An evaluation of the role and treatment of elevated male hormones in autism spectrum disorders.

Autism, Asperger's syndrome (AS), and pervasive developmental disorder - not otherwise specified (PDD-NOS) compose the overall diagnostic category of autism spectrum disorder (ASD). Subjects diagnosed with an ASD have a male:female ratio of 4:1, and among subjects diagnosed with AS the male:female ratio is as high as 9:1. The purpose of this study was to examine evidence of the association between hyperandrogenism and autistic traits (ATs) among subjects diagnosed with an ASD, and to evaluate the effectiveness of anti-androgen therapy as a means to help treat ATs in subjects diagnosed with an ASD. Evidence of hyperandrogenism in subjects diagnosed with an ASD is supported by multiple studies in the areas of psychological framework, brain pathology, tissue culture, and pre- and postnatal androgen levels. Data from subjects diagnosed with other conditions associated with elevated androgens reveals many of these individuals have ATs. Finally, in a placebo-controlled trial of testosterone administration to neurotypical subjects, testosterone was found to increase ATs. In addition, a controlled trial of human transsexuals revealed a significant increase in ATs in female-to-male transsexuals and a decrease in ATs in male-to-female transsexuals. Data from multiple animals and human clinical trials suggest that antiandrogen medications have the ability to significantly reduce ATs in patients diagnosed with an ASD. In light of the robust association between hyperandrogenism and ASD, it is recommended subjects diagnosed with an ASD should undergo routine screening for elevated androgens, and appropriate treatment should be initiated for those with elevated androgens.

[1]  M. P. Jiménez,et al.  Antiaggressive effect of cyproterone versus haloperidol in Alzheimer's disease: a randomized double-blind pilot study. , 2007, The Journal of clinical psychiatry.

[2]  Avshalom Caspi,et al.  Using sex differences in psychopathology to study causal mechanisms: unifying issues and research strategies. , 2003, Journal of child psychology and psychiatry, and allied disciplines.

[3]  David A Geier,et al.  A prospective assessment of androgen levels in patients with autistic spectrum disorders: biochemical underpinnings and suggested therapies. , 2007, Neuro endocrinology letters.

[4]  S Baron-Cohen,et al.  Sex-specific serum biomarker patterns in adults with Asperger's syndrome , 2011, Molecular Psychiatry.

[5]  M. New,et al.  Diagnosis and management of congenital adrenal hyperplasia. , 1998, Annual review of medicine.

[6]  C. Migeon Diagnosis and management of congenital adrenal hyperplasia. , 1977, Hospital practice.

[7]  C. Higano Side effects of androgen deprivation therapy: monitoring and minimizing toxicity. , 2003, Urology.

[8]  S. Chase,et al.  Increased Risk of Metabolic Syndrome, Diabetes Mellitus, and Cardiovascular Disease in Men Receiving Androgen Deprivation Therapy for Prostate Cancer , 2008, Pharmacotherapy.

[9]  Rebecca C. Knickmeyer,et al.  Edinburgh Research Explorer Fetal testosterone and autistic traits , 2014 .

[10]  S. Baron-Cohen,et al.  Foetal testosterone and autistic traits in 18 to 24-month-old children , 2010, Molecular autism.

[11]  P. Bolton,et al.  Brief Report Prevalence of Autism Spectrum Conditions in Children Aged 5-11 Years in Cambridgeshire, UK , 2002, Autism : the international journal of research and practice.

[12]  M. Wanjari,et al.  A possible participation of gonadotropin-releasing hormone in the neuroleptic and cataleptic effect of haloperidol , 2009, Neuropeptides.

[13]  J T Manning,et al.  The ratio of 2nd to 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen. , 1998, Human reproduction.

[14]  H. Judd,et al.  Amniotic Fluid Testosterone Levels in Midpregnancy , 1976, Obstetrics and gynecology.

[15]  D. Dewailly,et al.  Étude pilote préliminaire de l'acétate de cyprotérone dans les comportements agressifs associés aux démences sévères , 2005 .

[16]  S. Baron-Cohen,et al.  Foetal testosterone and vocabulary size in 18- and 24-month-old infants , 2001 .

[17]  T. L. MacLeod,et al.  Anaphylactic reaction to synthetic luteinizing hormone-releasing hormone. , 1987, Fertility and sterility.

[18]  G. Chrousos,et al.  The efficacy and safety of gonadotropin-releasing hormone analog treatment in childhood and adolescence: a single center, long-term follow-up study. , 2010, The Journal of clinical endocrinology and metabolism.

[19]  D. Geier,et al.  Autism spectrum disorder-associated biomarkers for case evaluation and management by clinical geneticists , 2008, Expert review of molecular diagnostics.

