Polycystic ovary syndrome and autism: A test of the prenatal sex steroid theory

Adriana Cherskov, Alexa Pohl, Carrie Allison, Heping Zhang, Rupert A Payne, Simon Baron-Cohen, Adriana Cherskov, Alexa Pohl, Carrie Allison, Heping Zhang, Rupert A Payne, Simon Baron-Cohen

Abstract

Elevated levels of prenatal testosterone may increase the risk for autism spectrum conditions (autism). Given that polycystic ovary syndrome (PCOS) is also associated with elevated prenatal testosterone and its precursor sex steroids, a hypothesis from the prenatal sex steroid theory is that women with PCOS should have elevated autistic traits and a higher rate of autism among their children. Using electronic health records obtained from the Clinical Practice Research Datalink (CPRD) in the UK between 1990 and 2014, we conducted three matched case-control studies. Studies 1 and 2 examined the risk of PCOS in women with autism (n = 971) and the risk of autism in women with PCOS (n = 26,263), respectively, compared with matched controls. Study 3 examined the odds ratio (OR) of autism in first-born children of women with PCOS (n = 8588), matched to 41,127 controls. In Studies 1 and 2 we found increased prevalence of PCOS in women with autism (2.3% vs. 1.1%; unadjusted OR: 2.01, 95% CI: 1.22-3.30) and elevated rates of autism in women with PCOS (0.17% vs. 0.09%, unadjusted OR: 1.94 CI: 1.37-2.76). In Study 3 we found the odds of having a child with autism were significantly increased, even after adjustment for maternal psychiatric diagnoses, obstetric complications, and maternal metabolic conditions (unadjusted OR: 1.60, 95% CI: 1.28-2.00; adjusted OR: 1.35, 95% CI: 1.06-1.73). These studies provide further evidence that women with PCOS and their children have a greater risk of autism.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Cohort inclusion for women with PCOS and their children

References

    1. Baron-Cohen S. The extreme male brain theory of autism. Trends Cogn. Sci. 2002;6:248–254. doi: 10.1016/S1364-6613(02)01904-6.
    1. Werling DM, Parikshak NN, Geschwind DH. Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders. Nat. Commun. 2016;7:11. doi: 10.1038/ncomms10717.
    1. Baron-Cohen S, et al. Why are autism spectrum conditions more prevalent in males? PLoS Biol. 2011;9:e1001081. doi: 10.1371/journal.pbio.1001081.
    1. Auyeung B, et al. Foetal testosterone and the child systemizing quotient. Eur. J. Endocrinol. 2006;155:S123–S130. doi: 10.1530/eje.1.02260.
    1. Chapman E, et al. Fetal testosterone and empathy: evidence from the empathy quotient (EQ) and the “reading the mind in the eyes” test. Soc. Neurosci. 2006;1:135–148. doi: 10.1080/17470910600992239.
    1. Baron-Cohen S, et al. Elevated fetal steroidogenic activity in autism. Mol. Psychiatry. 2015;20:369–376. doi: 10.1038/mp.2014.48.
    1. Abramovich DR, Rowe P. Fetal plasma testosterone levels at mid-pregnancy and at term-relationship to fetal sex. J. Endocrinol. 1973;56:621–622. doi: 10.1677/joe.0.0560621.
    1. Reyes FI, Boroditsky RS, Winter JSD, Faiman C. Studies on human sexual development. II. Fetal and maternal serum gonadotropin and sex steroid concentrations. J. Clin. Endocrinol. Metab. 1974;38:612–617. doi: 10.1210/jcem-38-4-612.
    1. Auyeung B, et al. Effects of fetal testosterone on visuospatial ability. Arch. Sex. Behav. 2012;41:571–581. doi: 10.1007/s10508-011-9864-8.
    1. Knickmeyer R, Baron-Cohen S, Raggatt P, Taylor K. Foetal testosterone, social relationships, and restricted interests in children. J. Child Psychol. Psychiatry. 2005;46:198–210. doi: 10.1111/j.1469-7610.2004.00349.x.
    1. Auyeung B, et al. Fetal testosterone and autistic traits. Br. J. Psychol. (Lond., Engl.: 1953. 2009;100(Part 1):1–22.
    1. Auyeung B, Taylor K, Hackett G, Baron-Cohen S. Foetal testosterone and autistic traits in 18 to 24-month-old children. Mol. Autism. 2010;1:11. doi: 10.1186/2040-2392-1-11.
    1. Lombardo MV, et al. Fetal testosterone influences sexually dimorphic gray matter in the human brain. J. Neurosci. 2012;32:674–680. doi: 10.1523/JNEUROSCI.4389-11.2012.
