Maternal polycystic ovary syndrome (PCOS) and autism yet again

Another mash-up post for you today as I bring two papers to the blogging table discussing a topic which has already had quite a bit of airtime on this blog: maternal diagnosis of polycystic ovary syndrome (PCOS) and risk of offspring diagnosis of autism (see here and see here). The papers in question are from Maria Katsigianni and colleagues [1] and Carolyn Cesta and colleagues [2] and, via different experimental means, both papers suggest that women with PCOS have a significantly greater risk of having a child diagnosed with autism or autism spectrum disorder (ASD).

PCOS, in case you didn't know, is a fairly common condition according to the NHS entry. It's characterised by three main features: irregular periods, the presence of high levels of androgens (male hormones) and polycystic ovaries ("ovaries become enlarged and contain many fluid-filled sacs (follicles) that surround the eggs"). Mention of (male) sex hormones in relation to PCOS have led quite a few researchers to suspect a connection between PCOS and autism but another important angle to the diagnosis is a link between PCOS and insulin (the hormone involved in blood sugar control)...

Anyhow, the Katsigianni paper first. This was a systematic review and meta-analysis of the existing peer-reviewed science on the topic of "whether women with PCOS have increased odds of having a child with ASD, while, secondarily, if these women themselves are at high risk of having the disease." Now just before anyone gets shirty with the use of the word 'disease', those are the authors words not mine. I fully go with the idea that autism is not a disease. Their 'boiling down the research literature' efforts yielded 10 studies which included over 30,000 children with autism and some 320,000 "non-ASD children." The results: "Diagnosed PCOS was associated with a 1.66 times increase in the odds of ASD in the offspring" and: "Women with PCOS were 1.78 times more likely to be diagnosed with ASD." Most data on which those findings were based were deemed to be of 'good quality'.

Then to the Cesta study. The primary aim was to "measure, in the general population, the association between maternal PCOS and offspring neuropsychiatric disorders where prenatal androgen levels and/or altered androgen function have been implicated in their etiology." That population was the Sweden, and yet another example of those fantastic Scandinavian population registries being put to good research use. Autism, by the way, wasn't the only label looked at by Cesta et al: "offspring attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and Tourette's disorder and chronic tic disorders (TD/CTD)."

Results: based on detecting some 20,000 PCOS-exposed offspring and 200,000 "unrelated PCOS-unexposed offspring" authors concluded that: "PCOS-exposed offspring had increased risk of being diagnosed with ADHD, ASD, and TD/CTD compared with unrelated PCOS-unexposed offspring." Interestingly Cesta observed that the association between maternal PCOS and autism and ADHD was stronger in girl offspring than boy offspring. They then go on to talk about prenatal androgen exposure "leading to ‘hyper-masculine’ behavioral and cognitive traits" in offspring as being one potential biological mechanism.

What's more to say? Well, despite the whole 'male sex hormone' *link* to autism I'd like to see a lot more investigation looking at biological mechanisms. Going back to the insulin link with PCOS, there is a requirement for further study in light of other findings (see here and see here). Insofar as implications for policy, well, preferential screening for autism in offspring when mum has a diagnosis of PCOS could be indicated. This adds to the growing number of other circumstances where such preferential screening seems to be indicated.

Oh, and there could be other areas of potential investigation to consider too (see here)...

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[1] Katsigianni M. et al. Maternal polycystic ovarian syndrome in autism spectrum disorder: a systematic review and meta-analysis. Molecular Psychiatry. 2019. March 13.

[2] Cesta CE. et al. Maternal polycystic ovary syndrome and risk of neuropsychiatric disorders in offspring: prenatal androgen exposure or genetic confounding? Psychol Med. 2019 Mar 12:1-9.

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"Progesterone hormone treatment significantly increased the risk of ASD"

The quote titling this post - "Progesterone hormone treatment significantly increased the risk of ASD [autism spectrum disorder]" - comes from the findings reported by Michael Davidovitch and colleagues [1].

Researchers set out to examine whether there was any *association* between the receipt of infertility treatments and offspring risk of a diagnosis of autism spectrum disorder (ASD). They concluded that use of IVF treatment - in vitro fertilisation, where a woman's egg(s) are removed and fertilised outside of the body then 'put back in' - probably doesn't show any significantly enhanced risk for offspring autism. When however it came to the use of progesterone hormone treatment complementing such assisted reproductive methods, there may be something to see...

Before going further into these findings, I want to hark back to some discussions (see here) on the previous research in this area. The paper by Liang Liu and colleagues [2] meta-analysing the peer-reviewed literature on the use of assisted reproductive technology (ART) and offspring risk of autism did suggest there might be something more to see; albeit concluding that: "The complexity of ART treatment renders the identification of individual risk factors extremely challenging." I say this on the basis that various different 'pregnancy and birth' factors have been *correlated* with offspring autism risk down the years (see here for example) and teasing apart which ones are the more 'important' is difficult to say the least.