[20]  M. Hines,et al.  Human behavioral sex differences: a role for gonadal hormones during early development? , 1995, Psychological bulletin.

[21]  D. Geier,et al.  The potential importance of steroids in the treatment of autistic spectrum disorders and other disorders involving mercury toxicity. , 2005, Medical hypotheses.

[22]  D. Geier,et al.  A clinical trial of combined anti-androgen and anti-heavy metal therapy in autistic disorders. , 2006, Neuro endocrinology letters.

[23]  R. Benson Total androgen blockade: the United States experience. , 1993, European urology.

[24]  Rebecca C. Knickmeyer,et al.  Fetal testosterone and empathy: Evidence from the Empathy Quotient (EQ) and the “Reading the Mind in the Eyes” Test , 2006, Social neuroscience.

[25]  A. Rogol,et al.  Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children , 2009, Pediatrics.

[26]  S. Baron-Cohen,et al.  Brief Report: Female-To-Male Transsexual People and Autistic Traits , 2011, Journal of Autism and Developmental Disorders.

[27]  F. Ramus,et al.  Motion and Form Coherence Detection in Autistic Spectrum Disorder: Relationship to Motor Control and 2:4 Digit Ratio , 2006, Journal of autism and developmental disorders.

[28]  Hyoung-Gon Lee,et al.  Down‐regulation of serum gonadotropins is as effective as estrogen replacement at improving menopause‐associated cognitive deficits , 2010, Journal of neurochemistry.

[29]  S. Purdon,et al.  Effects on behavior of modulation of gonadal function in men with gonadotropin-releasing hormone antagonists. , 1994, The American journal of psychiatry.

[30]  Eric Fombonne,et al.  The Changing Epidemiology of Autism. , 2005 .

[31]  P. Bhutada,et al.  Leuprolide – A luteinizing hormone releasing hormone agonist attenuates ethanol withdrawal syndrome and ethanol-induced locomotor sensitization in mice , 2008, Neuropeptides.

[32]  S. Baron-Cohen,et al.  Foetal testosterone and eye contact in 12-month-old human infants , 2002 .

[33]  D. Ostatníková,et al.  2D:4D finger ratio in Slovak autism spectrum population. , 2011, Bratislavske lekarske listy.

[34]  N. Lee,et al.  Gene Expression Profiling of Lymphoblasts from Autistic and Nonaffected Sib Pairs: Altered Pathways in Neuronal Development and Steroid Biosynthesis , 2009, PloS one.

[35]  W. Manish,et al.  LHRH antagonist attenuates the effect of fluoxetine on marble-burying behavior in mice. , 2007, European journal of pharmacology.

[36]  R. Malone,et al.  The Role of Antipsychotics in the Management of Behavioural Symptoms in Children and Adolescents with Autism , 2012, Drugs.

[37]  M. Axthelm,et al.  Self-Injurious Behavior Is Decreased by Cyproterone Acetate in Adult Male Rhesus (Macaca mulatta) , 1999, Hormones and Behavior.

[38]  Rebecca C. Knickmeyer,et al.  Androgens and autistic traits: A study of individuals with congenital adrenal hyperplasia , 2006, Hormones and Behavior.

[39]  Rebecca C. Knickmeyer,et al.  2nd to 4th digit ratios, fetal testosterone and estradiol. , 2004, Early human development.

[40]  Minyi Xu,et al.  Sex Hormones in Autism: Androgens and Estrogens Differentially and Reciprocally Regulate RORA, a Novel Candidate Gene for Autism , 2011, PloS one.

[41]  S. Berenbaum,et al.  Prenatal sex hormone effects on child and adult sex-typed behavior: methods and findings , 2005, Neuroscience & Biobehavioral Reviews.

[42]  S. Baron-Cohen The extreme male brain theory of autism , 2002, Trends in Cognitive Sciences.

[43]  C. Vögele,et al.  Prepubertal gonadotropin-releasing hormone analog leads to exaggerated behavioral and emotional sex differences in sheep , 2011, Hormones and Behavior.

[44]  David A. Geier,et al.  A Clinical and Laboratory Evaluation of Methionine Cycle-Transsulfuration and Androgen Pathway Markers in Children with Autistic Disorders , 2006, Hormone Research in Paediatrics.

[45]  M. Hines,et al.  Language lateralization and handedness in women prenatally exposed to diethylstilbestrol (DES) , 2000, Psychoneuroendocrinology.

[46]  J. K. Finegan,et al.  A window for the study of prenatal sex hormone influences on postnatal development. , 1989, The Journal of genetic psychology.

[47]  K. Desdicioglu,et al.  Fetal development of the hand, digits and digit ratio (2D:4D). , 2006, Early human development.

