Elevated Prenatal Estradiol in Mothers/Babies – a protective reaction to stress that also predicts who will develop Autism? Time for Fetal Medicine?

There has been little mention in this blog about fetal medicine, but it is an area that does hold great promise.  At the Children’s Hospital of Philadelphia, they have been surgically treating babies with spina bifida prior to their birth for nearly twenty years. Early surgical intervention to the spine even allows for malformation of the brain to be self-repaired and this is visible on MRI scans. Such prenatal treatment can be 100% successful, resulting in there being no physical disability in adulthood. 

The more you read about neuroscience the more you realize how little we really know and so encouraging the brain to self-repair may indeed be the best strategy.  This is an avenue of research and not just with stem cells.  A similar approach is proving successful in treating skin cancer, you do not attack the cancer with drugs, you modify the immune system with a drug so it "wakes up" and does its job and kills the cancer cells.

        Skin cancer: Half of people surviving advanced melanoma

Hormones are an often-ignored area of autism research, but they are they on my Venn diagram simplification of autism.

We have seen how female hormones can be highly neuroprotective and that the estradiol/testosterone balance affects a key “switch” that controls gene expression RORalpha.

Today we see that researchers in Utah suggest that stress in the developing fetus with autism causes an increase in estradiol, as a protective mechanism, and this increase in estradiol can then be measured in the mother’s blood. They propose that this elevated estradiol is an advance warning of a baby with autism.

Utah researchers find link between hormone change and autism risk

University of Utah researchers have discovered a link between increased levels of a type of estrogen in babies in their second trimester and risk for autism, according to a new study.

The findings could eventually help doctors identify babies at risk of autism early in their mothers’ pregnancies and monitor them more closely, as well as provide early interventions to ensure the children’s well-being, said Dr. Deborah A. Bilder, the study’s first author.

Both the control group and the group of mothers whose children had autism were selected so that 50% of each group had an exposure to a condition such as gestational diabetes, hypertension and preeclampsia. Previous studies have shown links between those conditions and autism risk.

The researchers looked at several different steroids in the blood samples. Bilder said she expected to find increased levels of steroids that were known to be associated with the conditions, like testosterone. She found those steroids, but they did not reach a statistical significance, according to Bilder.

Bilder also expected progesterone and testosterone in the kids who developed autism to be elevated.

“But that’s not what I found. Instead, what I found, is estradiol being elevated in the children who developed autism,” she said.

Estradiol is a type of estrogen. Lower levels of estradiol in a baby usually indicate a concern with the baby, and high estrogen levels are not currently associated with abnormal conditions.

But as the researchers looked at the steroid hormones that were measured, “what we realized is that the higher estrogen levels being produced by the placenta actually may be stimulating the baby’s development of his or her stress response.”

Usually, a baby’s stress response takes time so that when the pregnancy reaches full term, the baby has developed its own stress response. But elevated levels of estrogen cause the baby’s stress response to develop early, Bilder said.

That prepares babies, when there is an issue, to survive outside the mom. It causes early growth of the lungs, gut and skin so that if the baby doesn’t make it all the way through pregnancy, it’s more likely to survive, she said.

The findings indicated that in the babies with autism, something set off their stress response early.

Studies have shown that children with autism have an abnormal stress response, according to Bilder. She believes the mechanism that triggers the early stress response during pregnancy may still be affecting children with autism past delivery.

Bilder doesn’t think doctors should target the higher estradiol levels or try to lower them. Instead, because it signals a “protective mechanism, that baby is surviving,” doctors should target something that doesn’t jeopardize the baby’s survival.

“By being able to have a way of looking at the baby’s well-being in that regard, I think that opens up the door to considering how can you reduce the stress on that baby?” Bilder explained.

