Hormonal Changes in Autism |
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Standard findingsChildren with autism are not sterile, go through puberty at the same time, are the same size and strength and will show other hormonal factors similarly to controls. However, many investigations of hormones in autistic children have shown differences when measuring the actual levels. Section Heading Goes HereThe quick brown fox jumps over the lazy dog. The quick brown fox jumps over the lazy dog. The quick brown fox jumps over the lazy dog. The quick brown fox jumps over the lazy dog. The quick brown fox jumps over the lazy dog.
Section Heading Goes HereThe quick brown fox jumps over the lazy dog. The quick brown fox jumps over the lazy dog. The quick brown fox jumps over the lazy dog. The quick brown fox jumps over the lazy dog. The quick brown fox jumps over the lazy dog. |
Production of
melatonin |
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Melatonin
A simple
compound produced in the pineal gland in the brain by biochemistry from tryptophan. It is not essential but changes according to
the light cycle of the day and can be used to alter this and avoid ‘jet lag’.
Edward R. Ritvo,
Riva Ritvo, Arthur Yuwiler, Anne Brothers,
B. J. Freeman and Selma Plotkin. Elevated
daytime melatonin concentrations in autism: A pilot study. European
Child & Adolescent Psychiatry Volume
2, Number 2 / April, 1993 Concentrations of melatonin in
overnight and first-voiding urine samples from 10 people with autism, 15
parents, 1 grandparent, 9 sibs without autism, and 10 healthy, unrelated
volunteers, were measured by radioimmunoassay. Those with autism had
significantly higher melatonin concentrations in the first voiding samples than
controls. Groups did not differ in overnight melatonin concentrations.
Nir I, Meir D, Zilber N, Knobler H, Hadjez J, Lerner Y. Brief report:
circadian melatonin, thyroid-stimulating hormone, prolactin and cortisol
levels in serum of young adults with autism. J Autism Dev Disord
1995;25(6):641-54. Showed loss of
circadian rhythms chemically with melatonin and cortisol testing. This in some degree is similar to the
findings of the loss of the changes seen throughout the day in cortisol.
Konturek SJ, Konturek PC, Brzozowska I, Pawlik M, Sliwowski Z, Cześnikiewicz-Guzik M, Kwiecień S, Brzozowski T, Bubenik GA, Pawlik WW. Localization and biological activities of melatonin in intact and diseased gastrointestinal tract (GIT). J Physiol Pharmacol. 2007 Sep;58(3):381-405. Review (This review focuses on the localization, production, metabolism and the functions of MT in GIT and the duodenal unit (liver, biliary routes and pancreas), where multi-step biosynthetic pathways of this indole, similar to those in pinealocytes, have been identified. Interesting to read about the involvement of the cells of the gut in its production and significance)
Ishizaki
A, Sugama
M, Takeuchi
N [Usefulness of melatonin for
developmental sleep and emotional/behavior disorders--studies of melatonin
trial on 50 patients with developmental disorders] No To Hattatsu. 1999 Sep;31(5):428-37.[Article in Japanese]
(they found melatonin to be useful in 35 of 50 patients)
Jan JE, O'Donnell ME. Use of melatonin in the treatment of paediatric sleep disorders. J Pineal Res. 1996 Nov;21(4):193-9. Review
Giannotti F, Cortesi F, Cerquiglini A, Bernabei P. An open-label study of controlled-release melatonin in treatment of sleep disorders in children with autism. J Autism Dev Disord. 2006 Aug;36(6):741-52. (25 children, aged 2.6-9.6 years with autism without other coexistent pathologies was evaluated openly. During treatment sleep patterns of all children improved. After discontinuation 16 children returned to pre-treatment score, readministration of melatonin was again effective. They had no side effects reported. This is a very encouraging study)
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These are adrenaline, noradrenaline, dopamine, and their breakdown products e.g. homovanillic acid (HVA) found in the urine. They are used for a nerve to stimulate another. The actual reason for the increased level of the HVA and other breakdown products is not at all clear in that large amounts of the compounds are used in the gut and elsewhere. The raised levels of the catecholamines in blood have the same problem in that their source is still unclear. Also changes in these levels as a result of drug treatment does also not seem to have been followed.
C. Barthelemy,
N. Bruneau, J. M. Cottet-Eymard, J. Domenech-Jouve,
B. Garreau, G. Lelord, J. P. Muh and L. Peyrin. Journal
of Autism and Developmental Disorders Volume
18, Number 4 / December, 1988 Urinary catecholamines
(dopamine,DA, norepinephrine NE, epinephrine E) and their main metabolites
(HVA, DOPAC, MHPG) were made both as free and conjugates in eight children
diagnosed as autistic according to DSM-III criteria and eight normal children.
