From the pages of the Journal of the Endocrine Society, Endocrine News talks with Alan Rogol, MD, PhD, about the rarest of rare cases that involved growth hormone, Creutzfeldt-Jakob disease, and Alzheimer disease in a tale through time that involves rats, cadavers, and how one treatment evolved through scientific refinement.
Has there ever been a more aptly titled research paper? In “The Unfolding Story of Protein Misfolding Causing Alzheimer Disease in Recipients of Human Pituitary Growth Hormone,” published in Journal of the Endocrine Society in March, a collaborative research team traces a medical story that spans more than a century — from the early therapeutic hopes of growth hormone (GH) extracted from beef pituitaries and tested in a bioassay in female rats through the tragic recognition of Creutzfeldt-Jakob disease (CJD) transmission from cadaveric human GH (hGH), to emerging questions about whether Alzheimer disease (AD) may also be iatrogenically transmissible.
How this paper came together happened almost by chance at a History Committee meeting of the Pediatric Endocrine Society (PES), recalls corresponding author Alan D. Rogol, MD, PhD, professor emeritus of Pediatrics and Pharmacology at the University of Virginia in Charlottesville, as well as past vice president of the Endocrine Society and then-chair of the PES history committee. PES Executive Committee member Tandy Aye, MD, from Stanford University brought up Banerjee et al.’s paper “Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-extracted growth hormone,” published in Nature Medicine in February 2024, that, as the title makes clear, posits that AD may be iatrogenically transmissible. “We thought it would be a good time to remind people about human growth hormone: how it started, how safe it was, how safe it wasn’t, and the whole story,” he says.
The collaboration that emerged was uniquely positioned to tell this tale. Aye’s colleague Darrell M. Wilson, MD (a coauthor of this paper) had been there at the beginning; he and Raymond L. Hintz, MD (also formerly at Stanford) were among the first to see a patient with CJD. In May of 1985, Hintz filed a letter with the U.S. Food and Drug Administration explaining that one of his patients who had been treated with cadaveric GH for 14 years may have contracted CJD as a result. Rogol himself had close connections to Robert M. Blizzard, PhD (also at the University of Virgina), who treated another very early patient who eventually died from CJD. “We had the collective memory of what happened in 1985 as well as what led going up to it,” Rogol notes.
How It Started
hGH began to be used to treat children with severe GH deficiency in the 1950s; however, access was initially an obstacle. Because GH is species specific, GH from other animals was inactive in humans, so extracting pituitary glands from human cadavers was then the only way to obtain hGH.
This species specificity created an unprecedented challenge and the need to find alternatives, as Rogol’s own research illustrates: “So many more children needed to be treated than we had material for,” he recounts. “It was such a problem that I did my PhD dissertation 55 years ago on the structure of bovine growth hormone because we thought that its active cores might work in humans, which of course seems unrealistic in retrospect.”
How Safe It Was
hGH was, of course, believed to be safe. Rogol notes that the only known side effects were reduced efficacy in those who produced antibodies in response to treatment as well as scoliosis and slipped capital femoral epiphysis, which occur from growing. “That wasn’t specific to growth hormone; it was specific to growth promotion,” said Rogol.
In 1958, scientists discovered how to purify hGH in greater quantities, and ultimately more than 7,700 children were treated with it. The Hartree-modified Wilhelmi procedure (HWP) added a few more steps to the original procedure pioneered by Alfred E. Wilhelmi, PhD, at Emory University. The modifications by Anne Stockell Hartree, PhD, allowed more efficient extraction of hGH from cadaveric pituitaries, Rogol explains. “It worked perfectly well,” he says.
How Safe It Wasn’t
The tragedy lay not in the concept but in the execution — specifically, in the purification methods used. CJD is now known to be caused by prions, infectious agents composed of misfolded proteins that can trigger other normal proteins to misfold, creating a chain reaction. Among the multitudes of extracted pituitaries, some would have been contaminated with prions, leading to the development of iatrogenic CJD (iCJD) in more than 200 recipients worldwide.