                                                                                 

The full paper:-

Early Second Trimester Maternal Serum Steroid-Related Biomarkers Associated with Autism Spectrum Disorder

Epidemiologic studies link increased autism spectrum disorder (ASD) risk to obstetrical conditions associated with inflammation and steroid dysregulation, referred to as prenatal metabolic syndrome (PNMS). This pilot study measured steroid-related biomarkers in early second trimester maternal serum collected during the first and second trimester evaluation of risk study. ASD case and PNMS exposure status of index offspring were determined through linkage with autism registries and birth certificate records. ASD case (N = 53) and control (N = 19) groups were enriched for PNMS exposure. Higher estradiol and lower sex hormone binding globulin (SHBG) were significantly associated with increased ASD risk. Study findings provide preliminary evidence to link greater placental estradiol activity with ASD and support future investigations of the prenatal steroid environment in ASD.

Fig. 1 The placenta produces estradiol from DHEA of both maternal and fetal origin and shunts over 90% of estradiol into the maternal circulation. The volume of DHEA substrate determines placental estradiol production and subsequently maternal serum estradiol levels. DHEA exists primarily in its conjugated form DHEAS

This is interesting as are some other findings linking steroid hormones to future autism. Another paper highlights a mechanism where maternal stress only has damaging effects on the male fetus (Placental adaptation in response to PNMS is sex-dependent, leading to an increased risk of adverse neurodevelopmental effect in male compared to female).

This paper looks at the effect of maternal stress on serotonin and another group of hormones (Glucocorticoids).

Effects of prenatal maternal stress on serotonin and fetal development

Fetuses are exposed to many environmental perturbations that can influence their development. These factors can be easily identifiable such as drugs, chronic diseases or prenatal maternal stress. Recently, it has been demonstrated that the serotonin synthetized by the placenta was crucial for fetal brain development. Moreover, many studies show the involvement of serotonin system alteration in psychiatric disease during childhood and adulthood. This review summarizes existing studies showing that prenatal maternal stress, which induces alteration of serotonin systems (placenta and fetal brain) during a critical window of early development, could lead to alteration of fetal development and increase risks of psychiatric diseases later in life.

`

         Fig. 1. Proposed mechanism of fetal programming of psychiatric disorders involving placental serotonin system. Cortisol and placental serotonin are essential for fetal brain development. Prenatal maternal stress alters glucocorticoid (11b-HSD2, GR and CRH) and serotonin (SERT, 5-HT1A and 5-HT2A) systems as well as serotonin and glucocorticoid interaction in the placenta. These placental alterations lead to adverse neurodevelopment and programming leading to psychiatric disorders later in life. Placental adaptation in response to PNMS is sex-dependent, leading to an increased risk of adverse neurodevelopmental effect in male compared to female. 11b-HSD2: Type 2 11-beta hydroxysteroid dehydrogenase, GR: Glucocorticoid receptor, CRH: Corticotrophin releasing hormone, SERT: Serotonin transporter, 5-HT1A: Serotonin 1A receptor, 5-HT2A: Serotonin 2A receptor

Conclusion    

         

It should be noted that estradiol is supposed to be elevated during pregnancy. Indeed, this elevation is suggested to explain why females with ADHD have far less symptoms during pregnancy (estradiol is good for ADHD). The study is highlighting a level of estradiol during pregnancy that is even higher than that normally expected.

Spina bifida is normally detected by ultrasound before 18 weeks of pregnancy. This is around the same time that in autism there appears to be elevated estradiol.  Hopefully other biomarkers will also be found.

Given this advance warning, there is potential for fetal medicine.

Only very recently was the first person in the UK treated for spina bifida using fetal surgery, almost two decades after the first operations in the US.

Fetal medicine for autism would not be surgical, rather pharmacological.  In mouse models it has already started.

Estradiol has many effects and I did write about DHED, an orally active, centrally selective estrogen and a biosynthetic prodrug of estradiol. DHED is estradiol just for the brain, without affecting the rest of the body.  I think many people would benefit from DHED, across the range from ADHD to TBI (Traumatic Brain Injury).

DHED, delivering Estradiol only to the Brain, also Lupron and Spironolactone

Estradiol may indeed prove to be a fetal biomarker for autism and DHED might be a useful drug for someone with autism (via ERβ and RORalpha).

The Singing Statin, the BCL-2 Gene and Epigenetics

This post has something for both the casual reader and the scientists among you.  Today I will start with the science.