[48]  P. Bhutada,et al.  Increased marble-burying behavior in ethanol-withdrawal state: modulation by gonadotropin-releasing hormone agonist. , 2008, European journal of pharmacology.

[49]  P. Roubertoux,et al.  Androgenic activity in autism. , 1997, The American journal of psychiatry.

[50]  W. Sippell,et al.  Treatment of central precocious puberty. , 2002, Best practice & research. Clinical endocrinology & metabolism.

[51]  T. Yamagishi,et al.  Salivary testosterone levels and autism-spectrum quotient in adults. , 2010, Neuro endocrinology letters.

[52]  J. Kern,et al.  The biological basis of autism spectrum disorders: Understanding causation and treatment by clinical geneticists. , 2010, Acta neurobiologiae experimentalis.

[53]  R. Ferdinand,et al.  Differences in finger length ratio between males with autism, pervasive developmental disorder-not otherwise specified, ADHD, and anxiety disorders. , 2006, Developmental medicine and child neurology.

[54]  N. Minshew,et al.  Brain Volume in Autism , 2001, Journal of child neurology.

[55]  E. Krenning,et al.  Longitudinal follow-up of bone density and body composition in children with precocious or early puberty before, during and after cessation of GnRH agonist therapy. , 2002, The Journal of clinical endocrinology and metabolism.

[56]  Pongsak Noipayak The ratio of 2nd and 4th digit length in autistic children. , 2009, Journal of the Medical Association of Thailand = Chotmaihet thangphaet.

[57]  J. Piven,et al.  Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years. , 2005, Archives of general psychiatry.

[58]  V. Torri,et al.  Cyproterone acetate in the therapy of prostate carcinoma. , 2005, Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica.

[59]  D. Schutter,et al.  Testosterone administration impairs cognitive empathy in women depending on second-to-fourth digit ratio , 2011, Proceedings of the National Academy of Sciences.

[60]  Peter A. Lee,et al.  Leuprolide Acetate 1-Month Depot for Central Precocious Puberty: Hormonal Suppression and Recovery , 2010, International journal of pediatric endocrinology.

[61]  T. Eriksson Anti-androgenic treatment of obsessive–compulsive disorder: an open-label clinical trial of the long-acting gonadotropin-releasing hormone analogue triptorelin , 2007, International clinical psychopharmacology.

[62]  Rebecca C. Knickmeyer,et al.  Foetal testosterone, social relationships, and restricted interests in children. , 2005, Journal of child psychology and psychiatry, and allied disciplines.

[63]  M. Hines,et al.  Spatial abilities following prenatal androgen abnormality: targeting and mental rotations performance in individuals with congenital adrenal hyperplasia , 2003, Psychoneuroendocrinology.

[64]  Z. Laron,et al.  Experience with Cyproterone Acetate in the Treatment of Precocious Puberty , 2000, Journal of pediatric endocrinology & metabolism : JPEM.

[65]  S. Resnick,et al.  Early androgen effects on aggression in children and adults with congenital adrenal hyperplasia , 1997, Psychoneuroendocrinology.

[66]  A. Schindler Hormones in human amniotic fluid. , 1982, Monographs on endocrinology.

[67]  L. Dorn,et al.  Biopsychological and Cognitive Differences in Children With Premature vs On-Time Adrenarche , 1999 .

[68]  M. Wanjari,et al.  Effects of central administration of gonadotropin-releasing hormone agonists and antagonist on elevated plus-maze and social interaction behavior in rats , 2008, Behavioural pharmacology.

[69]  Jagath C. Rajapakse,et al.  Quantitative Magnetic Resonance Imaging of Human Brain Development: Ages 4–18 , 1996 .

[70]  K. Tachibana,et al.  Results of long-term follow-up after treatment of central precocious puberty with leuprorelin acetate: evaluation of effectiveness of treatment and recovery of gonadal function. The TAP-144-SR Japanese Study Group on Central Precocious Puberty. , 2005, The Journal of clinical endocrinology and metabolism.

[71]  Rebecca C. Knickmeyer,et al.  Foetal testosterone and the child systemizing quotient , 2006 .

[72]  S. Baron-Cohen,et al.  Increased serum androstenedione in adults with autism spectrum conditions , 2011, Psychoneuroendocrinology.

[73]  J T Manning,et al.  The 2nd to 4th digit ratio and autism , 2001, Developmental medicine and child neurology.

[74]  P. Bhutada,et al.  Gonadotropin-releasing hormone agonist blocks anxiogenic-like and depressant-like effect of corticotrophin-releasing hormone in mice , 2008, Neuropeptides.

[75]  S. Bertelloni,et al.  Treatment of central precocious puberty by GnRH analogs: long-term outcome in men. , 2008, Asian journal of andrology.

[76]  A. Rogol,et al.  Children Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in , 2012 .