Preventing Miscarriages/Autism using Progesterone? And Sex-Specific Fetal and Placental Responses to Adversity

 

Today’s post returns to the theme of reducing the incidence/severity of future autism and introduces another factor that helps explain why girls have some degree of protection from autism.

The focus today is on female hormones and progesterone in particular.

It does look like hormones can play a role in both triggering and potentially treating some autism, but it is not an area likely to be followed up on in the mainstream.

We have seen previously in this blog that some infertility experts find an association between miscarriage and autism. One US fertility doctor has a prevent miscarriages website and a prevent autism website, because his feeling is that by reducing miscarriage risk, you may also reduce autism risk. He was shocked by how many of his fertility patients have other offspring with autism.

This should really be common sense.

·        In-utero stress increases the chance of a miscarriage

·        In-utero stress increases the chance of autism

The common solution would be to reduce sources of in-utero stress.  Which sounds simpler than it is.

I have previously looked in some detail into therapies that improve outcomes in traumatic brain injury (TBI), because much damage done in a TBI from a car crash, or skiing accident, occurs after the accident, as the brain over-reacts to the trauma and this then causes irreparable damage. Both the female hormones estradiol and progesterone, if given promptly, improve the outcome in TBI.  Another highly neuroprotective drug is Atorvastatin, from my son’s Polypill therapy, which has also been shown to improve outcomes in TBI; we even know how this happens. Atorvastatin, given intravenously, can extinguish a cytokine storm. Cytokine storms even play a key role in severe Covid-19, when lungs and other organs are damaged by the over-response of the immune system.

I was pleased to see that progesterone has recently been adopted as an approved therapy to prevent miscarriages in the United Kingdom.  I am actually really surprised that they were allowed to make the necessary clinical trials.  I would have thought this would be seen as unethical and risky.

 

Progesterone recommended to prevent early miscarriage

One of those behind the Tommy's National Centre for Miscarriage Research research, Prof Arri Coomarasamy, from the University of Birmingham, said  "This is a very significant moment.  We have an intervention that works that can stop a miscarriage. This gives hope to thousands of couples throughout UK. But it's really important to appreciate that only some miscarriages can be prevented by progesterone. There are other causes for miscarriages. We still need to study them. We need to find other effective treatment. About one in four pregnancies ends in miscarriage - the vast majority in the first few months or trimester.” 

 

Progesterone could prevent 8,450 miscarriages a year, finds new research 

PRISM studied 4,153 women with early pregnancy bleeding at 48 hospitals in the UK and found there was a 5% increase in the number of babies born to those who were given progesterone who had previously had one or more miscarriages, compared to those given a placebo.

The benefit was even greater for the women who had previous ‘recurrent miscarriages’ (i.e., three or more miscarriages) – with a 15% increase in the live birth rate in the progesterone group compared to the placebo group.

 

A 5% increase does not sound much.

A 5% reduction in autism incidence probably would not be seen as statistically significant. 5% would not be a very high hurdle for an autism prevention therapy. With a package of therapies, I think you could do very much better. I would consider “good” to be at least a one third reduction in genuine cases. Of course, it would be more complex, since in reality you would be reducing severity of autism. Autism is not binary, more like shades of grey.

 

Would progesterone reduce the risk of future autism?

I do not think we will ever get the answer that question.

Preventing miscarriage is seen as much more important than preventing autism.

The evidence for immediate treatment with progesterone or atorvastatin, after a head injury, has not led to its widespread adoption.  Try explaining that one to Mrs Schumacher (wife of the Formula One racing star, who had a traumatic brain injury while skiing)

The key take away from the PRISM miscarriage study is that progesterone treatment in pregnant women is safe.  It is also inexpensive.

 

Prenatal Hormones in Autism

In a perfect world, you would study hormone levels in pregnant women and find clear associations with autism incidence in offspring. We do not live in such a world.

In the research, hormone levels are all over the place and vary from study to study.

