The link between autism and testosterone is an interesting one. I know of no studies comparing testosterone in the autistic population compared to the NT population. (Surely this hypothesis would not be difficult or expensive to test for.)
I was at autism one this year and heard the Geiers' talk on their clinical experiences. They did see a link in their practice; as I recall they found that girls in particular who were autistic almost always had high testosterone and usually responded well to Lupron therapy. Warning: googling "autism testosterone geier" will bring up lots of vitriol.
In another talk,
Prof. Boyd Haley showed that added testosterone greatly worsened rat's health in the presence of mercury, providing a hypothesis for a causative relationship. Those experiments injecting rats seemed like good, straightforward science to me.
It does make one wonder. According to the finger length test (ring finger longer than the index finger), I and my son have above average testosterone. For me I should maybe say 'had', since my finger length hasn't changed that much lately. ;)
In my family's case with our 7-year-old, we have had good results in our biomedical interventions without chelation or any intervention related to testosterone, so for us it hasn't been a question of exploring these therapies.
Stephen
We can't afford all biomedical interventions.
There are many kids (both male and female) with increased levels of testosterone. My son is one of them. His testosterone level was in the 200¡¯s (a normal reference range is under 10) There is an alternative to Lupron. We used Spironolactone. Here is Dr. Bradstreet¡¯s report on Spironolactone.
Medical Hypothesis Submission
Spironolactone may be an ideal immunological and hormonal intervention in autism spectrum disorders.
J. Bradstreet MD1, S. Smith PA-C1, D. Granpeesheh PhD2, J El-Dahr3
1International Child Development Resource Center, Melbourne and Florida Hospital, Celebration, Florida
2 Center for Autism Related Disorders, Tarzana, California
3 Tulane University Medical School, Department of Pediatrics and Medicine and Section of Pediatric Allergy, Immunology and Rheumatology
Introduction
Classical thinking regarding autism defines it as a developmental disorder with abnormalities in language, socialization and stereotypical unusual behaviors. Autism spectrum disorders (ASD) are increasingly reported as being both common and linked to various triggers. Two recent studies on prevalence increases concerns over the expansion of this disease, with indications 1 to 2 % of boys may be affected - . Both studies confirm previous observations that approximately 4 times as many males are affected as females. However a genetic link to the XY chromosome axis is lacking, implying a likely hormonal vulnerability to certain environmental triggers. Abnormally high levels of androgens have been an inconsistent finding in autism, however several studies confirm that at least a subset of children can be documented to have elevated testosterone and/or dehydroepiandrosterone (DHEA) levels in ASD , & . This spectrum of disorders are also widely recognized as having a degree of gene ?environment interaction as recently reviewed by the CHARGE study .
Recognition has been growing over the past 30 years that autism spectrum disorders are often associated with abnormal immune function. In 1976, Stubbs first noted the absence of a normal response to rubella vaccination in a group of children with autism. Then in 1977, Stubbs and Crawford went onto to demonstrate suppressed responsiveness to in vitro phytohemagglutinin (PHA) stimulation of lymphocyte cultures . Then as early as 1982, Weizman and colleagues demonstrated abnormal cell-mediated immune response to brain tissue in ASD . The understanding of cell-mediated immune dysfunction was expanded by 1986 to including reduced responsiveness in the lymphocyte blastogenesis, decreased numbers of T lymphocytes, and an altered ratio of helper to suppressor T cells . Then Warren next demonstrated reduced natural killer cell activity in ASD affected children . As further evidence regarding immune abnormalities mounted in the neuroimmunopsychiatry literature, , & Francesetti and colleagues advanced the hypothesis on the role of the immune system in the pathogenesis of both schizophrenia and infantile autism .