    1. Knickmeyer R, et al. Androgens and autistic traits: a study of individuals with congenital adrenal hyperplasia. Horm. Behav. 2006;50:148–153. doi: 10.1016/j.yhbeh.2006.02.006.
    1. Ingudomnukul E, Baron-Cohen S, Wheelwright S, Knickmeyer R. Elevated rates of testosterone-related disorders in women with autism spectrum conditions. Horm. Behav. 2007;51:597–604. doi: 10.1016/j.yhbeh.2007.02.001.
    1. Pohl A, Cassidy S, Auyeung B, Baron-Cohen S. Uncovering steroidopathy in women with autism: a latent class analysis. Mol. Autism. 2014;5:27. doi: 10.1186/2040-2392-5-27.
    1. Azziz R, Chang WY, Stanczyk FZ, Woods K. Effect of bilateral oophorectomy on adrenocortical function in women with polycystic ovary syndrome. Fertil. Steril. 2013;99:599–604. doi: 10.1016/j.fertnstert.2012.10.016.
    1. Ruta L, Ingudomnukul E, Taylor K, Chakrabarti B, Baron-Cohen S. Increased serum androstenedione in adults with autism spectrum conditions. Psychoneuroendocrinology. 2011;36:1154–1163. doi: 10.1016/j.psyneuen.2011.02.007.
    1. Schwarz E, et al. Sex-specific serum biomarker patterns in adults with Asperger’s syndrome. Mol. Psychiatry. 2011;16:1213–1220. doi: 10.1038/mp.2010.102.
    1. Herguner S, Harmanci H, Herguner A, Toy H. Autistic traits in women with polycystic ovary syndrome. Res. Autism Spectr. Disord. 2012;6:1019–1022. doi: 10.1016/j.rasd.2012.01.003.
    1. Palomba S, et al. Pervasive developmental disorders in children of hyperandrogenic women with polycystic ovary syndrome: a longitudinal case-control study. Clin. Endocrinol. (Oxf.) 2012;77:898–904. doi: 10.1111/j.1365-2265.2012.04443.x.
    1. Kosidou K, et al. Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: a population-based nationwide study in Sweden. Mol. Psychiatr. 2016;21:1441–1448. doi: 10.1038/mp.2015.183.
    1. MHRA. The Clinical Practice Research Datalink.
    1. Charlton RACM, de Vries CS, Weil JG. Data resources for investigating drug exposure during pregnancy and associated outcomes: the General Practice Research Database (GPRD) as an alternative to pregnancy registries. Drug Saf. 2008;31:39–51. doi: 10.2165/00002018-200831010-00004.
    1. Agency MaHPR (ed.) Mother Baby Link Documentation (GPRD Group, London, 2010).
    1. Fombonne E, et al. Validation of the diagnosis of autism in general practitioner records. BMC Public Health. 2004;4:9. doi: 10.1186/1471-2458-4-5.
    1. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav. Res. Methods. 2007;39:175–191. doi: 10.3758/BF03193146.
    1. RStudio Team. RStudio: Integrated Development for R. RStudio, Inc., Boston, MA URL (2015).
    1. Therneau T. A Package for Survival Analysis in S. version 2.38, (2015).
    1. Palomba S, et al. Pervasive developmental disorders in children of hyperandrogenic women with polycystic ovary syndrome: a longitudinal case-control study. Clin. Endocrinol. 2012;77:898–904. doi: 10.1111/j.1365-2265.2012.04443.x.
    1. Cesta CE, et al. Polycystic ovary syndrome and psychiatric disorders: co-morbidity and heritability in a nationwide Swedish cohort. Psychoneuroendocrinology. 2016;73:196–203. doi: 10.1016/j.psyneuen.2016.08.005.
    1. Breedlove SM, Arnold AP. Hormore accumulation in a sexually dimorphic motor nucleus of the rat spinal-cord. Science. 1980;210:564–566. doi: 10.1126/science.7423210.
    1. Arnold AP, Gorski RA. Gonadal-steroid induction of sstructural sex-differences in the central nervous-system. Annu. Rev. Neurosci. 1984;7:413–442. doi: 10.1146/annurev.ne.07.030184.002213.
    1. Cooke B, Hegstrom CD, Villeneuve LS, Breedlove SM. Sexual differentiation of the vertebrate brain: principles and mechanisms. Front. Neuroendocrinol. 1998;19:323–362. doi: 10.1006/frne.1998.0171.
    1. Forger NG. Cell death and sexual differentiation of the nervous system. Neuroscience. 2006;138:929–938. doi: 10.1016/j.neuroscience.2005.07.006.
