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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"Maternal diabetes, especially GDM, is probably a risk factor for ADHD"

It's coincidental that as I write this post about the findings reported by Lifeng Zhao and colleagues [1] talking about how "Maternal diabetes, especially GDM [gestational diabetes mellitus], is probably a risk factor for ADHD [attention-deficit hyperactivity disorder]" so the BBC news website highlights how screening for gestational diabetes here in Blighty is still a bit of a hit-and-miss affair (see here).

That news report mentions how about a quarter of those mums-to-be who are most at risk of developing pregnancy diabetes - "having a high BMI [body mass index] or being of South Asian or Black Caribbean ethnicity" - did not get screened at all. Left untreated, gestational or pregnancy diabetes can increase the risk of various adverse events including "a baby that grows larger than usual, leading to problems in labour; premature birth; pre-eclampsia and stillbirth."

The Zhao findings - a meta-analysis - continue a theme suggesting that exposure to maternal diabetes, including pregnancy diabetes, seems to increase the risk of various other developmental and behavioural diagnoses also being present in offspring. The primary source material of this blog - autism - has been talked about on various occasions as being one of those developmental/behavioural diagnoses (see here and see here). That ADHD is quite often mentioned in the diagnostic mix when it comes to autism (see here) is another point to make.

The basics of the Zhao paper: a search of the peer-reviewed science literature was undertaken revealing nine studies that fitted the inclusion criteria including "7,218,903 participants." The quality of most studies was ranked as high. The results were interesting in that researchers "did not find significant association between maternal diabetes and ADHD risk (OR: 1.20, 95% CI: 0.96–1.49)." This observation is slightly at odds with the quote titling this post, which Zhao et al put down to the "high heterogeneity" detected among the included studies and their subgroup analysis of case-control studies (n=3).

Also... when it came to looking at another type of study - a cohort study (n=6) - "the meta-analysis demonstrated that maternal diabetes increased the risk of ADHD in offspring by 40%." Further, and bearing in mind the description 'diabetes' covers quite a bit of diagnostic ground, authors zoomed in on one particular 'type of diabetes', that called gestational diabetes (GDM) and looked at any effect. This is where things got a little more interesting as their results, based on four studies, indicated that "GDM exposure increased the risk of ADHD for children by 164%" in Caucasian children. Ergo, although a little mixed, the existing research literature at the time of analysis indicated that maternal diabetes during pregnancy, particularly GDM, *might* have some important effect on risk of offspring ADHD.

I'm not going to say much more at this point in time in terms of potential mechanisms that *might* elevate the risk of ADHD in offspring exposed to pregnancy diabetes. It's likely to be pretty complicated. Given also that GDM appears more often than not alongside other conditions (see here), it's not going to be easy to tease apart what might be the more important issues. Is it inflammation? Is something to do with blood sugar or insulin? At the moment, we just don't know enough...

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[1] Zhao L. et al. The association of maternal diabetes with attention deficit and hyperactivity disorder in offspring: a meta-analysis. Neuropsychiatr Dis Treat. 2019;15:675–684.
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Pioglitazone for autism?

Enjoyed Christmas? Welcome back. Onward...

"Pioglitazone is well-tolerated and shows a potential signal in measures of social withdrawal, repetitive, and externalizing behaviors."

So said the findings reported by Lucia Capano and colleagues [1] (open-access) describing preliminary efforts to "elucidate the maximum tolerated dose, safety, preliminary evidence of efficacy, and appropriate outcome measures in autistic children ages 5–12 years old" taking the hypoglycemic medicine called pioglitazone. The results obtained from this phase II pilot study - "a 16-week prospective cohort, single blind, single arm, 2-week placebo run-in, dose-finding study of pioglitazone" - suggest that further research on this medicine in the context of autism is warranted.

Capano et al provide quite a lot of information about the whys-and-wherefores of pioglitazone use in the context of autism. They talk about immune system 'issues' and inflammation being no strangers to autism research. They talk about various findings in relation to immune signalling and autism, drawing on data from several investigations that have looked at compounds like the cytokines and chemokines. Pioglitazone fits into this story by way of it being "an agonist of peroxisome proliferator activated receptor (PPAR)-ϒ." Activation of PPAR-ϒ leads to "insulin sensitization and enhances glucose metabolism." It also seemingly has an anti-inflammatory role to play too. Through the use of  pioglitazone ramping up the action of PPAR-ϒ, so researchers opined that this could be useful for some people diagnosed with autism where immune system and behaviour might meet...

