I thought I’d seen it all.
Ever since I found myself critically examining the claim that autism and autistic spectrum disorders are caused by mercury found in the preservative(thimerosal) used until recently in childhood vaccines, I thought that I’d heard of every dubious or quack autism therapy there is out there. Indeed, it is from that concept (that “autism is a misdiagnosis for mercury poisoning,”, which is not supported by epidemiological or preclinical evidence) that flows all sorts of dubious therapies to “remove” the mercury. Foremost among these questionable therapies is chelation therapy, using a chelating agent like EDTA or DMSA to bind to and remove this supposed mercury excess. This therapy is touted as being extremely effective in improving the behavioral abnormalities in autism, but, contrary to what its proponents say, it is neither efficacious nor safe. Indeed, six months ago it resulted in the death of an autistic boy named Abubakar Tariq Nadama at the hands of a quack named Dr. Roy Kerry in a clinic near Pittsburgh. There are many variations of chelation therapy, including Dr. Rashid Buttar‘s famous “transdermal” chelation. Despite the fact that Dr. Buttar has never been able to demonstrate scientifically that his DMSA-laced cream chelates anything or is even absorbed through the skin, parents line up to pay him big bucks to administer this therapy. Not long after Abubakar’s death, I learned of another variant that Dr. Buttar has come up with that involves intravenous minerals, intravenous ozone, and an unnamed “environmental detoxifier,” to treat autism. (One wonders if it’s because even Dr. Buttar is starting to realize that chelation therapy doesn’t do anything for autism.)
Yes, I thought I’d seen it all. I thought that no proposed treatment for autism could be so bizarre, so unbased in science, so risky, that it would shock me anymore.
Or so I thought until I read a rather lengthy account by Kathleen Seidel, who runs the Neurodiversity website about how the concept of “testosterone regulation” has risen from the underbelly of the fringe of the “mercury equals autism” community and started to make appearances in the mainstream press.
What caught my attention and shocked me so much? What therapy could once again make me wonder what these people are smoking or whether they’re on crack?
They’re talking about adding chemical castration with Lupron to chelation therapy as a “treatment” for autism.
Yes, chemical castration. Mark and David Geier, the father-son tag-team of VAERS database dumpster-divers who don’t seem to be too concerned about following Institutional Review Board guidelines while diving in, have latched on to the idea that lowering testosterone will “increase the efficacy” of chelation therapy. That’s why they want to give Lupron to children. Others (links at the end of the article) have weighed in on this issue extensively, making me wonder whether there was anything further I could contribute. After thinking about it, however, I realized that my unique contribution could be to look at the Geiers’ concept (I won’t dignify it with the word “hypothesis”) from a scientific point of view to explain why it’s such a bad idea. Before I dive into the “science” behind the Geier testosterone hypothesis, it behooves me to take a moment to explain just what Lupron is.
Lupron is the trade name for a drug called leuprolide acetate a synthetic analog of a hormone known as gonadotropin releasing hormone (GnRH, a.k.a. LH-RH). After causing an initial stimulation of gonadotropin receptors by binding to them, chronic administration of Lupron inhibits gonadotropin secretion, specifically leutenizing hormone (LH) and follicle stimulating hormone (FSH). The end result is the inhibition of the synthesis of steroid hormones in the testes in men and in the ovaries in women. In men, testosterone and androgen levels fall to castrate levels, and in women estrogens are reduced to postmenopausal levels.
This is a drug that doesn’t have very many uses. Perhaps the most common use is in men with metastatic prostate cancer, because prostate cancer is an androgen-dependent tumor. Back when I was a surgical resident, such patients were treated with surgical castration. These days, they are usually put on Lupron or a similar GnRH agonist, and this treatment works quite well to suppress the growth of prostate cancer for a while. Such tumors will inevitably develop androgen-independent growth and become resistant to hormonal suppression with Lupron, but in the meantime chemical castration with Lupron can provide excellent palliation. Another use for Lupron is in women with estrogen-dependent conditions, such as endometriosis and uterine fibroids. One troubling side effect of its use in women is the onset of menopausal symptoms, often quite severe, a problem that sometimes causes women to stop taking it. The other major use of Lupron is during cycles of in vitro fertilization, in which it is used to suppress ovarian function completely in order to allow complete control of hormone levels and ovarian follicle development through the use of hormone injections. Without Lupron or similar drugs, it is very difficult to get multiple ovarian follicles to develop and mature at the same time, allowing the harvest of many eggs.