By the 1990?the science of immunology was rapidly expanding being spurred on by the successes of AIDS-related research and large governmental grants. This permitted a more advanced investigation of the neuroimmune aspects of autism. Singh et al first reported in 1991 finding abnormal cytokine levels which indirectly indicated activation of a subpopulation of T cells in autism . The autoimmune aspect of autism was furthered by Warren et al when they found abnormalities in T cells compatible with an autoimmune disorder . Scifo et al reported a favorable decrease in autism symptoms directly related to normalization of immune abnormalities following intervention with naltrexone . The treatment resulted in a significant increase of the T-helper-inducers (CD4+CD8-) and a substantial reduction of the T-cytotoxic-suppressor (CD4-CD8+) thereby normalizing the CD4/CD8 ratio. Singh reported increased levels of interferon gamma and interleukin 12 and interpreted these as a further indication of autoimmunity . This autoimmune theory of autism was again reinforced by the observations of increased levels of urinary neopterin and biopterin, which was compatible with cell immune activation . Adding more weight to this argument were the observations of autoantibodies to the brain endothelium by researchers at Washington University in St. Louis . Connolly and associates then went to further define the association of brain directed sera autoimmune markers as related to brain derive neurotrophic factor (BDNF) . Recently, researchers at the University of Cincinnati, found a blood cytokine profile consistent with increased activation of both the Th2 and Th1 arms of the adaptive immune response, with aTh2 predominance, but without the compensatory increase in the regulatory cytokine IL-10 .
Simultaneous to this backdrop of brain related immune investigations; other researchers were studying the link between dietary proteins in autism. Jyonouchi et al observed that children with autism produced an excess of tumor necrosis factor alpha (TNF-alpha) in response to dietary proteins and bacterial endotoxin ?lipopolysaccharide (LPS) & . Of further interest in related research, others detected likely cross-reactivity of the wheat derived protein, gliadin, and Purkinje cell peptides . In this the researchers noted an eight amino acid shared sequence which would be more than adequate to trigger immune cross-reactivity and hence autoimmunity. This research would still fall short of a direct mechanism of peripheral activation of the immune system triggering neurodevelopmental disruption, but the immune state was become clearer.
As the immune disruptions in autism were being defined, another pathway of immune research looked at the observations of a distinct inflammatory bowel disease and other gastrointestinal disorders, including abnormal carbohydrate digestion and reflux esophogitis were being reported . While this remains an emotionally charged debate in medicine secondary to issues surrounding purported measles mumps and rubella vaccine reactions , the observations of panenteric bowel disease are now well recorded in the medical literature . The gastrointestinal inflammation features of autism are finding greater acceptance by diverse investigators , & .
The specific brain immune findings have been assisted by greater access to autism brain tissue banks. With this researchers are looking at details of the immunological changes within the brain. In what appears to be a landmark study, Vargas et al, observed neuroglial activation and evidence of inflammation in both children and adults with autism . Their observations were of unquestioned importance and included: marked activation of microglia and astroglia, and cytokine profiling indicated that macrophage chemoattractant protein (MCP)-1 and transforming growth factor-beta1, derived from neuroglia, were the most prevalent cytokines in brain tissues. Further the cerebrospinal fluid (CSF) showed a unique proinflammatory profile of cytokines, including a marked increase in MCP-1and interferon gamma. Intriguingly, researchers from the same institution were not able to reproduce similar findings in the CSF in a different population of children in a later study . The original study differed from the later by specifically looking at brain tissue levels of immune activators as well as documenting the histiological changes in both microglia and astroglial cells. The first study also histiologically documented perivascular neuroglial activation in the brain. This observation is consistent with either astrocytic defense of the blood-brain barrier or autoimmune activation and is concerning in light of the previously mentioned endovascular autoimmunity reported by Connolly et al.
Hypothesis
Spironolactone is an aldosterone antagonist - potassium sparing diuretic that possesses potent immune and hormone modifying properties which may make it ideally suited for use as an intervention in autism spectrum disorders.
