Download Neurodevelopmental Disorders Following Childhood

The Biochemical Basis of
Autistic Disorders :
The Mercury, Androgen (Testosterone), & Glutathione Connection
Mark R. Geier, MD, PhD, FABMG, FACE
President
The Genetic Centers of America
Phone: (301)989-0548
Email: [email protected]
David A. Geier
Vice-President
The Institute of Chronic Illnesses, Inc.
Copyright 2008
Mercury Exposure
Background Information
Thimerosal & Vaccines:

Thimerosal is an organic mercury compound
(50% mercury be weight) that is metabolized to
ethylmercury and thiosalicylate and has been
present since the 1930s as a preservative in
some vaccines and pharmaceutical products to
prevent bacterial and fungal contamination.

The FDA in 1999, under the recommended
childhood immunization schedule, determined
infants might be exposed to cumulative doses of
ethylmercury that exceed some federal safety
guidelines established for exposure to
methylmercury, another form of organic
mercury.
Thimerosal: The Early History
Source:
Geier DA, Sykes LK, Geier MR.
A Review of Thimerosal (Merthiolate) and its Ethylmercury Breakdown
Product: Specific Historical Considerations Regarding Safety & Effectivness.
Journal of Toxicology & Environmental Health: Part B Critical Reviews
2007;10:575-96.
Smithburn KC, Kempf GF, Zerfas LG, Gilman LH.
Meningococcic Meningitis: A Clinical Study of 144 Epidemic Cases.*
Journal of the American Medical Association 1930
“TREATMENT
The treatment has remained essentially the same throughout the
epidemic. The routine adopted included, on admission, a skin
sensitization test, rhacehicentesis and intratheceal serum
intramuscular serum and (especially during the second month
of the epidemic) serum intravenously. Intravenous
administration of an antiseptic solution was tried and found
wanting despite the in vitro activity of the agent.”
* From the Lilly Laboratories for Clinical Research, Indianapolis City Hospital
The bacteriologic and serologic studies were made by H. M. Powell, A.B., Sc.D., and F. G.
Jones, of the biologic department of the Lilly Research Laboratories.
Powell HM, Jamieson WA. Merthiolate as a Germicide.*
American Journal of Hygiene 1931
“Toxicity in Man. Merthiolate has been injected intravenously into 22 persons
in doses upt to 50 cubic centimeters of 1 per cent solution. As many as five
intravenous doses, or a total of 180 cubic centimeters of 1 per cent
Merthiolate, have been given to one individual (see table 7). These large doses
did not produce any anaphylacotid or shock symptoms. Neither did these
quantities in the repeated doses bring about any demonstrable later toxic
effects. The toleration of such intravenous doses indicates a very low order of
toxicity of Merthiolate for man. This information has been supplied through
the kindness of Dr K. C. Smithburn of Indianapolis who has had occasion to
use Merthiolate in a clinical way. Dr. Smithburn state that in these cases
‘beneficial effect of the drug was not definitely proven. It did not appear
however to have any deleterious action when used in rather large doses
intravenously when all the drug entered the vein.’”
* From the Research Laboratories, Eli Lilly Company, Indianapolis, Indiana.
We wish to express our thanks to Dr. G. H.A. Cloves; Director of Research of the Eli Lilly
Company, for assistance and suggestions in the course of this investigation.
Letter from the Director of Biological Laboratories
of Pitman-Moore Company to W. A. Jamieson,
Director of Biological Division, Eli Lilly & Company
(July 22, 1935)
“We have obtained marked local reaction in about 50
percent of the dogs injected with serum containing
dilutions of Merthiolate varying from 1 in 40,000 to 1
in 5,000…no connection between the lot of serum and
the reaction. In other words, Merthiolate is
unsatistifactory as a preservative for serum intended
for use on dogs…”
Engley FB. Mercurials as Disinfectants: Evaluation of Mercurial