Epigenetics

Epigenetics are chemical markers that can appear on your DNA as the result of some environmental exposure, like diet or stress.  Methylation is a type of epigenetic change in which methyl groups are added to DNA and switch on or off the underlying gene.  This can have severe consequences depending on which gene is affected.

Identical Twins

It seems that if one identical twin has autism, there is a 70% chance that the other twin will be autistic.  In 30% of the cases the twin is neurotypical.  Researchers have very cleverly started to analyse pairs of twins from this 30% group and look for epigenetic marks.  This would highlight genetic causes of autism.

Apoptosis

Apoptosis is a tricky word to spell, for somebody like me, but is actually something quite simple; it is programmed cell death.  Apoptosis happens in all of us, all day long.  If it gets out of control, it becomes bad and something called atrophy will occur.  Too little apoptosis can result in irregular cell growth and cancer.

 

Candidate Genes

Using the epigenetics approach, in 2010 a study was published that identified two “candidate” genes linked to autism.  They were BCL-2 and RORA.

According to that study, BCL-2 is an anti-apoptotic protein located in the outer mitochondrial membrane that is important for cell survival under a variety of stressful conditions.  In other words BCL-2 inhibits cell death.

According to another source, BCL-2 is “one of the foremost anti-apoptotic molecules”.

A very recent study has identified more such genes, using the same approach.

 

If you are really interested in the genetics of autism, there is actually a database of all the indicated genes, maintained by the Simons Foundation.

  

BCL-2 and autism

Going back to 2001, researchers had already noted that the autistic brain was deficient in BCL-2 and they suggested that:-

“These results indicate for the first time that autistic cerebellum may be vulnerable to pro-apoptotic stimuli and to neuronal atrophy as a consequence of decreased BCL-2 levels.”

The study is called :- Reduction in anti-apoptotic protein Bcl-2 in autistic cerebellum

As we have already learned, in the autistic brain the important Purkinje Cells are reduced in number by half due to atrophy.  If BCL-2 can indeed reduce this excessive apoptosis, it should be a friend indeed.

 

Stimulating production of Bcl-2

Fortunately the clever people working with Professor Wood, at the University of Minnesota, have been studying cholesterol regulation in the brain for some time.  Here is what they have been up to:-

“The lab has recently made the novel discovery that statins both in vivo and in vitro stimulate gene expression and protein levels of one of the foremost anti-apoptotic molecules, Bcl-2. Currently, studies are focused on mechanisms of statin-induction of Bcl-2”

Or in plainer English, statin drugs increase your level of BCL-2 and so reduce cell death.
 

If you want to read more here is an open access paper:-  Simvastatin Stimulates Production of the Antiapoptotic Protein Bcl-2 via Endothelin-1 and NFATc3 in SH-SY5Y Cells

 

The Singing Statin

Now we have finished with the pure science and we move back to the practical world of applied science.

Monty, aged 9, has been taking atorvastatin for a few weeks.  After day one, he developed the urge to play the piano outside of lesson time.  Every day since, he has played more and more.  Now his piano teacher says she thinks he has absolute pitch.  It turns out that this is far more common in the autistic population and there is a great deal of research that has been done on this and music/autism in general.  Here is a short article on the subject.

Now in an earlier post we established the importance of the stress hormone cortisol and also the interesting finding that you can reduce it by singing.  Then I got people asking about, “what about just listening to music” or “what about playing an instrument”.  I did not do the research, but I think nothing works like a good sing.

So yesterday I was delighted to hear that Monty has started to sing spontaneously in his room.  He put on his Mozart CD and started to sing, with his own lyrics and not just in English, but also in his second language.

I have to thank Mr Pfizer and in fact Mr Bruce Roth for bringing us Atorvastatin (called Lipitor or Sortis, depending on where you live).  Mr Roth invented it in 1985.

Perhaps BCL-2 could be better named the Singing Gene?

 

 

 

Cortisol, AVP, Oxytocin - Part II Stress Reactivity Model

I think today's post is going to be one of my better efforts.  We are continuing with the theme of Cortisol, depression and stress; but we are going to add two further chemicals, both "social neuropeptides".