Unlike other trials of pioglitazone in the context of autism [2], the Capano study was more exploratory than 'gold-standard' in it's design. It did however include both behavioural and biological components, where various behavioural outcome measures were included alongside the describing of various "research bloodwork" that included various cytokines ("IL1-β, IL-10, and TNF-α in plasma; IL-6 in serum") that have been discussed in other studies with autism in mind (see here for example).

Alongside those initial results mentioned in the opening sentence of this post, there are a few other important points to make. So: "Overall, pioglitazone was well tolerated." Welcome news indeed. Researchers also noted that: "There were no serious adverse events (SAEs) in any of the doses within the range tested (0.25 mg/kg, 0.5 mg/kg, and 0.75 mg/kg)." This is important in the context that all medicines have the propensity for 'adverse effects' for some people, and pioglitazone is no different. Given also the focus on medication and weight gain in the context of autism (see here for example), it's a bit of relief to see that, for the study period at least, authors reported that: "BMI [body mass index] did not change significantly during the study."

I'm not going to go to heavily into the behavioural changes noted over the study period on this occasion, because these are preliminary and one has to be careful with any interpretation. I do however want to mention some of the biological results; namely: "Significant changes with treatment occurred with both IL-6 and IL-10" and "IL-1β and TNF-α did not change significantly with treatment." The authors note that the IL-6 and IL-10 findings - "decreasing IL-6 and increasing IL-10" - were "consistent with the known effect of PPAR-gamma agonists like pioglitazone." This is an interesting finding.

Cumulatively, such results suggest that quite a bit more research focus is needed on pioglitazone in the context of [some] autism. But for now, it looks quite promising (again [3])...

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[1] Capano L. et al. A pilot dose finding study of pioglitazone in autistic children. Molecular Autism. 2018; 9: 59.

[2] Ghaleiha A. et al. A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: Effects on aberrant behavior in children with autism. Psychiatry Res. 2015 Sep 30;229(1-2):181-7.

[3] Boris M. et al. Effect of pioglitazone treatment on behavioral symptoms in autistic children. J Neuroinflammation. 2007;4:3.

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Polycystic ovary syndrome (PCOS) and autism continued

"These studies provide further evidence that women with PCOS [polycystic ovary syndrome] and their children have a greater risk of autism."

'These studies' refers to the studies conducted and reported on by Adriana Cherskov and colleagues [1] drawing on previous peer-reviewed research literature suggesting that there may be a *connection* between exposure to PCOS and autism or autistic traits (see here).

PCOS is a condition that affects how a woman's ovaries function. Although linked to an imbalance in certain sex hormones (specifically testosterone), one of the proposed starting points for PCOS is an elevation of insulin (a hormone that controls the amount of sugar in the blood). I'll return to this point shortly...

Cherskov et al report results from 3 studies included in their research strategy: study 1 "examined the risk of PCOS in women with autism compared to those without autism"; study 2 "examined the risk of autism in women with PCOS compared to those without PCOS"; and study 3 "examined the risk of autism in first-born children of mothers with PCOS compared to first-born children of mothers without PCOS." The autism *connection* is integrated into the idea that sex hormone exposure in-utero might play some role in the risk of autism to offspring. Bearing in mind that the participant numbers were not to be sniffed at, a few interesting results emerged from the collected studies.

So: "A significantly higher percentage of women with autism were diagnosed with PCOS than controls" (study 1). Looking at the percentages of PCOS among the groups, the results weren't exactly startling: 2.3-7.8% autism vs. 1.1-3.5% controls (depending on the PCOS criteria used) but a difference was noticed.

Then: "Autism was almost two times more prevalent in PCOS cases (n = 26,263) than in controls (n = 130,717)" (study 2). But... when authors took into account various 'psychiatric conditions' also present in mums, the results went from significant to non-significant ("p-value = 0.084"). And please, don't use the term 'approaching significance'...

Finally: "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."

What's to make of this collected data? Well, the use of anonymous electronic records derived from the Clinical Practice Research Datalink (CPRD) electronic health record database here in Blighty is a strength both in record number and quality. The associated feature that other clinical findings and diagnoses outside of PCOS were also included for study is very positive too. But one has to be slightly careful about making too many sweeping generalisations from the results of such studies. I can't disagree with the sentiments expressed by the authors that: "These studies provide further evidence that women with PCOS and their children have a greater risk of autism" but we can say that the picture is complicated and not straight-forward.