The cruel irony emerged only decades later when alternative purification methods were developed. To produce purer hGH and therefore fewer antibody-related problems, Albert F. Parlow, PhD, at The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, innovated an approach using size-exclusion chromatography, which essentially blocked prions, due to their large size. “That one step, by serendipity, did not permit these prions to go into the final product,” Rogol reflects.
Some of the Rest of the Story: Recombinant Growth Hormone
The transition to recombinant hGH (rhGH) brought its own challenges. The Genentech company began producing rhGH in the early 1980s in Escherichia coli, a revolutionary yet imperfect process, initially. “They would use a centrifuge to remove the bacteria, but some endotoxins and other bug proteins remained, which were quite inflammatory and triggered immune responses,” explains Rogol. Nevertheless, the cadaveric hGH extraction method was unsustainable — the pool of children needing treatment was just too large (“one pituitary per child per day”). “[Wilson] and I lived through this and learned it was really important to get rhGH right because we knew it worked.”
By 1985, truly purified rhGH became available, ending the era of cadaveric hormone extraction and its associated risks.
More of the Rest of the Story: What Does This Have to do with Alzheimer Disease?
Because AD is another protein misfolding disease (of amyloid-beta and tau), and because recent research has suggested that AD may be transmissible from a host to a recipient mouse — as well as the recent observation that tau protein can behave like prions — the question has arisen as to whether patients who received hGH could develop AD in a manner similar to how younger members of the cohort developed CJD (as reported in Banerjee et al.). Infection happens not from bacteria or viruses but from the “chain reaction” of misfolding that prions cause and, possibly amyloid-beta and tau proteins. When the autopsy reports of eight people who were treated with hGH and developed CJD demonstrated that four of them also had amyloid-beta and tau proteins consistent with AD in 2015, the question took on new urgency.
“I don’t have enough knowledge to be in any particular camp,” Rogol acknowledges, “but the statistics are such that to me it is very likely.” Not only did half of the above-mentioned eight patients develop AD, but an additional four patients had AD-consistent biomarker and/or imaging findings — the oldest of these patients was 57 years old. Experts like Ellen Leschek and colleagues at the National Institutes of Health in Bethesda, Md., who have followed CJD cases from the beginning, however, believe there are simply not enough data to draw conclusions as well as because possible alternative explanations for AD development existed in the patients in question. “The difference between us and [Leschek’s] group is that we are relatively more certain,” Rogol explains. “We’re not that far different; she’s more skeptical, but she’s also more knowledgeable.”
Enduring Questions
For Rogol, the critical questions about potential hGH-transmitted AD are temporal: “Do these people get Alzheimer-like conditions 10, 20, or 30 years earlier than they otherwise would have?” Additionally, he wonders about disease progression: “Might Alzheimer disease have a different trajectory — from good to bad to worse more quickly — if you got it this way? So, both earlier onset and potentially different symptom trajectory are probably the crux of whether it has been transmitted by growth hormone.”
“So many more children needed to be treated than we had material for. It was such a problem that I did my PhD dissertation 55 years ago on the structure of bovine growth hormone because we thought that its active cores might work in humans, which of course seems unrealistic in retrospect.” – Alan D. Rogol, MD, PhD, professor emeritus, Pediatrics and Pharmacology, University of Virginia, Charlottesville, Virginia
The role of genetics adds another layer of complexity. Animal experiments have shown that genetic susceptibility matters enormously. “If you put Alzheimer and non-Alzheimer brain bits into a genetically susceptible rat, the susceptible rat gets Alzheimer disease on one side, but nothing on the other. If you put them into a genetically non-susceptible rat, nothing happens on either side,” Rogol explains.
We will soon have a more complete genetic signature that reveals susceptibility, such as from genes like APOE ε4. What can clinicians do now? “The take-home message is that anybody who had been treated with cadaveric growth hormone and is at risk probably ought to be followed. You don’t need to worry about somebody else getting this,” Rogol says. Research into the use of human tissue from one individual to another should continue, he emphasizes, given this sobering lesson about unintended consequences, with nothing but the purest of intentions.
Horvath is a freelance writer based in Baltimore, Md. She wrote about the remarkable AI research presented at ENDO 2025 by the Elangovan siblings in the September issue.
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