The Davidovitch study relied on data for over 100,000 children (males) born between 1999 and 2008. Authors identified approaching one thousand children diagnosed with an ASD representing about 1% of the total cohort. As well as looking at IVF, they also examined "five hormone treatments" pertinent to ART, singling out progesterone hormone treatment as part of their observations.

There is lots more work to be done in this area before too many sweeping generalisations are made. Aside from the issue of teasing out exactly what conception/pregnancy variables *might* be related to offspring risk of autism (including reproduction itself!) there is a question of mechanism(s) to also consider. The authors refer to the term "epigenetic modification by progesterone" but only few details are provided. I might also at this point introduce a recent piece from Jill Escher [3] who provided some really interesting commentary on how synthetic hormone drugs *might* have played a role in her own family circumstances as a template for some further studies. I say this bearing in mind that progesterone should not be too readily confused with progestins [4].

To close, I also read some other work from Michael Davidovitch recently [5] talking about cell (mobile) phone use and "the development of joint attention in infants" pertinent to "the development of autistic features among a vulnerable subgroup of infants." I'm slightly less enthralled about such suggestions and the strength of any 'technology use cause autism' sentiments but am willing to keep an open mind on how our fascination with mobile phones *might* impact on parent-child interactions (but not necessarily in the context of autism)...

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[1] Davidovitch M. et al. Infertility treatments during pregnancy and the risk of autism spectrum disorder in the offspring. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2018. June 1.

[2] Liu L. et al. Association between assisted reproductive technology and the risk of autism spectrum disorders in the offspring: a meta-analysis. Scientific Reports. 2017; 7: 46207.

[3] Escher J. Bugs in the program: can pregnancy drugs and smoking disturb molecular reprogramming of the fetal germline, increasing heritable risk for autism and neurodevelopmental disorders? Environ Epigenet. 2018 Apr 26;4(2):dvy001.

[4] Spark MJ. Progesterone or progestogen or progestin; which is it? BMJ. 2009; 339: b4380.

[5] Davidovitch M. et al. The Role of Cellular Phone Usage by Parents in the Increase in ASD Occurrence A Hypothetical Framework. Medical Hypotheses. 2018. June 7.

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"CFS symptoms resemble a hypothyroid state" but...

I am a little late getting to the paper published by Begoña Ruiz-Núñez and colleagues [1] observing that, at least for some diagnosed with chronic fatigue syndrome (CFS), clinical findings related to thyroid function might "resemble a mild form of “non-thyroidal illness syndrome” and “low T3 syndrome” experienced by a subgroup of hypothyroid patients receiving T4 monotherapy." But I did get here eventually. Before heading into this paper, I'm gonna link to one of the 'already prepared' discussions on the Ruiz-Núñez findings (see here). My analysis is pretty similar but not entirely the same...

So: "We studied 98 CFS patients (21–69 years, 21 males) and 99 age- and sex-matched controls (19–65 years, 23 males)" was the starting point, as participants provided blood samples and 24-hour urine samples onward to various analyses being carried out. This included: "the measurement of routine hematological parameters [Hb, hematocrit, WBC, red blood cells (RBC), and thrombocytes]" and more specifically: "parameters of thyroid function, low-grade inflammation and gut wall integrity..., together with secondary markers of inflammation." Those 'parameters of thyroid function' included various measures of free and total levels of T3 and T4 required to ascertain the presence of "low-T3 syndrome." I was impressed to see that a measure of gut wall integrity was also on the research menu in the form of plasma zonulin levels being included (albeit analysed via ELISA and bearing in mind the issues that have emerged with that particular method).

Results: "Chronic fatigue syndrome patients exhibited lower FT3, TT4, TT3, %TT3, SPINA-GD, and SPINA-GT, lower ratios of TT3/TT4, FT3/FT4, TT3/FT3, and TT4/FT4; and higher %rT3 and rT3/TT3 ratio." These findings were based on 'group' comparisons with those sex-matched not-CFS controls, and point to some 'issues' with thyroid function in general. Coupled to other thyroid related findings, the Ruiz-Núñez suggest that lower levels of thyroid hormones were detected but "distinct from thyroidal disease" typical levels of thyroid-stimulating hormone (TSH) were also reported. TSH is the stuff that tells the thyroid gland to make thyroid hormone (thyroxine (T4)), where T4 is, in effect, the starting material for T3 (triiodothyronine). Where there are suitable levels of TSH but lower levels of T4 and/or T3, one gets the impression that it's more about what's 'happening' to T3 and T4 over and above issues with their production. Indeed, the collected findings led authors to talk about that 'low T3 [triiodothyronine]syndrome' as being potentially pertinent to their findings in relation to CFS. Going back to those plasma zonulin findings, and there is just a sentence from Ruiz-Núñez and colleagues: "Zonulin, a parameter of intestinal permeability... was lower in CFS patients as compared to controls" but not much else.