Evidence and Discussion
A favorable clinical response to immune modification when combined with the serological and immune cellular abnormalities encourages both the interest in immunological interventions for autism and supports the underlying immune-mediated etiology of the disorder. Gupta et al observed both immune dysregulation and a favorable response to treatment with human immunoglobulins (IVIG) . Not all investigators have been able to reproduce as favorable of a response to IVIG, but subpopulations of immune deficient children with autism have been reported to respond favorably to IVIG in the majority of cases . Several others have reported favorable reactions to elimination of dietary proteins which are now presumed to be potent inducers of proinflammatory cytokines. A study in 1978 evaluated the effects of a carefully constructed elimination ?reintroduction diet on disruptive and hyperactivity behavior in an 8 year-old boy . Results showed that foods such as wheat, corn, tomatoes, sugar, mushrooms, and dairy products were instrumental in producing behavioral disorders with this child. Several years before Jyonouchi and colleagues published the previously mentioned findings regarding marked increase in TNF alpha in response to milk proteins, 36 Italian children with autism were studied for response to milk elimination and also compared milk-related antibodies in the cases as compared to 20 control children . They noticed a marked improvement in the behavioral symptoms of patients after a two month milk elimination diet and higher antibody levels to milk proteins in the autism population. Dr Cade et al, at the University of Florida reported a significant improvement in 81% of children with autism who went on a gluten and casein elimination diet . A Norwegian cohort followed for four years with a similar diet also showed significant improvement in cognitive abilities and communicative skills . Gupta reviewed the medical literature on various immunological interventions for autism including : transfer factor (TF) which has been observed to confer immunity to the recipient, pentoxifylline, a phosphodiesterase inhibitor, which is known to have immunomodulatory, effects, IVIG which is the concentrated immunoglobulins, primarily IgG, which has been shown to be beneficial in other neuroimmune disorders as well as epileptic disorders. As mentioned previously Scifo et al found the therapeutic benefit of low dose naltrexone in children with autism was associated with reduction in cytotoxic T cells and normalization of the CD4/CD8 ratio.
Typically in refractory immune activation disorders, especially autoimmune disorders, clinicians eventually attempt systemic corticosteroids in an attempt to down-regulate the immune system. Little has been published regarding this intervention for autism, however, in an intriguing case-report; Shenoy et al described a child who rapidly developed autism with the onset of autoimmune lymphoproliferative syndrome (ALPS) . Low-dose steroid treatment resulted in rapid relief of the ALPS and eventual complete remission of the autism as well. Another report also showed significant improvement following corticosteroids in a child with pervasive development disorder .
Additionally, data from several previously mentioned sources on the possible role of elevated androgens in aggressive behaviors and possibly the pathogenesis of autism, lends support to interventions to reduce androgenic activity as well. In addition to their published works on the subject, Geier and Geier have presented their unpublished clinical findings regarding leuprolide acetate, a synthetic nonapeptide analog of naturally occurring gonadotropinreleasing hormone, as an intervention for children with concurrent autism and elevated androgens . While the application of the diagnosis of precocious puberty to the Geiers reported population is as controversial as the intervention itself, the parental and clinical observations are at least intriguing. Of concern is the simultaneous treatment with Succimer (DMSA) a heavy metal chelator. Without delving into the mercury-based research in autism, using a chelator with leuprolide acetate makes attributing the observed benefits to hormone manipulation more challenging. Despite this controversy, others have found leuprolide acetate beneficial in the management of troubling sexual behaviors in autism .
Given the large body of experimental and clinical observations regarding immunological and hormonal issues in autism, an ideal interventional agent could be conceived of as simultaneously addressing both issues. This agent might have the following properties: 1) downregulation of the TNF-alpha response to provoking agents, 2) decrease in MCP-1and interferon gamma in the brain with resultant decrease in glial activation/inflammation, 3) decrease in inflammation in the gastrointestinal tract, 4) and decreased androgenicity without interference with normal growth. Given these criteria, spironolactone would appear to have nearly ideal properties. Spironolactone is an aldosterone antagonist available only by prescription. It is generally known as a potassium sparing diuretic with a lengthy period of observation in both children and adults. Its common and indicated uses are for: congestive heart failure, hyperaldosteronism, edema associated with liver failure, nephrotic syndrome, hypertension, and hypokalemia (low serum potassium). It is considered safe for children when used in typical doses (ie, 1-3 mg/kg/day) , although the official FDA literature places it as having not been established. The oral LD50 of spironolactone is greater than 1,000 mg/kg in mice, rats, and rabbits .