Then back to the questions of 'how and why'? Thankfully, the authors don't just focus on the 'sex steroids' viewpoint but do also talk about how insulin - hyperinsulinemia - might also play a role. My gut feeling is that this is of central importance, particularly in light of observations about a diabetes connection to autism (see here for a 'meta-analysis' example) and similar observation in other studies on PCOS and autism too (see here). Add in the findings on pregnancy metabolic syndrome and autism (see here and see here), featuring an 'inability to control blood sugar levels' and things get even more interesting in this area.

Oh, and there could be other [speculative] factors to consider too (see here)...

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[1] Cherskov A. et al. Polycystic ovary syndrome and autism: A test of the prenatal sex steroid theory. Transl Psychiatry. 2018 Aug 1;8(1):136.

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"Schizophrenia confers a high endogenous risk for diabetes"

"Schizophrenia confers a high endogenous risk for diabetes, and the risk is further increased by both first-generation and second-generation antipsychotics."

So concluded Anto Rajkumar and colleagues [1] who relied on participant data in the thousands derived from several of those very helpful Scandinavian population registries (this time in Denmark) to add some further science to the idea that psychiatric diagnoses like schizophrenia seem to carry an elevated risk for all-manner of somatic conditions.

From a total population of 2.7 millions people born in Denmark between 1977 and 2013, researchers reported that: "14,118 (0.52%) developed diabetes, and 8,945 (0.33%) developed schizophrenia during follow-up (49,582,279 person-years)." When looking at the risk of developing diabetes (bearing in mind there is more than one type of diabetes) in those with schizophrenia not following any antipsychotic medication regime, researchers reported that: "The adjusted hazard ratio for diabetes was 3.07 (95% confidence interval [CI], 1.71–5.41) in antipsychotic-naive schizophrenia compared with the general population." In other words, compared with those without a diagnosis of schizophrenia, there was something of an increased risk of developing diabetes in those diagnosed with schizophrenia.

Then to the potential effect of antipsychotic medication, and as the authors note: "The risk for diabetes after starting antipsychotic treatment was significantly higher (adjusted hazard ratio, 3.64; 95% CI, 1.95–6.82) than the risk in antipsychotic-naive schizophrenia." The use of an adjusted hazard ratio means that researchers took into account potentially confounding variables such as a family history of diabetes known to potentially elevate the risk of the condition. The focus on medication is also perhaps the side of the whole schizophrenia-diabetes story that people might more readily recognise.

If all that wasn't enough to convince you that schizophrenia - medicated and unmedicated - might show a rather important relationship with diabetes, perhaps the results reported by Pillinger and colleagues [2] might ease your scepticism and the suggestion (from the authors) that "higher levels of insulin, and increased levels of insulin resistance" are a facet of quite a few cases of schizophrenia alongside demonstrating that "people with schizophrenia had higher levels of glucose in the blood." On the basis of these and various other studies, the onus is on regular screening for diabetes and its symptoms alongside other related measures (see here for example) when it comes to schizophrenia under multiple 'medicated or not' conditions.

Music to close, and having bumped into the excellent film 'Stand By Me' again recently, the song of the same name...

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[1] Rajkumar AP. et al. Endogenous and Antipsychotic-Related Risks for Diabetes Mellitus in Young People With Schizophrenia: A Danish Population-Based Cohort Study. Am J Psychiatry. 2017 Jan 20:appiajp201616040442.

[2] Pillinger T. et al. Impaired Glucose Homeostasis in First-Episode Schizophrenia: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2017 Jan 11.

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Rajkumar AP, Horsdal HT, Wimberley T, Cohen D, Mors O, Børglum AD, & Gasse C (2017). Endogenous and Antipsychotic-Related Risks for Diabetes Mellitus in Young People With Schizophrenia: A Danish Population-Based Cohort Study. The American journal of psychiatry PMID: 28103712

S100B and schizophrenia meta-analysed

I don't know if it's just me but this year (2014) I seem to be covering a lot more meta-analysis papers on this blog. I assume that's because of the increasing volume of peer-reviewed research being created year-on-year leading to greater volumes of research fodder for such grand reviews. Whatever the reason(s), there are some really interesting conclusions being reached in that literature as per the meta-analysis by Aleksovska and colleagues [1] (open-access) focusing on S100B blood levels and schizophrenia.