I'm not particularly au fait with all the details of low T3 syndrome in the context of CFS or anything else so can't really add too much more. From what I gather, this is not a CFS-exclusive condition but does seemingly tap into talk about CFS being reflective of a "hypometabolic state" (see here). Questions about how to 'treat' such thyroid-related issues in the context of CFS remain unanswered, despite authors talking about "trials with, e.g., T3 and iodide supplements" being potentially indicated. I say this bearing in mind that the focus on biochemistry in the Ruiz-Núñez paper could perhaps, have been complemented by a little more on the presentation of clinical symptoms too.

In short, quite a bit more investigation in this area is indicated...

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[1] Ruiz-Núñez B. et al. Higher Prevalence of “Low T3 Syndrome” in Patients With Chronic Fatigue Syndrome: A Case–Control Study. Front. Endocrinol. 2018. Mar 20.

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On hormonal contraception and suicide risk

I'll freely admit that the material covered in the paper by Charlotte Wessel Skovlund and colleagues [1] suggesting that: "Use of hormonal contraception was positively associated with subsequent suicide attempt and suicide" is (a) slightly outside of the typical remit of this blog and (b) not something that I'm particularly qualified to talk about. I was however minded to discuss this paper in the context that previous work from this research group has *linked* hormonal contraception use with depression [2] (see here for some of the media on this past paper) and in the more general context of blogging occasions where depression and risk of suicide have been discussed here (see here).

Similar to their last research outing where hormonal contraception - 'birth control methods that act on the endocrine system' - was analysed, some of those rather important Scandinavian population registries were the source study material. Denmark was the country of choice and "a nationwide prospective cohort study of all women in Denmark who had no psychiatric diagnoses, antidepressant use, or hormonal contraceptive use before age 15 and who turned 15 during the study period, which extended from 1996 through 2013." You'll note the words 'no psychiatric diagnoses, antidepressant use' were included, illustrating how researchers were already mindful of the role that depression has in such extreme behaviour(s). Researchers collected information "about use of hormonal contraception" and also suicide attempts and completions. This, based on resources such as the Danish National Prescription Register, illustrating once again the long Scandinavian tradition of "creating nationwide administrative and health registries" [3].

Results: "Compared with women who never used hormonal contraceptives, the relative risk among current and recent users was 1.97 (95% CI=1.85–2.10) for suicide attempt and 3.08 (95% CI=1.34–7.08) for suicide." I should put that in some context in terms of hundreds of thousands of women - "nearly half a million women" - who were tracked over the course of the study, and how nearly 7000 first suicide attempts were recorded and 71 [completed] suicides registered. The numbers were comparatively small; bearing in mind that behind each figure is a person, a life and a family.

Taking into account the tenet 'correlation is not the same as causation' and indeed, appreciating how complex and individual suicidal thoughts and behaviour can be, these are potentially important data minus any scaremongering. Certainly these are findings worthy of quite a lot more study, particularly in light of the large population included for study mimicking the authors' previous chosen study design, alongside the prospective nature of their investigation.

Mechanisms of effect? I don't think anyone is quite there yet with regards to definitive hows-and-whys. I note that others have talked about a possible *correlation* between elevations in progesterone and suicide attempts [4] but such observations need to be treated cautiously at this point, again reiterating how complex and individual the processes leading someone to suicidal thoughts and behaviours are. Skovlund and colleagues did talk about suicide risk potentially differing according to different contraceptive formulations used: "Risk estimates for suicide attempt were 1.91... for oral combined products, 2.29... for oral progestin-only products, 2.58... for vaginal ring, and 3.28... for patch" potentially suggesting that specific products might have differing risk profiles. This is something else that could perhaps help isolate any pertinent mechanisms.

Questions remain, not least: Are there particular groups of women, based on genetics or other biology, that may be at increased risk of depression and/or suicide when taking such contraception? The answer: we don't yet know. Bearing in mind that in this, and their other work on hormonal contraception and depression, age seemed to be an important variable as per the observation: "Adolescent women experienced the highest relative risk" thus representing a good place to start. And on the topic of adolescent women perhaps having an elevated risk, I might also draw your attention to the findings reported by Jean Twenge and colleagues [5] who discussed another potentially important variable to consider: "Since 2010, adolescents spent more time on social media and electronic devices, activities positively correlated with depressive symptoms and suicide-related outcomes." I wonder if this is something that perhaps needs to be controlled for in future studies?

To close, there's always someone to talk to (see here) if needs be, and please, talk to your medical professional (not Dr Google) if you're at all concerned by these latest findings.

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[1] Skovlund CW. et al. Association of Hormonal Contraception With Suicide Attempts and Suicides. Am J Psychiatry. 2017 Nov 17:appiajp201717060616.