The reason than today's post is worth reading is that it will bridge neurobiology and neuropsychology.   For me at least, psychology is light reading whereas biology needs more thought and understanding.  A social neuropeptide is a nice term not invented by me; it seems to come from Dr Stein from the University of Cape Town.

Rather than understand everything about human hormones, we are just trying to understand stress and coping mechanisms, so that we can reduce or  just better manage autistic behaviours. 


Cortisol

Cortisol is a hormone that is very easy to measure; saliva samples will do just fine.  Cortisol levels, or changes in cortisol levels, tell us about how the body is coping with emotion stress.  We are not talking about oxidative stress, but clearly there is direct linkage between the two.

We know that cortisol is a hormonal body clock (it maintains diurnal rhythms), cortisol levels should peak 30 minutes after waking, decline rapidly in the morning and then reach its lowest level in the evening.  This is well illustrated in the figure below, from an excellent study by Vahdettin Bayazit from Turkey.  He was studying the effect of exercise and stress on cortisol levels.

 

Children with ASD are known to have atypical response to stress and some have dysregulation of diurnal rhythms and abnormally high evening cortisol levels.  Among children with ASD there are significant individual differences, so the level of dysregulation is variable.  Note that many children with ASD have sleeping disorders; not surprising really if their body clock is malfunctioning.

 

In Bayazit's study he comments:-

"The more unexpected finding was that the evening values (of cortisol) for the children with autism tended to be consistently elevated in comparison with the neurotypical group."

I do not find this result surprising; in fact I would expect it.

 

He goes on to tell us that it is known that older children with depression have altered hormone levels, including hypersecretion of cortisol in the evening.

 

Now back to a stressful event.  In Turkey, a group of high functioning children with ASD were given a public speaking task; their heart rates and saliva cortisol were measured, before, after and during this "stressful event".

 

 

 

 

All we need to note is that the stress tended to cause a spike in cortisol level.


Stress Reactivity Model

Now we combine biology with psychology.  I took an existing model from an excellent book called "The neuropsychology of Autism".  Chapter 22 has a paper by Suma Jacob et al; she provided the biology and I just added the psychology (the opposite of what you might have expected)

 

 

 

 

This model shows how the equilibrium in managing stress is hopefully maintained.

The two little interlopers on the chart above, oxytocin and AVP are social neuropeptides.  Oxytocin is seen as beneficial; it reduces stress levels and gives a feeling of wellbeing.  AVP (Arginine Vasopressin) works in conjunction with CRH (Cortisol Releasing Hormone) to control the release of cortisol.  AVP seems to work in a "bad" way, in that it exaggerates/magnifies natural changes in cortisol.  So if you have a lot of AVP, a small spike in cortisol would become a big spike in cortisol.

Both AVP and cortisol have numerous other functions in the body. For example AVP is also known as the antidiuretic hormone (ADH) and a version of it is used in therapy in extreme cases of bedwetting by children. Whoever designed the human body was either short of chemicals, or likes to play practical jokes.

We already learned in Part I, that you can reduce your own level of cortisol just by singing.  It is reassuring to know that you do not always need drugs.  There are in fact other ways that you can maintain your own homeostatis and reduce cortisol.

A clever clinical psychologist from the University of Zurich, called Markus Heinrichs,  has provided us with an excellent study that compares the effect of social support vs oxytocin as regulators of stress.  What he did was to create two groups of people, in one group each subject brought along their best friend; the other group all came alone.  Then each subject was put through this stressful process:-

"During the introduction to the TSST (Trier Social Stress Test) they were then told that they would be required to give a 5-min mock job interview to an unknown panel (consisting of one man and one woman) on personal suitability for a job and to enumerate their strengths and qualifications in an unstructured manner, followed by 5 min of mental arithmetic performed out loud. To increase task engagement, the job description was matched to each participant, taking into consideration his own individual goals and aspirations. The panel of evaluators were presented as experts in the evaluation of nonverbal behavior."