"My name is Gladiator"

I've talked about S100B previously on this blog in relation to autism (see here) including some of the possible whys and wherefores. Very briefly, S100B - S100 calcium binding protein B - is a protein primarily secreted by glial cells which seems to be involved in various important functions including those in relation to synaptic plasticity and the innate immune response among others. S100B levels have also been examined in relation to brain injury, although some uncertainty seems to persist about their value here [2].

With schizophrenia in mind, there is a growing research base suggestive of some role for S100B in the condition (see here). Not all the evidence has universally pointed to a connection between protein and condition, bearing in mind the similar issue of heterogeneity and 'spectrums' being discussed in schizophrenia circles as they have in autism circles (albeit with caveats).

The Aleksovska paper reported that based on their analysis of the combined literature (using the PRISMA guidance) "S100B in peripheral blood was significantly increased in schizophrenia patients, with an almost double level in cases than controls". Results drawn from 20 studies which survived their filtering (all case-control reports) also indicated: "no evidence of difference in subgroups regarding detection of S100B in plasma or serum, medication status, stage of the disease, ethnicity, selection of cases and controls and source of controls". Interestingly too, the authors make reference to the "the traditional reductionist assessments based on single-pathways analyses and categorical diagnoses" used in schizophrenia as not being all that useful. They call their alternative 'Systems Medicine'. I would say however that they're describing something like RDoC (see here).

What's more to say on this area of schizophrenia research? Well, further investigations on the reason(s) for elevated S100B might be a good starting point including that related to glial cell activation in relation to schizophrenia [3]. But... and it is an important point, investigations also need to consider the variety of other factors which might account for elevated levels of S100B and are comorbid to psychiatric symptoms such as weight and insulin resistance [4], potentially all the more pertinent in light of the findings from van Beveren and colleagues [5] discussed in a recent post (see here).

Music to close. Cue the 70's detectives... Sabotage.

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[1] Aleksovska K. et al. Systematic Review and Meta-Analysis of Circulating S100B Blood Levels in Schizophrenia. PLoS One. 2014 Sep 9;9(9):e106342.

[2] Hansen-Schwartz J. & Bouchelouche PN. Use of biomarker S100B for traumatic brain damage in the emergency department may change observation strategy. Dan Med J. 2014 Sep;61(9):A4894.

[3] Rothermundt M. et al. Glial cell activation in a subgroup of patients with schizophrenia indicated by increased S100B serum concentrations and elevated myo-inositol. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Mar 30;31(2):361-4.

[4] Steiner J. et al. Elevated S100B levels in schizophrenia are associated with insulin resistance. Mol Psychiatry. 2010 Jan;15(1):3-4.

[5] van Beveren NJ. et al. Evidence for disturbed insulin and growth hormone signaling as potential risk factors in the development of schizophrenia. Transl Psychiatry. 2014 Aug 26;4:e430.

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Aleksovska K, Leoncini E, Bonassi S, Cesario A, Boccia S, & Frustaci A (2014). Systematic Review and Meta-Analysis of Circulating S100B Blood Levels in Schizophrenia. PloS one, 9 (9) PMID: 25202915

Insulin, growth hormone and risk of schizophrenia?

"Overall, the present findings suggest that metabolic and hormonal disturbances such as effects on insulin and growth hormone may represent a vulnerability factor to develop mental disorders". That was the conclusion reported by van Beveren and colleagues [1] (open-access) looking at "disruption of insulin and growth factor signaling pathways as an increased risk factor for schizophrenia".

"Years ago you served my father in the Clone Wars"

Drawing on data derived from participants taking part in the Genetic Risk and Outcome of Psychoses (GROUP) study [2] researchers looked at blood serum samples "to measure the levels of 184 molecules in serum from 112 schizophrenia patients, 133 siblings and 87 unrelated controls". Multiplex immunoassay was the analytical weapon of choice.

The results indicated that "10 proteins were present at significantly different levels between schizophrenia patients and controls" which can be seen here. The insulin synthesis pathway showed more than a passing connection to group differences as per the appearance of insulin and precursor molecules such as proinsulin and C-peptide (connecting peptide). Some of these pathway molecules were also reported to be altered in the sibling group(s) too. Growth hormone also featured as a potentially distinguishing marker, as did adiponectin among others.

The authors conclude (again) their findings for "the presence of a molecular endophenotype involving disruption of insulin and growth factor signaling pathways as an increased risk factor for schizophrenia". Perhaps even more interesting is their view of the body of work [3] suggesting that "antipsychotic drugs are known to increase peripheral glucose levels" and how, in light of their findings, "these effects may be intrinsically related to the therapeutic mechanism of action by increasing the peripheral blood glucose levels and thereby increasing glucose availability in the brain".