    1. McCarthy MM. Estradiol and the developing brain. Physiol. Rev. 2008;88:91–124. doi: 10.1152/physrev.00010.2007.
    1. Dominique Toran-Allerand C. Sex steroids and the development of the newborn mouse hypothalamus and preoptic areain vitro: implications for sexual differentiation. Brain Res. 1976;106:407–412. doi: 10.1016/0006-8993(76)91038-6.
    1. Sakamoto H, Mezaki Y, Shikimi H, Ukena K, Tsutsui K. Dendritic growth and spine formation in response to estrogen in the developing Purkinje cell. Endocrinology. 2003;144:4466–4477. doi: 10.1210/en.2003-0307.
    1. McCarthy MM, et al. The epigenetics of sex differences in the brain. J. Neurosci. 2009;29:12815–12823. doi: 10.1523/JNEUROSCI.3331-09.2009.
    1. Abbott DH, et al. Nonhuman primate models of polycystic ovary syndrome. Mol. Cell. Endocrinol. 2013;373:21–28. doi: 10.1016/j.mce.2013.01.013.
    1. Padmanabhan V, Veiga-Lopez A. Sheep models of polycystic ovary syndrome phenotype. Mol. Cell. Endocrinol. 2013;373:8–20. doi: 10.1016/j.mce.2012.10.005.
    1. Dumesic DA, Abbott DH, Padmanabhan V. Polycystic ovary syndrome and its developmental origins. Rev. Endocr. Metab. Disord. 2007;8:127–141. doi: 10.1007/s11154-007-9046-0.
    1. Filippou P, Homburg R. Is foetal hyperexposure to androgens a cause of PCOS? Hum. Reprod. Update. 2017;23:421–432. doi: 10.1093/humupd/dmx013.
    1. Puttabyatappa M, Cardoso RC, Padmanabhan V. Effect of maternal PCOS and PCOS-like phenotype on the offspring’s health. Mol. Cell. Endocrinol. 2016;435:29–39. doi: 10.1016/j.mce.2015.11.030.
    1. Sir-Petermann T, et al. Metabolic and reproductive features before and during puberty in daughters of women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2009;94:1923–1930. doi: 10.1210/jc.2008-2836.
    1. Falbo A, et al. Changes in androgens and insulin sensitivity indexes throughout pregnancy in women with polycystic ovary syndrome (PCOS): relationships with adverse outcomes. J. Ovarian Res. 2010;3:23. doi: 10.1186/1757-2215-3-23.
    1. Maliqueo M, et al. Placental steroidogenesis in pregnant women with polycystic ovary syndrome. Eur. J. Obstet. Gynecol. Reprod. Biol. 2013;166:151–155. doi: 10.1016/j.ejogrb.2012.10.015.
    1. Sir-Petermann TMM, Angel B, Lara HE, Perez-Bravo F, Recabarren SE. Maternal serum androgens in pregnant women with polycystic ovary syndrome: possible implications in prenatal androgenization. Hum. Reprod. 2002;17:2573–2579. doi: 10.1093/humrep/17.10.2573.
    1. Maliqueo M, et al. Continuous administration of a P450 aromatase inhibitor induces polycystic ovary syndrome with a metabolic and endocrine phenotype in female rats at adult age. Endocrinology. 2013;154:434–445. doi: 10.1210/en.2012-1693.
    1. Wang L, et al. The expression of sex steroid synthesis and inactivation enzymes in subcutaneous adipose tissue of PCOS patients. J. Steroid Biochem. Mol. Biol. 2012;132:120–126. doi: 10.1016/j.jsbmb.2012.02.003.
    1. Xita N, Tsatsoulis A. Review: fetal programming of polycystic ovary syndrome by androgen excess: evidence from experimental, clinical, and genetic association studies. J. Clin. Endocrinol. Metab. 2006;91:1660–1666. doi: 10.1210/jc.2005-2757.
    1. Chakrabarti B, et al. Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome. Autism Res. 2009;2:157–177. doi: 10.1002/aur.80.
    1. Krakowiak P, et al. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics. 2012;129:e1121–e1128. doi: 10.1542/peds.2011-2583.
    1. Uzelac PS, et al. Gestational diabetes augments hyperandrogenemia in the third trimester of pregnancy. J. Soc. Gynecol. Invest. 2005;12:282A–282A.
    1. Uzelac PS, et al. Dysregulation of leptin and testosterone production and their receptor expression in the human placenta with gestational diabetes mellitus. Placenta. 2010;31:581–588. doi: 10.1016/j.placenta.2010.04.002.
    1. Ashrafi M, et al. Gestational diabetes mellitus risk factors in women with polycystic ovary syndrome (PCOS) Eur. J. Obstet. Gynecol. Reprod. Biol. 2014;181:195–199. doi: 10.1016/j.ejogrb.2014.07.043.