Significant differences appeared for the urinary excretion of both DA and NE
and their respective metabolites: Autistic children showed low DA, high HVA,
high NE, low MHPG urinary levels. These results are consistent with previous
findings on altered catecholamine metabolism in autistic children. They suggest
that autistic behaviour might be related to an abnormal functional imbalance
among monoamines either at a molecular level or at a system level. Furthermore,
they emphasize the special interest of urinary assays in pediatric research.
Garreau B, Barthélémy C, Jouve J, Bruneau N, Muh JP, Lelord G. Urinary homovanillic acid levels of autistic children. Dev Med Child Neurol. 1988 Feb;30(1):93-8. (increased levels in urine suggested by authors to be due to dopamine turnover)
Barthelemy C, Bruneau N, Cottet-Eymard JM, Domenech-Jouve J, Garreau B, Lelord G, Muh JP, Peyrin L. Urinary free and conjugated catecholamines and metabolites in autistic children. J Autism Dev Disord. 1988 Dec;18(4):583-91. (increased levels found of the free form)
Martineau J, Barthélémy C, Jouve J, Muh JP, Lelord G. Monoamines (serotonin and catecholamines) and their derivatives in infantile autism: age-related changes and drug effects. Dev Med Child Neurol. 1992 Jul;34(7):593-603. 156 autistic children aged two to 12 years 6 months, compared with matched mentally retarded and normal controls. Very significant group and age effects were found for dopamine (DA), Homovanillinic acid (HVA), 3methoxy-tryptamine (3MT), norepinephrine and epinephrine (NE + E) and serotonin (5HT). High HVA, 3MT, NE + E and 5HT levels were found in autistic and non-autistic children. The DA, HVA, 3MT, NE + E, 5HT and its metabolite 5HIAA levels decreased significantly with age in the three groups. Significantly decreased levels of DA and HVA were observed in autistic children on haloperidol)
Israngkun PP, Newman HA, Patel ST, Duruibe VA, Abou-Issa H. Potential
biochemical markers for infantile autism. Neurochem
Pathol. 1986 Aug;5(1):51-70.
(raised epinephrine, norepinephrine, serotonin in blood)
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Secretin
The importance of secretin in autism came about after the small publication of Horvath in 1998. The finding was that some of the children responded dramatically. It was followed by a huge demand for initially porcine then artificial human secretin and extended studies were carried out as to whether there was good evidence as to whether it did the children any advantage. The best result from this is from the Cochrane Database below, which simply says that secretin could not be stated as an advantage to autistic children. However, various parents swear by it and in the various studies there does appear to be some uncommon cases that may improve.
Secretin is a hormone produced by the Langhans cells of the pancreas and other similar cells in the upper part of the small bowel. Its main activity is to cause the gut to produce and release enzymes for the breakdown of foods. It does appear to have activity in causing the growth of the gut, and the induction of the enzyme genes in very young animals.
Roberts W, Weaver L, Brian J, Bryson S, Emelianova S, Griffiths AM, MacKinnon B, Yim C, Wolpin J, Koren G. Repeated doses of porcine secretin in the treatment of autism: a permutation, placebo-controlled trial. Pediatrics. 2001 May;107(5):E71. (minimal effect seen except in an occasional i.e. not statistical case)
Horvath K,
Stefanatos G, Sokolski K, et al. Improved social and language skills after
secretin administration in patients with autistic spectrum disorders. J
Assoc Acad Minor Phys. 1998;9:9–15
(the first three given secretin)
Esch BE, Carr JE. Secretin as a treatment for autism: a review of the evidence. J Autism Dev Disord. 2004 Oct;34(5):543-56. (clinical review of 13 studies showing that 12 showed no advantage)
Sandler A,
Sutton K, DeWeese J, et al. Lack of benefit of a single dose of synthetic
human secretin in the treatment of autism and pervasive developmental disorder.