As the authors point out, there is still quite a bit more to do in this area including examining larger samples sizes and importantly, looking at blood glucose levels as a measure of insulin resistance to further complement their findings. I note however that issues with insulin function being potentially related to mood and other psychiatric conditions are nothing new as per the various literature in this area. Anderson and colleagues [4] for example, talked about a diagnosis of diabetes doubling the odds of comorbid depression. Bearing in mind, the possible interfering effect of medication, Verma and colleagues [5] found that in drug-naive (unmedicated) patients with first-episode psychosis there was a significantly increased likelihood of diabetes to be present compared with age and sex-matched asymptomatic control participants. I don't doubt however, that any relationship is going to be complicated.

Finally, and bearing in mind the prime directive of this blog (no medical or clinical advice given or intended), there is the question of how this research might translate into therapeutic intervention. A final quote from the authors on this and the possibility of: "novel disease prevention approaches, which could involve nutrition modification, stress reduction and pharmaco-therapeutic interventions, including the application of well-tolerated drugs that combat insulin resistance". Alongside the dietary aspect (which is something very favourable to this blog for lots of reasons), I am wondering whether we could also learn something from times gone by [6]? Perhaps even the appliance of prophylactic psychiatry [7]?

Music to close and Andrea Bocelli sings Funiculì, Funiculà...

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[1] van Beveren NJM. et al. Evidence for disturbed insulin and growth hormone signaling as potential risk factors in the development of schizophrenia. Translational Psychiatry. 2014; 4: e430.

[2] Korver N. et al. Genetic Risk and Outcome of Psychosis (GROUP), a multi-site longitudinal cohort study focused on gene-environment interaction: objectives, sample characteristics, recruitment and assessment methods. Int J Methods Psychiatr Res. 2012 Sep;21(3):205-21.

[3] Wirshing DA. et al. The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry. 2002 Oct;63(10):856-65.

[4] Anderson RJ. et al. The prevalence of comorbid depression in adults with diabetes: a meta-analysis. Diabetes Care. 2001 Jun;24(6):1069-78.

[5] Verma SK. et al. Metabolic risk factors in drug-naive patients with first-episode psychosis. J Clin Psychiatry. 2009 Jul;70(7):997-1000.

[6] Anderson K. et al. Salsalate, an old, inexpensive drug with potential new indications: a review of the evidence from 3 recent studies. Am Health Drug Benefits. 2014 Jun;7(4):231-5.

[7] Sawa A. & Seidman LJ. Is Prophylactic Psychiatry around the Corner? Combating Adolescent Oxidative Stress for Adult Psychosis and Schizophrenia. Neuron. 2014; 83: 991-993.

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van Beveren NJ, Schwarz E, Noll R, Guest PC, Meijer C, de Haan L, & Bahn S (2014). Evidence for disturbed insulin and growth hormone signaling as potential risk factors in the development of schizophrenia. Translational psychiatry, 4 PMID: 25158005

PCOS, DOGMA and autism with a pinch of salt

I really have to stop doing this. Speculating. Taking a few scoops of relatively small scale research, often in quite disparate areas and making a meal out of them. I don't know if it is the freedom of a lack of peer-review that follows with blogging or just my silly brain making mountains out of molehills, but tenuous links seem to be coming thick and fast at the moment. Perhaps I need a break and some sunshine...

But just before I do, and with a rather large pinch of salt in hand...

Polycystic ovary syndrome (PCOS) has been coming to my attention a few times over the last few days. I readily admit that my knowledge of PCOS is fairly limited, but from what I understand here is a condition which is said to affect anywhere from round about 6% to 10-12% of women. I wouldn't wish to provide a definitive definition of PCOS aside from the fact that it is an endocrine disorder defined by an imbalance in the androgenic sex hormones (hyperandrogenism) which affects ovulation. I should point out that endocrine disorder is not to be confused with endocrine disruptor as per some recent discussions on phthalates and autism.

What else to say about PCOS? Well, there is a suggestion of association with lifestyle-related health conditions such as type-2 diabetes, high blood pressure and weight gain / obesity. This is something I remember seeing on a TV program recently - the Food Hospital - which quite nicely explained how insulin resistance might lead to PCOS, and how higher levels of insulin being produced leads to higher levels of testosterone. I'll come back to testosterone shortly.