    1. Joham AE, Ranasinha S, Zoungas S, Moran L, Teede HJ. Gestational diabetes and type 2 diabetes in reproductive-aged women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2014;99:E447–E452. doi: 10.1210/jc.2013-2007.
    1. Lim SS, Norman RJ, Davies MJ, Moran LJ. The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Obes. Rev. 2013;14:95–109. doi: 10.1111/j.1467-789X.2012.01053.x.
    1. Sir-Petermann T, et al. Serum adiponectin and lipid concentrations in pregnant women with polycystic ovary syndrome. Hum. Reprod. 2007;22:1830–1836. doi: 10.1093/humrep/dem090.
    1. Lugnegard T, Hallerback MU, Gillberg C. Psychiatric comorbidity in young adults with a clinical diagnosis of Asperger syndrome. Res. Dev. Disabil. 2011;32:1910–1917. doi: 10.1016/j.ridd.2011.03.025.
    1. Simonoff E, et al. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J. Am. Acad. Child Adolesc. Psychiatry. 2008;47:921–929. doi: 10.1097/CHI.0b013e318179964f.
    1. Benson S, et al. Prevalence and implications of anxiety in polycystic ovary syndrome: results of an internet-based survey in Germany. Hum. Reprod. 2009;24:1446–1451. doi: 10.1093/humrep/dep031.
    1. Kerchner A, Lester W, Stuart SP, Dokras A. Risk of depression and other mental health disorders in women with polycystic ovary syndrome: a longitudinal study. Fertil. Steril. 2009;91:207–212. doi: 10.1016/j.fertnstert.2007.11.022.
    1. Mansson M, et al. Women with polycystic ovary syndrome are often depressed or anxious—a case control study. Psychoneuroendocrinology. 2008;33:1132–1138. doi: 10.1016/j.psyneuen.2008.06.003.
    1. Uguz F, Akman C, Sahingoz M, Kaya N, Kucur R. One year follow-up of post-partum-onset depression: the role of depressive symptom severity and personality disorders. J. Psychosom. Obstet. Gynecol. 2009;30:141–145. doi: 10.1080/01674820802545818.
    1. Hollinrake E, Abreu A, Maifeld M, Van Voorhis BJ, Dokras A. Increased risk of depressive disorders in women with polycystic ovary syndrome. Fertil. Steril. 2007;87:1369–1376. doi: 10.1016/j.fertnstert.2006.11.039.
    1. Jedel E, et al. Sex steroids, insulin sensitivity and sympathetic nerve activity in relation to affective symptoms in women with polycystic ovary syndrome. Psychoneuroendocrinology. 2011;36:1470–1479. doi: 10.1016/j.psyneuen.2011.04.001.
    1. Gunnes N, et al. Interpregnancy interval and risk of autistic disorder. Epidemiology. 2013;24:906–912. doi: 10.1097/01.ede.0000434435.52506.f5.
    1. Azziz R, et al. The prevalence and features of the polycystic ovary syndrome in an unselected population. J. Clin. Endocrinol. Metab. 2004;89:2745–2749. doi: 10.1210/jc.2003-032046.
    1. Morgan CL, Jenkins-Jones S, Currie CJ, Rees DA. Evaluation of adverse outcome in young women with polycystic ovary syndrome versus matched, reference controls: a retrospective, observational study. J. Clin. Endocrinol. Metab. 2012;97:3251–3260. doi: 10.1210/jc.2012-1690.
    1. Rees DA, Jenkins-Jones S, Morgan CL. Contemporary reproductive outcomes for patients with polycystic ovary syndrome: a retrospective observational study. J. Clin. Endocrinol. Metab. 2016;101:1664–1672. doi: 10.1210/jc.2015-2682.
    1. Brugha T., et al. Autism Spectrum Disorders in Adults Living in Households Throughout England--Report from the Adult Psychiatric Morbidity Survey 2007. Leeds, England NHS Information Centre (2009).
    1. Burd LFW, Kerbeshian J. A prevalence study of pervasive developmental disorders in North Dakota. J. Am. Acad. Child Adolesc. Psychiatry. 1987;26:700–703. doi: 10.1097/00004583-198709000-00014.
    1. Giarelli E, et al. Sex differences in the evaluation and diagnosis of autism spectrum disorders among children. Disabil. Health J. 2010;3:107–116. doi: 10.1016/j.dhjo.2009.07.001.
    1. Estes A, et al. Long-term outcomes of early intervention in 6-year-old children with autism spectrum disorder. J. Am. Acad. Child Adolesc. Psychiatry. 2015;54:580–587. doi: 10.1016/j.jaac.2015.04.005.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever