hood and inner side of the labia minora, and the clitoris is formed by reducing and transposing the penile glans. If the patient had a small penis and not enough tissue for the reconstruction, skin flaps from various other sites can be used.

Among more than 1,200 patients, 92% could achieve orgasm. Rectovaginal fistulas occurred in 4 patients, 19 needed repositioning of the urethra, 21 needed an operation to lengthen the vagina, and 95 needed aesthetic correction of the vulva. Dr. Monstrey said many patients have asked him when they should tell their new boyfriends about their transformation, meaning that the surgery was quite convincing even with penetrative sex.

If the first operation does not work, another technique is to use an isolated piece of colon or sigmoid bowel, which has been performed completely laparoscopically by a very skilled gastroenterologic surgeon at the hospital in Ghent.

Speaking to a roomful of endocrinologists, Dr. Monstrey told them, “I’ll be the first one to agree with you that indeed puberty blockers are a very good thing. However, we as surgeons are not so enthusiastic about them because … it is impossible to create a normal vagina” because of a lack of available tissue from the underdeveloped penis.

Transmen: Female to male

“Transmen react much better to hormonal therapy than do transwomen,” he said. “If they hide their breasts they really look like men. The disadvantage is that the surgical treatment is much more complex.” The most important operation for them is subcutaneous mastectomy and male contouring. A small, semiareolar incision leaves almost no scar. Most patients still require excision of redundant skin of the breasts.

Phalloplasty is a complex operation aimed at giving the patient an aesthetic phallus, a normal scrotum, the ability to void while standing, and to perform sexual intercourse, all while protecting erogenous sensation, with minimal morbidity and mortality. Dr. Monstrey reported that he has performed 600-700 phalloplasties.

The most common technique has been to use a free vascularized flap from another bodily site with the artery, vein, and nerves to reconnect at the phalloplasty site. Because the skin is very thin on the inner forearm, it is often used and allows forming an inner tube for the urethra and an outer tube for the penis. The surgery may have to be done in three or four stages for the best results. From pictures that Dr. Monstrey showed, it was obvious that the constructed penises were not absolutely natural in appearance, but he said most patients were “rather happy” with them, despite many of these patients being quite demanding. A scrotum is constructed from transposition of the labia minora.

Unfortunately, voiding while standing is often a problem, with 197 out of 562 patients (35%) having a fistula and urine leakage, but this issue frequently corrects itself. “More difficult to treat are the strictures with stenosis, which can be a problem voiding,” he said (occurring in 78/562). Other complications were 5 complete and 43 partial flap failures, 4 cases of compression syndrome, 58 cases of delayed wound healing, and 15 cases of transient ischemia. Flap failures occurred mainly in smokers, “so we don’t operate on smokers anymore,” he said.

One year after the constructive surgery, a penile prosthesis is implanted for those who want it, allowing sexual intercourse. Most individuals had orgasmic function, not because of reconnected nerves in the flap, but, Dr. Monstrey said he believes, because the clitoris, placed beneath the phallus, is denuded and stimulated during sexual activity. He said the problem is that the prostheses are usually intended for elderly men “who have sex a couple of times a month and who have a normal anatomy.” Young transmen may engage in more sexual activity, “so we have a lot of problems with exposure [of the prosthesis], infection, technical defects, and so on,” he said.

A technique gaining popularity is to use a skin flap from the groin area to make a urethra and one from the thigh to construct a penis. Although a penile transplant has recently been performed for a patient who had lost his penis to cancer, transplants are not being considered at this point, both for surgical technical reasons and because of a need for lifelong immunosuppressive drugs.

Proper referrals and counseling

The World Professional Association for Transgender Health in its Standard of Care guidelines 7 recommends one mental health professional referral for the breast surgery and two such referrals for genital surgery. The issue of possible parenthood should be discussed with patients, along with early counseling about fertility options. The age of majority and consent in different countries is important. Dr. Monstrey said genital surgery may be possible before the age of 18 years if all members of a multidisciplinary team of health professionals agree on a case by case basis that the adolescent can understand the risks, benefits, and alternatives to the surgery with the same degree of competence as someone 18 years of age or older.

Dr. Monstrey reported having no financial disclosures.

ORLANDO – Gender reassignment surgery is the most extreme step for those transgender individuals who wish to complete the transformation to the opposite sex. While many transgender people do not opt to take this step, it may be an option for people who still have gender dysphoria after a thorough diagnostic work-up by a mental health professional, hormonal treatment, and having lived in the desired gender role as a “real-life test.”

Dr. Stan Monstrey, of Ghent University Hospital, Belgium, is an experienced gender reassignment surgeon and reported at the annual meeting of the American Academy of Clinical Endocrinology that between 1995 and 2005, he saw about 20-30 new patients a year. But now, he said, “We operate on a weekly basis between a minimum of three and sometimes six or seven transsexuals, so ... in our practice, probably between 90% and 95% are still going the whole way, still want what was called initially binary surgery.”

Transwomen: Male to female

The transformation procedure for male to female begins with feminizing aesthetic procedures, such as reducing the Adam’s apple (laryngeal prominence of the thyroid cartilage) and chin, frontal boss of the forehead, and possibly other facial work such as rhinoplasty. “Sometimes minor changes can have a huge effect on the face of the patient,” Dr. Monstrey said. “This is becoming, in our opinion, increasingly important for transwomen.”

Then, in about 75% of cases, Dr. Monstrey performs at least two surgeries under the same anesthesia – breast augmentation and perineal transformation. He said even after years of hormone therapy, most such patients have only a limited amount of breast tissue but want more prominent breasts. Implants can be placed behind or in front of the pectoralis muscle via inframammary, transaxillary, or occasionally periareolar approaches. Results are immediate, and complications are rare.

Another technique, which has become very popular over the past 5-10 years, is lipofilling to fill defects and depressions in the breasts. Stem cells contained in the fat may help soften scars. But when faced with a patient who had a BRCA1 mutation, the surgeons would not use lipofilling, fearing the potential for breast cancer, and would use prostheses instead (J Sex Med. 2014 Oct;11:2496-9). Still, questions remain about even using hormone treatments in such a patient.

Dr. Monstrey mentioned that in Belgium, breast augmentation for transwomen is considered reconstructive surgery and is always reimbursed whereas it is considered aesthetic surgery and never reimbursed for non-transwomen who want larger breasts. (For transmen, breast amputation is similarly reimbursed.)

The second operation is genital transformation. Basically, the interior of the penis is removed and the skin is invaginated to form a vagina of 8-18.5 cm and a scrotal flap, along with castration and removal of the penile bulb erectile tissue (corpus spongiosum) posteriorly. It is important to protect the rectal wall, which is not very strong. The foreskin becomes the new clitoral hood and inner side of the labia minora, and the clitoris is formed by reducing and transposing the penile glans. If the patient had a small penis and not enough tissue for the reconstruction, skin flaps from various other sites can be used.

Among more than 1,200 patients, 92% could achieve orgasm. Rectovaginal fistulas occurred in 4 patients, 19 needed repositioning of the urethra, 21 needed an operation to lengthen the vagina, and 95 needed aesthetic correction of the vulva. Dr. Monstrey said many patients have asked him when they should tell their new boyfriends about their transformation, meaning that the surgery was quite convincing even with penetrative sex.

If the first operation does not work, another technique is to use an isolated piece of colon or sigmoid bowel, which has been performed completely laparoscopically by a very skilled gastroenterologic surgeon at the hospital in Ghent.

Speaking to a roomful of endocrinologists, Dr. Monstrey told them, “I’ll be the first one to agree with you that indeed puberty blockers are a very good thing. However, we as surgeons are not so enthusiastic about them because … it is impossible to create a normal vagina” because of a lack of available tissue from the underdeveloped penis.

Transmen: Female to male

“Transmen react much better to hormonal therapy than do transwomen,” he said. “If they hide their breasts they really look like men. The disadvantage is that the surgical treatment is much more complex.” The most important operation for them is subcutaneous mastectomy and male contouring. A small, semiareolar incision leaves almost no scar. Most patients still require excision of redundant skin of the breasts.

Phalloplasty is a complex operation aimed at giving the patient an aesthetic phallus, a normal scrotum, the ability to void while standing, and to perform sexual intercourse, all while protecting erogenous sensation, with minimal morbidity and mortality. Dr. Monstrey reported that he has performed 600-700 phalloplasties.

The most common technique has been to use a free vascularized flap from another bodily site with the artery, vein, and nerves to reconnect at the phalloplasty site. Because the skin is very thin on the inner forearm, it is often used and allows forming an inner tube for the urethra and an outer tube for the penis. The surgery may have to be done in three or four stages for the best results. From pictures that Dr. Monstrey showed, it was obvious that the constructed penises were not absolutely natural in appearance, but he said most patients were “rather happy” with them, despite many of these patients being quite demanding. A scrotum is constructed from transposition of the labia minora.

Unfortunately, voiding while standing is often a problem, with 197 out of 562 patients (35%) having a fistula and urine leakage, but this issue frequently corrects itself. “More difficult to treat are the strictures with stenosis, which can be a problem voiding,” he said (occurring in 78/562). Other complications were 5 complete and 43 partial flap failures, 4 cases of compression syndrome, 58 cases of delayed wound healing, and 15 cases of transient ischemia. Flap failures occurred mainly in smokers, “so we don’t operate on smokers anymore,” he said.

One year after the constructive surgery, a penile prosthesis is implanted for those who want it, allowing sexual intercourse. Most individuals had orgasmic function, not because of reconnected nerves in the flap, but, Dr. Monstrey said he believes, because the clitoris, placed beneath the phallus, is denuded and stimulated during sexual activity. He said the problem is that the prostheses are usually intended for elderly men “who have sex a couple of times a month and who have a normal anatomy.” Young transmen may engage in more sexual activity, “so we have a lot of problems with exposure [of the prosthesis], infection, technical defects, and so on,” he said.

A technique gaining popularity is to use a skin flap from the groin area to make a urethra and one from the thigh to construct a penis. Although a penile transplant has recently been performed for a patient who had lost his penis to cancer, transplants are not being considered at this point, both for surgical technical reasons and because of a need for lifelong immunosuppressive drugs.

Proper referrals and counseling

The World Professional Association for Transgender Health in its Standard of Care guidelines 7 recommends one mental health professional referral for the breast surgery and two such referrals for genital surgery. The issue of possible parenthood should be discussed with patients, along with early counseling about fertility options. The age of majority and consent in different countries is important. Dr. Monstrey said genital surgery may be possible before the age of 18 years if all members of a multidisciplinary team of health professionals agree on a case by case basis that the adolescent can understand the risks, benefits, and alternatives to the surgery with the same degree of competence as someone 18 years of age or older.

Dr. Monstrey reported having no financial disclosures.

ORLANDO – Gender reassignment surgery is the most extreme step for those transgender individuals who wish to complete the transformation to the opposite sex. While many transgender people do not opt to take this step, it may be an option for people who still have gender dysphoria after a thorough diagnostic work-up by a mental health professional, hormonal treatment, and having lived in the desired gender role as a “real-life test.”

Dr. Stan Monstrey, of Ghent University Hospital, Belgium, is an experienced gender reassignment surgeon and reported at the annual meeting of the American Academy of Clinical Endocrinology that between 1995 and 2005, he saw about 20-30 new patients a year. But now, he said, “We operate on a weekly basis between a minimum of three and sometimes six or seven transsexuals, so ... in our practice, probably between 90% and 95% are still going the whole way, still want what was called initially binary surgery.”

Transwomen: Male to female

The transformation procedure for male to female begins with feminizing aesthetic procedures, such as reducing the Adam’s apple (laryngeal prominence of the thyroid cartilage) and chin, frontal boss of the forehead, and possibly other facial work such as rhinoplasty. “Sometimes minor changes can have a huge effect on the face of the patient,” Dr. Monstrey said. “This is becoming, in our opinion, increasingly important for transwomen.”

Then, in about 75% of cases, Dr. Monstrey performs at least two surgeries under the same anesthesia – breast augmentation and perineal transformation. He said even after years of hormone therapy, most such patients have only a limited amount of breast tissue but want more prominent breasts. Implants can be placed behind or in front of the pectoralis muscle via inframammary, transaxillary, or occasionally periareolar approaches. Results are immediate, and complications are rare.

Another technique, which has become very popular over the past 5-10 years, is lipofilling to fill defects and depressions in the breasts. Stem cells contained in the fat may help soften scars. But when faced with a patient who had a BRCA1 mutation, the surgeons would not use lipofilling, fearing the potential for breast cancer, and would use prostheses instead (J Sex Med. 2014 Oct;11:2496-9). Still, questions remain about even using hormone treatments in such a patient.

Dr. Monstrey mentioned that in Belgium, breast augmentation for transwomen is considered reconstructive surgery and is always reimbursed whereas it is considered aesthetic surgery and never reimbursed for non-transwomen who want larger breasts. (For transmen, breast amputation is similarly reimbursed.)

The second operation is genital transformation. Basically, the interior of the penis is removed and the skin is invaginated to form a vagina of 8-18.5 cm and a scrotal flap, along with castration and removal of the penile bulb erectile tissue (corpus spongiosum) posteriorly. It is important to protect the rectal wall, which is not very strong. The foreskin becomes the new clitoral hood and inner side of the labia minora, and the clitoris is formed by reducing and transposing the penile glans. If the patient had a small penis and not enough tissue for the reconstruction, skin flaps from various other sites can be used.

Among more than 1,200 patients, 92% could achieve orgasm. Rectovaginal fistulas occurred in 4 patients, 19 needed repositioning of the urethra, 21 needed an operation to lengthen the vagina, and 95 needed aesthetic correction of the vulva. Dr. Monstrey said many patients have asked him when they should tell their new boyfriends about their transformation, meaning that the surgery was quite convincing even with penetrative sex.