Antimicrobic Action & Comparative Toxicity for Skin Tissue Cells.
Presented May 21, 1956 at 42nd Midyear Meeting of the Chemical
Specialties Manufacturers Association, Chicago, IL.
The Dose, Makes the Poison:
Late 1980s to Early 2000s:
•
Rh-negative mothers were routinely administered Thimerosal
containing Rho(D)-immune globulins at 28 weeks gestation (10.5 to
in some instances more than 40 µg mercury per dose).
•
Infants may have been exposed a total of 237.5 µg mercury during
the first 18-24 months of life, if all Thimerosal-containing vaccines
were administered.
Early 2000s – Present:
•
All pregnant women to receive flu vaccine anytime during
pregnancy (25 µg mercury / dose).
•
Infants to receive 3 flu vaccines during first 18-24 months of life
(12.5 µg mercury / dose) = 37.5 µg mercury.
•
Children from 3 years-old through 18 years-old are to receive yearly
flu vaccines (25 µg mercury / dose) = 375 µg mercury.
● US Hot Spots Have Mercury Levels in Excess of US Government Regulations
Source: Commission for Environmental Cooperation, 2008.
Thimerosal (Mercury) Doses** Infants Received:
Source: Bigham M, Copes R. “Thiomersal in vaccines: balancing the risk of adverse effects with the
risk of vaccine-preventable disease,” Drug Saf, 2005;28:89-101.
__________________________
** Assuming an infant receiving 187.5 μg of mercury from Thimerosalcontaining vaccines during the first 6 months of life from the routine
childhood vaccination schedule, in combination with environmental
exposure from mercury in breast milk (164 μg of mercury).
1
•
“Learning and developmental disabilities (LDDs) include but are
not limited to deficits in learning and memory, reduced IQ, attention
deficit hyperactivity disorder (ADHD), autism spectrum disorder,
conduct disorders and developmental delays.”
•
“There is no doubt that mercury exposure causes learning and
developmental disorders”
Increased Mercury
Exposure in
Autistic Disorders
The Centers For Disease Control & Prevention
(CDC)
Vaccine Safety Datalink (VSD)
Thimerosal Dose-Response Studies
Simpsonwood Meeting (7-8 June
2000) in Norcross, GA where the
findings of the Vaccine Safety
Datalink (VSD) analysis showing a
link between Thimerosal-containing
vaccines and neurodevelopmental
outcomes were discussed in a closed
meeting by employees from the CDC,
FDA, & the vaccine manufacturers.
Dr. Brenier: Page 113: “We have asked you to keep this information confidential…”
Dr. Johnston: Page 198: “Forgive this personal comment, but I got called out a
eight o’clock emergency call and my daughter-in-law delivered a son by C-Section.
Our first male in the line of the next generation, and I do not want that grandson to
get a thimerosal containing vaccine”
Dr. Weil: Page 207: “The number of dose related relationships are linear and
statistically significant. You can play with this all you want. They are linear. They
are statistically significant. The positive relationships are those that one might
expect from the Faeroe Islands studies. They are also related to those data we do
have on experimental animal data and similar to the neurodevelopmental tox data
on other substances, so that I think you can’t accept that this is out of the ordinary.
It isn’t out of the ordinary. ”
Dr. Brent: Page 229: “…we are in a bad position from the standpoint of defending
lawsuits if they were initiated and I am concerned.”
Dr. Clements: Page 247: “I am really concerned that we have taken off like a
boat going down one arm of the mangrove swamp at high speed, when in fact
there was not enough discussion really early on about which way the boat
should go at all. And I really do want to risk offending everyone in the room by
saying that perhaps this study should not have been done at all, because the
outcome of it could have to some extent, been predicted, and we have all
reached this point now where we are left hanging…”