[2] Skovlund CW. et al. Association of Hormonal Contraception With Depression. JAMA Psychiatry. 2016 Nov 1;73(11):1154-1162.

[3] Pottegård A. et al. Data Resource Profile: The Danish National Prescription Registry. Int J Epidemiol. 2017 Jun 1;46(3):798-798f.

[4] Mousavi SG. et al. Recurrent suicide attempt and female hormones. Advanced Biomedical Research. 2014;3:201. doi:10.4103/2277-9175.142046

[5] Twenge J. et al. Increases in Depressive Symptoms, Suicide-Related Outcomes, and Suicide Rates Among U.S. Adolescents After 2010 and Links to Increased New Media Screen Time. Clinical Psychological Science. 2017. Nov 14.

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Gastrin-releasing peptide and autism?

"Gastrin-releasing peptide was safe and well tolerated by most subjects and may be effective for core symptoms of autism."

So said the results of the study - open trial - by Michele Michelin Becker and colleagues [1] continuing a research theme from this author [2] on the potential need for further scientific scrutiny when it comes to the use of gastrin-releasing peptides (GRP) and autism. Emphasising again that results were based on the use of an open trial (everyone knew what was being taken) alongside the small participant group included for study (N=10), researchers suggested that there may be more to see in this area as per the idea that 6 of 10 of the participants "responded to GRP" based on scores on a suite of autism-related assessment schedules. I might add that authors also importantly noted 'adverse reactions' in 3 of the 10 participants so perhaps slightly reducing the impact of that 'safe and well tolerated' sentence above.

For those with long autism research memories, mention of the word 'gastrin', as in the idea that GRP stimulates the release of gastrin in the stomach, might take you back to another gut hormone with a place in autism research history: secretin. Gastrin and secretin (and cholecystokinin (CCK)) show some important relationships with one another, but under typical circumstances secretin normally inhibits the release of gastrin. Just to add to the complexity here, older research had also suggested that GRP (and its homolog bombesin) might also "elicit secretin secretion" [3] under certain circumstances. It's all rather complicated as gut hormone chemistry tends to be.

I note that over the course of their research interest in this area, Becker et al have tended to focus on the idea that their intravenous (IV) application of GRP is probably working on the 'first brain' not the second one as per their discussions about GRP being "released by glutamatergic neurons and acts as a neurotransmitter that regulates neuronal excitability." I might add that other research has talked about GRP in the context of neurogenesis too [4]. Unfortunately as the research currently stands, we don't know very much which biological parameters are being affected by administration of GRP in cases of autism so we can't say too much. There is some suggestion that "neonatal blockade of GRPr [gastrin-releasing peptide receptor]" might have behavioural implications in rats pertinent to the "expression of autism-relevant phenotypes" [5] but again, very little on GRP and gastrin itself in people with autism.

I'm hoping that lessons have been learned when it comes to the potential future investigation of GRP and autism from the secretin story and any prejudice is minimised by mere mention of gut hormones potentially being implicated in some autism. Accepting that case reports are normally the starting point for quite a lot of science, I couldn't help but notice that the 3 case reports paper by Becker et al [2] on the use of GRP in cases of autism was not a million miles away from the 3 case reports paper by Horvath et al [6] on secretin and autism....


To close, I really hope the picture shown here is not a sign of things to come but just in case, on behalf of the UK, we're sorry...

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[1] Becker MM. et al. Improvement in Symptoms of Autism Spectrum Disorder in Children With the Use of Gastrin-Releasing Peptide: An Open Trial. Clin Neuropharmacol. 2016 Jun 21.

[2] Becker MM. et al. Improvement of autism spectrum disorder symptoms in three children by using gastrin-releasing peptide. J Pediatr (Rio J). 2016 May-Jun;92(3):302-6.

[3] Chang CH. et al. Modulation of secretin release by neuropeptides in secretin-producing cells. Am J Physiol. 1998 Aug;275(2 Pt 1):G192-202.

[4] Walton NM. et al. Gastrin-releasing peptide contributes to the regulation of adult hippocampal neurogenesis and neuronal development. Stem Cells. 2014 Sep;32(9):2454-66.

[5] Merali Z. et al. Long-term behavioral effects of neonatal blockade of gastrin-releasing peptide receptors in rats: similarities to autism spectrum disorders. Behav Brain Res. 2014 Apr 15;263:60-9.

[6] Horvath K. et al. Improved social and language skills after secretin administration in patients with autistic spectrum disorders. J Assoc Acad Minor Phys. 1998;9(1):9-15.

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Becker MM, Riesgo RS, Roesler R, Bosa C, Ohlweiler L, Backes B, Endres RG, Zanon RB, Marchezan J, & Schwartsmann G (2016). Improvement in Symptoms of Autism Spectrum Disorder in Children With the Use of Gastrin-Releasing Peptide: An Open Trial. Clinical neuropharmacology PMID: 27332629

Prenatal hormone involvement in autism risk?

The findings reported by Gayle Windham and colleagues [1] caught my eye recently and their observations based on the examination of mid-pregnancy serum hormone and protein markers for some 2500 mothers of children diagnosed with an autism spectrum disorder (ASD) compared with 600,000 controls.

Detailing results based on: "Second trimester levels of unconjugated estriol (uE3), human chorionic gonadotropin (hCG), and maternal serum alpha-fetoprotein (MSAFP)", researchers reported that their results: "further support prenatal hormone involvement in ASD risk."

I perhaps need to do a little 'defining' before progressing any further with this post. Unconjugated estriol (uE3) refers to an estrogen. It becomes the dominant oestrogen during pregnancy; produced by the baby's liver and placenta. Measured levels of uE3 during the 2nd trimester of pregnancy have been linked to various 'outcomes' including the possibility of Down's syndrome and neural tube defects.

Human chorionic gonadotropin (hCG) is another hormone; one that is normally used to confirm pregnancy. During pregnancy, levels of hCG can also be used to determine Down's syndrome. Serum alpha-fetoprotein (MSAFP) is the most abundant plasma protein found in the developing foetus. During pregnancy, extremes in levels of MSAFP can indicate issues in pregnancy. Combined together, these various hormones/proteins make up the so-called triple test, that when added to information such as maternal age and stage of pregnancy, can classify a pregnancy as being high or low risk for chromosomal abnormalities. That being said, the test is by no means perfect.

Windham et al report some rather complicated results based on adjusted odds ratios (AOR) when it came to autism vs control samples. So: "Lower uE3 (AOR for < 10th percentile vs. 25th-74th percentiles = 1.21, 95 % CI 1.06-1.37), and higher MSAFP (AOR = 1.21, 95 % CI 1.07-1.37 for > 90th percentile) were significantly associated with ASD. A U-shaped relationship was seen for hCG (AOR = 1.16, 95 % CI 1.02-1.32 for < 10th percentile; AOR = 1.19, 95 % CI 1.05-1.36 for > 90th percentile)." Lower uE3 is a trend found in relation to Down's syndrome. Higher MSAFP however runs slightly counter to what has been discussed in relation to Down's syndrome. By contrast, elevations in MSAFP tend to be more readily linked to pregnancies where neural tube defects may be present. What this all means is that yes, these results could indicate the involvement of prenatal hormones and chromosomal issues in relation to 'some' autism, but science still needs to go a little way before anyone talks about a triple test being applied to autism (and the ethical issues that this might bring).

I think it's also worthwhile briefly bringing in a few caveats to such pregnancy testing that could be pertinent to other autism research findings. As per other information, a mother's weight during pregnancy can affect what results you get - "Serum marker levels tend to be decreased in heavier women, and increased in lighter women." If you map this on to the research talking about maternal obesity linked to some autism (being careful not to generalise here), you can see how adjustments might have been / have to be made. Ethnicity is another factor that needs to be kept in mind. Also: "AFP and uE3 levels tend to be low (about 8% and 6% respectively) in women with insulin dependent diabetes mellitus." This is particularly interesting in view of the quite consistent literature detailing how gestational diabetes seems to show a connection to risk of offspring autism (see here). Various other factors (vaginal bleeding) can similarly affect results.

The Windham results are nevertheless interesting and are strengthened somewhat by the large participant numbers included for study. That other groups have similarly talked about elevations in MSAFP in relation to autism [2] increases the confidence that there may something further to see in this area, at least for some autism.

Music: Al Green - Tired of Being Alone.

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[1] Windham GC. et al. Autism Spectrum Disorder Risk in Relation to Maternal Mid-Pregnancy Serum Hormone and Protein Markers from Prenatal Screening in California. J Autism Dev Disord. 2015 Sep 14.

[2] Abdallah MW. et al. Autism spectrum disorders and maternal serum α-fetoprotein levels during pregnancy. Can J Psychiatry. 2011 Dec;56(12):727-34.

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Windham GC, Lyall K, Anderson M, & Kharrazi M (2015). Autism Spectrum Disorder Risk in Relation to Maternal Mid-Pregnancy Serum Hormone and Protein Markers from Prenatal Screening in California. Journal of autism and developmental disorders PMID: 26370672

Bisphenol A Exposure in Children With Autism

The paper by T. Peter Stein and colleagues [1] suggesting an "association" between BPA (Bisphenol-A) and autism spectrum disorder (ASD) was always bound to create some interest. Reporting results based on the analysis of urine samples from a group of children diagnosed with an autism spectrum disorder (ASD) (n=46) compared to controls (n=52), authors concluded that: "there is an association between BPA and ASD." Association... note that word.

C'mon. Let's go see how much
we're going for on eBay

BPA has been around for quite a few years. An important chemical in the production of certain plastics and resins, in more recent times quite a volume of science has suggested that caution should be applied to the use of and exposure to BPA particularly with reference to its potential estrogenic properties [2]. As with everything in life, the effects or not of BPA continue to be the source of some discussion, with concerns even been raised about the alternatives to BPA (see here) being put forward. In short, it's very, very complicated.

Stein and colleagues started from the premise that: "The major pathway for BPA metabolism and excretion is via glucuronidation." Glucuronidation involves the addition of glucuronic acid to a particular metabolite thus aiding the removal of said metabolite from the body. Those of you who have come across the whole sulphation and autism story might remember how glucuronidation and sulphation share some history with [some] autism in mind as per papers like the one from Alberti and colleagues [3]. Stein et al have some research form when it comes to glucuronidation and autism as per papers such as this one [4] (open-access) that concluded that: "The glucuronidation pathway may differ in some children with ASD." They reported lower levels of glucuronidation which impacted on the metabolism of phthalates among other things (see here).

Anyhow, the analytical weapon of choice in the BPA-autism study by Stein et al was mass spectrometry (MS). Again, this research group have some interest/experience in this area as per other research of theirs which has crossed my blogging path (see here). Looking at those urine samples from participants with ASD vs asymptomatic controls, researchers reported a few important details including that: "about 20% of the ASD children had BPA levels beyond the 90th percentile (>50 ng/mL) of the frequency distribution for the total sample of 98 children." They also reported "significant differences (P < 0.05) between the groups in total and % bound BPA" (bound BPA referring to BPA glucuronide). Reiterating their conclusion: "The results suggest there is an association between BPA and ASD."

Bearing in mind how the word 'chemical' has been mis-represented down the years, there is quite a body of work emerging suggestive that there is quite a bit more to do when it comes to environmental exposures potentially linking into at least some cases of autism. This is not the first time that BPA has been examined with autism in mind as per discussions like the one from de Cock and colleagues [5] and some animal model work such as that from Wolstenholme et al [6]. The paper from Kaur and colleagues [7] suggesting that: "BPA may act as an environmental risk factor for autism in genetically susceptible children by inducing oxidative stress and mitochondrial dysfunction" offers some tantalising areas of further research tallying with other non-autism research [8]. I might also bring your attention to the paper by Lichtensteiger and colleagues [9] (thanks to @autismepi) perhaps providing another important area for further research.

Further study is of course implied from the Stein work and other research in this area. That and quite a bit more investigation of the biological systems implicated in any effect from BPA on cases of autism brings the focus back to a model of genes and environment [variably] interacting on the very wide autism spectrum...

Music: Madonna - Papa Don't Preach. Well, preaching is what we do best!

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[1] Stein TP. et al. Bisphenol A Exposure in Children With Autism Spectrum Disorders. Autism Research. 2015. Jan 13.

[2] Sharpe RM. Is it time to end concerns over the estrogenic effects of bisphenol A? Toxicol Sci. 2010 Mar;114(1):1-4.

[3] Alberti A. et al. Sulphation deficit in "low-functioning" autistic children: a pilot study. Biol Psychiatry. 1999 Aug 1;46(3):420-4.

[4] Stein TP. et al. Autism and Phthalate Metabolite Glucuronidation. J Autism Dev Disord. Nov 2013; 43(11): 2677–2685.

[5] de Cock M. et al. Does perinatal exposure to endocrine disruptors induce autism spectrum and attention deficit hyperactivity disorders? Review. Acta Paediatr. 2012 Aug;101(8):811-8.

[6] Wolstenholme JT. et al. Gestational exposure to low dose bisphenol A alters social behavior in juvenile mice. PLoS One. 2011;6(9):e25448.

[7] Kaur K. et al. Bisphenol A induces oxidative stress and mitochondrial dysfunction in lymphoblasts from children with autism and unaffected siblings. Free Radic Biol Med. 2014 Nov;76:25-33.

[8] Veiga-Lopez A. et al. Impact of Gestational Bisphenol A on Oxidative Stress and Free Fatty Acids: Human Association and Interspecies Animal Testing Studies. Endocrinology. 2015. Jan 20.

[9] Lichtensteiger W. et al. Differential Gene Expression Patterns in Developing Sexually Dimorphic Rat Brain Regions Exposed to Anti-androgenic, Estrogenic, or Complex Endocrine Disruptor Mixtures: Glutamatergic Synapses as Target. Endocrinology. 2015 Jan 21: en20141504.

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Stein, T., Schluter, M., Steer, R., Guo, L., & Ming, X. (2015). Bisphenol A Exposure in Children With Autism Spectrum Disorders Autism Research DOI: 10.1002/aur.1444

Altered ghrelin levels in boys with autism

"Honey, it's the '90s, remember?"

Saudi Arabia and autism research? It must be at least one author from the research tag-team that is Mostafa and Al-Ayadhi.

Indeed, in today's post it is Laila Al-Ayadhi featured on the paper by Felwah S. Al-Zaid and colleagues [1] (open-access) who concluded on: "a potential role for the hormone ghrelin in the pathogenesis of autism".

Ghrelin, by the way, is often called the 'hunger hormone' as a result of its effects in relation to energy homoeostasis. Alongside another hormone called leptin (which has also been implicated in cases of autism) the long-and-short of food intake regulation seem to be covered by these hormones [2].

The Al-Zaid paper is open-access but I'll direct you to a few important points...

• A case-control study, authors looked at various measures for 31 boys diagnosed with autism compared with 28 age- and sex-matched controls.
• Alongside various anthropometric measures, plasma and serum levels of "acyl ghrelin (AG), des-acyl ghrelin (DG), total testosterone (TT), free testosterone (FT), leptin and growth hormone (GH)" were measured. These were single spot measures with samples taken "after an overnight fast". 
• Results: the autism group were on average heavier than controls but aside from that, no other physical measure was significantly different (mean height was greater in the autism group but just escaped significance). Both acyl ghrelin and des-acyl ghrelin levels were significantly lower in the autism group. By contrast, leptin levels were higher in the autism group (as per other independent findings) and free and total testosterone levels were significantly elevated compared to controls. Taking into account the effect of weight and it's link to adiposity, authors also showed that an analysis of a smaller subgroup (autism, n=27; controls, n=28) where mean weight was controlled for, found a similar trend in hormone levels (see this link to Table 3 of the paper) bearing in mind how body fat can influence the parameters.
• Various correlational analyses were completed on the data but given the relatively small participant groups and the use of spot samples I'm not particularly minded to read too much into these findings at this time.
• The authors conclude that their study: "contributes significantly to the understanding of hormonal dysregulation in the pathophysiology of autism, as it provides baseline data regarding hormonal profiles in autism and substantiates potential clinical interventions".

Small participants numbers and a "lack of female subjects with autism" kinda prohibit me from reading too much into these findings as they stand. I've already made mention of the research trend when it comes to elevated leptin levels and autism (see the paper from Rodrigues and colleagues [3] as one example). Likewise, testosterone levels and autism have received quite a bit of autism research attention down the years (see here). Indeed, elevations in testosterone levels not described in-utero with some potential relationship to foetal programming, has been the stuff of controversy in autism research circles [4].

Going back to the primary ghrelin findings and the observations of lower levels detected in their autism group, the authors speculate on some of the hows and whys of their findings. Gastrointestinal (GI) issues get a call-out and how some of the variety of GI issues noted in cases of autism "could affect the gastric mucosa and interfere with the normal function of ghrelin-secreting cells". although no particulars about GI issues are included in their descriptions of their cohort. One additional issue that I would perhaps add to the whole inflammation, dysbiosis et al discussions would be how ghrelin seems to play some role in GI motility [5] too. That being said, 'wide-ranging' is perhaps the best way to describe what biological processes ghrelin might impact on [6].

I was a touch surprised that the more usual role for ghrelin in terms of hunger and energy homoeostasis was not given more prominence in the Al-Zaid article on autism. Food and feeding patterns are important topics when it comes to autism as per discussions on the extremes sometimes noted in cases of autism (see here) and the increasingly important issue of weight (see here) (which also seemed to be picked up in the authors' findings). One might speculate that hunger and signals linked to hunger might be similarly tied into at least some of the feeding issues reported in autism?

As I seem to do in many discussions these days, I'll reiterate that there is quite a bit more to see and do in research terms on the relationship between ghrelin and related hormones and autism. The additional suggestion from Ghanizadeh [7] about the ghrelin being a "promising therapeutic target for co-occurring autism and epilepsy" might also be worthy of greater inspection.

Music to close. Iggy Pop and Lust for Life.

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[1] Al-Zaid FS. et al. Altered ghrelin levels in boys with autism: a novel finding associated with hormonal dysregulation. Sci Rep. 2014 Sep 26;4:6478.

[2] Klok MD. et al. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007 Jan;8(1):21-34.

[3] Rodrigues DH. et al. Changes in Adipokine Levels in Autism Spectrum Disorders. Neuropsychobiology 2014;69:6-10

[4] Geier DA. & Geier MR. A prospective assessment of androgen levels in patients with autistic spectrum disorders: biochemical underpinnings and suggested therapies. Neuro Endocrinol Lett. 2007 Oct;28(5):565-73.

[5] Greenwood-Van Meerveld B. et al. Ghrelin as a target for gastrointestinal motility disorders. Peptides. 2011 Nov;32(11):2352-6.

[6] Delporte C. Structure and physiological actions of ghrelin. Scientifica (Cairo). 2013;2013:518909.

[7] Ghanizadeh A. Ghrelin as a promising therapeutic target for co-occurring autism and epilepsy. Epilepsy Behav. 2011 Feb;20(2):420-1.