This can be seen as good news, since the range is so wide you can very likely increase the level of certain hormones without any unintended consequences.

  

Foetal oestrogens and autism

Oestradiol, oestrone, oestriol and progesterone each related to autism in univariate analyses after correction with false discovery rate. A comparison of standardised odds ratios showed that oestradiol, oestrone and progesterone had the largest effects on autism likelihood. These results for the first time show that prenatal oestrogens contribute to autism likelihood,

 

When I look at the above graph my conclusion is that the fetal estradiol (oestradiol, in UK English) level is all over the place.  It is nonsense to conclude that high levels are associated with autism. 

 

Autism Spectrum Disorder Risk in Relation to Maternal Mid-Pregnancy Serum Hormone and Protein Markers from Prenatal Screening in California

Results from this large, population-based study suggest that prenatal levels of the hormones, estriol and a gonadotropin (hCG), as well as MSAFP are associated with altered risks of having a child who later develops autism. Consistently, the risk of ASD was increased at lower levels of uE3; modelled both categorically or continuously, and examining the distribution graphically, the curve seems shifted to the left for cases. Further, the risk of ASD was increased with higher levels of MSAFP, while the associations with hCG were with both low and high levels. Although associations were modest, the fact that our results are based on levels of these prenatal markers measured during a developmentally-relevant period, and account for potential confounders, p

 

Our results suggest that continued investigation of prenatal hormones and possible mechanisms for an association with ASD is warranted. The associations we report were not of a large magnitude, which may make replication of the findings difficult in other studies that do not have access to the large numbers and unique resources we used. The 90th percentiles reflect MoMs of 1.7–2.0, which are not particularly high, but approach prenatal screening risk cut-points currently in use for other conditions (usually 2.0–2.5 MoM). The 10th percentile of uE3 is about 0.75 MoM. Measurement of additional estrogens, as well as androgens, from blood samples collected during pregnancy would be an interesting avenue for future research, if available in large enough studies. In addition, studies of endocrine-disrupting chemicals and genes involved in steroid hormone metabolism may yield further clues to a hormonal etiology for autism. Though modest increases in risk were seen in this large study, converging evidence suggests that ASD has multiple causes, and thus, identifying factors with small associated risks may help to better understand ASD and potential mechanistic pathways.

  

The Prenatal Hormone Milieu in Autism Spectrum Disorder

Though the etiology of autism spectrum disorder (ASD) remains largely unknown, recent findings suggest that hormone dysregulation within the prenatal environment, in conjunction with genetic factors, may alter fetal neurodevelopment. Early emphasis has been placed on the potential role of in utero exposure to androgens, particularly testosterone, to theorize ASD as the manifestation of an “extreme male brain.” The relationship between autism risk and obstetric conditions associated with inflammation and steroid dysregulation merits a much broader understanding of the in utero steroid environment and its potential influence on fetal neuroendocrine development. The exploration of hormone dysregulation in the prenatal environment and ASD development builds upon prior research publishing associations with obstetric conditions and ASD risk. The insight gained may be applied to the development of chronic adult metabolic diseases that share prenatal risk factors with ASD. Future research directions will also be discussed.

 

Female placentas are “superior” to male placentas.  Note the placenta has the same sex as the fetus and yes, it is a binary choice.

  

Sex-Specific Fetal and Placental Responses to Adversity

Fetal growth, development, and HPA axis programming in the setting of obstetric adversity differ by fetal sex (173–175). These sex-specific responses serve as additional mechanisms in which to consider male ASD predominance (see Figure 2). As the placenta is derived from extra-embryonic tissues, the placenta has the same sex as the fetus (178). Evidence suggests that the placentas of male and female fetuses differ in response to adverse prenatal environments through modulation of steroid pathways, placental genes, and protein synthesis (176). Placental growth and structure differ by sex, with male placentas being smaller in size but more efficient at nutrient and oxygen delivery (179, 180). Fetal growth depends upon the limited capacity of the maternal-placental interface to deliver oxygen and nutrients. Thus, greater placental efficiency among males precipitates faster somatic growth while increasing vulnerability to in utero perturbations (179, 181). This may have deleterious neurodevelopmental consequences, as fetal brain development relies on the availability of oxygen and nutrients such as fatty acids, glucose, and amino acids (131, 182, 183). In contrast, female placentas may have superior ability to buffer and adapt to suboptimal prenatal conditions (180).