The subjects were typical males in their early 20s.  Half the subjects had social support of a friend being present, and then each group had either a placebo or had a dose of oxytocin.  Here are the results:-

The base case is the "No social support + placebo".  This shows the highest increase in cortisol (i.e. stress).  The calmest group had "social support + oxytocin".  Of great interest is that the "social support + placebo" ended up less stressed than the "no social support + oxytocin".

This experiment showed the clear positive effect of both social support and oxytocin.

So in the stress reactivity model (the blue one up top) I decided to add social support and singing.  Clearly there are plenty of other social/psychological strategies that would likely have a similar cortisol reducing effect. 


Another dose of cortisol will come shortly in Part III.






 

Cortisol, AVP, Oxytocin - Part I Depression & Stress

Today starts a mini-series inspired by a reader’s comment about depression.  Angie, from Australia, pointed out that while the kids with ASD might not be depressed, many of the parents certainly are.  Not only will we address Angie’s point, but we will extend it a little and show how this can also help in our quest for the grail.

Many people have stressful lives, but some have discovered a special way to overcome this.  I was reading an English newspaper recently and there was an article about a celebrity cook, Nigella Lawson, who is very popular on the BBC.  While Jamie Oliver appears not to overindulge on his own cooking, it appears that Nigella does. Nigella was giving her tips to losing those excess pounds or kilograms.  The interesting part was not the treadmill in the spare room, but her comment about singing extremely loudly while using it.  

Here comes the science part.  Cortisol is an important hormone; and as we learnt previously when studying TRH, while a hormone may have a well-documented primary function, there may also have numerous additional effects.  The most important roles of cortisol are the activation of three metabolic pathways:-

1.    Generating glucose

2.    Anti-stress

3.    Anti-inflammation

The function that Nigella has stumbled upon is number two.  While we all need cortisol, too much is not good for you.

Cortisol is released in response to stress and while short term increases serve a valuable purpose, prolonged cortisol secretion, perhaps caused by chronic stress, can cause damaging physiological changes.

It would be nice if there was a way to reduce excess, stress-induced, cortisol and then you would feel calm, refreshed and ready to fight on.  While exercise is also very good for you, it is actually the singing that really makes Nigella feel good.

It is scientifically established that singing substantially reduces your level of cortisol, which in turn makes you feel much better.  Here is a link to simple study done in Angie’s home country and with the help of the Macquarie University Choir.

I could now tell you all about music therapy and its application in psychiatry.  If you are interested, do look into it; it is used to treat everything from autism to alcoholism.

In essence music is good for you; but it seems that making your own music is far more beneficial than just listening to other people.

Tip for parents

Follow Nigella’s example (and mine) and sing.
I will check to see if Angie does.

Back to ASD

Have you noticed that an autistic child is at their most stressed first thing in the morning?  I certainly have; this was particularly marked when Monty’s behaviour regressed.  My approach was and remains to have Monty through this possible trouble zone quickly; so once he is up, he should have breakfast, brush teeth and get dressed promptly. It proved an effective strategy.
I did wonder what the reason for this phenomenon was.  Originally, I thought it was just the fact that he had not eaten for a long time and so his blood sugar level had dropped.  This applies with all kids; if they have not eaten, they will get cranky.

Now I have an alternative explanation, and probably a better one. It is likely to do with the natural variation in cortisol levels in the blood that apparently peaks at about 8am and falls to a low for the day at bed time.  Wait to read more in Part II.

Autism, Depression and Suicidal Tendencies

It may not make cheerful reading, but one factor these three groups all have in common is dysregulation of the HPA, which is the Hypothalamic-Pituitary-Adrenal Axis.  There is also the well documented phenomenon of enhanced cortisol response to stress in children in autism. This will be continued in a science-heavy Part II and quite possibly will result in another hypothesis regarding a practical intervention.

Just to let you know, that my very long recent post about the TRH hypothesis has now gone for review to a clever and interested neuroscientist in the US.  I have a feeling that it will shortly be joined by my CRH (corticotropin releasing hormone) hypothesis; but maybe it should be called Angie’s CRH hypothesis?   

Cortisol, AVP, Oxytocin - Depression & Stress Part II