If the first operation does not work, another technique is to use an isolated piece of colon or sigmoid bowel, which has been performed completely laparoscopically by a very skilled gastroenterologic surgeon at the hospital in Ghent.

Speaking to a roomful of endocrinologists, Dr. Monstrey told them, “I’ll be the first one to agree with you that indeed puberty blockers are a very good thing. However, we as surgeons are not so enthusiastic about them because … it is impossible to create a normal vagina” because of a lack of available tissue from the underdeveloped penis.

Transmen: Female to male

“Transmen react much better to hormonal therapy than do transwomen,” he said. “If they hide their breasts they really look like men. The disadvantage is that the surgical treatment is much more complex.” The most important operation for them is subcutaneous mastectomy and male contouring. A small, semiareolar incision leaves almost no scar. Most patients still require excision of redundant skin of the breasts.

Phalloplasty is a complex operation aimed at giving the patient an aesthetic phallus, a normal scrotum, the ability to void while standing, and to perform sexual intercourse, all while protecting erogenous sensation, with minimal morbidity and mortality. Dr. Monstrey reported that he has performed 600-700 phalloplasties.

The most common technique has been to use a free vascularized flap from another bodily site with the artery, vein, and nerves to reconnect at the phalloplasty site. Because the skin is very thin on the inner forearm, it is often used and allows forming an inner tube for the urethra and an outer tube for the penis. The surgery may have to be done in three or four stages for the best results. From pictures that Dr. Monstrey showed, it was obvious that the constructed penises were not absolutely natural in appearance, but he said most patients were “rather happy” with them, despite many of these patients being quite demanding. A scrotum is constructed from transposition of the labia minora.

Unfortunately, voiding while standing is often a problem, with 197 out of 562 patients (35%) having a fistula and urine leakage, but this issue frequently corrects itself. “More difficult to treat are the strictures with stenosis, which can be a problem voiding,” he said (occurring in 78/562). Other complications were 5 complete and 43 partial flap failures, 4 cases of compression syndrome, 58 cases of delayed wound healing, and 15 cases of transient ischemia. Flap failures occurred mainly in smokers, “so we don’t operate on smokers anymore,” he said.

One year after the constructive surgery, a penile prosthesis is implanted for those who want it, allowing sexual intercourse. Most individuals had orgasmic function, not because of reconnected nerves in the flap, but, Dr. Monstrey said he believes, because the clitoris, placed beneath the phallus, is denuded and stimulated during sexual activity. He said the problem is that the prostheses are usually intended for elderly men “who have sex a couple of times a month and who have a normal anatomy.” Young transmen may engage in more sexual activity, “so we have a lot of problems with exposure [of the prosthesis], infection, technical defects, and so on,” he said.

A technique gaining popularity is to use a skin flap from the groin area to make a urethra and one from the thigh to construct a penis. Although a penile transplant has recently been performed for a patient who had lost his penis to cancer, transplants are not being considered at this point, both for surgical technical reasons and because of a need for lifelong immunosuppressive drugs.

Proper referrals and counseling

The World Professional Association for Transgender Health in its Standard of Care guidelines 7 recommends one mental health professional referral for the breast surgery and two such referrals for genital surgery. The issue of possible parenthood should be discussed with patients, along with early counseling about fertility options. The age of majority and consent in different countries is important. Dr. Monstrey said genital surgery may be possible before the age of 18 years if all members of a multidisciplinary team of health professionals agree on a case by case basis that the adolescent can understand the risks, benefits, and alternatives to the surgery with the same degree of competence as someone 18 years of age or older.

Dr. Monstrey reported having no financial disclosures.

ORLANDO – The diagnosis of hypertension with its origin in the endocrine system may appear complex, but it does not have to be. Primary aldosteronism may be underappreciated and underdiagnosed. On the other hand, catecholamine-secreting tumors are rare, but they often come to mind in making a diagnosis of endocrine hypertension. Dr. William Young Jr., professor of medicine at the Mayo Clinic, Rochester, Minn., presented cases in a lively session of audience participation at the annual meeting of the America Association of Clinical Endocrinologists. Later, Dr. Young summarized some of the key points in an interview, which has been edited for brevity.

Frontline Medical News: What is the endocrinologist’s role in working up the patient who has hypertension of suspected endocrine origin?

Dr. William Young Jr.: The first is knowing when to suspect endocrine hypertension. The most common form of endocrine hypertension is primary aldosteronism. So this is the adrenal-dependent autonomous production of aldosterone, which leads to high blood pressure, volume expansion, and sometimes hypokalemia. One of the concepts that many clinicians forget is that only about 30% of patients with primary aldosteronism present with hypokalemia. So 70% of patients with this disorder don’t have hypokalemia. They look like any other person with high blood pressure.

So when should we look for primary aldosteronism? Onset of high blood pressure at a young age, for example, less than age 30, drug resistant hypertension – so three drugs [with] poor control. Twenty percent of those patients will prove to have primary aldosteronism. Simply poorly controlled hypertension is another group; [or] family history of primary aldosteronism, so all first degree relatives should be tested. Or a patient who has hypertension and has had an incidental discovery of an adrenal mass should also be tested for primary aldosteronism.

Unfortunately, most primary care providers ... think that this is a complicated and dense endocrine disorder, and they frequently will not look for it, but it’s actually very simple. Some of the complexities are historical in nature in that when this disorder was first described, several rules were made for what medications a patient could be on, for example. And it’s difficult to comply with those rules. For example, if you have a patient who’s on five drugs and has poor control, you’re not going to switch him to the two drugs that are recommended because they are weak antihypertensives. It wouldn’t be ethical to do so. [The two drug classes are the calcium channel blocker verapamil and the alpha-1 antagonists doxazosin (Cardura) and terazosin (Hytrin).]

So the best thing to do regardless of what drugs the patient is on – it doesn’t matter if they’re on ACE inhibitors or angiotensin-receptor blockers or diuretics – just get a morning blood sample as your aldosterone and plasma renin activity. If aldosterone is high or generous, greater than 15 ng/dL, if the plasma renin activity is less than 1 ng/mL per hour, that’s a positive case detection test.

That doesn’t prove the patient has primary aldosteronism. The sensitivity/specificity of aldosterone and renin case detection testing is about 75%. So most patients need confirmatory testing, which would either be the saline infusion test or the 24-hour urine for aldosterone on a high-sodium diet. And once primary aldosteronism is confirmed, then we would do an adrenal-directed CT scan.

The problem with the findings in the adrenal glands on CT is that the prevalence of adrenal nodularity increases with age. So people in their 60s and 70s can have adrenal nodules that have nothing to do with aldosterone production. So whereas if the patient is less than age 35 and CT shows a unilateral macroadenoma, the contralateral adrenal is perfectly normal appearing, and the patient has a marked primary aldosteronism – so spontaneous hypokalemia, plasma aldosterone over 30 ng/dL – that subset of patients could go straight to surgery and skip adrenal vein sampling. However, everyone else over age 35 if they want to pursue the surgical option, adrenal vein sampling is a key test.

FMN: Is there anything that rules out primary aldosteronism?

Dr. Young: If the plasma aldosterone level is less than 10 ng/dL it makes primary aldosteronism very unlikely, and if the renin level is higher than 1 ng/mL per hour, that makes primary aldosteronism very unlikely.

FMN: What about working up pheochromocytoma?

Dr. Young: Clinicians, unlike with primary aldosteronism, where they don’t look for it enough, for pheochromocytoma they look for it a lot, and it’s really rare. Between 0.1 and 0.01% of the hypertensive population will prove to have pheochromocytoma.

The false positive rate with our case detection testing of plasma metanephrines about 15%. So based on how rare pheochromocytoma is and a 15% false positive rate with plasma metanephrines, 97% of patients with elevated plasma normetanephrines do not have pheochromocytoma.

So we have a real problem with case detection testing. The 24-hour urine metanephrines and catecholamines using appropriate reference ranges are probably a better way to do case detection testing for pheochromocytoma, but there’s still a false positive rate with urinary normetanephrine.

Never mistake a benign adrenal adenoma for a pheo. In terms of the imaging phenotype, pheos are dense and vascular. As they enlarge, they get cystic hemorrhagic areas within them.

FMN: What goes on with other paragangliomas?

Dr. Young: Pheochromocytoma is the term we use when you have a catecholamine-secreting tumor in the adrenal gland itself. It develops in the adrenal medulla. Paraganglioma is an identical tumor, but it’s outside of the adrenal gland. It’s somewhere in the pelvis, could be in the chest, could be in the skull base, or neck. Most commonly it’s in the abdomen. So the case detection testing is the same.

But patients we should consider testing for pheochromocytoma and paraganglioma are those with paroxysmal symptoms like episodes of pounding heartbeat, sweating, headache, tremor, and pallor. Young people with new onset hypertension, hypertension that’s poorly controlled, and vascular adrenal masses should also be tested for pheochromocytoma.

FMN: Are there things that can confound any of these tests we discussed or any drugs that should be noted that could get in the way?

Dr. Young: For pheochromocytoma, the good news is now that most reference labs use tandem mass spectrometry technology, the hypertension drugs that potentially interfered in the past like labetalol and sotalol no longer interfere. So these days the clinician doesn’t need to stop any blood pressure–related medications.

The medications that can cause false positive testing are primarily tricyclic antidepressants. Flexeril, which is cyclobenzaprine, is commonly used to treat fibromyalgia, and that is a tricyclic antidepressant, and that will cause false positive testing ... with norepinephrine and normetanephrine. Tricyclic antidepressants can increase those levels three, four, or fivefold. Levodopa, which is in Sinemet, can cause false positive testing. Antipsychotics can cause false positive testing, and MAO inhibitors ... So the clinician shouldn’t worry about blood pressure medications but should worry about the other medications the patient is taking.

FMN: When someone looks at laboratory values, should you be comparing these values to people with hypertension who do not have these conditions, and do labs have adjusted values?

Dr. Young: That’s a good question, and in the Mayo medical lab, our reference range that we use is based on patients who were tested for pheochromocytoma [and] proved not to have it. So our cutoffs are 50% to 100% higher than some other reference labs.

These other reference labs use normal laboratory volunteers who have normal blood pressure and who are taking no medications, and I’ve never tested such a patient for pheochromocytoma, so why would we use that group of people to determine our reference range? So we should use reference ranges based on patients tested for pheo but who prove to not have pheo. And that leads to higher accuracy of our case detection tests.

FMN: What are the treatments for these conditions and follow-up? I take it if there’s an adrenal mass, you get a surgeon, and I think you also noted that you need an experienced endocrine surgeon.

Dr. Young: For primary aldosteronism, if the patient has a unilateral aldosterone-producing adenoma, the outstanding treatment is laparoscopic adrenalectomy. Patients are in the hospital one night, [and] they’re back at work in 7-10 days, but that does require an expert laparoscopic adrenal surgeon. And in the United States we have a 1-year endocrine surgery program. It’s optimal that patients are referred to surgeons who have done that unique training.

For pheochromocytoma less than 8-9 cm, laparoscopic adrenalectomy with an experienced endocrine surgeon is an excellent treatment option. When the adrenal pheochromocytoma is larger than 8 or 9 cm, especially if it’s cystic, the surgeon may want to do it as open [surgery] because it’s critical that the capsule of the pheochromocytoma is not ruptured intraoperatively. If it is ruptured, a benign pheochromocytoma has just been transformed to malignant, incurable disease.

If it’s a paraganglioma, typically that requires an open operation whether it’s in the neck or the chest or the pelvis or lower abdomen.

FMN: What is the follow-up to any of these conditions?

Dr. Young: The follow-up once you’ve resected an adrenal pheochromocytoma depends on whether there is a germline mutation. If there is a germline mutation, for example, succinate dehydrogenase mutation [SDH], these patients are at higher risk for developing recurrent pheochromocytoma or paraganglioma, and they’re at risk for developing malignant pheochromocytoma or paraganglioma.

One of our challenges is when we resect a pheochromocytoma or paraganglioma, the pathologist doesn’t have the tools to tell us if it’s benign or malignant ... So all patients need lifelong biochemical follow-up, basically a 24-hour urine for metanephrines and catecholamines annually or plasma metanephrines for life.

If the patients have an underlying mutation like succinate dehydrogenase, they’re at risk for developing nonfunctioning paragangliomas. So these patients need periodic imaging in addition to the annual biochemical testing. For example, if a patient had an abdominal paraganglioma with an SDHB [succinate dehydrogenase complex iron sulfur subunit B], we would do abdominal MRI scans every 1-2 years. That would include the pelvis. We would screen for paragangliomas elsewhere with MRI of the skull base and neck and the chest every 3-5 years, and a total body scan every 5 years or so, either FDG-PET [¹⁸F-fluorodeoxyglucose positron emission tomography] scan or ¹²³I-MIBG [metaiodobenzyl-guanidine] scan.

FMN: Is there anything that is particularly new in the past couple of years?

Dr. Young: Some of the innovations lately have been in the area of metastatic pheochromocytoma and paraganglioma. These are in patients who have limited metastatic disease that’s localized to bone or to liver, and we’ve been using ablative therapies. This includes cryoablation ... and radiofrequency ablation, which is killing the tumor with hot temperature, and that’s very effective for patients who have limited metastatic lesions in the bone or liver.

For patients with complex tumors in difficult areas of the body, for example, in the mediastinum or surrounding the heart, we’ve been using 3D printer technology to print [a replica of the structures and] the tumor preoperatively, and this assists in surgical planning.

FMN: And what do you see coming?

Dr. Young: I think we’re getting close to something near curative for patients with malignant pheochromocytoma and paraganglioma. We’re understanding the basic biology better [and] pathophysiology, and I think that’s going to lead to some novel treatments.

Also, what I see coming is that we’ll be able to use germline mutation information and somatic tumor mutation information to guide us on specific imaging modalities, to guide us on forms of preventative therapy so that we prevent the paraganglioma from ever developing and also provide us with additional treatment options.

ORLANDO – The diagnosis of hypertension with its origin in the endocrine system may appear complex, but it does not have to be. Primary aldosteronism may be underappreciated and underdiagnosed. On the other hand, catecholamine-secreting tumors are rare, but they often come to mind in making a diagnosis of endocrine hypertension. Dr. William Young Jr., professor of medicine at the Mayo Clinic, Rochester, Minn., presented cases in a lively session of audience participation at the annual meeting of the America Association of Clinical Endocrinologists. Later, Dr. Young summarized some of the key points in an interview, which has been edited for brevity.

Frontline Medical News: What is the endocrinologist’s role in working up the patient who has hypertension of suspected endocrine origin?

Dr. William Young Jr.: The first is knowing when to suspect endocrine hypertension. The most common form of endocrine hypertension is primary aldosteronism. So this is the adrenal-dependent autonomous production of aldosterone, which leads to high blood pressure, volume expansion, and sometimes hypokalemia. One of the concepts that many clinicians forget is that only about 30% of patients with primary aldosteronism present with hypokalemia. So 70% of patients with this disorder don’t have hypokalemia. They look like any other person with high blood pressure.

So when should we look for primary aldosteronism? Onset of high blood pressure at a young age, for example, less than age 30, drug resistant hypertension – so three drugs [with] poor control. Twenty percent of those patients will prove to have primary aldosteronism. Simply poorly controlled hypertension is another group; [or] family history of primary aldosteronism, so all first degree relatives should be tested. Or a patient who has hypertension and has had an incidental discovery of an adrenal mass should also be tested for primary aldosteronism.

Unfortunately, most primary care providers ... think that this is a complicated and dense endocrine disorder, and they frequently will not look for it, but it’s actually very simple. Some of the complexities are historical in nature in that when this disorder was first described, several rules were made for what medications a patient could be on, for example. And it’s difficult to comply with those rules. For example, if you have a patient who’s on five drugs and has poor control, you’re not going to switch him to the two drugs that are recommended because they are weak antihypertensives. It wouldn’t be ethical to do so. [The two drug classes are the calcium channel blocker verapamil and the alpha-1 antagonists doxazosin (Cardura) and terazosin (Hytrin).]

So the best thing to do regardless of what drugs the patient is on – it doesn’t matter if they’re on ACE inhibitors or angiotensin-receptor blockers or diuretics – just get a morning blood sample as your aldosterone and plasma renin activity. If aldosterone is high or generous, greater than 15 ng/dL, if the plasma renin activity is less than 1 ng/mL per hour, that’s a positive case detection test.

That doesn’t prove the patient has primary aldosteronism. The sensitivity/specificity of aldosterone and renin case detection testing is about 75%. So most patients need confirmatory testing, which would either be the saline infusion test or the 24-hour urine for aldosterone on a high-sodium diet. And once primary aldosteronism is confirmed, then we would do an adrenal-directed CT scan.

The problem with the findings in the adrenal glands on CT is that the prevalence of adrenal nodularity increases with age. So people in their 60s and 70s can have adrenal nodules that have nothing to do with aldosterone production. So whereas if the patient is less than age 35 and CT shows a unilateral macroadenoma, the contralateral adrenal is perfectly normal appearing, and the patient has a marked primary aldosteronism – so spontaneous hypokalemia, plasma aldosterone over 30 ng/dL – that subset of patients could go straight to surgery and skip adrenal vein sampling. However, everyone else over age 35 if they want to pursue the surgical option, adrenal vein sampling is a key test.

FMN: Is there anything that rules out primary aldosteronism?

Dr. Young: If the plasma aldosterone level is less than 10 ng/dL it makes primary aldosteronism very unlikely, and if the renin level is higher than 1 ng/mL per hour, that makes primary aldosteronism very unlikely.

FMN: What about working up pheochromocytoma?

Dr. Young: Clinicians, unlike with primary aldosteronism, where they don’t look for it enough, for pheochromocytoma they look for it a lot, and it’s really rare. Between 0.1 and 0.01% of the hypertensive population will prove to have pheochromocytoma.

The false positive rate with our case detection testing of plasma metanephrines about 15%. So based on how rare pheochromocytoma is and a 15% false positive rate with plasma metanephrines, 97% of patients with elevated plasma normetanephrines do not have pheochromocytoma.

So we have a real problem with case detection testing. The 24-hour urine metanephrines and catecholamines using appropriate reference ranges are probably a better way to do case detection testing for pheochromocytoma, but there’s still a false positive rate with urinary normetanephrine.

Never mistake a benign adrenal adenoma for a pheo. In terms of the imaging phenotype, pheos are dense and vascular. As they enlarge, they get cystic hemorrhagic areas within them.

FMN: What goes on with other paragangliomas?

Dr. Young: Pheochromocytoma is the term we use when you have a catecholamine-secreting tumor in the adrenal gland itself. It develops in the adrenal medulla. Paraganglioma is an identical tumor, but it’s outside of the adrenal gland. It’s somewhere in the pelvis, could be in the chest, could be in the skull base, or neck. Most commonly it’s in the abdomen. So the case detection testing is the same.

But patients we should consider testing for pheochromocytoma and paraganglioma are those with paroxysmal symptoms like episodes of pounding heartbeat, sweating, headache, tremor, and pallor. Young people with new onset hypertension, hypertension that’s poorly controlled, and vascular adrenal masses should also be tested for pheochromocytoma.

FMN: Are there things that can confound any of these tests we discussed or any drugs that should be noted that could get in the way?

Dr. Young: For pheochromocytoma, the good news is now that most reference labs use tandem mass spectrometry technology, the hypertension drugs that potentially interfered in the past like labetalol and sotalol no longer interfere. So these days the clinician doesn’t need to stop any blood pressure–related medications.

The medications that can cause false positive testing are primarily tricyclic antidepressants. Flexeril, which is cyclobenzaprine, is commonly used to treat fibromyalgia, and that is a tricyclic antidepressant, and that will cause false positive testing ... with norepinephrine and normetanephrine. Tricyclic antidepressants can increase those levels three, four, or fivefold. Levodopa, which is in Sinemet, can cause false positive testing. Antipsychotics can cause false positive testing, and MAO inhibitors ... So the clinician shouldn’t worry about blood pressure medications but should worry about the other medications the patient is taking.

FMN: When someone looks at laboratory values, should you be comparing these values to people with hypertension who do not have these conditions, and do labs have adjusted values?

Dr. Young: That’s a good question, and in the Mayo medical lab, our reference range that we use is based on patients who were tested for pheochromocytoma [and] proved not to have it. So our cutoffs are 50% to 100% higher than some other reference labs.

These other reference labs use normal laboratory volunteers who have normal blood pressure and who are taking no medications, and I’ve never tested such a patient for pheochromocytoma, so why would we use that group of people to determine our reference range? So we should use reference ranges based on patients tested for pheo but who prove to not have pheo. And that leads to higher accuracy of our case detection tests.

FMN: What are the treatments for these conditions and follow-up? I take it if there’s an adrenal mass, you get a surgeon, and I think you also noted that you need an experienced endocrine surgeon.

Dr. Young: For primary aldosteronism, if the patient has a unilateral aldosterone-producing adenoma, the outstanding treatment is laparoscopic adrenalectomy. Patients are in the hospital one night, [and] they’re back at work in 7-10 days, but that does require an expert laparoscopic adrenal surgeon. And in the United States we have a 1-year endocrine surgery program. It’s optimal that patients are referred to surgeons who have done that unique training.

For pheochromocytoma less than 8-9 cm, laparoscopic adrenalectomy with an experienced endocrine surgeon is an excellent treatment option. When the adrenal pheochromocytoma is larger than 8 or 9 cm, especially if it’s cystic, the surgeon may want to do it as open [surgery] because it’s critical that the capsule of the pheochromocytoma is not ruptured intraoperatively. If it is ruptured, a benign pheochromocytoma has just been transformed to malignant, incurable disease.

If it’s a paraganglioma, typically that requires an open operation whether it’s in the neck or the chest or the pelvis or lower abdomen.

FMN: What is the follow-up to any of these conditions?

Dr. Young: The follow-up once you’ve resected an adrenal pheochromocytoma depends on whether there is a germline mutation. If there is a germline mutation, for example, succinate dehydrogenase mutation [SDH], these patients are at higher risk for developing recurrent pheochromocytoma or paraganglioma, and they’re at risk for developing malignant pheochromocytoma or paraganglioma.

One of our challenges is when we resect a pheochromocytoma or paraganglioma, the pathologist doesn’t have the tools to tell us if it’s benign or malignant ... So all patients need lifelong biochemical follow-up, basically a 24-hour urine for metanephrines and catecholamines annually or plasma metanephrines for life.

If the patients have an underlying mutation like succinate dehydrogenase, they’re at risk for developing nonfunctioning paragangliomas. So these patients need periodic imaging in addition to the annual biochemical testing. For example, if a patient had an abdominal paraganglioma with an SDHB [succinate dehydrogenase complex iron sulfur subunit B], we would do abdominal MRI scans every 1-2 years. That would include the pelvis. We would screen for paragangliomas elsewhere with MRI of the skull base and neck and the chest every 3-5 years, and a total body scan every 5 years or so, either FDG-PET [¹⁸F-fluorodeoxyglucose positron emission tomography] scan or ¹²³I-MIBG [metaiodobenzyl-guanidine] scan.

FMN: Is there anything that is particularly new in the past couple of years?

Dr. Young: Some of the innovations lately have been in the area of metastatic pheochromocytoma and paraganglioma. These are in patients who have limited metastatic disease that’s localized to bone or to liver, and we’ve been using ablative therapies. This includes cryoablation ... and radiofrequency ablation, which is killing the tumor with hot temperature, and that’s very effective for patients who have limited metastatic lesions in the bone or liver.

For patients with complex tumors in difficult areas of the body, for example, in the mediastinum or surrounding the heart, we’ve been using 3D printer technology to print [a replica of the structures and] the tumor preoperatively, and this assists in surgical planning.

FMN: And what do you see coming?

Dr. Young: I think we’re getting close to something near curative for patients with malignant pheochromocytoma and paraganglioma. We’re understanding the basic biology better [and] pathophysiology, and I think that’s going to lead to some novel treatments.

Also, what I see coming is that we’ll be able to use germline mutation information and somatic tumor mutation information to guide us on specific imaging modalities, to guide us on forms of preventative therapy so that we prevent the paraganglioma from ever developing and also provide us with additional treatment options.

ORLANDO – The diagnosis of hypertension with its origin in the endocrine system may appear complex, but it does not have to be. Primary aldosteronism may be underappreciated and underdiagnosed. On the other hand, catecholamine-secreting tumors are rare, but they often come to mind in making a diagnosis of endocrine hypertension. Dr. William Young Jr., professor of medicine at the Mayo Clinic, Rochester, Minn., presented cases in a lively session of audience participation at the annual meeting of the America Association of Clinical Endocrinologists. Later, Dr. Young summarized some of the key points in an interview, which has been edited for brevity.

Frontline Medical News: What is the endocrinologist’s role in working up the patient who has hypertension of suspected endocrine origin?

Dr. William Young Jr.: The first is knowing when to suspect endocrine hypertension. The most common form of endocrine hypertension is primary aldosteronism. So this is the adrenal-dependent autonomous production of aldosterone, which leads to high blood pressure, volume expansion, and sometimes hypokalemia. One of the concepts that many clinicians forget is that only about 30% of patients with primary aldosteronism present with hypokalemia. So 70% of patients with this disorder don’t have hypokalemia. They look like any other person with high blood pressure.

So when should we look for primary aldosteronism? Onset of high blood pressure at a young age, for example, less than age 30, drug resistant hypertension – so three drugs [with] poor control. Twenty percent of those patients will prove to have primary aldosteronism. Simply poorly controlled hypertension is another group; [or] family history of primary aldosteronism, so all first degree relatives should be tested. Or a patient who has hypertension and has had an incidental discovery of an adrenal mass should also be tested for primary aldosteronism.

Unfortunately, most primary care providers ... think that this is a complicated and dense endocrine disorder, and they frequently will not look for it, but it’s actually very simple. Some of the complexities are historical in nature in that when this disorder was first described, several rules were made for what medications a patient could be on, for example. And it’s difficult to comply with those rules. For example, if you have a patient who’s on five drugs and has poor control, you’re not going to switch him to the two drugs that are recommended because they are weak antihypertensives. It wouldn’t be ethical to do so. [The two drug classes are the calcium channel blocker verapamil and the alpha-1 antagonists doxazosin (Cardura) and terazosin (Hytrin).]

So the best thing to do regardless of what drugs the patient is on – it doesn’t matter if they’re on ACE inhibitors or angiotensin-receptor blockers or diuretics – just get a morning blood sample as your aldosterone and plasma renin activity. If aldosterone is high or generous, greater than 15 ng/dL, if the plasma renin activity is less than 1 ng/mL per hour, that’s a positive case detection test.

That doesn’t prove the patient has primary aldosteronism. The sensitivity/specificity of aldosterone and renin case detection testing is about 75%. So most patients need confirmatory testing, which would either be the saline infusion test or the 24-hour urine for aldosterone on a high-sodium diet. And once primary aldosteronism is confirmed, then we would do an adrenal-directed CT scan.

The problem with the findings in the adrenal glands on CT is that the prevalence of adrenal nodularity increases with age. So people in their 60s and 70s can have adrenal nodules that have nothing to do with aldosterone production. So whereas if the patient is less than age 35 and CT shows a unilateral macroadenoma, the contralateral adrenal is perfectly normal appearing, and the patient has a marked primary aldosteronism – so spontaneous hypokalemia, plasma aldosterone over 30 ng/dL – that subset of patients could go straight to surgery and skip adrenal vein sampling. However, everyone else over age 35 if they want to pursue the surgical option, adrenal vein sampling is a key test.

FMN: Is there anything that rules out primary aldosteronism?

Dr. Young: If the plasma aldosterone level is less than 10 ng/dL it makes primary aldosteronism very unlikely, and if the renin level is higher than 1 ng/mL per hour, that makes primary aldosteronism very unlikely.

FMN: What about working up pheochromocytoma?

Dr. Young: Clinicians, unlike with primary aldosteronism, where they don’t look for it enough, for pheochromocytoma they look for it a lot, and it’s really rare. Between 0.1 and 0.01% of the hypertensive population will prove to have pheochromocytoma.

The false positive rate with our case detection testing of plasma metanephrines about 15%. So based on how rare pheochromocytoma is and a 15% false positive rate with plasma metanephrines, 97% of patients with elevated plasma normetanephrines do not have pheochromocytoma.

So we have a real problem with case detection testing. The 24-hour urine metanephrines and catecholamines using appropriate reference ranges are probably a better way to do case detection testing for pheochromocytoma, but there’s still a false positive rate with urinary normetanephrine.

Never mistake a benign adrenal adenoma for a pheo. In terms of the imaging phenotype, pheos are dense and vascular. As they enlarge, they get cystic hemorrhagic areas within them.

FMN: What goes on with other paragangliomas?

Dr. Young: Pheochromocytoma is the term we use when you have a catecholamine-secreting tumor in the adrenal gland itself. It develops in the adrenal medulla. Paraganglioma is an identical tumor, but it’s outside of the adrenal gland. It’s somewhere in the pelvis, could be in the chest, could be in the skull base, or neck. Most commonly it’s in the abdomen. So the case detection testing is the same.

But patients we should consider testing for pheochromocytoma and paraganglioma are those with paroxysmal symptoms like episodes of pounding heartbeat, sweating, headache, tremor, and pallor. Young people with new onset hypertension, hypertension that’s poorly controlled, and vascular adrenal masses should also be tested for pheochromocytoma.

FMN: Are there things that can confound any of these tests we discussed or any drugs that should be noted that could get in the way?

Dr. Young: For pheochromocytoma, the good news is now that most reference labs use tandem mass spectrometry technology, the hypertension drugs that potentially interfered in the past like labetalol and sotalol no longer interfere. So these days the clinician doesn’t need to stop any blood pressure–related medications.

The medications that can cause false positive testing are primarily tricyclic antidepressants. Flexeril, which is cyclobenzaprine, is commonly used to treat fibromyalgia, and that is a tricyclic antidepressant, and that will cause false positive testing ... with norepinephrine and normetanephrine. Tricyclic antidepressants can increase those levels three, four, or fivefold. Levodopa, which is in Sinemet, can cause false positive testing. Antipsychotics can cause false positive testing, and MAO inhibitors ... So the clinician shouldn’t worry about blood pressure medications but should worry about the other medications the patient is taking.

FMN: When someone looks at laboratory values, should you be comparing these values to people with hypertension who do not have these conditions, and do labs have adjusted values?

Dr. Young: That’s a good question, and in the Mayo medical lab, our reference range that we use is based on patients who were tested for pheochromocytoma [and] proved not to have it. So our cutoffs are 50% to 100% higher than some other reference labs.

These other reference labs use normal laboratory volunteers who have normal blood pressure and who are taking no medications, and I’ve never tested such a patient for pheochromocytoma, so why would we use that group of people to determine our reference range? So we should use reference ranges based on patients tested for pheo but who prove to not have pheo. And that leads to higher accuracy of our case detection tests.

FMN: What are the treatments for these conditions and follow-up? I take it if there’s an adrenal mass, you get a surgeon, and I think you also noted that you need an experienced endocrine surgeon.

Dr. Young: For primary aldosteronism, if the patient has a unilateral aldosterone-producing adenoma, the outstanding treatment is laparoscopic adrenalectomy. Patients are in the hospital one night, [and] they’re back at work in 7-10 days, but that does require an expert laparoscopic adrenal surgeon. And in the United States we have a 1-year endocrine surgery program. It’s optimal that patients are referred to surgeons who have done that unique training.

For pheochromocytoma less than 8-9 cm, laparoscopic adrenalectomy with an experienced endocrine surgeon is an excellent treatment option. When the adrenal pheochromocytoma is larger than 8 or 9 cm, especially if it’s cystic, the surgeon may want to do it as open [surgery] because it’s critical that the capsule of the pheochromocytoma is not ruptured intraoperatively. If it is ruptured, a benign pheochromocytoma has just been transformed to malignant, incurable disease.

If it’s a paraganglioma, typically that requires an open operation whether it’s in the neck or the chest or the pelvis or lower abdomen.

FMN: What is the follow-up to any of these conditions?

Dr. Young: The follow-up once you’ve resected an adrenal pheochromocytoma depends on whether there is a germline mutation. If there is a germline mutation, for example, succinate dehydrogenase mutation [SDH], these patients are at higher risk for developing recurrent pheochromocytoma or paraganglioma, and they’re at risk for developing malignant pheochromocytoma or paraganglioma.

One of our challenges is when we resect a pheochromocytoma or paraganglioma, the pathologist doesn’t have the tools to tell us if it’s benign or malignant ... So all patients need lifelong biochemical follow-up, basically a 24-hour urine for metanephrines and catecholamines annually or plasma metanephrines for life.

If the patients have an underlying mutation like succinate dehydrogenase, they’re at risk for developing nonfunctioning paragangliomas. So these patients need periodic imaging in addition to the annual biochemical testing. For example, if a patient had an abdominal paraganglioma with an SDHB [succinate dehydrogenase complex iron sulfur subunit B], we would do abdominal MRI scans every 1-2 years. That would include the pelvis. We would screen for paragangliomas elsewhere with MRI of the skull base and neck and the chest every 3-5 years, and a total body scan every 5 years or so, either FDG-PET [¹⁸F-fluorodeoxyglucose positron emission tomography] scan or ¹²³I-MIBG [metaiodobenzyl-guanidine] scan.

FMN: Is there anything that is particularly new in the past couple of years?

Dr. Young: Some of the innovations lately have been in the area of metastatic pheochromocytoma and paraganglioma. These are in patients who have limited metastatic disease that’s localized to bone or to liver, and we’ve been using ablative therapies. This includes cryoablation ... and radiofrequency ablation, which is killing the tumor with hot temperature, and that’s very effective for patients who have limited metastatic lesions in the bone or liver.

For patients with complex tumors in difficult areas of the body, for example, in the mediastinum or surrounding the heart, we’ve been using 3D printer technology to print [a replica of the structures and] the tumor preoperatively, and this assists in surgical planning.

FMN: And what do you see coming?

Dr. Young: I think we’re getting close to something near curative for patients with malignant pheochromocytoma and paraganglioma. We’re understanding the basic biology better [and] pathophysiology, and I think that’s going to lead to some novel treatments.

Also, what I see coming is that we’ll be able to use germline mutation information and somatic tumor mutation information to guide us on specific imaging modalities, to guide us on forms of preventative therapy so that we prevent the paraganglioma from ever developing and also provide us with additional treatment options.

orlando – A digital device that patients swallow every time they take a medication may be an answer to improving compliance and disease control. An aim of this digital health system is to encourage patient engagement and provider interaction. Despite available and efficacious medicines, only slightly more than half of patients with type 2 diabetes mellitus have glycated hemoglobin (HbA1c), hypertension, or LDL cholesterol under good control. One study showed only 17% had all three under control (Endocr Pract. 2016;22:689-98).

“Important in this are the facts of medication nonadherence by the patient, poor patient engagement frequently in their care, as well as from a clinician perspective, therapeutic inertia,” said Dr. Juan Frias at the annual meeting of the American Association of Clinical Endocrinologists. Approximately half of patients with chronic diseases do not take their medications as prescribed (Circulation. 2013;128:29-41).

To improve treatment adherence, diagnose the reasons for a patient not reaching therapeutic goals, address those issues with patient education or counseling or changes in medication, and engage with the patient to reinforce adherence goals. A digital system called Proteus Discover has been designed to assist patients and clinicians with all these tasks.

Proteus uses ingestible sensor-detectable medications. Each medication and dose of medication has a unique marker. A compounding pharmacy co-encapsulates a tiny detectable chip about the size of a grain of sand with a medication as prescribed by a physician. The patient wears a Band-Aid sized skin patch sensor that transmits to a mobile device that uploads to a secure cloud server. The sensor can tell if a medication has been taken and also serves as a pedometer and activity gauge.

The information is available to the patient, who can gain insight into medication taking, activity, and rest, along with other health parameters that are entered into the system. Entering the system through a provider portal and with the patient’s permission, the clinician can see patient behavior patterns outside of the clinic, including medication adherence, which helps to determine the best treatment for that patient. The system provides a report to the clinician that can be a point of discussion when the patient visits the clinic.

Trial demonstrates better medication adherence and goal attainment

Dr. Frias, CEO and principal investigator of National Research Institute in Los Angeles, described a 12 week multicenter cluster-randomized pilot study involving 90 patients with uncontrolled hypertension and type 2 diabetes to investigate the effect of Proteus on blood pressure, HbA1c, and LDL cholesterol reduction. Other goals of the trial were to promote medication adherence and physical activity and alert providers to a need to make more medical decisions.

Cluster randomization meant that each of the 16 trial sites randomized patients to one of three treatment arms within that site. The arms were: Proteus Discover for 4 or 12 weeks or usual care. Patients had to have systolic blood pressure of 140 mm Hg or greater, have failed therapy with 2 or more antihypertensive agents, and have HbA1c at 7% or greater on metformin or a sulfonylurea. Two-thirds of the subjects also had dyslipidemia and were treated with statins. Subjects were excluded if they had a history of acute or chronic dermatitis, had a skin allergy or sensitivity to adhesive medical tape, or had secondary causes for uncontrolled hypertension or type 2 diabetes.

Usual care consisted of all standard interventions, including medication titrations, patient education, and lifestyle coaching. All subjects took medications for 12 weeks and were followed for 12 weeks after enrollment. Available medications were various doses of lisinopril, losartan, hydrochlorothiazide, amlodipine, atorvastatin, metformin, and glipizide.

All the arms were fairly well balanced as to age (58-62 years), ethnicity, employment, education, and income. About one quarter had incomes in the $20,000-$40,000 range, and about half had incomes of $20,000 or less. Body mass index was 32 kg/m² in the Proteus and usual care arms. Total cholesterol was similar for the Proteus and usual care groups at 173-177 mg/dL, but LDL was slightly higher in the Proteus arms (103 vs. 95 mg/dL).

Better adherence and outcomes for patients using Proteus

Dr. Frias presented 4-week results for blood pressure and cholesterol reduction. The 4- and 12-week Proteus arms were combined for this analysis, since up to 4 weeks they received the same intervention. Blood pressure, LDL cholesterol, and total cholesterol were all significantly reduced in the Proteus group, compared with the usual care group. At week 4, 83% of the subjects in the Proteus group had reached a blood pressure goal of less than 140/90 mm Hg vs. 33% in the usual care arm (difference of 50%; 95% confidence interval, 24%, 76%). Across all 11 medications/doses, the adherence was between 80% and 89% for every one.

The system spurred clinicians to make more treatment decisions for their patients. Providers made more changes to treatment for the Proteus patients, compared with the usual care providers (50% vs. 36%), gave more adherence counseling (28% vs. 0%), and provided more patient education (42% vs. 9%). Patients using the Proteus Discover system expressed high levels of satisfaction and acceptance of the technology (83%-100%), including ease of use in one’s daily routine, learning to use it, motivation to manage one’s health, better discussions with providers, understanding their care plan, seeing how they take their medications, and applying and wearing the sensor patch.

Safety was excellent. Twenty-seven adverse effects occurred in the Proteus arms, none of them serious, and about half were attributed to the device, mostly self-limited rashes. Seven adverse effects were attributed to the medications, mostly gastrointestinal side effects. There were four adverse effects in the usual care group, two of them serious.

Overall, compared with about 50% typical medication adherence, Proteus users had 84% adherence, which was associated with better blood pressure and LDL cholesterol control, compared with usual care.

Session moderator Dr. David Lieb, associate professor of medicine at Eastern Virginia Medical School in Norfolk, said the Proteus system may be very helpful for patients who are taking multiple medications to prompt them when to take them. “I could easily see somebody who has this system in place where they’re also able to measure their blood pressure and get that information to their provider and for their provider to make changes in their medicine dose,” he said.

This research study of 90 patients was quite manageable, but “what about when you have 300 people on this therapy and all those data are starting to come in? Who’s going to manage those data... and look at it all?” Dr. Lieb wondered. Patients may have to be taught to understand the data and make changes on their own to their medication behavior, exercise, and other factors within their control.

Half the patients in the study made $20,000 or less a year. “If you could help underserved patients with their compliance and all those other things... that would be fantastic. It’s a huge area of need,” he said. People will need internet access to upload their data to the cloud server.

Another question is how the data can interface with the various electronic health records in use and generate reports.

Proteus Discover is approved by the U.S. Food and Drug Administration and is available now.

[email protected]

orlando – A digital device that patients swallow every time they take a medication may be an answer to improving compliance and disease control. An aim of this digital health system is to encourage patient engagement and provider interaction. Despite available and efficacious medicines, only slightly more than half of patients with type 2 diabetes mellitus have glycated hemoglobin (HbA1c), hypertension, or LDL cholesterol under good control. One study showed only 17% had all three under control (Endocr Pract. 2016;22:689-98).

“Important in this are the facts of medication nonadherence by the patient, poor patient engagement frequently in their care, as well as from a clinician perspective, therapeutic inertia,” said Dr. Juan Frias at the annual meeting of the American Association of Clinical Endocrinologists. Approximately half of patients with chronic diseases do not take their medications as prescribed (Circulation. 2013;128:29-41).

To improve treatment adherence, diagnose the reasons for a patient not reaching therapeutic goals, address those issues with patient education or counseling or changes in medication, and engage with the patient to reinforce adherence goals. A digital system called Proteus Discover has been designed to assist patients and clinicians with all these tasks.

Proteus uses ingestible sensor-detectable medications. Each medication and dose of medication has a unique marker. A compounding pharmacy co-encapsulates a tiny detectable chip about the size of a grain of sand with a medication as prescribed by a physician. The patient wears a Band-Aid sized skin patch sensor that transmits to a mobile device that uploads to a secure cloud server. The sensor can tell if a medication has been taken and also serves as a pedometer and activity gauge.

The information is available to the patient, who can gain insight into medication taking, activity, and rest, along with other health parameters that are entered into the system. Entering the system through a provider portal and with the patient’s permission, the clinician can see patient behavior patterns outside of the clinic, including medication adherence, which helps to determine the best treatment for that patient. The system provides a report to the clinician that can be a point of discussion when the patient visits the clinic.

Trial demonstrates better medication adherence and goal attainment

Dr. Frias, CEO and principal investigator of National Research Institute in Los Angeles, described a 12 week multicenter cluster-randomized pilot study involving 90 patients with uncontrolled hypertension and type 2 diabetes to investigate the effect of Proteus on blood pressure, HbA1c, and LDL cholesterol reduction. Other goals of the trial were to promote medication adherence and physical activity and alert providers to a need to make more medical decisions.

Cluster randomization meant that each of the 16 trial sites randomized patients to one of three treatment arms within that site. The arms were: Proteus Discover for 4 or 12 weeks or usual care. Patients had to have systolic blood pressure of 140 mm Hg or greater, have failed therapy with 2 or more antihypertensive agents, and have HbA1c at 7% or greater on metformin or a sulfonylurea. Two-thirds of the subjects also had dyslipidemia and were treated with statins. Subjects were excluded if they had a history of acute or chronic dermatitis, had a skin allergy or sensitivity to adhesive medical tape, or had secondary causes for uncontrolled hypertension or type 2 diabetes.

Usual care consisted of all standard interventions, including medication titrations, patient education, and lifestyle coaching. All subjects took medications for 12 weeks and were followed for 12 weeks after enrollment. Available medications were various doses of lisinopril, losartan, hydrochlorothiazide, amlodipine, atorvastatin, metformin, and glipizide.

All the arms were fairly well balanced as to age (58-62 years), ethnicity, employment, education, and income. About one quarter had incomes in the $20,000-$40,000 range, and about half had incomes of $20,000 or less. Body mass index was 32 kg/m² in the Proteus and usual care arms. Total cholesterol was similar for the Proteus and usual care groups at 173-177 mg/dL, but LDL was slightly higher in the Proteus arms (103 vs. 95 mg/dL).

Better adherence and outcomes for patients using Proteus

Dr. Frias presented 4-week results for blood pressure and cholesterol reduction. The 4- and 12-week Proteus arms were combined for this analysis, since up to 4 weeks they received the same intervention. Blood pressure, LDL cholesterol, and total cholesterol were all significantly reduced in the Proteus group, compared with the usual care group. At week 4, 83% of the subjects in the Proteus group had reached a blood pressure goal of less than 140/90 mm Hg vs. 33% in the usual care arm (difference of 50%; 95% confidence interval, 24%, 76%). Across all 11 medications/doses, the adherence was between 80% and 89% for every one.

The system spurred clinicians to make more treatment decisions for their patients. Providers made more changes to treatment for the Proteus patients, compared with the usual care providers (50% vs. 36%), gave more adherence counseling (28% vs. 0%), and provided more patient education (42% vs. 9%). Patients using the Proteus Discover system expressed high levels of satisfaction and acceptance of the technology (83%-100%), including ease of use in one’s daily routine, learning to use it, motivation to manage one’s health, better discussions with providers, understanding their care plan, seeing how they take their medications, and applying and wearing the sensor patch.

Safety was excellent. Twenty-seven adverse effects occurred in the Proteus arms, none of them serious, and about half were attributed to the device, mostly self-limited rashes. Seven adverse effects were attributed to the medications, mostly gastrointestinal side effects. There were four adverse effects in the usual care group, two of them serious.

Overall, compared with about 50% typical medication adherence, Proteus users had 84% adherence, which was associated with better blood pressure and LDL cholesterol control, compared with usual care.

Session moderator Dr. David Lieb, associate professor of medicine at Eastern Virginia Medical School in Norfolk, said the Proteus system may be very helpful for patients who are taking multiple medications to prompt them when to take them. “I could easily see somebody who has this system in place where they’re also able to measure their blood pressure and get that information to their provider and for their provider to make changes in their medicine dose,” he said.

This research study of 90 patients was quite manageable, but “what about when you have 300 people on this therapy and all those data are starting to come in? Who’s going to manage those data... and look at it all?” Dr. Lieb wondered. Patients may have to be taught to understand the data and make changes on their own to their medication behavior, exercise, and other factors within their control.

Half the patients in the study made $20,000 or less a year. “If you could help underserved patients with their compliance and all those other things... that would be fantastic. It’s a huge area of need,” he said. People will need internet access to upload their data to the cloud server.

Another question is how the data can interface with the various electronic health records in use and generate reports.

Proteus Discover is approved by the U.S. Food and Drug Administration and is available now.

[email protected]

orlando – A digital device that patients swallow every time they take a medication may be an answer to improving compliance and disease control. An aim of this digital health system is to encourage patient engagement and provider interaction. Despite available and efficacious medicines, only slightly more than half of patients with type 2 diabetes mellitus have glycated hemoglobin (HbA1c), hypertension, or LDL cholesterol under good control. One study showed only 17% had all three under control (Endocr Pract. 2016;22:689-98).

“Important in this are the facts of medication nonadherence by the patient, poor patient engagement frequently in their care, as well as from a clinician perspective, therapeutic inertia,” said Dr. Juan Frias at the annual meeting of the American Association of Clinical Endocrinologists. Approximately half of patients with chronic diseases do not take their medications as prescribed (Circulation. 2013;128:29-41).

To improve treatment adherence, diagnose the reasons for a patient not reaching therapeutic goals, address those issues with patient education or counseling or changes in medication, and engage with the patient to reinforce adherence goals. A digital system called Proteus Discover has been designed to assist patients and clinicians with all these tasks.

Proteus uses ingestible sensor-detectable medications. Each medication and dose of medication has a unique marker. A compounding pharmacy co-encapsulates a tiny detectable chip about the size of a grain of sand with a medication as prescribed by a physician. The patient wears a Band-Aid sized skin patch sensor that transmits to a mobile device that uploads to a secure cloud server. The sensor can tell if a medication has been taken and also serves as a pedometer and activity gauge.

The information is available to the patient, who can gain insight into medication taking, activity, and rest, along with other health parameters that are entered into the system. Entering the system through a provider portal and with the patient’s permission, the clinician can see patient behavior patterns outside of the clinic, including medication adherence, which helps to determine the best treatment for that patient. The system provides a report to the clinician that can be a point of discussion when the patient visits the clinic.

Trial demonstrates better medication adherence and goal attainment

Dr. Frias, CEO and principal investigator of National Research Institute in Los Angeles, described a 12 week multicenter cluster-randomized pilot study involving 90 patients with uncontrolled hypertension and type 2 diabetes to investigate the effect of Proteus on blood pressure, HbA1c, and LDL cholesterol reduction. Other goals of the trial were to promote medication adherence and physical activity and alert providers to a need to make more medical decisions.

Cluster randomization meant that each of the 16 trial sites randomized patients to one of three treatment arms within that site. The arms were: Proteus Discover for 4 or 12 weeks or usual care. Patients had to have systolic blood pressure of 140 mm Hg or greater, have failed therapy with 2 or more antihypertensive agents, and have HbA1c at 7% or greater on metformin or a sulfonylurea. Two-thirds of the subjects also had dyslipidemia and were treated with statins. Subjects were excluded if they had a history of acute or chronic dermatitis, had a skin allergy or sensitivity to adhesive medical tape, or had secondary causes for uncontrolled hypertension or type 2 diabetes.

Usual care consisted of all standard interventions, including medication titrations, patient education, and lifestyle coaching. All subjects took medications for 12 weeks and were followed for 12 weeks after enrollment. Available medications were various doses of lisinopril, losartan, hydrochlorothiazide, amlodipine, atorvastatin, metformin, and glipizide.

All the arms were fairly well balanced as to age (58-62 years), ethnicity, employment, education, and income. About one quarter had incomes in the $20,000-$40,000 range, and about half had incomes of $20,000 or less. Body mass index was 32 kg/m² in the Proteus and usual care arms. Total cholesterol was similar for the Proteus and usual care groups at 173-177 mg/dL, but LDL was slightly higher in the Proteus arms (103 vs. 95 mg/dL).

Better adherence and outcomes for patients using Proteus

Dr. Frias presented 4-week results for blood pressure and cholesterol reduction. The 4- and 12-week Proteus arms were combined for this analysis, since up to 4 weeks they received the same intervention. Blood pressure, LDL cholesterol, and total cholesterol were all significantly reduced in the Proteus group, compared with the usual care group. At week 4, 83% of the subjects in the Proteus group had reached a blood pressure goal of less than 140/90 mm Hg vs. 33% in the usual care arm (difference of 50%; 95% confidence interval, 24%, 76%). Across all 11 medications/doses, the adherence was between 80% and 89% for every one.

The system spurred clinicians to make more treatment decisions for their patients. Providers made more changes to treatment for the Proteus patients, compared with the usual care providers (50% vs. 36%), gave more adherence counseling (28% vs. 0%), and provided more patient education (42% vs. 9%). Patients using the Proteus Discover system expressed high levels of satisfaction and acceptance of the technology (83%-100%), including ease of use in one’s daily routine, learning to use it, motivation to manage one’s health, better discussions with providers, understanding their care plan, seeing how they take their medications, and applying and wearing the sensor patch.

Safety was excellent. Twenty-seven adverse effects occurred in the Proteus arms, none of them serious, and about half were attributed to the device, mostly self-limited rashes. Seven adverse effects were attributed to the medications, mostly gastrointestinal side effects. There were four adverse effects in the usual care group, two of them serious.

Overall, compared with about 50% typical medication adherence, Proteus users had 84% adherence, which was associated with better blood pressure and LDL cholesterol control, compared with usual care.

Session moderator Dr. David Lieb, associate professor of medicine at Eastern Virginia Medical School in Norfolk, said the Proteus system may be very helpful for patients who are taking multiple medications to prompt them when to take them. “I could easily see somebody who has this system in place where they’re also able to measure their blood pressure and get that information to their provider and for their provider to make changes in their medicine dose,” he said.

This research study of 90 patients was quite manageable, but “what about when you have 300 people on this therapy and all those data are starting to come in? Who’s going to manage those data... and look at it all?” Dr. Lieb wondered. Patients may have to be taught to understand the data and make changes on their own to their medication behavior, exercise, and other factors within their control.

Half the patients in the study made $20,000 or less a year. “If you could help underserved patients with their compliance and all those other things... that would be fantastic. It’s a huge area of need,” he said. People will need internet access to upload their data to the cloud server.

Another question is how the data can interface with the various electronic health records in use and generate reports.

Proteus Discover is approved by the U.S. Food and Drug Administration and is available now.

[email protected]

ORLANDO – A single injection of liraglutide can prevent ketogenesis in fasting patients with type 1 diabetes who were on basal insulin, findings from a small study have shown.

Husam Ghanim, Ph.D., research associate professor at the State University of New York at Buffalo, presented the results in a late-breaking oral presentation session at the annual meeting of the American Association of Clinical Endocrinologists.

In a previous trial (Diabetes Care. 2016;39:1027-35) of patients with type 1 diabetes who took liraglutide, which does not have Food and Drug Administration approval for use in type 1 diabetes, for 12 weeks, investigators observed decreases in blood glucose levels compared with placebo and decreases in glucagon concentrations following a meal compared with before starting liraglutide. When patients already taking liraglutide and insulin were put on dapagliflozin for 12 weeks, glucagon levels rose more with dapagliflozin compared to placebo, and urinary acetoacetate and beta-hydroxybutyrate (adjusted to creatinine) rose over baseline levels.

Some researchers have hypothesized that liraglutide might stimulate residual beta cells (or beta cell stem cells) in patients with type 1 diabetes to produce insulin, thereby reducing the need for exogenous insulin. Promising data from animal studies suggesting that the drug stimulated residual beta cells were not duplicated in human studies. But some evidence shows it may reduce insulin doses anyway, even in cases of patients with no C-peptide, which means they are not producing any insulin on their own (Diabetes Care 2011. 34:1463-8).

In their study, Dr. Ghanim and his associates therefore wanted to test the effect on glucagon, free fatty acid, and ketone levels of acute administration of liraglutide to patients with type 1 diabetes in an insulinopenic condition. They randomly assigned patients with type 1 diabetes, aged 18-75 years, with undetectable C-peptide and hemoglobin A_1c less than 8.5%, to receive an injection of 1.8 mg of liraglutide (n = 8) or placebo (n = 8) the morning after an overnight fast, which continued for the 5 hours of the study.

Patients had their basal insulin dose from the night before but no further insulin unless they were on an infusion pump, which they continued. Subjects were excluded if they were taking a glucagon-like peptide-1 (GLP-1) receptor agonist or a sodium/glucose cotransporter-2 (SGLT2) inhibitor, if they had renal impairment, had type 1 diabetes for less than 1 year, or had various other comorbidities.

The liraglutide group was slightly older than the placebo group (46 vs. 43 years), had a higher HbA_1c (7.7% vs. 7.6%), and higher systolic but lower diastolic blood pressure (130/73 vs. 121/78 mm Hg). Body mass index was around 30 kg/m² for both groups.

In the placebo group, there was no change in the blood glucose concentrations during the study period, whereas the liraglutide group showed a decrease from a baseline of 175 mg/dL to 135 mg/dL at 5 hours (P less than .05). Glucagon levels were maintained in the placebo group but showed significant suppression from 82 ng/L to 65 ng/L in the liraglutide arm (P less than .05).

“Free fatty acid increased in both groups, but the increase in the placebo arm was significantly higher than that in the liraglutide group,” Dr. Ghanim said. Ketones increased in the placebo group but actually dropped in the liraglutide arm. Ghrelin levels rose by 20% in the placebo group and fell by 10% with liraglutide. Hormone-sensitive lipase decreased about 10% in both arms over the study period.

Dr. Ghanim proposed that since ghrelin is a mediator of lipolysis, possibly the suppression of ghrelin, as well as glucagon, by liraglutide “could contribute to the lower free fatty acid levels, which therefore leads to a lower ketogenic process and reduced ketone bodies.

“With the significant risk of DKA [diabetic ketoacidosis] in type 1 diabetics, especially when you have a drug like an SGLT2 inhibitor, which has been shown to be ketogenic, it is very important to know that liraglutide actually attenuates that response and reduces ketogenesis and therefore reduces the risk of DKA,” he said.

He suggested that these study results should lead to larger randomized trials of GLP-1 receptor agonists and SGLT2 inhibitors, also not approved for use in type 1 diabetes, for use in this population because most of them are not presently well controlled and need additional agents.

Dr. John Miles, professor of both medicine and endocrinology, diabetes, and metabolism at the University of Kansas Medical Center in Kansas City, Kansas, asked Dr. Ghanim why the study subjects did not vomit when receiving the dose of liraglutide. Dr. Ghanim responded that the subjects were not naive to it and had been on it previously.

Session moderator Dr. David Lieb, associate professor of medicine at Eastern Virginia Medical School in Norfolk, said that liraglutide may be a good option for type 1 diabetes patients who are obese and want to lose weight. “I think if there is a drug that can potentially help with glucose control, because liraglutide is not all about causing insulin secretion by the pancreas – it also affects glucagon levels, and it affects appetite and satiety – [so] it may also help with weight loss. I think there’s a role for those sorts of medications in type 1 diabetics on a case-by-case, individual basis,” he said.

However, he wondered if there are any negative effects of suppressing glucagon because patients with type 1 diabetes may be at increased risk for hypoglycemia because of their insulin use, their activities, and their sensitivity to insulin. “Glucagon … allows glucose to be released by the liver,” he said, so (hypothetically) suppressing glucose release may exacerbate hypoglycemia. He said he looks forward to further studies of these drugs for type 1 diabetes and seeing the rate of occurrence of hypoglycemic episodes and how patients respond to them.

There was no funding for the study. Dr. Ghanim and Dr. Lieb reported having no financial disclosures.

ORLANDO – A single injection of liraglutide can prevent ketogenesis in fasting patients with type 1 diabetes who were on basal insulin, findings from a small study have shown.

Husam Ghanim, Ph.D., research associate professor at the State University of New York at Buffalo, presented the results in a late-breaking oral presentation session at the annual meeting of the American Association of Clinical Endocrinologists.

In a previous trial (Diabetes Care. 2016;39:1027-35) of patients with type 1 diabetes who took liraglutide, which does not have Food and Drug Administration approval for use in type 1 diabetes, for 12 weeks, investigators observed decreases in blood glucose levels compared with placebo and decreases in glucagon concentrations following a meal compared with before starting liraglutide. When patients already taking liraglutide and insulin were put on dapagliflozin for 12 weeks, glucagon levels rose more with dapagliflozin compared to placebo, and urinary acetoacetate and beta-hydroxybutyrate (adjusted to creatinine) rose over baseline levels.

Some researchers have hypothesized that liraglutide might stimulate residual beta cells (or beta cell stem cells) in patients with type 1 diabetes to produce insulin, thereby reducing the need for exogenous insulin. Promising data from animal studies suggesting that the drug stimulated residual beta cells were not duplicated in human studies. But some evidence shows it may reduce insulin doses anyway, even in cases of patients with no C-peptide, which means they are not producing any insulin on their own (Diabetes Care 2011. 34:1463-8).

In their study, Dr. Ghanim and his associates therefore wanted to test the effect on glucagon, free fatty acid, and ketone levels of acute administration of liraglutide to patients with type 1 diabetes in an insulinopenic condition. They randomly assigned patients with type 1 diabetes, aged 18-75 years, with undetectable C-peptide and hemoglobin A_1c less than 8.5%, to receive an injection of 1.8 mg of liraglutide (n = 8) or placebo (n = 8) the morning after an overnight fast, which continued for the 5 hours of the study.

Patients had their basal insulin dose from the night before but no further insulin unless they were on an infusion pump, which they continued. Subjects were excluded if they were taking a glucagon-like peptide-1 (GLP-1) receptor agonist or a sodium/glucose cotransporter-2 (SGLT2) inhibitor, if they had renal impairment, had type 1 diabetes for less than 1 year, or had various other comorbidities.

The liraglutide group was slightly older than the placebo group (46 vs. 43 years), had a higher HbA_1c (7.7% vs. 7.6%), and higher systolic but lower diastolic blood pressure (130/73 vs. 121/78 mm Hg). Body mass index was around 30 kg/m² for both groups.

In the placebo group, there was no change in the blood glucose concentrations during the study period, whereas the liraglutide group showed a decrease from a baseline of 175 mg/dL to 135 mg/dL at 5 hours (P less than .05). Glucagon levels were maintained in the placebo group but showed significant suppression from 82 ng/L to 65 ng/L in the liraglutide arm (P less than .05).

“Free fatty acid increased in both groups, but the increase in the placebo arm was significantly higher than that in the liraglutide group,” Dr. Ghanim said. Ketones increased in the placebo group but actually dropped in the liraglutide arm. Ghrelin levels rose by 20% in the placebo group and fell by 10% with liraglutide. Hormone-sensitive lipase decreased about 10% in both arms over the study period.

Dr. Ghanim proposed that since ghrelin is a mediator of lipolysis, possibly the suppression of ghrelin, as well as glucagon, by liraglutide “could contribute to the lower free fatty acid levels, which therefore leads to a lower ketogenic process and reduced ketone bodies.

“With the significant risk of DKA [diabetic ketoacidosis] in type 1 diabetics, especially when you have a drug like an SGLT2 inhibitor, which has been shown to be ketogenic, it is very important to know that liraglutide actually attenuates that response and reduces ketogenesis and therefore reduces the risk of DKA,” he said.

He suggested that these study results should lead to larger randomized trials of GLP-1 receptor agonists and SGLT2 inhibitors, also not approved for use in type 1 diabetes, for use in this population because most of them are not presently well controlled and need additional agents.

Dr. John Miles, professor of both medicine and endocrinology, diabetes, and metabolism at the University of Kansas Medical Center in Kansas City, Kansas, asked Dr. Ghanim why the study subjects did not vomit when receiving the dose of liraglutide. Dr. Ghanim responded that the subjects were not naive to it and had been on it previously.

Session moderator Dr. David Lieb, associate professor of medicine at Eastern Virginia Medical School in Norfolk, said that liraglutide may be a good option for type 1 diabetes patients who are obese and want to lose weight. “I think if there is a drug that can potentially help with glucose control, because liraglutide is not all about causing insulin secretion by the pancreas – it also affects glucagon levels, and it affects appetite and satiety – [so] it may also help with weight loss. I think there’s a role for those sorts of medications in type 1 diabetics on a case-by-case, individual basis,” he said.

However, he wondered if there are any negative effects of suppressing glucagon because patients with type 1 diabetes may be at increased risk for hypoglycemia because of their insulin use, their activities, and their sensitivity to insulin. “Glucagon … allows glucose to be released by the liver,” he said, so (hypothetically) suppressing glucose release may exacerbate hypoglycemia. He said he looks forward to further studies of these drugs for type 1 diabetes and seeing the rate of occurrence of hypoglycemic episodes and how patients respond to them.

There was no funding for the study. Dr. Ghanim and Dr. Lieb reported having no financial disclosures.

ORLANDO – A single injection of liraglutide can prevent ketogenesis in fasting patients with type 1 diabetes who were on basal insulin, findings from a small study have shown.

Husam Ghanim, Ph.D., research associate professor at the State University of New York at Buffalo, presented the results in a late-breaking oral presentation session at the annual meeting of the American Association of Clinical Endocrinologists.

In a previous trial (Diabetes Care. 2016;39:1027-35) of patients with type 1 diabetes who took liraglutide, which does not have Food and Drug Administration approval for use in type 1 diabetes, for 12 weeks, investigators observed decreases in blood glucose levels compared with placebo and decreases in glucagon concentrations following a meal compared with before starting liraglutide. When patients already taking liraglutide and insulin were put on dapagliflozin for 12 weeks, glucagon levels rose more with dapagliflozin compared to placebo, and urinary acetoacetate and beta-hydroxybutyrate (adjusted to creatinine) rose over baseline levels.

Some researchers have hypothesized that liraglutide might stimulate residual beta cells (or beta cell stem cells) in patients with type 1 diabetes to produce insulin, thereby reducing the need for exogenous insulin. Promising data from animal studies suggesting that the drug stimulated residual beta cells were not duplicated in human studies. But some evidence shows it may reduce insulin doses anyway, even in cases of patients with no C-peptide, which means they are not producing any insulin on their own (Diabetes Care 2011. 34:1463-8).

In their study, Dr. Ghanim and his associates therefore wanted to test the effect on glucagon, free fatty acid, and ketone levels of acute administration of liraglutide to patients with type 1 diabetes in an insulinopenic condition. They randomly assigned patients with type 1 diabetes, aged 18-75 years, with undetectable C-peptide and hemoglobin A_1c less than 8.5%, to receive an injection of 1.8 mg of liraglutide (n = 8) or placebo (n = 8) the morning after an overnight fast, which continued for the 5 hours of the study.

Patients had their basal insulin dose from the night before but no further insulin unless they were on an infusion pump, which they continued. Subjects were excluded if they were taking a glucagon-like peptide-1 (GLP-1) receptor agonist or a sodium/glucose cotransporter-2 (SGLT2) inhibitor, if they had renal impairment, had type 1 diabetes for less than 1 year, or had various other comorbidities.

The liraglutide group was slightly older than the placebo group (46 vs. 43 years), had a higher HbA_1c (7.7% vs. 7.6%), and higher systolic but lower diastolic blood pressure (130/73 vs. 121/78 mm Hg). Body mass index was around 30 kg/m² for both groups.

In the placebo group, there was no change in the blood glucose concentrations during the study period, whereas the liraglutide group showed a decrease from a baseline of 175 mg/dL to 135 mg/dL at 5 hours (P less than .05). Glucagon levels were maintained in the placebo group but showed significant suppression from 82 ng/L to 65 ng/L in the liraglutide arm (P less than .05).

“Free fatty acid increased in both groups, but the increase in the placebo arm was significantly higher than that in the liraglutide group,” Dr. Ghanim said. Ketones increased in the placebo group but actually dropped in the liraglutide arm. Ghrelin levels rose by 20% in the placebo group and fell by 10% with liraglutide. Hormone-sensitive lipase decreased about 10% in both arms over the study period.

Dr. Ghanim proposed that since ghrelin is a mediator of lipolysis, possibly the suppression of ghrelin, as well as glucagon, by liraglutide “could contribute to the lower free fatty acid levels, which therefore leads to a lower ketogenic process and reduced ketone bodies.

“With the significant risk of DKA [diabetic ketoacidosis] in type 1 diabetics, especially when you have a drug like an SGLT2 inhibitor, which has been shown to be ketogenic, it is very important to know that liraglutide actually attenuates that response and reduces ketogenesis and therefore reduces the risk of DKA,” he said.

He suggested that these study results should lead to larger randomized trials of GLP-1 receptor agonists and SGLT2 inhibitors, also not approved for use in type 1 diabetes, for use in this population because most of them are not presently well controlled and need additional agents.

Dr. John Miles, professor of both medicine and endocrinology, diabetes, and metabolism at the University of Kansas Medical Center in Kansas City, Kansas, asked Dr. Ghanim why the study subjects did not vomit when receiving the dose of liraglutide. Dr. Ghanim responded that the subjects were not naive to it and had been on it previously.

Session moderator Dr. David Lieb, associate professor of medicine at Eastern Virginia Medical School in Norfolk, said that liraglutide may be a good option for type 1 diabetes patients who are obese and want to lose weight. “I think if there is a drug that can potentially help with glucose control, because liraglutide is not all about causing insulin secretion by the pancreas – it also affects glucagon levels, and it affects appetite and satiety – [so] it may also help with weight loss. I think there’s a role for those sorts of medications in type 1 diabetics on a case-by-case, individual basis,” he said.

However, he wondered if there are any negative effects of suppressing glucagon because patients with type 1 diabetes may be at increased risk for hypoglycemia because of their insulin use, their activities, and their sensitivity to insulin. “Glucagon … allows glucose to be released by the liver,” he said, so (hypothetically) suppressing glucose release may exacerbate hypoglycemia. He said he looks forward to further studies of these drugs for type 1 diabetes and seeing the rate of occurrence of hypoglycemic episodes and how patients respond to them.

There was no funding for the study. Dr. Ghanim and Dr. Lieb reported having no financial disclosures.

ORLANDO – Whether to start a patient with newly diagnosed type 2 diabetes mellitus on combination therapy or monotherapy should be based on experimentation and observation rather than expert opinion, according to Dr. Alan Garber, president of the American College of Endocrinology and professor of medicine, biochemistry, and molecular and cellular biology at Baylor College of Medicine in Houston.

Monotherapy for type 2 diabetes with stepwise addition of other antihyperglycemic agents has long been the accepted way to initiate therapy in this population. Beginning in the 1990s, investigators began to compare the efficacy of monotherapy with combination therapy, first with metformin and glyburide alone or together, and then testing metformin in combination with glipizide, rosiglitazone, and sitagliptin, he said.

For metformin and glyburide, each agent alone lowered glycated hemoglobin (HbA_1c), compared with placebo, but adding one to the other enhanced lowering. Combining the two drugs had the greatest benefit for higher HbA_1c entry levels (e.g., HbA_1c strata of 9%-9.9% or 10% or greater vs. less than 8%). At the highest-entry HbA_1c levels, half doses of each of metformin and glyburide (250 mg/1.25 mg, respectively) were more efficacious than full doses of each (500 mg/2.5 mg). “This is called drug sparing,” he said.

In a trial of metformin and rosiglitazone, the combination was superior to either alone, producing significantly greater mean reductions in HbA_1c and in fasting plasma glucose (FPG) at 32 weeks from their respective baselines, again, with greater reductions for higher-entry HbA_1c levels. The combination was also better than either drug alone in the speed of reducing HbA_1c or FPG, and in the final attained levels.

The combination of metformin and a sulfonylurea presents a risk of hypoglycemia, but Dr. Garber said the results are “much cleaner” using combinations of metformin with agents such as a thiazolidinedione, a dipeptidyl peptidase-4 inhibitor, or a sodium/glucose cotransporter-2 inhibitor.

Also noteworthy are findings from the EDICT (Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes) trial using insulin-sensitizing and insulin-secreting agents metformin/pioglitazone/exenatide in combination vs. escalating doses of metformin with sequential addition of a sulfonylurea and glargine insulin to treat patients with newly diagnosed type 2 diabetes. Over 2 years, the subjects receiving combination therapy had lower HbA_1c, a mean weight loss, compared with weight gain, in the sequential therapy group, and a 7.5-fold lower rate of hypoglycemia, compared with the sequential treatment group (Diabetes Obes Metab. 2015;17:268-75).

Although the agents used in the two treatment strategies were not strictly equivalent, “it’s clear that testing multiple therapeutic mechanisms tends to produce better outcomes than fewer therapeutic mechanisms,” Dr. Garber said. The conclusions are fairly straightforward. “Look for evidence to support what strategies you want to use for your patients’ care.”

Using the Kaiser Permanente database, investigators found that the mean time of having an HbA_1c above 8% was 3 years before a second agent was added, and the mean HbA_1c was 9%. Many people have ascribed this sort of delay to a problem with the physician. But Dr. Garber said it is more related to patients, who often resist prescriptions for more drugs. So starting with two drugs may produce better efficacy faster as well as overcome the psychological issues of trying to add another one later (Am J Manag Care. 2003;9:213-7).

Session moderator Dr. Daniel Einhorn, medical director of the Scripps Whittier Diabetes Institute in La Jolla, California, raised the possibility of “subtraction therapy, where you start with three agents no matter what, and then if things go well, you subtract. And so you reverse the situation that Alan discussed.” In the patient’s view, “you have a celebration that night instead of a wake,” he said.

Dr. Garber has received honoraria or consulting fees as a member of the advisory boards of Novo Nordisk, Janssen, and Merck. Dr. Einhorn is on the scientific advisory boards of Eli Lilly, Novo Nordisk, Janssen, Boehringer Ingelheim, Sanofi, and Adocia, is a consultant for Halozyme, Glysens, Freedom-Meditech, and Epitracker, and has research funding from Lilly, Novo, Janssen, AstraZeneca, Mannkind, Freedom-Meditech, Merck, Sanofi, and Boehringer Ingelheim.

ORLANDO – Whether to start a patient with newly diagnosed type 2 diabetes mellitus on combination therapy or monotherapy should be based on experimentation and observation rather than expert opinion, according to Dr. Alan Garber, president of the American College of Endocrinology and professor of medicine, biochemistry, and molecular and cellular biology at Baylor College of Medicine in Houston.

Monotherapy for type 2 diabetes with stepwise addition of other antihyperglycemic agents has long been the accepted way to initiate therapy in this population. Beginning in the 1990s, investigators began to compare the efficacy of monotherapy with combination therapy, first with metformin and glyburide alone or together, and then testing metformin in combination with glipizide, rosiglitazone, and sitagliptin, he said.

For metformin and glyburide, each agent alone lowered glycated hemoglobin (HbA_1c), compared with placebo, but adding one to the other enhanced lowering. Combining the two drugs had the greatest benefit for higher HbA_1c entry levels (e.g., HbA_1c strata of 9%-9.9% or 10% or greater vs. less than 8%). At the highest-entry HbA_1c levels, half doses of each of metformin and glyburide (250 mg/1.25 mg, respectively) were more efficacious than full doses of each (500 mg/2.5 mg). “This is called drug sparing,” he said.

In a trial of metformin and rosiglitazone, the combination was superior to either alone, producing significantly greater mean reductions in HbA_1c and in fasting plasma glucose (FPG) at 32 weeks from their respective baselines, again, with greater reductions for higher-entry HbA_1c levels. The combination was also better than either drug alone in the speed of reducing HbA_1c or FPG, and in the final attained levels.

The combination of metformin and a sulfonylurea presents a risk of hypoglycemia, but Dr. Garber said the results are “much cleaner” using combinations of metformin with agents such as a thiazolidinedione, a dipeptidyl peptidase-4 inhibitor, or a sodium/glucose cotransporter-2 inhibitor.

Also noteworthy are findings from the EDICT (Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes) trial using insulin-sensitizing and insulin-secreting agents metformin/pioglitazone/exenatide in combination vs. escalating doses of metformin with sequential addition of a sulfonylurea and glargine insulin to treat patients with newly diagnosed type 2 diabetes. Over 2 years, the subjects receiving combination therapy had lower HbA_1c, a mean weight loss, compared with weight gain, in the sequential therapy group, and a 7.5-fold lower rate of hypoglycemia, compared with the sequential treatment group (Diabetes Obes Metab. 2015;17:268-75).

Although the agents used in the two treatment strategies were not strictly equivalent, “it’s clear that testing multiple therapeutic mechanisms tends to produce better outcomes than fewer therapeutic mechanisms,” Dr. Garber said. The conclusions are fairly straightforward. “Look for evidence to support what strategies you want to use for your patients’ care.”

Using the Kaiser Permanente database, investigators found that the mean time of having an HbA_1c above 8% was 3 years before a second agent was added, and the mean HbA_1c was 9%. Many people have ascribed this sort of delay to a problem with the physician. But Dr. Garber said it is more related to patients, who often resist prescriptions for more drugs. So starting with two drugs may produce better efficacy faster as well as overcome the psychological issues of trying to add another one later (Am J Manag Care. 2003;9:213-7).

Session moderator Dr. Daniel Einhorn, medical director of the Scripps Whittier Diabetes Institute in La Jolla, California, raised the possibility of “subtraction therapy, where you start with three agents no matter what, and then if things go well, you subtract. And so you reverse the situation that Alan discussed.” In the patient’s view, “you have a celebration that night instead of a wake,” he said.

Dr. Garber has received honoraria or consulting fees as a member of the advisory boards of Novo Nordisk, Janssen, and Merck. Dr. Einhorn is on the scientific advisory boards of Eli Lilly, Novo Nordisk, Janssen, Boehringer Ingelheim, Sanofi, and Adocia, is a consultant for Halozyme, Glysens, Freedom-Meditech, and Epitracker, and has research funding from Lilly, Novo, Janssen, AstraZeneca, Mannkind, Freedom-Meditech, Merck, Sanofi, and Boehringer Ingelheim.

ORLANDO – Whether to start a patient with newly diagnosed type 2 diabetes mellitus on combination therapy or monotherapy should be based on experimentation and observation rather than expert opinion, according to Dr. Alan Garber, president of the American College of Endocrinology and professor of medicine, biochemistry, and molecular and cellular biology at Baylor College of Medicine in Houston.

Monotherapy for type 2 diabetes with stepwise addition of other antihyperglycemic agents has long been the accepted way to initiate therapy in this population. Beginning in the 1990s, investigators began to compare the efficacy of monotherapy with combination therapy, first with metformin and glyburide alone or together, and then testing metformin in combination with glipizide, rosiglitazone, and sitagliptin, he said.

For metformin and glyburide, each agent alone lowered glycated hemoglobin (HbA_1c), compared with placebo, but adding one to the other enhanced lowering. Combining the two drugs had the greatest benefit for higher HbA_1c entry levels (e.g., HbA_1c strata of 9%-9.9% or 10% or greater vs. less than 8%). At the highest-entry HbA_1c levels, half doses of each of metformin and glyburide (250 mg/1.25 mg, respectively) were more efficacious than full doses of each (500 mg/2.5 mg). “This is called drug sparing,” he said.

In a trial of metformin and rosiglitazone, the combination was superior to either alone, producing significantly greater mean reductions in HbA_1c and in fasting plasma glucose (FPG) at 32 weeks from their respective baselines, again, with greater reductions for higher-entry HbA_1c levels. The combination was also better than either drug alone in the speed of reducing HbA_1c or FPG, and in the final attained levels.

The combination of metformin and a sulfonylurea presents a risk of hypoglycemia, but Dr. Garber said the results are “much cleaner” using combinations of metformin with agents such as a thiazolidinedione, a dipeptidyl peptidase-4 inhibitor, or a sodium/glucose cotransporter-2 inhibitor.

Also noteworthy are findings from the EDICT (Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes) trial using insulin-sensitizing and insulin-secreting agents metformin/pioglitazone/exenatide in combination vs. escalating doses of metformin with sequential addition of a sulfonylurea and glargine insulin to treat patients with newly diagnosed type 2 diabetes. Over 2 years, the subjects receiving combination therapy had lower HbA_1c, a mean weight loss, compared with weight gain, in the sequential therapy group, and a 7.5-fold lower rate of hypoglycemia, compared with the sequential treatment group (Diabetes Obes Metab. 2015;17:268-75).

Although the agents used in the two treatment strategies were not strictly equivalent, “it’s clear that testing multiple therapeutic mechanisms tends to produce better outcomes than fewer therapeutic mechanisms,” Dr. Garber said. The conclusions are fairly straightforward. “Look for evidence to support what strategies you want to use for your patients’ care.”

Using the Kaiser Permanente database, investigators found that the mean time of having an HbA_1c above 8% was 3 years before a second agent was added, and the mean HbA_1c was 9%. Many people have ascribed this sort of delay to a problem with the physician. But Dr. Garber said it is more related to patients, who often resist prescriptions for more drugs. So starting with two drugs may produce better efficacy faster as well as overcome the psychological issues of trying to add another one later (Am J Manag Care. 2003;9:213-7).

Session moderator Dr. Daniel Einhorn, medical director of the Scripps Whittier Diabetes Institute in La Jolla, California, raised the possibility of “subtraction therapy, where you start with three agents no matter what, and then if things go well, you subtract. And so you reverse the situation that Alan discussed.” In the patient’s view, “you have a celebration that night instead of a wake,” he said.

Dr. Garber has received honoraria or consulting fees as a member of the advisory boards of Novo Nordisk, Janssen, and Merck. Dr. Einhorn is on the scientific advisory boards of Eli Lilly, Novo Nordisk, Janssen, Boehringer Ingelheim, Sanofi, and Adocia, is a consultant for Halozyme, Glysens, Freedom-Meditech, and Epitracker, and has research funding from Lilly, Novo, Janssen, AstraZeneca, Mannkind, Freedom-Meditech, Merck, Sanofi, and Boehringer Ingelheim.

ORLANDO – Radiofrequency (RF) ablation is a safe and effective procedure for treating focal adrenal tumors in patients who are poor surgical candidates or who refuse adrenalectomy. With a short treatment time and minimal hospital stay, RF ablation can provide rapid clinical and biochemical improvement.

Dr. Lima Lawrence, an internal medicine resident at the University of Illinois at Chicago/Advocate Christ Medical Center in Oak Lawn, presented a case report and a review of the literature during an oral abstract session at the annual meeting of the American Association of Clinical Endocrinologists. The patient was a 65-year-old woman who presented with weight gain, decreased energy, and muscle weakness. On physical exam, she was hypertensive, anxious, obese, and had prominent supraclavicular fat pads. Salivary cortisol and overnight dexamethasone suppression tests were both elevated, and ACTH levels were depressed, confirming the diagnosis of a cortisol-secreting tumor causing adrenal Cushing’s syndrome. Computed tomography (CT) surveillance showed a progressively enlarging right-sided adrenal mass. A peritoneal biopsy revealed a low-grade serous neoplasm of peritoneal origin.

Her medical history included type 2 diabetes, uncontrolled hypertension, mixed connective tissue disease, depression, and total abdominal hysterectomy with bilateral salpingo-oophorectomy for ovarian cancer.

Dr. Lawrence said the patient had been scheduled for adrenalectomy, but it was not performed because of an intraoperative finding of peritoneal studding from what turned out to be metastatic ovarian cancer. Therefore, she underwent CT-guided RF ablation of the adrenal mass using a 14-gauge probe that heated a 3.5-cm ablation zone to 50-60 C for 8-10 minutes to achieve complete tumor necrosis.

The patient showed dramatic “clinical and biochemical improvement,” Dr. Lawrence said. The patient had no procedural complications and no blood loss and was observed for 23 hours before being discharged to home. A CT scan 8 weeks later showed a slightly decreased mass with marked decreased radiographic attenuation post-contrast from 30.2 Hounsfield Units (HU) preoperatively to 17 HU on follow-up.

Potential adverse outcomes using RF ablation include a risk of pneumothorax, hemothorax, and tumor seeding along the catheter track, but this last possibility can be mitigated by continuing to heat the RF probe as it is withdrawn.

Published evidence supports use of RF ablation. “To date there have been no randomized clinical trials comparing the safety, efficacy, and survival benefits of adrenalectomy vs. radio frequency ablation,” she said. It may not be feasible to do a randomized trial. But a review of the literature generally supports the efficacy of the technique although the publications each involved a small series of patients, Dr. Lawrence said in an interview.

A 2003 series (Cancer. 2003;97:554-60) of 15 primary or metastatic adrenal cell carcinomas that were unresectable or were in patients who were not surgical candidates showed nonenhancement and no growth in 8 (53%) at a mean follow-up of 10.3 months. Eight of the 12 tumors of 5 cm or smaller had complete loss of radiographic enhancement and a decrease in size.

From a retrospective series of 13 patients with functional adrenal neoplasms over 7 years, there was 100% resolution of biochemical abnormalities and clinical symptoms at a mean follow-up of 21.2 months. One small pneumothorax and one limited hemothorax occurred, neither of which required hospital admission. There were two instances of transient, self-remitting hypertension associated with the procedures (Radiology. 2011;258:308-16).

In 2015, one group of investigators followed 11 patients for 12 weeks postprocedure. Eight of nine patients with Conn’s syndrome attained normal serum aldosterone levels. One with a nodule close to the inferior vena cava had incomplete ablation. Two of two Cushing’s patients had normal cortisol levels after the procedure (J Vasc Interv Radiol. 2015;26:1459-64).

A retrospective analysis of 16 adrenal metastases showed that 13 (81%) had no local progression over 14 months after ablation. In two of three functional adrenal neoplasms, clinical and biochemical abnormalities resolved (Eur J Radiol. 2012.81:1717-23).

A retrospective series of 10 adrenal metastases showed that one recurred at 7 months after image-guided thermal ablation, with no recurrence of the rest at 26.6 months. There was no tumor recurrence for any of the cases of metastatic disease localized to the RF ablation site (J Vasc Interv Radiol. 2014;25:593-8).

Results were somewhat less good in a retrospective evaluation of 35 patients with unresectable adrenal masses over 9 years. Although 33 of 35 (94%) lost tumor enhancement after the initial adrenal RF ablation, there was local tumor progression in 8 of 35 (23%) patients at a mean follow-up of 30.1 months (Radiology. 2015;277:584-93).

Finally, Dr. Lawrence discussed a systematic literature review on adrenalectomy vs. stereotactic ablative body radiotherapy (SABR) and percutaneous catheter ablation (PCA) in the treatment of adrenal metastases: 30 papers on adrenalectomy on 818 patients; 9 papers on SABR on 178 patients; and 6 papers on PCA, including RF ablation, on 51 patients. The authors concluded that there was “insufficient evidence to determine the best local treatment modality for isolated or limited adrenal metastases.” Adrenalectomy appeared to be a reasonable treatment for suitable patients. SABR was a valid alternative for nonsurgical candidates, but they did not recommend PCA until more long-term outcomes were available (Cancer Treat Rev. 2014;40:838-46).

Dr. Lawrence concurred, based on her case study and literature review. She said RF ablation “offers patients a minimally invasive option for treating focal adrenal tumors” and is a “safe and effective procedure … in patients who are poor surgical candidates or refuse adrenalectomy.” More long-term follow-up studies are needed before RF ablation could replace adrenalectomy, she noted.

ORLANDO – Radiofrequency (RF) ablation is a safe and effective procedure for treating focal adrenal tumors in patients who are poor surgical candidates or who refuse adrenalectomy. With a short treatment time and minimal hospital stay, RF ablation can provide rapid clinical and biochemical improvement.

Dr. Lima Lawrence, an internal medicine resident at the University of Illinois at Chicago/Advocate Christ Medical Center in Oak Lawn, presented a case report and a review of the literature during an oral abstract session at the annual meeting of the American Association of Clinical Endocrinologists. The patient was a 65-year-old woman who presented with weight gain, decreased energy, and muscle weakness. On physical exam, she was hypertensive, anxious, obese, and had prominent supraclavicular fat pads. Salivary cortisol and overnight dexamethasone suppression tests were both elevated, and ACTH levels were depressed, confirming the diagnosis of a cortisol-secreting tumor causing adrenal Cushing’s syndrome. Computed tomography (CT) surveillance showed a progressively enlarging right-sided adrenal mass. A peritoneal biopsy revealed a low-grade serous neoplasm of peritoneal origin.

Her medical history included type 2 diabetes, uncontrolled hypertension, mixed connective tissue disease, depression, and total abdominal hysterectomy with bilateral salpingo-oophorectomy for ovarian cancer.

Dr. Lawrence said the patient had been scheduled for adrenalectomy, but it was not performed because of an intraoperative finding of peritoneal studding from what turned out to be metastatic ovarian cancer. Therefore, she underwent CT-guided RF ablation of the adrenal mass using a 14-gauge probe that heated a 3.5-cm ablation zone to 50-60 C for 8-10 minutes to achieve complete tumor necrosis.

The patient showed dramatic “clinical and biochemical improvement,” Dr. Lawrence said. The patient had no procedural complications and no blood loss and was observed for 23 hours before being discharged to home. A CT scan 8 weeks later showed a slightly decreased mass with marked decreased radiographic attenuation post-contrast from 30.2 Hounsfield Units (HU) preoperatively to 17 HU on follow-up.

Potential adverse outcomes using RF ablation include a risk of pneumothorax, hemothorax, and tumor seeding along the catheter track, but this last possibility can be mitigated by continuing to heat the RF probe as it is withdrawn.

Published evidence supports use of RF ablation. “To date there have been no randomized clinical trials comparing the safety, efficacy, and survival benefits of adrenalectomy vs. radio frequency ablation,” she said. It may not be feasible to do a randomized trial. But a review of the literature generally supports the efficacy of the technique although the publications each involved a small series of patients, Dr. Lawrence said in an interview.

A 2003 series (Cancer. 2003;97:554-60) of 15 primary or metastatic adrenal cell carcinomas that were unresectable or were in patients who were not surgical candidates showed nonenhancement and no growth in 8 (53%) at a mean follow-up of 10.3 months. Eight of the 12 tumors of 5 cm or smaller had complete loss of radiographic enhancement and a decrease in size.

From a retrospective series of 13 patients with functional adrenal neoplasms over 7 years, there was 100% resolution of biochemical abnormalities and clinical symptoms at a mean follow-up of 21.2 months. One small pneumothorax and one limited hemothorax occurred, neither of which required hospital admission. There were two instances of transient, self-remitting hypertension associated with the procedures (Radiology. 2011;258:308-16).

In 2015, one group of investigators followed 11 patients for 12 weeks postprocedure. Eight of nine patients with Conn’s syndrome attained normal serum aldosterone levels. One with a nodule close to the inferior vena cava had incomplete ablation. Two of two Cushing’s patients had normal cortisol levels after the procedure (J Vasc Interv Radiol. 2015;26:1459-64).

A retrospective analysis of 16 adrenal metastases showed that 13 (81%) had no local progression over 14 months after ablation. In two of three functional adrenal neoplasms, clinical and biochemical abnormalities resolved (Eur J Radiol. 2012.81:1717-23).

A retrospective series of 10 adrenal metastases showed that one recurred at 7 months after image-guided thermal ablation, with no recurrence of the rest at 26.6 months. There was no tumor recurrence for any of the cases of metastatic disease localized to the RF ablation site (J Vasc Interv Radiol. 2014;25:593-8).

Results were somewhat less good in a retrospective evaluation of 35 patients with unresectable adrenal masses over 9 years. Although 33 of 35 (94%) lost tumor enhancement after the initial adrenal RF ablation, there was local tumor progression in 8 of 35 (23%) patients at a mean follow-up of 30.1 months (Radiology. 2015;277:584-93).

Finally, Dr. Lawrence discussed a systematic literature review on adrenalectomy vs. stereotactic ablative body radiotherapy (SABR) and percutaneous catheter ablation (PCA) in the treatment of adrenal metastases: 30 papers on adrenalectomy on 818 patients; 9 papers on SABR on 178 patients; and 6 papers on PCA, including RF ablation, on 51 patients. The authors concluded that there was “insufficient evidence to determine the best local treatment modality for isolated or limited adrenal metastases.” Adrenalectomy appeared to be a reasonable treatment for suitable patients. SABR was a valid alternative for nonsurgical candidates, but they did not recommend PCA until more long-term outcomes were available (Cancer Treat Rev. 2014;40:838-46).

Dr. Lawrence concurred, based on her case study and literature review. She said RF ablation “offers patients a minimally invasive option for treating focal adrenal tumors” and is a “safe and effective procedure … in patients who are poor surgical candidates or refuse adrenalectomy.” More long-term follow-up studies are needed before RF ablation could replace adrenalectomy, she noted.

ORLANDO – Radiofrequency (RF) ablation is a safe and effective procedure for treating focal adrenal tumors in patients who are poor surgical candidates or who refuse adrenalectomy. With a short treatment time and minimal hospital stay, RF ablation can provide rapid clinical and biochemical improvement.

Dr. Lima Lawrence, an internal medicine resident at the University of Illinois at Chicago/Advocate Christ Medical Center in Oak Lawn, presented a case report and a review of the literature during an oral abstract session at the annual meeting of the American Association of Clinical Endocrinologists. The patient was a 65-year-old woman who presented with weight gain, decreased energy, and muscle weakness. On physical exam, she was hypertensive, anxious, obese, and had prominent supraclavicular fat pads. Salivary cortisol and overnight dexamethasone suppression tests were both elevated, and ACTH levels were depressed, confirming the diagnosis of a cortisol-secreting tumor causing adrenal Cushing’s syndrome. Computed tomography (CT) surveillance showed a progressively enlarging right-sided adrenal mass. A peritoneal biopsy revealed a low-grade serous neoplasm of peritoneal origin.

Her medical history included type 2 diabetes, uncontrolled hypertension, mixed connective tissue disease, depression, and total abdominal hysterectomy with bilateral salpingo-oophorectomy for ovarian cancer.

Dr. Lawrence said the patient had been scheduled for adrenalectomy, but it was not performed because of an intraoperative finding of peritoneal studding from what turned out to be metastatic ovarian cancer. Therefore, she underwent CT-guided RF ablation of the adrenal mass using a 14-gauge probe that heated a 3.5-cm ablation zone to 50-60 C for 8-10 minutes to achieve complete tumor necrosis.

The patient showed dramatic “clinical and biochemical improvement,” Dr. Lawrence said. The patient had no procedural complications and no blood loss and was observed for 23 hours before being discharged to home. A CT scan 8 weeks later showed a slightly decreased mass with marked decreased radiographic attenuation post-contrast from 30.2 Hounsfield Units (HU) preoperatively to 17 HU on follow-up.

Potential adverse outcomes using RF ablation include a risk of pneumothorax, hemothorax, and tumor seeding along the catheter track, but this last possibility can be mitigated by continuing to heat the RF probe as it is withdrawn.

Published evidence supports use of RF ablation. “To date there have been no randomized clinical trials comparing the safety, efficacy, and survival benefits of adrenalectomy vs. radio frequency ablation,” she said. It may not be feasible to do a randomized trial. But a review of the literature generally supports the efficacy of the technique although the publications each involved a small series of patients, Dr. Lawrence said in an interview.

A 2003 series (Cancer. 2003;97:554-60) of 15 primary or metastatic adrenal cell carcinomas that were unresectable or were in patients who were not surgical candidates showed nonenhancement and no growth in 8 (53%) at a mean follow-up of 10.3 months. Eight of the 12 tumors of 5 cm or smaller had complete loss of radiographic enhancement and a decrease in size.

From a retrospective series of 13 patients with functional adrenal neoplasms over 7 years, there was 100% resolution of biochemical abnormalities and clinical symptoms at a mean follow-up of 21.2 months. One small pneumothorax and one limited hemothorax occurred, neither of which required hospital admission. There were two instances of transient, self-remitting hypertension associated with the procedures (Radiology. 2011;258:308-16).

In 2015, one group of investigators followed 11 patients for 12 weeks postprocedure. Eight of nine patients with Conn’s syndrome attained normal serum aldosterone levels. One with a nodule close to the inferior vena cava had incomplete ablation. Two of two Cushing’s patients had normal cortisol levels after the procedure (J Vasc Interv Radiol. 2015;26:1459-64).

A retrospective analysis of 16 adrenal metastases showed that 13 (81%) had no local progression over 14 months after ablation. In two of three functional adrenal neoplasms, clinical and biochemical abnormalities resolved (Eur J Radiol. 2012.81:1717-23).

A retrospective series of 10 adrenal metastases showed that one recurred at 7 months after image-guided thermal ablation, with no recurrence of the rest at 26.6 months. There was no tumor recurrence for any of the cases of metastatic disease localized to the RF ablation site (J Vasc Interv Radiol. 2014;25:593-8).

Results were somewhat less good in a retrospective evaluation of 35 patients with unresectable adrenal masses over 9 years. Although 33 of 35 (94%) lost tumor enhancement after the initial adrenal RF ablation, there was local tumor progression in 8 of 35 (23%) patients at a mean follow-up of 30.1 months (Radiology. 2015;277:584-93).

Finally, Dr. Lawrence discussed a systematic literature review on adrenalectomy vs. stereotactic ablative body radiotherapy (SABR) and percutaneous catheter ablation (PCA) in the treatment of adrenal metastases: 30 papers on adrenalectomy on 818 patients; 9 papers on SABR on 178 patients; and 6 papers on PCA, including RF ablation, on 51 patients. The authors concluded that there was “insufficient evidence to determine the best local treatment modality for isolated or limited adrenal metastases.” Adrenalectomy appeared to be a reasonable treatment for suitable patients. SABR was a valid alternative for nonsurgical candidates, but they did not recommend PCA until more long-term outcomes were available (Cancer Treat Rev. 2014;40:838-46).

Dr. Lawrence concurred, based on her case study and literature review. She said RF ablation “offers patients a minimally invasive option for treating focal adrenal tumors” and is a “safe and effective procedure … in patients who are poor surgical candidates or refuse adrenalectomy.” More long-term follow-up studies are needed before RF ablation could replace adrenalectomy, she noted.