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Growth Hormone Therapy Found to be Associated with Stroke in Adulthood

Fallik, Dawn

doi: 10.1097/01.NT.0000453574.34146.df
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Experts warn that an elevated risk of stroke is possible in people who were treated with growth hormone as children. The study reviewed medical records and other data from 6,874 people who had been treated with a growth hormone in childhood. At a mean follow-up of 17.4 years, there were 11 incidents of stroke at a mean age of 24 years; four children died from subarachnoid hemorrhage.

Every year, some children who receive growth hormone treatment (GHT) do so for cosmetic reasons — they are short in a world that admires being tall. But a new study raises concerns that GHT might have dangerous consequences in the long-term, with an associated risk for stroke in adulthood.

Endocrinologists and a neurologist who reviewed the report for Neurology Today said these findings should be considered when prescribing the treatment.

The study, published in the Aug. 13 online edition of Neurology, reviewed adult morbidity data on 6,874 people collected from the French cohort of the Safety and Appropriateness of Growth hormone treatments in Europe trial — or SAGhE — a multinational prospective European study that assessed long-term mortality and cancer morbidity in people who were treated with GH in childhood.

For the current study, the authors collected data on the children with idiopathic isolated GH deficiency or short stature who started GHT between 1985 and 1996. About 75 percent of the group had isolated GH deficiency and 13 percent had idiopathic short stature.

An earlier analysis, published in 2012 in the Journal of Clinical Endocrinology and Metabolism, showed increased cardiac and cerebrovascular mortality among the French cohort of SAGhE.

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For the Neurology paper, the research team reviewed medical records, imaging data, and questionnaires that had been sent to patients, specifically looking at cerebrovascular events that were validated by stroke neurologists. They compared the results with data on stroke incidence obtained from population-based registries in Dijon, France, and Oxford, United Kingdom. They concluded that there was a higher risk of stroke among patients treated with GH in childhood — with a standardized incidence ratio of 2.2-5.3 for all stroke subtypes, and 5.7-7.0 for hemorrhagic stroke.

At an average follow-up of 17.4 years, there were 11 incident strokes at a mean age of 24 years — three intracerebral hemorrhages, three ischemic strokes, and five cases of subarachnoid hemorrhage (SAH); four of the patients died from SAH.

“Patients treated with GH worldwide should be advised about this association and further studies should evaluate the potentially causal role of GH treatment in these findings,” the study authors wrote.

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Experts who were not involved with the study had mixed reactions to the findings. They were surprised by the results, but said the findings were cause for more investigation. They also pointed out that 11 cases of stroke out of almost 7,000 patients was not evidence of direct causation, and that the risk of stroke was very small.

“My own feeling is that anytime there are safety concerns from growth hormone we need to pay a great deal of attention,” said Andrew R. Hoffman, MD, vice chair for academic affairs in the department of medicine at Stanford University and chief of endocrinology at the VA Palo Alto Health Care System. “This is part of a larger, earlier French study that also showed problems with mortality and GHT, but it has not yet been confirmed by others.”

Among their criticisms of the study, experts said the control group consisted of a general adult population and not adults with growth hormone deficiency that had not received growth hormone treatment. It was hard to know if stroke occurred more often in those with GH issues or if it was related to the treatment.

Ron Rosenfeld, MD, an emeritus professor of pediatrics at Stanford University and Oregon Health & Science University, said: “It's a very real limitation; you can't compare a population that has some morbidity to begin with to a population that is supposedly totally healthy. Even if the findings are true, causality is not at all proven.”

Rebecca N. Ichord, MD, director of the Pediatric Stroke Program at the Children's Hospital of Philadelphia, wrote the editorial that accompanied the study. She said the study had “striking results,” a large sample size, and a long duration of follow-up. She also raised concerns about the absence of an untreated comparison group, but said it would be hard to find a control group of that size that would inform questions of causation.

Previously, concerns about the long-term effects of GHT focused on diabetes and cancer, Dr. Ichord pointed out. As the treatment promotes cellular division, there are concerns about increased occurrences of tumors and malignancies, but that has not turned out to be the case in children with isolated GH deficiency or idiopathic short stature, said Dr. Ichord.

The increase in stroke might be attributed to GHT because it is given during a developmental period and might affect the growth of blood vessels in the same way as other tissues in the body, she said.

Most patients who receive GHT do so to treat hormone deficiencies, and although the number of strokes reported in the study was small, Dr. Ichord said it is sufficiently concerning that practitioners should reconsider the risks versus benefits of using GHT for the subset of children with idiopathic short stature, at least until the problem has been further studied.

“The patients in the study who had strokes were very young — in their 20s — and many died,” she said. “Although the total number is low, it was still a very morbid condition.”

“The results stand as a warning that we need to look at this possible causal relationship more rigorously, and my opinion is that we might need to exercise greater caution for treating children with idiopathic short stature,” she said.

When the French report first came out in 2012 addressing concerns about growth hormone and mortality, there was a concern about vascular issues, said David B. Allen, MD, professor of pediatrics and head of endocrinology at the University of Wisconsin's American Family and Children's Hospital. But a similar Scandinavian study did not have the same results, Dr. Allen said.

The original SAGhE report did spark discussion about risks and benefits for GHT, which has been important for all those involved with prescribing growth hormone for children, he said.

“It is important, in the process of gaining informed assent for GHT, to acknowledge and talk to families about uncertainties still being investigated regarding long-term post-treatment safety of GHT, particularly when treating children who are otherwise healthy, with short stature being their only concern,” said Dr. Allen.

Both the researchers and the independent experts said further studies were needed to study the potentially causal role of GHT in hemorrhagic stroke. The question is how to address former patients — now adults — who received GHT as children, as well as discuss the potential risk for current and future patients.

Dr. Ichord suggested that those who have already received treatment should be counseled so that they are aware of stroke symptoms and be particularly aware of managing their lifestyle in terms of stroke prevention, such as obesity and hypertension.

Dr. Allen, of Wisconsin, said he usually does not discuss stroke as a potential consequence of GHT, but it might be something to consider.

“If there is even a small risk for such a potentially severe and important disabling complication, and benefits of improved stature are uncertain, it is challenging to draw the line between cosmetic concerns and necessity,” he said. “It requires asking how much risk for unlikely but possible long-term adverse effects is acceptable when exposing otherwise healthy children to treatment.”

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•. Poidvin A, Touzéc E, Ecossea E, et al. Growth hormone treatment for childhood short stature and risk of stroke in early adulthood. Neurology 2014; Epub 2014 Aug. 13.
    •. Ichord RN. Adult stroke risk after growth hormone treatment in childhood: First do no harm. Neurology 2014; Epub 2014 Aug.13.
      •. Carel JC, Ecosse E., Landier F, et al. Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature. Preliminary report of the French SAGhE study. J Clin Endocrin Metabol 2012; 97:416–425.
        © 2014 American Academy of Neurology