But we’re not talking about adults here. We’re talking about children. Are there any medically accepted uses of Lupron in children? Yes, but only one: Precocious puberty. Precocious puberty is defined as the onset of secondary sexual characteristics before 8 years old in girls and 9 years old in boys. It can be the result of tumors, central nervous system injury, or congenital anomalies. The package insert for Lupron emphasizes that children should not be treated with Lupron unless they meet the following criteria:
- Onset of secondary sexual characteristics before age 8 in females and age 9 in males.
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The clinical diagnosis must be confirmed by a pubertal response to GnRH (adequate secretion of LH in response to a challenge with injected GnRH) and bone age advanced at least one year beyond chronological age.
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Baseline evaluation has to include: Height and weight measurements; sex steroid levels; adrenal steroid level to rule out congenital adrenal hyperplasia; beta-chorionic gonadotropin (beta-HCG) to rule out a beta-HCG-secreting tumor; pelvic and adrenal ultrasound to rule out a steroid-secreting tumor; and a CT of the head to rule out an intracranial tumor.
Also, precocious puberty is a rare condition.
Any bet as to whether the Geiers will adhere to these guidelines? (That is, of course, a sucker’s bet.) In my book, if you’re going to give a potent drug like Lupron to children, a drug that can almost completely shut down the synthesis of both male and female steroid hormones, you’d better have damned good evidence that it’s likely to help to make it worth the risk.
So do the Geiers have good evidence? Take a guess. As pointed out by Kathleen, the Geiers seem quite excited about manipulating testosterone levels and are recruiting children for a trial, having presented their concept last year at the Autism One quackfest in Chicago. Prior to that, they had published their idea in a medical journal known as Medical Hypotheses, giving it the patina of respectability. The problem is, Medical Hypotheses is a fringe journal that is not well respected. For one thing, it’s not peer-reviewed. The other reason that it exists to publish “radical” ideas that “conflict with current theory and practice,” as stated on its website:
Medical Hypotheses takes a deliberately different approach to peer review. Most contemporary practice tends to discriminate against radical ideas that conflict with current theory and practice. Medical Hypotheses will publish radical ideas, so long as they are coherent and clearly expressed. Furthermore, traditional peer review can oblige authors to distort their true views to satisfy referees, and so diminish authorial responsibility and accountability. In Medical Hypotheses, the authors’ responsibility for the integrity, precision and accuracy of their work is paramount. The editor sees his role as a ‘chooser’, not a ‘changer’: choosing to publish what are judged to be the best papers from those submitted.
Papers in Medical Hypotheses take a standard scientific form in terms of style, structure and referencing. The journal therefore constitutes a bridge between cutting-edge theory and the mainstream of medical and scientific communication, which ideas must eventually enter if they are to be critiqued and tested against observations.
Not surprisingly, the Geiers have published in this journal before touting their belief that mercury causes autism. One can see why. All it takes is a reasonably well-written paper espousing a “radical” idea to be accepted for publication. Not surprisingly their paper containing their speculations that testosterone contributes to autism and that lowering testosterone levels might be a treatment that “increases the efficacy of chelation” fit right in.
The paper is a mess, full of unsupported speculation. Its first flaw is apparent right from the beginning. First, the Geiers implicitly assume that mercury is the cause of autism and that chelation is the cure. As evidence, they cite the usual suspects, such as the Hornig “rain mouse” study; the Redwood et al study using a model to predict the hair level of mercury due to vaccines (while ignoring the Pichichero et al, which actually measured the levels and showed that mercury levels in infants given thimerosal-containing vaccines according to a standard schedule had blood levels well within what is considered safe); papers studying cultured cells treated with ridiculously high concentrations of thimerosal, concentrations unattainable in humans; and the infamous Boyd Haley study that showed lower levels of mercury in the hair of autistic babies compared to normals, leading him to speculate without evidence that autistics do not secrete mercury as well, leading it to accumulate in the brain. They also cited the Bradstreet article that looked at mercury levels excreted in response to a “challenge” with the chelating agent DMSA and supposedly found that autistic children secrete more mercury than nonautistic children. The problem was, Bradstreet used a nonstandard method of normalizing their mercury concentrations in the urine, didn’t measure total mercury excretion, not to mention that they didn’t match the ages of their groups very well. Worse, their data is so full of scatter that it’s hard to tell how they made any conclusions. (Not surprisingly, this article was published in the Journal of American Physicians and Surgeons, a really crappy journal that’s chock full of antivaccination rhetoric, antifluoridation articles, and an article defending Alan Yurko, an antivaccination activist who was tried for shaking a baby to death but got off by claiming it was the result of vaccines causing encephalitis. Many of the rest of the articles cited had been written by the Geiers themselves, and they ignore important studies that cast serious doubt on any link between mercury and autism. Worse, through it all, the Geiers state as fact that chelation therapy is effective, when there is in fact no credible evidence suggesting that it is.
The new twist that the Geiers have placed on their mercury madness is the concept that testosterone somehow increases the toxicity of mercury. The way the Geiers come to this concept is rather roundabout. First they cite a paper suggesting that there are increased markers of increased oxidative stress in autistic patients. (To me this begs the question of why there is so much focus on mercury rather than abnormalities in oxidative metabolism in autism. But I digress.) They also present a paper in which the investigators treated cultured neuroblastoma and glioblastoma tumor cells with high concentrations of thimerosal and show that pretreatment with glutathione (an antioxidant) is protective against thimerosal toxicity. However, the authors themselves state:
Acute high dose exposures to Thimerosal (mmol/L) in cultured cells were used to study mechanistic aspects of Thimerosal toxicity and not intended to mimic exposures of developing brain cells in vivo to Thimerosal in vaccines (nmol/kg).
Little details like that never stopped the Geiers from representing the study as strong “evidence” that defects in oxidative metabolism potentiate thimerosal toxicity as a cause of autism. At best the study shows that very high concentrations of thimerosal are toxic to brain cancer cells and that glutathione can protect these cells.
So how do the Geiers link oxidative metabolism defects observed in some autistics, testosterone, and mercury? Well, if you’re the Geiers, it’s easy. You wave your hands and point out that one of the one enzyme (hydroxysteroid transferase) that modifies a testosterone precursor DHEA to DHEA-S (a sulfate group added) requires glutathione and is inhibited by mercury. Of course the Geiers cite a 30-year old paper and don’t even use the name of the enzyme that I find in the more recent literature, namely DHEA sulfotransferase. In any case, DHEA is the main precursor to androgens like testosterone, and DHEA sulfotransferase adds a sulfate group to it, “shuttling” DHEA away from the pathway to make testosterone by turning it into DHEA-S. DHEA-S is thought to be a “storage” form of DHEA, and DHEA and DHEA-S are freely interconverable. If something prevents DHEA from being converted to DHEA-S, there’s more precursor for testosterone synthesis. Elevated DHEA and DHEA-S levels have been implicated in polycystic ovary syndrome.
This all sounds well and good, but there’s no evidence that any of this, at least as explained by the Geiers, has anything to do with autism. The abnormalities in oxidative metabolism observed in some autistics may be a cause of autism or they may simply be a consequence of other genetic abnormalities that are responsible for autism. It is impossible to know their significance with the current state of our data. Worse, as Kathleen pointed out, the Geiers have been quoted as saying that mercury binds to testosterone and forms “sheets” in the brain, leading to a complex that can’t pass the blood-brain barrier and keeps mercury in the body. Besides the fact that there is no persuasive evidence that mercury causes autism in the first place, there is even less evidence that testosterone in any way prevents the elimination of mercury from the body. I can’t help but note that the claim that testosterone binds mercury and prevents it from being excreted was not in the Medical Hypotheses paper, suggesting that it’s too far out even for that far out journal,. Instead, the Geiers included large figures showing complex pathways of steroid biosynthesis and wildly speculated that the combination of testosterone and decreased glutathione might inhibit the activity of DHEA sulfotransferase. Thus even if mercury were the cause of autism, there would be no biochemical justification for the shotgun approach of using Lupron to suppress steroid hormone synthesis in boys. Remember, Lupron doesn’t just suppress testosterone production; it suppresses both the androgenic and estrogenic pathways.
Once again, if you’re going to propose doing something as radical as shutting down steroid hormone synthesis in children, you’d better have damned good evidence to justify it, and the Geiers don’t. The best piece of clinical evidence that suppressing testosterone might help autistic boys they can muster is a case report in which a 24-year old autistic man exhibiting severe frequent inappropriate sexual behavior who frequently masturbated in public and became sexually aroused around young children was placed on Lupron. Surprise, surprise! His inappropriate sexual behavior decreased markedly. Chemical castration will do that. This case report says nothing about what treating children with Lupron would do. (It also raises some rather touchy ethical questions.)
It isn’t that there hasn’t been at least some evidence suggesting that abnormal testosterone levels to autism. There’s just one problem. Nearly all of the evidence supporting such this link has correlated high levels of prenatal exposure of the fetus to testosterone with autism and autism spectrum disorders. The main proponent of this hypothesis is Simon Baron-Cohen, who has published papers showing correlations between elevated fetal testosterone and empathy, decreased quality of social relations, gender-typed play, and autism. This has led to Baron-Cohen’s concept that autism is due to an “extreme male brain.” This is a controversial concept in the autism research community, and I can see why. Personally, I found the evidence supporting this concept to be a somwhat shaky after reading several papers describing it. Even so, the concept is probably worth further study. Of course, none of Baron-Cohen’s data provides any real support for the Geiers’ concept that lowering testosterone will help autistics. Nearly all of the evidence implicating testosterone in autism pathogenesis come from correlations with prenatal testosterone levels and markers for high prenatal levels of testosterone. Presumably, treating children several years after birthwould be too late; the brain has already been shaped by the prenatal testosterone. Only one study cited looked at postnatal testosterone levels. This study, reported in a letter to the editor rather than as peer-reviewed journal article, only studied 9 children, three of which were observed to have elevated testosterone levels. Of course the very same authors’ previous paper (which was actually published in a peer-reviewed journal) found no elevation of testosterone levels in prepubertal autistic patients. Funny that the Geiers didn’t cite that one. (Actually, no it isn’t.)
What I’d like to know is how the Geiers can get away with starting a clinical trial on such flimsy or nonexistent evidence. To protect patients from dangerous or unethical experiments, all studies involving human subjects by law must be approved by an approved Institutional Review Board, and there is no IRB that I know of that would approve a study giving Lupron to autistic children without a hell of a lot more preclinical evidence that it might do some good at an acceptable risk-benefit ratio. Of course, the Geiers have never been too much for the niceties of clinical research rules designed to protect patients, such as abiding by IRB restrictions. IRB approval or no IRB approval, as Kathleen pointed out, they are recruiting children for their Lupron protocol and implying that insurance would pay. (Anyone want to take any bets on how long it is before there is a flood of autistic boys with the diagnosis of “precocious puberty”?)
What the Geiers propose goes way beyond “off label” use; it’s strictly experimental. One has to wonder whether TAP Pharmaceuticals, the maker of Lupron, has any idea what the Geiers plan. Fortunately, Kathleen Seidel and others plan to make sure that they do. Even from a strictly financial perspective, it’s unlikely that the relatively small number of parents who would take this path would add enough to TAP’s bottom line to be worth the hit the company’s reputation would take from being associated with this quackery. There’s also the matter of cost. I happen to know from speaking to a friend who underwent in vitro fertilization that, at least as of three or four years ago, Lupron did not cost anywhere near $2,000 a shot. It was more like 1/10 that, $250 for a multidose vial; at least that’s what the insurance company was billed. (And remember that a child’s dose would be much less than the adult dose.) This implies that, if the Geiers are, as described by one mother, charging that much to administer this drug…well, you do the math. Perhaps inflation is worse than I thought, or perhaps the insurance company got a huge discount, which parents trying to get Lupron for this unapproved and inappropriate use don’t have access to. Perhaps.
The truly odd thing about this development is that it goes against so much of the rest of the movement for biomedical therapies for autism, most of which involve a fair amount of altie treatments. In fact, it’s hard for me not to wonder if the Geiers are becoming “pharma shills.” Indeed, the irony of the Geiers recommending a heavy-duty high risk pharmacological therapy for autism so much like “conventional medical therapies” that so many of the “mercury equals autism” crowd eschew is just oo rich. It is this “big pharma” approach that has caused even some die-hard chelationists to balk at this new folly coming from the Geiers.
But not enough, I predict, to prevent the Geiers from subjecting a number of autistic children to an expensive, risky, and almost certainly ineffective course of treatment, chemical castration. Sure, such a treatment will probably make autistic boys more docile, but at what cost?
Some previous posts on this topic:
More:
Autism & Lupron: Playing With Fire
Lupron rears its head
Autism & Lupron
Loopy Lupron, a Horrible Mistake or Something Worse?
Playing With Fire
ADDENDUM 8/31/2006: Due to a comment spam attack that sseems to like this post in particular (among a few others), I’m shutting down comments and trackbacks.