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Al-Zaid FS, Alhader AA, & Al-Ayadhi LY (2014). Altered ghrelin levels in boys with autism: a novel finding associated with hormonal dysregulation. Scientific reports, 4 PMID: 25257829

Elevated amniotic fluid steroid hormones and autism risk

"These results provide the first direct evidence of elevated fetal steroidogenic activity in autism". Such were the sentiments of the paper by Simon Baron-Cohen and colleagues [1] (open-access) looking at amniotic fluid samples for the presence of various sex steroid levels: Progesterone, 17α-Hydroxy-progesterone, Androstenedione, Testosterone and Cortisol. Most compounds are found in the Δ4 pathway. Suffice to say that the media kinda liked the press release for this study (see here) and the study findings have been reported by quite a few outlets (see here and see here).

The paper is open-access but as always, I'd like to give a brief overview:

• Based on amniotic samples collected in Denmark (yet again those Scandinavian registries are proving their scientific worth), "all amniotic fluid samples of males born between 1993 and 1999 who later received ICD-10 (International Classification of Diseases, 10th Revision) diagnoses of autism, Asperger syndrome or PDD-NOS (pervasive developmental disorder not otherwise specified) (n=128)" were compared with 217 asymptomatic controls. Note the focus on males only.
• Samples were in storage for quite a few years (average of 14 years) but were eventually thawed and prepared for analysis by a favourite technique of mine: liquid chromatography tandem mass spectrometry. If you're really interested, the mass spec used was a triple quadrupole system operated in positive ion mode relying on chemical ionisation.
• Results: rather than any one of the sex steroids being singled out as a biomarker for the autism samples, "a latent steroidogenic factor is elevated, which includes all hormones in the Δ4 pathway, as well as cortisol". Further: "This observation suggests dysregulation of pathways mediated by cytochrome P450-containing enzymes that catalyze the conversion of hormones along the Δ4 and glucocorticoid pathways". One of the figures included in the paper provides a good overview on the extent of the group elevations noted in the study (see here).
• "The source of elevated steroidogenic activity in the fetal development of autism was not tested in the current study, and more research will be needed to understand how different sources such as the fetus, mother, placenta or other environmental factors might contribute to such elevations". In other words, researchers were only recording sex steroid values in samples not looking at the hows and whys of such elevations.

Those who are familiar with the autism research scene will probably know about Prof SBC and his work going back some years (see here). In more recent times, I note that quite a bit more of his work is focusing on the sex hormones and how they may relate to cognitive phenotypes such as systemisers and empathisers (see here and see here) potentially overlapping with facets of the autism and other spectrums. Perhaps more interesting to me has been some shift away from grand sweeping psychological theories of autism to other disciplines pertinent to autism research such as those similar to his analytical chemistry work shown in this post [2]. 

I note in the current paper mention of the words "epigenetic fetal programming" as being one suggestion for how being 'bathed' in elevated levels of these 'male' hormones might potentially explain why a child goes on to develop autism. I know this is a trendy area to talk about these days; David Barker (RIP) must be casting a smile over how far and wide his writings are now seemingly reaching. That being said, I'd be interested to see how subsequent research fares in this area particularly when taking into account other placental-related autism findings and the rise and rise of epigenetics in autism research (see here). The authors also for example write: "The current results may also be relevant to the literature on prenatal stress and autism. We found that cortisol, a biomarker typically associated with stress, is elevated early in the fetal development of autism". Knowing what we think we know about cortisol and autism (see here) again, it will be interesting to see where this research leads. Interestingly too, the authors also talk about GABA and cytokines in their discussion of results hinting at the multitude of possible effects that may stem from their findings.

Finally, I note the authors do add quite a big caveat to their findings: "From a clinical standpoint, the current results say nothing about the potential for such data as a prospective prenatal test of autism risk". This based on an issue that Prof SBC has talked about before in the lay arena (see here) which heads down a potentially quite uncomfortable path. Treading carefully, I await replication of these results and that all-important focus on the hows and whys of elevated foetal steroidogenic activity potentially associated with elevated autism risk.

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[1] Baron-Cohen S. et al. Elevated fetal steroidogenic activity in autism.  Molecular Psychiatry. 2014. June 3.

[2] Steeb H. et al. Serum proteomic analysis identifies sex-specific differences in lipid metabolism and inflammation profiles in adults diagnosed with Asperger syndrome. Mol Autism. 2014 Jan 27;5(1):4.

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Baron-Cohen, S., Auyeung, B., Nørgaard-Pedersen, B., Hougaard, D., Abdallah, M., Melgaard, L., Cohen, A., Chakrabarti, B., Ruta, L., & Lombardo, M. (2014). Elevated fetal steroidogenic activity in autism Molecular Psychiatry DOI: 10.1038/mp.2014.48