It was first known to possess anti-inflammatory properties as early as 1961 However that observation seems to have gone largely unnoticed until the last few years. In a recent study, Japanese researchers looking for a reduction in cardiovascular risk factors related to inflammation found spironolactone was the most potent anti-inflammatory the studied . Specifically, it was found to potently reduce both TNF-alpha and MCP-1 in cultured human monocytes. These effects occurred at levels obtainable during routine oral administration of the medication. In a Danish population of rheumatoid arthritis patients (including juvenile idiopathic arthritis), a modest dose of 1-3 mg/kg/day resulted in significant reduction in proinflammatory cytokines as well as the decreased gene transcription for many regulators of inflammation . In this study incubated human whole blood treated with spironolactone dramatically reduced interferon gamma and substantially reduced TNF-alpha. None of the juvenile arthritis patients had to withdraw from the study and 8 of 9 children (mean age 12) responded favorably to spironolactone at a dose range of 2-3 mg/kg/day. One female patient had disruption of her menstrual cycle, a known side-effect. In an extensive analysis of the use of spironolactone for hirsutism and acne in female patients, the reviewers concluded the published literature demonstrated that six months treatment with 100 mg/day spironolactone compared with placebo was associated with a statistically significant subjective reduction in abnormal hair growth . They observed spironolactone at a dose of 100mg/day was superior to either finasteride or cyproterone acetate (other common anti-androgens). Spironolactone by itself had little effect on DHEA, DHEA-S, or testosterone levels in the studies evaluated in this Cochrane Review. Rather, the mechanism of action is related to the binding of spironolactone with dihydrotestosterone (DHT) receptors on cell surfaces, thereby inhibiting the binding of DHT .
Other authors have termed the recent discovery of the immunological benefits of spironolactone as its renaissance . Our clinical experience with spironolactone and autism leads us to believe it may extend its successes to this population as well. As an example, a 12 year old boy with well established autism, immune dysregulation, food allergies and hypertestosteronism showed significant reduction in the severity and frequency of several aberrant symptoms within four weeks of administration of spironolactone at a daily dose of 2mg/kg. Specifically, administrations of the Aberrant Behavior Checklist (ABC) prior to and following implementation of spironolactone indicated a 21% improvement in irritability, a 17% decrease in lethargy, a 40% reduction of stereotypy, a 28% reduction of hyperactivity and a 33% decrease in inappropriate speech. (table 1).
In addition, pre and post administrations of the Peabody Picture Vocabulary Test (PPVT III) demonstrated a receptive language gain of 1 year 9 months in this same four week period, indicating an increase in vocabulary greater than one standard deviation at either age level.
Table 1. Change the ABC subset scores pre and post spironolactone at a dose of 2 mg/kg for 4 weeks.
Levels of immunoglobulins were measured immediately prior to treatment with spirolactone 100 mg daily (approximately 2 mg/kg/day). Cellular immune parameters and testosterone were assessed within one year and for androgens, again at 6 months prior to treatment. Laboratory results are shown in Table 2.
TABLE 2
Conclusion
Spironolactone is a low-cost, easily available oral agent with a desirable safety profile, and with nearly ideal immune modification properties. Its secondary benefits as an anti-androgen may further enhance its appeal in autism, particularly in a definable subset of hyperandrogenic children. It therefore justifies more extensive research in controlled trials to further define its risks and benefits in children with autism Thought I would re-post the concerns and questions I posted (with a couple of new thoughts) when this above informational piece was posted a while ago on this site.