N Engl J Med. 1999;341:1801–1806
Chez MG, Buchanan CP, Bagan BT, et al. Secretin and autism: a two part
clinical investigation. J Autism Dev Disord. 2000;30:87–94
Owley T, Steele E, Corsello C, et al. A double-blind, placebo-controlled trial of secretin for the treatment of autistic disorder. MedGenMed. October 6, 1999
Williams KW, Wray JJ, Wheeler DM. Intravenous secretin for autism spectrum disorder. Cochrane Database Syst Rev. 2005 July 20;(3):CD003495. (Review showing that secretin injections cannot be advised currently as, even the advances seen in occasional patients as the likelihood must be very low)
Pollack
PF, Wood
JG, Solomon
T. Effect of secretin on growth of stomach, small intestine, and pancreas
of developing rats. Dig Dis Sci.
1990 Jun;35(6):749-58. (caused the
development of the intestine and organs)
Harada
E, Syuto B. Secretin induces
precocious cessation of intestinal macromolecular transmission and maltase
development in the suckling rat. Biol
Neonate. 1993;63(1):52-60. (causes the
intestine to stop absorbing molecules that previously came in from the gut e.g.
neonatal milk).
Molloy CA, Manning-Courtney P, Swayne S, Bean J, Brown JM, Murray DS, Kinsman AM, Brasington M, Ulrich CD 2nd. Lack of benefit of intravenous synthetic human secretin in the treatment of autism. J Autism Dev Disord. 2002 Dec;32(6):545-51. (this is just one of the studies that found this. Originally Horvath’s 3 cases to which he gave secretin have been interesting and certainly specific cases claim great improvements but the statistics will not stand up over larger studies)
Connors
SL, Crowell
DE. Secretin and autism: the role
of cysteine. J Am Acad
Child Adolesc Psychiatry. 1999 Jul;38(7):795-6 (no further data)
Secretin as a neuropeptide: Also see discussions on brain biochemistry
Ng
SS, Yung WH, Chow BK. Secretin as a neuropeptide. Mol Neurobiol. 2002 Aug;26(1):97-107.
(a review of the action of secretin neuropeptide: realising that there is a
complex activity of secretin)
Banks WA, Goulet M, Rusche JR, Niehoff ML, Boismenu R. Differential transport of a secretin analog across the blood-brain and blood-cerebrospinal fluid barriers of the mouse. J Pharmacol Exp Ther. 2002 Sep;302(3):1062-9. (shows how the drug is passed across into the brain from the blood system)
Toda
Y, Mori K, Hashimoto T, Miyazaki M, Nozaki S, Watanabe Y, Kuroda Y, Kagami S.
Administration of secretin for autism alters dopamine metabolism in the central
nervous system. Brain Dev. 2006 Mar;28(2):99-103. (a complex study in which they gave 12
autistic children some i.v. secretin and looked for improvements in biopterin,
5HIAA, and homovanillinic acid –taken as signs of irritation, serotonin
turnover and dopamine turnover- these were found in 7 but all of those with
raised biopterin results initially)
Welch MG, Keune JD, Welch-Horan TB, Anwar N, Anwar M, Ludwig RJ, Ruggiero DA. Secretin: hypothalamic distribution and hypothesized neuroregulatory role in autism. Cell Mol Neurobiol. 2004 Apr;24(2):219-41.
Welch MG, Keune JD, Welch-Horan TB, Anwar N, Anwar M, Ruggiero DA. Secretin activates visceral brain regions in the rat including areas abnormal in autism. Cell Mol Neurobiol. 2003 Oct;23(4-5):817-37 (they are working their way through specific brain regions and staining sites that secretin will interact with and showing using immunostaining the secretin itself, they also stained for secretin-activated regions by looking for c-fos gene expression).
Nishijima
I, Yamagata
T, Spencer
CM, Weeber
EJ, Alekseyenko
O, Sweatt
JD, Momoi
MY, Ito
M, Armstrong
DL, Nelson
DL, Paylor
R, Bradley
A. Secretin receptor-deficient mice exhibit impaired synaptic plasticity
and social behavior. Hum Mol
Genet. 2006 Nov 1;15(21):3241-50.
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Oxytocin
Like secretin this is a hormone and a neuropeptide. Levels in the brain have not been measured in
autism properly but they have been shown to be raised in the blood. It is well known in the body for the
stimulation of certain muscular tissues in the body (e.g. the uterus during
giving birth, and gut).
Modahl
C, Fein D, Waterhouse L, Newton N.
Does oxytocin deficiency mediate social deficits in autism? J Autism Dev
Disord. 1992 Sep;22(3):449-51. (suggest that if there is low levels then it may cause
autistic symptoms)
Modahl
C, Green L, Fein D, Morris M, Waterhouse L, Feinstein C, Levin H. Plasma oxytocin levels in
autistic children.