“…But nonetheless, we know from many experiences in history that the pure
scientist has done research because of pure science. But that pure science has
resulted in splitting the atom or some other process which is completely
beyond the power of the scientists who did the research to control it. And what
we have here is people who have, for every best reason in the world, pursued a
direction of research. But there is now the point at which the research results
have to be handled, and even if this committee decides that there is no
association and that information gets out, the work that has been done and
through the freedom of information that will be taken by others and will be used
in ways beyond the control of this group. An I am very concerned about that as
I suspect it is already too late to do anything regardless of any professional
body and what they say. My mandate as I sit here in this group is to make sure
at the end of the day that 100,000,000 are immunized with DTP, Hepatitis B and
if possible Hib, this year, next year and for many years to come, and that will
have to be with Thimerosal containing vaccines…”
A Prospective Assessment of the Association between ThimerosalContaining Rho(D)-Immune Globulin and Autistic Disorders
By Geier DA, Geier MR
Journal of Maternal, Fetal, & Neonatal Medicine 2007;20:385-90
________________________________
Increased Mercury
Body-Burden in
Autistic Disorders:
A Clinical Perspective
Conclusions:
** There was a significant increase in the brain
concentration of the Hg / Se ratio in autistics vs
controls.
** There was a significant increased in brain
oxidative stress markers in autistics vs controls.
** There was a significant correlation between
brain mercury concentrations and oxidative stress
markers in autistics vs controls.
Low Glutathione in
Autistic Disorders
Methionine Cycle & Transsulfuration Pathway
Source: James SJ, et al**. Metabolic biomarkers of increased oxidative stress and impaired
methylation capacity in children with autism. Am J Clin Nutr. 2004 Dec;80(6):1611-7.
g
________
** Mercury Excretion is Directly Related to Glutathione Secretion
Source: Clarkson TW, Nordberg GF, Sager PR. Reproductive and developmental toxicity of metals. Scan J Work Environ
Health 1985;11:145-54.
Biochemical Markers in Autistics:
Sourece: James SJ, et al. Metabolic biomarkers of increased oxidative stress and impaired
methylation capacity in children with autism. Am J Clin Nutr. 2004 Dec;80(6):1611-7.
___________________
___________________
Visual Evidence of Thimerosal
Induced
Human Neuron Damage
Human Neuroblastoma Cells
24 Hrs Incubation
No Thimerosal
Human Neuroblastoma Cells
24 Hrs Incubation
100 nM Thimerosal
[20 ppb Mercury]
Human Fetal Cells
24 Hrs Incubation
No Thimerosal
Human Fetal Cells
24 Hrs Incubation
10 nM Thimerosal
[2 ppb Mercury]
Mercury & Testosterone
Toxicity
** Observed that female hormones afforded total protection against Thimerosal toxicity.
** Observed testosterone at 1.0 µM levels that by itself did not significantly increase neuron death,
within 3 hours when added with 50 nM Thimerosal caused 100% neuron death [50 nM Thimerosal at
this time point did not significantly cause any cell death].
Geier MR, Geier DA. The potential
importance of steroids in the
treatment of autistic spectrum
disorders and other disorders
involving mercury toxicity. Med
Hypotheses 2005;64:946-54.
Manning JT, Baron-Cohen S, Wheelwright S, Sanders G. The 2nd to 4th digit ratio and
autism. Dev Med Child Neurol 2001;43:160-4.
The authors examined 72 children with autism, including 23 children with Asperger
syndrome, 34 siblings, 88 fathers, 88 mothers, and sex and age-matched controls. The
authors demonstrated that the more severely affected the children were the higher the
levels of prenatal testosterone.
Lower Testosterone/
Higher Estrogen
Higher Testosterone/
Lower Estrogen
AS = Asperger Syndrome
Steroidogenic Pathway:
Cholesterol
DHEA-S
Progestogens