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This is all a fascinating and deliberately confusing presentation by the researchers but still actually provides very little information about real kids in real time and with regards to real numbers. Autism has genetic and potential immuno system involvement. But autism is also absolutely not an homogeneous disorder with a common etiology (like diabetes or juvenile arthritis) and etiological foundations must first be established before such dense medical preentations are offered and consistent treatments provided. Besides everything else, this means at the minimum that all of these very dense medical statements simply are not uniformly applicable¡if applicable much at all.
As one reads through this information, there are constant references to individual case studies (one child) and very small numbers of children targeted. Furthermore, the authors use words like ¡°subsets,¡± ¡°interpreted these¡.,¡± ¡°¡further observations¡,¡± ¡°intriguing,¡± ¡°conceived as¡,¡± and ¡°others detected..¡± At another point, this piece notes that ¡°Intriguingly, researchers from the same institution were not able to reproduce similar findings in the CSF in a different population of children in a later study¡± but then failed to actually dismiss any of the original findings.
The statement which reads that ¡°not all investigators have been able to reproduce as favorable of a response to IVIG, but subpopulations of immune deficient children with autism have been reported to respond favorably to IVIG in the majority of cases¡± raises a handful of questions. First, why can¡¯t more investigators ¡®reproduce¡¯ a ¡®favorable¡¯ response and who are the ¡°subpopulations of immune deficient children¡± to whom a reference is made?
Without further comment, the author then writes that ¡°several others have reported favorable reactions to elimination of dietary proteins which are now presumed to be potent inducers of proinflammatory cytokines¡± and makes a quick cite of one 29 year old study of diet on one 8 year old child. Well, one study of one child nearly 30 years ago is hardly the data base to make any kind of broad outcome statement or treatment decisions as it might apply to other children. I would also want to know who the ¡°several others¡± are, what they did, how many children did they provide the intervention for, and what, exactly, is a ¡®favorable¡¯ outcome? Outcomes must be clearly described in valid research.
At still another spot, there was a statement that ¡°using a chelator with leuprolide acetate makes attributing the observed benefits to hormone manipulation more challenging.¡± Even though the observed benefits of this treatment were ¡°more challenging,¡± the authors still wrote that ¡°despite this controversy, others have found leuprolide acetate beneficial in the management of troubling sexual behaviors in autism.¡± Even though success has not been clearly documented, the author makes a reference to the unknown ¡®others¡¯who have found the intervention ¡®beneficial¡¯ for not very well defined behavioral needs. Again, this is all very unclear and not a basis for treatment recommendations in and of itself.
As one highly trained in advance research methdology and autism, please accept my observation that the fact that unamed ¡°others¡± have found something ¡°beneficial¡± does not warrant its utilization¡even if it had been more clearly described. I would also be MOST curious to read the very quickly referenced study from the U of Florida which claimed a ¡°significant improvement in 81% of children with autism who went on a gluten and casein elimination diet¡± since there is absolutely no otherwise evidence of such tremedously high outcomes with dietary interventions in autism (which, of course, does not mean that diet does not remain an important target for children with autism). There seems a very distinct effort here to collect a huge amount of very fragmented medical information and make it appear as a cohesive unit.
It is very likely that buried deep inside this medispeak is some worthwhile information that can benefit some children both with and without autism. But inasmuch as autism remains a developmental behavioral disorder of unknown and highly varied etiologies and physiology, a single intervention construct or medical etiology is not yet definable across the larger number of children considered autistic.
So, presuming a standardized medical model (to which this piece certainly never comes close¡though it may sound like it based on the language employed) remains counterproductive. I wonder how much these authors understand about the contextual-behavioral and instructional models for the support of children with autism and their families? I would highly doubt that they are even generally familiar with the behavioral and instructional intervention literature available.
http://www.autism-world.com/index.php/2007/03/30/lower-testo sterone-cure-autism/