 

Sex-specific fetal and placental adaptations to maternal adversity. Placentas of male and female fetuses respond differently to mild forms of maternal adversity. In the placenta of female fetuses, multiple changes in glucocorticoid barrier enzyme activity, gene expression, and protein synthesis occur leading to decreased growth (176, 177). This is advantageous as it preserves fetal oxygen and nutrient delivery. In the placenta of male fetuses, minimal changes in gene and protein expression occur, and the male fetus continues to grow incurring increased vulnerability to adverse outcomes (176). 

Figure 3 links heightened in utero stress from inflammation, stressors, and metabolic disturbances to perturbation within the prenatal hormone milieu. Through pCRH stimulation, the placenta upregulates fetal HPA axis activity in response to in utero stress. Subsequently, the fetal adrenal glands increase DHEA(S) synthesis leading to elevated placental estradiol production. Higher placental estradiol and pCRH production promotes HPA axis maturation denoted by fetal adrenal de novo cortisol synthesis. In response to in utero stress, the placental also increases hCG production which stimulates fetal gonadal testosterone synthesis.

 

Linking in utero stress to increased fetal steroidogenic activity and ASD biomarkers at mid-gestation.

 

In utero stress we see raises estradiol in the mother, but also increases testosterone in the males fetus.

The stress hormone, cortisol is elevated in the fetus.

You might imagine that less testosterone and more estradiol would be neuroprotective.

We know that progesterone is neuroprotective and now we know that its use is safe.

 

Conclusion 

Nature does sometimes stumble short of perfection and this is inevitable.  Going too far preventing miscarriages would not be wise, but improving the outlook of a viable fetus looks like a good idea.

Miscarriage is defined as pregnancy loss before 23 weeks’ gestation.

More than 80% of miscarriages occur before the 12th week, and the rate decreases rapidly thereafter.

Chromosomal anomalies cause at least half of these early miscarriages; for example, male fetuses with Rett Syndrome.  This is nature’s way of dealing with a non-viable fetus.  Only girls with Rett Syndrome can survive, since they have one good copy of the the MECP2 gene, males have none. MECP2 is on the X chromosome (girls have XX and boys have XY).

A little helping hand from Progesterone looks like a wise idea.

But, how slowly things move in medical science. The paper below is from 2013.

Use of progestagens during early pregnancy

“During the past 50 years several trials investigated the use of progestagens for the prevention of miscarriage. Actually the therapeutic value of progestagens remains to be established. This might be due to the poor design of the studies which evaluated hormone effectiveness”

 

The issue with using any hormone to prevent/minimize autism is the potential for harm.  This did not seem to worry people in 60 years of trials in miscarriage.

I think we can conclude that progesterone for the prevention/reduction in severity of autism is very likely entirely safe.  Would it be beneficial?

We know that women with Polycystic ovary syndrome (PCOS), a condition in which the ovaries produce an abnormal amount of androgens (male hormones), have an increased chance of producing children with autism.  They might be a good place to start with a clinical trial.

The fact that female placentas give more protection against adversity during pregnancy is interesting and another contributing factor to the lower prevalence of autism in girls.  It is only certain types of autism where girls have protection. In the case of severe autism, girls are more likely to have detectable genetic anomalies than boys, making whole exome sequencing (WES) well worthwhile. It looks like girls are protected somewhat from multifactorial autism, which I think makes sense; they might just end up with some dyslexia or sub-clinical autism.

Multifactorial autism should be the type that you can minimize, by lightening the contributing adverse burdens.  This itself requires a multifactorial approach.