Biol
Psychiatry. 1998 Feb 15;43(4):270-7. (they found specifically lower levels of oxytocin in
the blood of the autistic children and did not show the normal increase with
age)
Panksepp
J. Commentary on the
possible role of oxytocin in autism. J Autism Dev Disord. 1993 Sep;23(3):567-9.
(suggest that excess may cause
autism)
Winslow J,
Insel T. The social deficits of the
oxytocin knockout mouse. Neuropeptides
2002;36:221-9. A difficult but helpful
indicator if it is involved in autism.
Welch MG, Ruggiero DA. Predicted role of secretin and oxytocin in the treatment of behavioral and developmental disorders: implications for autism. Int Rev Neurobiol. 2005;71:273-315.
Green L, Fein D, Modahl C, Feinstein C, Waterhouse L, Morris M. Oxytocin (OT) and autistic disorder: alterations in peptide forms (OT-X). Biol Psychiatry. 2001 Oct 15;50(8):609-13 (T tests showed that there was a decrease in plasma OT (t = 4.4, p <.0001), an increase in OT-X (t = 2.3, p <.03) and an increase in the ratio of OT-X/OT (t = 4.5, p <.0001) in the autistic sample, compared with control subjects. CONCLUSIONS: The results suggest that children with autistic disorder show alterations in the endocrine OT system. Deficits in OT peptide processing in children with autism may be important in the development of this syndrome. In other words the method of measuring the oxytocin may be picking up the OT-X and not the OT)
Hollander E, Bartz J, Chaplin W, Phillips A, Sumner J, Soorya L, Anagnostou E, Wasserman S. Oxytocin increases retention of social cognition in autism. Biol Psychiatry. 2007 Feb 15;61(4):498-503. (All subjects showed improvements in affective speech comprehension from pre- to post-infusion; however, whereas those who received placebo first tended to revert to baseline after a delay, those who received oxytocin first retained the ability to accurately assign emotional significance to speech intonation on the speech comprehension task.)
Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S, Gruppe H, Mattay VS, Gallhofer B, Meyer-Lindenberg A. Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci. 2005 Dec 7;25(49):11489-93. We used functional magnetic resonance imaging to image amygdala activation by fear-inducing visual stimuli in 15 healthy males after double-blind crossover intranasal application of placebo or oxytocin. The author considered that this may be involved with autism
Wu S, Jia M, Ruan Y, Liu J, Guo Y, Shuang M, Gong X, Zhang Y, Yang X, Zhang D. Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biol Psychiatry. 2005 Jul 1;58(1):74-7.
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Growth
hormone
A peptide hormone that is released by the pituitary gland in the
brain. The studies done here are
interesting in that they have tried to see if the growth hormone release will
change according to certain drugs that the patient is receiving. Its specific aim is to cause the growth of
the body as a whole according to a specific rate and plan. It is, however, much more complex than this
simple idea and so when elevated levels of GH related hormones were found in
the blood of autism it was difficult to interpret.
Deutsch SI, Campbell M, Sachar EJ, Green WH, David R. Plasma growth hormone response to L-DOPA in infantile autism. J Autism Dev Disord 1985;15:205-12.
Realmuto GM, Jensen JB, Reeve E, Garfinkel BD. Growth hormone
response in autistic children to DA and NE agonists. In: Proceedings
of the American Academy of Child and Adolescent Psychiatry. Los Angeles
(CA): American Academy of Child and Adolescent Psychiatry;
1986.
p. 35. (normal levels of GH but blunted response to levodopa in autistic
adults)
Mills JL, Hediger ML, Molloy CA, Chrousos GP, Manning-Courtney P, Yu KF, Brasington M, England LJ. Elevated levels of growth-related hormones in autism and autism spectrum disorder. Clin Endocrinol (Oxf). 2007 Aug;67(2):230-7. Epub 2007 Jun 4. (Children with autism/ASD had significantly higher levels of many growth-related hormones: IGF-1, IGF-2, IGFBP-3 and GHBP. The IGFs are the peptide insulin-like growth related factors and the GHBP is the Growth Hormone Binding Protein. They also looked for androgens and found no increased level.)
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Cortisol (look at these findings along with
ACTH below)
This is an adrenal hormone that is released into the blood and will change many factors
throughout the body in terms of the usage of glucose to the immunity of the
body. The finding of low levels of
cortisol in autism and high levels of adrenocortitrophic hormone (ACTH), which
causes cortisol’s production and release suggests that the adrenal gland has
just decided not to make it at the level that the brain (which produces the
ACTH) would want. Also the
non-suspression of cortisol by dexamethasone (which causes the decrease in
level of ACTH), and its level not changing during the circadian rhythm are
exceptionally significant. Also, as a neurosteroid, it is found to be low.
