As I was writing the February article about sex hormones regulating autism-associated genes and the associated risk of high fetal testosterone levels, a thought occurred to me: if women with Polycystic Ovarian Syndrome (PCOS) have higher testosterone levels, do women with PCOS have a higher risk for having children with autism?
Turns out that yes, they do, according to two corroborating population-based studies performed in Sweden and in the UK. 1,2 To date there has not been a population study of this magnitude in the United States, but their findings do show how interwoven hormonal dysregulations seen in autism, PCOS, and obesity may be, and we may find similar evidence here in America.
Both studies used their country’s medical database to closely look at women who had been diagnosed with PCOS, comparing them to women who did not have PCOS, and measuring their relative risks for having a child diagnosed with autism.
Autism spectrum disorder (ASD) disproportionally affects boys at a rate of 3:1, but both boys and girls are marked by the presence of brain morphology typical of males – larger total brain volume, amygdalae, and asymmetries in the hemispheres that are testosterone related.2 It is known that sex hormones are able to influence parts of the brain in charge of communication and social interaction, and that specifically prenatal androgens may be a contributing factor to the development of autism. Testosterone and androstenedione have actually been found to be at higher levels in the amniotic fluid of children who were subsequently diagnosed with ASD.3 It is thought between the 8th-24th week of pregnancy is the critical window for when neural sexual differentiation occurs in the developing baby; second trimester high testosterone levels within this timeframe could cause atypical brain patterning.1
Women with PCOS suffer varying degrees of hormonal complications including hyperandrogenemia (excess androgens) and hyperinsulinemia (excess insulin in the blood), both of which can be exacerbated by obesity and pregnancy. Indeed they found a greater number of women with PCOS had higher BMIs compared to women without PCOS – 57.4% women with PCOS were overweight or obese compared to 28.5% of those who did not have PCOS.2 Gestational hyperinsulinemia has been shown to associated with increased steroid activity in the placenta and amniotic fluid.
According to the Swedish study, they found that “maternal diagnosis of PCOS increased the risk of ASD… [and] obesity among women with PCOS appeared to further increase the risk of ASD in the offspring.”2 In cases of obesity, the body compensates for insulin resistance and consequently the liver produces less of what is called sex hormone binding globulin (SHBG).4 Normally this hormone binds androgens in the blood, so a decrease in SHBG in the blood causes there to be an increased amount of free androgens circulating in the body. The result is a further worsening of the hyperandrogenemia that is already present in women with PCOS. So couple (triple?) the insulin resistance due to PCOS, and obesity, and gestational diabetes, the maternal environment may be overwhelmed by hormonal dysregulation, and the fetal environment bombarded by an excessive amount of androgens.
The Swedish study found the odds of having a child with autism was 56% higher in women with PCOS; the UK study calculated the risk of having a first-born child was only 35% higher. The discrepancy here is the Swedish study looked at all children born to a mother with PCOS, instead of just the first-born child; prior studies have found a woman’s first child is fortunate to have a lower risk of autism in comparison to any of their siblings who come after.5 Interestingly, both studies found that this risk was not greater in one sex over the other, despite the fact that more boys are born with autism.
In the UK study, in addition to looking at the risk of autism in the offspring, they also looked at two sides of the same coin: the chances of a woman with PCOS to also be on the spectrum, and the chances of a woman with autism to concurrently have PCOS.
The researchers found a statistically significant number of women with ASD were diagnosed with PCOS in comparison to women without ASD; diabetes, depression, anxiety, and schizophrenia-related conditions were also common among the ASD patients. Among patients with PCOS, they found a coincident diagnosis of ASD was twice as likely. They, too, had a greater incidence of diabetes and obesity, as well as depression, anxiety, and schizophrenia-related conditions.1
Though this intertwined relationship between the two is not fully teased apart, the UK paper discusses there may be a genetic component connected with steroidogeneis – the creation of steroids – involved in this interplay as well. CYP19A and CYP17A are both enzymes involved in the synthesis of different sex hormones – CYP19A is involved in the conversion from testosterone to estradiol, while CYP17A is crucial to the synthesis of androstenedione. Malfunctions in the genes coding for these enzymes could lead to sex hormone dysregulation; both have been implicated in both PCOS and autism.1
One final important point the researchers from the UK study wanted to convey: “We would also underline that our study suggests that autism in children of women with PCOS is still very rare, so the chance of having a child with autism should not be overstated. The association of PCOS and autism therefore may inform new clinical interventions for both disorders.”1
So, if you or someone you love suffer from PCOS or are on the spectrum, do not overwhelm yourself with worry. The chances are still low, but it is good to know that a connection exists. In cases of children of women with PCOS, parents and doctors may be able to catch signs earlier; in women with ASD, it could help in leading to a PCOS diagnosis that may have otherwise go undiagnosed.
In addition to genetic factors, it is becoming clearer that there is a molecular interplay going on between PCOS, obesity, and autism, all three of which are linked by endocrine system disfunction, including metabolic hormone complications and sex-steroid imbalance – a relationship between androgens and insulin.
Though how much is chicken and how much is egg, I’m not sure. It even gives rise to the thought that one can cause the other – if PCOS in the mother can lead to autism in the daughter, which may then manifest into PCOS in that same child, it has hard to know where one complication began and the other ended. Even if one doesn’t directly cause the other, there is definitely a molecular link between them. However, it is important to understand the hormonal interactions in the body are very seldom linear, and more like a web with many different spokes and connections – a disruption in one hormone can affect several others, and may result in a multitude of consequences.
1Cherskov, A., Pohl, A., Allison, C., Zhang, H., Payne, R. A., & Baron-Cohen, S. (2018). Polycystic ovary syndrome and autism: A test of the prenatal sex steroid theory. Translational Psychiatry,8(1). doi:10.1038/s41398-018-0186-7
2Kosidou, K., Dalman, C., Widman, L., Arver, S., Lee, B. K., Magnusson, C., & Gardner, R. M. (2015). Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: A population-based nationwide study in Sweden. Molecular Psychiatry,21(10), 1441-1448. doi:10.1038/mp.2015.183
3Baron-Cohen, S., Auyeung, B., Nørgaard-Pedersen, B., Hougaard, D. M., Abdallah, M. W., Melgaard, L., . . . Lombardo, M. V. (2014). Elevated fetal steroidogenic activity in autism. Molecular Psychiatry,20(3), 369-376. doi:10.1038/mp.2014.48
4Messinis, I. E., Messini, C. I., & Dafopoulos, K. (2013). Obesity in PCOS and Infertility. Obesity,99-116. doi:10.1016/b978-0-12-416045-3.00008-x
5Gunnes, N., Surén, P., Bresnahan, M., Hornig, M., Lie, K. K., Lipkin, W. I., . . . Stoltenberg, C. (2013). Interpregnancy Interval and Risk of Autistic Disorder. Epidemiology,24(6), 906-912. doi:10.1097/01.ede.0000434435.52506.f5