High testosterone, no growth benefit for boys treated with letrozole

SAN DIEGO – The aromatase inhibitor letrozole didn’t help boys with short stature grow taller, but it did boost their testosterone to concerning levels in a small study at Children’s Hospital Los Angeles.

Estrogens are thought to help close epiphyseal growth plates; the idea of giving aromatase inhibitors (AIs) is to block aromatase from converting androgens to estrogens in boys so that their growth plates stay open a bit longer and they grow taller. In the United States, the drugs are frequently prescribed off label for that purpose in boys with short-stature or rapid-tempo puberty.

It didn’t seem to work, however, in the 16 boys in the study, who were an average of about 12.5 years old when they were started on letrozole.

The seven boys who started out at Tanner stages 1-3 were on the drug for an average of 2.7 years; their Bayley-Pinneau predicted adult height (PAH) fell from 66.9 inches to 66.5 inches. The nine boys who started out at Tanner stages 4-5 went from a PAH of 65.3 inches to 65.4 inches. The changes were not statistically significant.

Meanwhile, testosterone increased from 155 ng/dL to 728 ng/dL in stage 1-3 boys and from 417 ng/dL to 1,192 ng/dL in stage 4-5 boys. Those changes were statistically significant, and testosterone levels were significantly above the upper limit of normal in six (67%) of the later Tanner stage boys. There was a corresponding increase from no or mild acne to moderate acne in later stage boys, and a significant increase in hematocrit, from 43% to 47.5%. Seven (78%) of the later Tanner stage boys had hematocrit levels above the upper limit of normal.

“Short-term AIs were not effective in increasing PAH, regardless of pubertal age. [The] potential consequences of these findings are of concern and require careful long-term study, especially when AIs are started in late puberty,” the team concluded.

The findings “will change my practice with regard to” letrozole, said senior author Dr. Mitchell Geffner, professor of pediatrics at the hospital and president of the Pediatric Endocrine Society. Dr. Geffner treated all but one of the children in the study.

“I might still use” anastrozole, a less-potent AI, “but I have to get a better sense of all the parameters we measured here, a number of which are potentially unhealthy. These drugs are used to treat” boys with short stature and rapid-tempo puberty “very frequently in the United States,” but “I think we’re entering uncharted territory” with them. “We don’t really have a lot of data with use as single agents. We have to be very careful because we are giving a drug that alters, at least in the short term, reproductive hormones. Reproductive health in the future is completely unknown,” he said.

Despite having elevated testosterone levels, all the children had significant change in estradiol levels; in fact, there was a trend toward higher levels in the Tanner stage 4-5 boys, who also had significant increases in follicle-stimulating hormone and luteinizing-hormone levels that were often above the upper limit of normal.

“I was surprised by the results, and how high testosterone went in some of these boys. There’s conflicting data on whether these drugs help gain extra height, but we have to be very careful because we are causing very high testosterone levels,” which – although not seen in the study – could affect bone health and even cause stroke if hematocrit is pushed high enough, said lead investigator Dr. Jessica Ferris of Children’s Hospital Los Angeles.

There was no outside funding for the work. Dr. Ferris had no disclosures. Dr. Geffner is an investigator, consultant, or adviser for several companies, including Eli Lilly, Endo Pharmaceuticals, Genentech, Ipsen, Novo Nordisk, and Pfizer.

aotto@frontlinemedcom.com

SAN DIEGO – The aromatase inhibitor letrozole didn’t help boys with short stature grow taller, but it did boost their testosterone to concerning levels in a small study at Children’s Hospital Los Angeles.

Estrogens are thought to help close epiphyseal growth plates; the idea of giving aromatase inhibitors (AIs) is to block aromatase from converting androgens to estrogens in boys so that their growth plates stay open a bit longer and they grow taller. In the United States, the drugs are frequently prescribed off label for that purpose in boys with short-stature or rapid-tempo puberty.

It didn’t seem to work, however, in the 16 boys in the study, who were an average of about 12.5 years old when they were started on letrozole.

The seven boys who started out at Tanner stages 1-3 were on the drug for an average of 2.7 years; their Bayley-Pinneau predicted adult height (PAH) fell from 66.9 inches to 66.5 inches. The nine boys who started out at Tanner stages 4-5 went from a PAH of 65.3 inches to 65.4 inches. The changes were not statistically significant.

Meanwhile, testosterone increased from 155 ng/dL to 728 ng/dL in stage 1-3 boys and from 417 ng/dL to 1,192 ng/dL in stage 4-5 boys. Those changes were statistically significant, and testosterone levels were significantly above the upper limit of normal in six (67%) of the later Tanner stage boys. There was a corresponding increase from no or mild acne to moderate acne in later stage boys, and a significant increase in hematocrit, from 43% to 47.5%. Seven (78%) of the later Tanner stage boys had hematocrit levels above the upper limit of normal.

“Short-term AIs were not effective in increasing PAH, regardless of pubertal age. [The] potential consequences of these findings are of concern and require careful long-term study, especially when AIs are started in late puberty,” the team concluded.