Jensen JB, Realmuto GM, Garfinkel BD. The dexamethasone suppression test in infantile autism. J Am Acad Child Psychiatry 1985;24:263-5.
Marinović-Ćurin J, Marinović-Terzić I, Bujas-Petković Z, Zekan L, Skrabić V, Dogaš Z, Terzić J. Slower cortisol response during ACTH stimulation test in autistic children. Eur Child Adolesc Psychiatry. 2007 Sep 14;
Corbett BA, Mendoza S, Abdullah M, Wegelin JA, Levine S. Cortisol circadian rhythms and response to stress in children with autism. Psychoneuroendocrinology. 2006 Jan;31(1):59-68. (The results suggest that children with autism process and respond idiosyncratically to novel and threatening events resulting in an exaggerated cortisol response.)
Strous RD, Golubchik P, Maayan R, Mozes T, Tuati-Werner D, Weizman A, Spivak B. Lowered DHEA-S plasma levels in adult individuals with autistic disorder. Eur Neuropsychopharmacol. 2005 May;15(3):305-9.
Richdale AL, Prior MR. Urinary cortisol circadian rhythm in a group of high-functioning children with autism. J Autism Dev Disord. 1992 Sep;22(3):433-47. (They found that there was not a great difference between the ASD group and the controls except as a response)
Hoshino
Y, Yokoyama F, Watanabe M, Murata S, Kaneko M, Kumashiro H. The diurnal
variation and response to dexamethasone suppression test of saliva cortisol
level in autistic children. Jpn J Psychiatry Neurol. 1987 Jun;41(2):227-35. Some ASD children showed a poor diurnal
variation.
Hoshino Y, Ohno Y, Murata S, Yokoyama F, Kaneko M, Kumashiro H. Dexamethasone suppression test in autistic children. Folia Psychiatr Neurol Jpn. 1984;38(4):445-9. Not great but minor results suggesting an alteration in the hypothalamo-pituitary axis. It needed to be restudied.
ACTH raised
Tordjman S, Anderson GM, McBride PA, Hertzig ME, Snow ME, Hall LM, Thompson SM, Ferrari P, Cohen DJ. Plasma beta-endorphin, adrenocorticotropin hormone, and cortisol in autism. J Child Psychol Psychiatry. 1997 Sep;38(6):705-15. Higher serum endorphin and ACTH taken by authors to be due to stress responses. Comparison of log transformed data from the three groups revealed that levels of BE and ACTH were significantly higher (p < .05) in the autistic individuals than in normal control
Tani P, Lindberg N, Matto V, Appelberg B, Nieminen-von Wendt T, von Wendt L, Porkka-Heiskanen T. Higher plasma ACTH levels in adults with Asperger syndrome. J Psychosom Res. 2005 Jun;58(6):533-6.
Curin JM, Terzić J, Petković ZB, Zekan L, Terzić IM, Susnjara IM. Lower cortisol and higher ACTH levels in individuals with autism. J Autism Dev Disord. 2003 Aug;33(4):443-8. (also prolactin concentrations in autistic patients with epilepsy were significantly higher when compared with normal subjects). This suggests that the ACTH was unable to cause a specific rise in cortisol and the feedback had been lost.
e.g. Cytokines acting as hormones
Suzuki K, Hashimoto K, Iwata Y, Nakamura K, Tsujii M, Tsuchiya KJ, Sekine Y, Suda S, Sugihara G, Matsuzaki H, Sugiyama T, Kawai M, Minabe Y, Takei N, Mori N. Decreased serum levels of epidermal growth factor in adult subjects with high-functioning autism. Biol Psychiatry. 2007 Aug 1;62(3):267-9. Epub 2006 Nov 21. (the importance of this type of finding is that due to the presence of certain growth factors there might be a change in the formation of the brain early in its development)
Sugihara
G, Hashimoto
K, Iwata
Y, Nakamura
K, Tsujii
M, Tsuchiya
KJ, Sekine
Y, Suzuki
K, Suda
S, Matsuzaki
H, Kawai
M, Minabe
Y, Yagi
A, Takei
N, Sugiyama
T, Mori
N. Decreased serum levels of
hepatocyte growth factor in male adults with high-functioning autism. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Mar
30;31(2):412-5.
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