Pregnenolone


17-hydroxypregnenolone



Progesterone
17 hydroxyprogesterone


11 deoxycorticosterone
11-deoxycortisol


Corticosterone
Cortisol


Corticoids
Androgens


DHEA
Androstenediol



Androstenedione


Testosterone

Estrone



Estradiol

Estrogens

Estriol
→
←
→
→
→
Hydroxysteroid Sulfotransferase
→
→
→
→
→
→
→
→
→
___________________________________________
Elevated Testosterone
(Androgens) in Children with
Neurodevelopmental
Disorders:
Potential Insights into Levels
&
Potential Adverse Effects
Developmental Medicine & Child Neurology
1999;41:392–395
Discussion
Studies on precocious puberty have primarily focused on
children with typical patterns of growth and cognitive
development. This study reviewed diagnostic data from the
records of 15,719 patients with neurodevelopmental
disabilities for diagnoses associated with premature sexual
development/precocious puberty. Thirty-two individuals
with premature sexual development were identified…
The US Department of Health and Human
Services and the National Institute of
Child Health and Development (NICHD)
of the National Institutes of Health (NIH)
estimate the incidence of precocious
puberty in the general population to be
approximately one in 10,000 children (US
Department of Health and Human
Services 1997). The incidence of
precocious puberty has been estimated to
be higher in children with
neurodevelopmental disabilities than in
children without neurodevelopmental
disabilities.
Our retrospective review of this
population with neurodevelopmental
disabilities suggested that a child with a
neurodevelopmental disability was at least
20 times more likely to experience early
pubertal changes.
Am J Psychiatry 1997;154:1626-7
• In 4 of 12 prepubertal autistic children (6–10 years old) in our inpatient child
psychiatry department, we have observed precocious secondary sexual
characteristics (growth of pubic hair, increase of testis volume) that suggest high
androgenic activity in infantile autism.
• To test our hypothesis of a hyperandrogeny and autism association, we measured
plasma testosterone and adrenal androgen in nine drug-free inpatients with DSMIV autism and 62 normal subjects of same age, sex, weight (within 2 kg), and stage
of puberty.
• Results showed that three of the nine autistic subjects had an abnormally high
plasma testosterone concentration (over two standard deviations above the mean
for the comparison subjects), with values above that of the highest in the
comparison subjects.
Other Effects of Elevated
Testosterone (Androgens) in
ASDs
• Testosterone levels are positively correlated with a number of autistic
traits and inversely correlated with social development and empathy.
• A medical questionnaire was completed by n=54 women with ASDs,
n=74 mothers of children with ASDs, and n=183 mothers of typically
developing children.
• Compared to controls, significantly more women with ASDs reported
(a) hirsutism, (b) bisexuality or asexuality, (c) irregular menstrual cycle,
(d) dysmenorrhea, (e) polycystic ovary syndrome, (f) severe acne, (g)
epilepsy, (h) tomboyism, and (i) family history of ovarian, uterine, and
prostate cancers, tumors, or growths.
• Compared to controls, significantly more mothers of ASD children
reported (a) severe acne, (b) breast and uterine cancers, tumors, or
growths, and (c) family history of ovarian and uterine cancers, tumors,
or growths.
• These results suggest current hormone abnormalities in women with
ASC and their mothers.
A summary of the interaction between the transsulfuration and androgen pathways in
autistic spectrum disorders
PAPS = 3’-phosphoadenosine 5’-phophosulfate
BHMT = Betaine Homocysteine Methyltransferase
MS = Methionine Synthase
SAM = S-adenosylmethionine
MTase = Methyltransferase
SAH = S-adenosylhomocysteine
CBS = Cystathionine β-Synthase
THF = Tetrohydrofolate
5-MTHF = 5-Methyltetrahydrofolate
5, 10-MTHF = 5, 10-Methyltetrahydrofolate
SAHH = SAH Hydrolase
DHEA-S = Dehydroepiandrosterone-sulfate
DHEA = Dehydroepiandrosterone
Treatment Overview:
The Protocol
• Furthermore, in our own clinical experience we have
observed that leuprolide acetate (LUPRON®) administration
to nearly 200 patients diagnosed with ASDs significantly
lowered androgen levels and has resulted in very
significant overall clinical improvements in socialization,
sensory/cognitive awareness, and health/physical/behavior
skills, with few non-responders and minimal adverse
clinical effects to the therapy.
• The following are some specific areas of significant clinical
ameliorations in frequent symptoms that occur in patients
diagnosed with ASDs observed:
• hyperactivity/impulsivity
• stereotypy
• aggression
• self-injury
• abnormal sexual behaviors
• irritability behaviors