The findings “will change my practice with regard to” letrozole, said senior author Dr. Mitchell Geffner, professor of pediatrics at the hospital and president of the Pediatric Endocrine Society. Dr. Geffner treated all but one of the children in the study.

“I might still use” anastrozole, a less-potent AI, “but I have to get a better sense of all the parameters we measured here, a number of which are potentially unhealthy. These drugs are used to treat” boys with short stature and rapid-tempo puberty “very frequently in the United States,” but “I think we’re entering uncharted territory” with them. “We don’t really have a lot of data with use as single agents. We have to be very careful because we are giving a drug that alters, at least in the short term, reproductive hormones. Reproductive health in the future is completely unknown,” he said.

Despite having elevated testosterone levels, all the children had significant change in estradiol levels; in fact, there was a trend toward higher levels in the Tanner stage 4-5 boys, who also had significant increases in follicle-stimulating hormone and luteinizing-hormone levels that were often above the upper limit of normal.

“I was surprised by the results, and how high testosterone went in some of these boys. There’s conflicting data on whether these drugs help gain extra height, but we have to be very careful because we are causing very high testosterone levels,” which – although not seen in the study – could affect bone health and even cause stroke if hematocrit is pushed high enough, said lead investigator Dr. Jessica Ferris of Children’s Hospital Los Angeles.

There was no outside funding for the work. Dr. Ferris had no disclosures. Dr. Geffner is an investigator, consultant, or adviser for several companies, including Eli Lilly, Endo Pharmaceuticals, Genentech, Ipsen, Novo Nordisk, and Pfizer.

aotto@frontlinemedcom.com

SAN DIEGO – The aromatase inhibitor letrozole didn’t help boys with short stature grow taller, but it did boost their testosterone to concerning levels in a small study at Children’s Hospital Los Angeles.

Estrogens are thought to help close epiphyseal growth plates; the idea of giving aromatase inhibitors (AIs) is to block aromatase from converting androgens to estrogens in boys so that their growth plates stay open a bit longer and they grow taller. In the United States, the drugs are frequently prescribed off label for that purpose in boys with short-stature or rapid-tempo puberty.

It didn’t seem to work, however, in the 16 boys in the study, who were an average of about 12.5 years old when they were started on letrozole.

The seven boys who started out at Tanner stages 1-3 were on the drug for an average of 2.7 years; their Bayley-Pinneau predicted adult height (PAH) fell from 66.9 inches to 66.5 inches. The nine boys who started out at Tanner stages 4-5 went from a PAH of 65.3 inches to 65.4 inches. The changes were not statistically significant.

Meanwhile, testosterone increased from 155 ng/dL to 728 ng/dL in stage 1-3 boys and from 417 ng/dL to 1,192 ng/dL in stage 4-5 boys. Those changes were statistically significant, and testosterone levels were significantly above the upper limit of normal in six (67%) of the later Tanner stage boys. There was a corresponding increase from no or mild acne to moderate acne in later stage boys, and a significant increase in hematocrit, from 43% to 47.5%. Seven (78%) of the later Tanner stage boys had hematocrit levels above the upper limit of normal.

“Short-term AIs were not effective in increasing PAH, regardless of pubertal age. [The] potential consequences of these findings are of concern and require careful long-term study, especially when AIs are started in late puberty,” the team concluded.

The findings “will change my practice with regard to” letrozole, said senior author Dr. Mitchell Geffner, professor of pediatrics at the hospital and president of the Pediatric Endocrine Society. Dr. Geffner treated all but one of the children in the study.

“I might still use” anastrozole, a less-potent AI, “but I have to get a better sense of all the parameters we measured here, a number of which are potentially unhealthy. These drugs are used to treat” boys with short stature and rapid-tempo puberty “very frequently in the United States,” but “I think we’re entering uncharted territory” with them. “We don’t really have a lot of data with use as single agents. We have to be very careful because we are giving a drug that alters, at least in the short term, reproductive hormones. Reproductive health in the future is completely unknown,” he said.

Despite having elevated testosterone levels, all the children had significant change in estradiol levels; in fact, there was a trend toward higher levels in the Tanner stage 4-5 boys, who also had significant increases in follicle-stimulating hormone and luteinizing-hormone levels that were often above the upper limit of normal.

“I was surprised by the results, and how high testosterone went in some of these boys. There’s conflicting data on whether these drugs help gain extra height, but we have to be very careful because we are causing very high testosterone levels,” which – although not seen in the study – could affect bone health and even cause stroke if hematocrit is pushed high enough, said lead investigator Dr. Jessica Ferris of Children’s Hospital Los Angeles.

There was no outside funding for the work. Dr. Ferris had no disclosures. Dr. Geffner is an investigator, consultant, or adviser for several companies, including Eli Lilly, Endo Pharmaceuticals, Genentech, Ipsen, Novo Nordisk, and Pfizer.

aotto@frontlinemedcom.com