Indeed the potential elevation of such lifestyle conditions brings me to the first paper which caught my eye; a speculative paper by Tremellen & Pearce* in a speculative journal. Tremellen & Pearce make an interesting (speculative) suggestion that Dysbiosis Of Gut Microbiota (DOGMA) might be implicated in cases of PCOS. I was always going to be drawn to this paper, simply because (a) who wouldn't with an acronym like DOGMA and (b) it making mention of a mechanism which seems to be coming up time and time again whereby gut bacterial disturbances lead to the so-called leaky gut (gut hyperpermeability) which allows passage of bits of gut bacteria into places they shouldn't really be found which in turn switches the immune system into 'eye of Sauron' mode with potential onward effects on health. The recent Sutterella-autism paper suggested something quite similar. The authors speculate that the immune activation resulting from detection of these foreign bodies interferes with insulin receptor functioning which starts the cascade of rising insulin levels and PCOS as a possible end-point. I'm not really in a position to argue for or against this immune-insulin link but have blogged before about a potential link between diabetes, inflammation and gut permeability. Make of that what you will.

The second paper in this grand speculative post is this one by Palomba and colleagues** looking at offspring of women with PCOS in terms of their scores on various measures of autistic traits. MJ over at Autism Jabberwocky recently discussed everyone's favourite sweeping autism generalisation theory 'the Extreme Male Brain Theory' which has graced previous posts on this blog before. The connection between PCOS and autism (apparently) is testosterone and how the sex hormone biological fingerprint might confer some risk for autistic traits. Interestingly Palomba and co. reported higher levels of autistic traits in children of mums with PCOS compared to non-PCOS controls. Interesting also that female offspring of mums with PCOS seemed to be the ones who quote: "seem to have a higher risk for PDDs".

The final piece [bear with me] of this jagged little post goes back to that very interesting paper by Brent Williams and colleagues*** on carbohydrate metabolism and gut dysbiosis in a small group of children with autism which was discussed here and here. To reiterate: issues with the 'starting material' for enzymes used to process carbohydrates in cases of autism and potential signs of gut bacteria dysbiosis. No specific mention of gut permeability issues, but the words 'maldigestion' and 'malabsorption' are used a few times.

Taken as a whole and with quite a few pinches of salt, I'm speculating on a few things with this post. So for example, dysbiosis is a starting point; where, for whatever reason, disturbances to gut bacteria begin a cycle of physiological changes eventually resulting in elevated levels of insulin and further elevations in testosterone in PCOS. I know some people will look at a concept like dysbiosis and think that it is something fresh out of the 'alt-med' camp complete with lashings of new-age, tofu tomfoolery. The fact of the matter however is that DOGMA(!) is quite a widely reported phenomenon and not just the stuff of fluffy organic dreams.

A second speculation is that, accepting a link between increasing insulin levels and increasing testosterone levels, albeit not necessarily the only way that testosterone levels can be increased, one questions the possibility that testosterone levels could be artificially inflated by environment or lifestyle means (as per this recent study) and what implications this might have for the testosterone-autism hypothesis. Understanding that not every woman with PCOS will have a child with autism, I do wonder about the recent obesity-autism hypothesis and whether there may be grounds for a study looking at maternal insulin and testosterone levels as a function of offspring risk of autism. When saying this I am also sensitive to the fact that maternal obesity / signs of metabolic syndrome are not a universal connection in autism and that quite a few mums (and dads) with children with autism might be getting a little tired of all the 'risks' being reported in relation to autism.

I think I've exhausted my salt supplies with the speculation in this post. Readers are advised that nothing should be taken as fact in this post aside from the results presented in the peer-reviewed journals. I am truly interested to see how the work in these various areas advances and whether issues like DOGMA are indeed able to crack some of the other dogma present in autism and other research circles.

To finish, some Salt-n-Peppa going easy on the salt please.

* Tremellen K & Pearce K. Dysbiosis of Gut Microbiota (DOGMA) - A novel theory for the development of Polycystic Ovarian Syndrome. Medical Hypotheses. April 2012

** Palomba S. et al. Pervasive developmental disorders in children of hyperandrogenic women with polycystic ovary syndrome: a longitudinal case-control study. Clinical Endocrinology. May 2012.
DOI: 10.1111/j.1365-2265.2012.04443.x

*** Williams B. et al. Impaired carbohydrate digestion and transport and mucosal dysbiosis in the intestines of children with autism and gastrointestinal disturbances. PLoS ONE. September 2011.