Estradiol/Aromatase Deficiency in Autism, Schizophrenia and Bipolar

There was a rather complicated post in which I was linking some of the odd biological features of autism to something called RORα.

This was one of those posts that appeals to the scientist readers like Tyler.

The Purkinje-RORa-Estradiol-Neuroligin-KCC2 axis in Autism

Happy with his elevated estradiol level

Today’s post is more like the Psychiatrist's take on the same subject, so it is less complicated.

I was thinking that a logical way to treat boys, post puberty, and girls with autism would be to target RORα. In males this would be the treating aromatase deficiency.  You would start by measuring by measuring the level of testosterone and estradiol in both boys and girls.

My assumption is that there will be a substantial group of males who will have high testosterone and low estradiol.  In autism and its big brothers (and sisters) Schizophrenia and Bipolar, there are disturbed levels of these hormones.  One logical therapy would be estradiol, which is much less problematic for girls than boys.

Boys with genetically caused aromatase deficiency lack the female hormone estradiol, but are not treated with transdermal estradiol until after puberty.  Girls are treated with estradiol from a younger age.

Untreated males with aromatase deficiency have retarded bone age, but end up as very tall adults. They also have a problem with low bone density and so have weak bones.

Clinical Features of Aromatase Deficiency

	Female	Male
Fetal life:	Masculinization of the mother during pregnancy	Masculinization of the mother during pregnancy
Genitalia at birth:	Severe clitoromegaly and posterior labioscrotal fusion	Normal male
Childhood:	Multi-cystic ovaries	Unremarkable
Puberty:	Absent growth spurt Absent breast development Primary amenorrhea Further enlargement of clitoris Enlarged cystic ovaries Normal development of pubic and axillary hair	Absent growth spurt Normal pubertal development
Adult:	Severe estrogen deficiency Virilization Enlarged cystic ovaries Continued linear bone growth	Tall, eunucoid proportions with continued linear growth into adulthood Osteoporosis Genu valgum

Source: AROMATASE DEFICIENCY

I have commented before that I think retarded bone age is a useful marker of some types of autism. You just need an X-ray of your hand and some interpretation that looks at the gaps between the small bones.

We have also seen in the comments section of this blog that numerous readers have low bone density problems in their families.

Extreme aromatase deficiency is very rare and is caused by mutations in the CYP19A1 gene.

We saw that RORα seems to be a hub for where things go wrong in autism (also schizophrenia and bipolar); I am not suggesting a problem with the CYP19A1 gene.

One approach in psychiatry research is to just try things, without bothering too much about the underlying science.  This has been the case with Estradiol, where there have been several very positive studies in schizophrenia and bipolar.  

Estradiol in Clinical Trials

Nobody is going get approval to use Estradiol in young boys, other than those who are promoting gender reassignment. These people want to chemically block puberty and then use high doses of estradiol to feminize the male body.

Estradiol is widely used in post-menopausal women, but also in clinical trials of middle aged women with schizophrenia or bipolar, where it appears to provide a clear improvement.

Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age.

Many women with schizophrenia remain symptomatic despite optimal use of current therapies. While previous studies suggest that adjunctive oestrogen therapy might be effective, large-scale clinical trials are required before clinical applications are possible. This study is the first large-scale randomized-controlled trial in women with treatment-resistant schizophrenia. This Definitive Oestrogen Patch Trial was an 8-week, three-arm, double-blind, randomized-controlled trial conducted between 2006 and 2011. The 183 female participants were aged between 18 and 45 (mean = 35 years), with schizophrenia or schizoaffective disorder and ongoing symptoms of psychosis (Positive and Negative Syndrome Scale, PANSS score>60) despite a stable dose of antipsychotic medication for at least 4 weeks. Mean duration of illness was more than 10 years. Participants received transdermal estradiol 200 μg, transdermal estradiol 100 μg or an identical placebo patch. For the 180 women who completed the study, the a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56. Cognition was assessed at baseline and day 56 using the Repeatable Battery of Neuropsychological Status. Data were analysed using latent growth curve modelling. Both estradiol groups had greater decreases in PANSS positive, general and total symptoms compared with the placebo this study shows estradiol is an effective and clinically significant adjunctive therapy for women with treatment-resistant schizophrenia, particularly for positive symptoms.

A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings

The role of estrogen in bipolar disorder, a review.

BACKGROUND:

It appears that the female reproductive events and hormonal treatments may impact the course of bipolar disorder in women. In particular, childbirth is known to be associated with onset of affective episodes in women with bipolar disorder. During the female reproductive events the sex hormones, e.g. estrogen, are fluctuating and particularly postpartum there is a steep fall in the levels of serum estrogen. The role of estrogen in women with bipolar disorder is, however, not fully understood.

AIM:

The main objective of this review is to evaluate the possible relation between serum estrogen levels and women with bipolar disorder including studies of the anti-manic effects of the selective estrogen receptor modulator tamoxifen.

METHOD:

A systematically literature search on PubMed was conducted: two studies regarding the connection between serum estrogen levels and women with bipolar disorder were identified. Furthermore, four studies were found concerning the antimanic effects of tamoxifen.

RESULTS:

Both studies in the estrogen studies showed very low levels of estrogen in women with postpartum psychosis and significant improvement of symptoms after treatment with estrogen. The four tamoxifen studies found that tamoxifen was effective in producing antimanic effects.

CONCLUSION:

These results indicate that estrogen fluctuations may be an important factor in the etiology of bipolar disorder and it is obvious that more research on this topic is needed to clarify the role of estrogen in women with bipolar disorder.

Men also need to have a certain level of estradiol, but as they age, and particularly if they get overweight, they often end up with too much.  So the usual problem is too much estradiol.

In males, estrogen is produced in fat (adipose) tissue by the action of the enzyme aromatase on testosterone.  So it would not be surprising if males with five times more adipose tissue produced more estrogen/estradiol. This would might explain mild feminization of the body and the lack of more aggressive male behaviors.

Many males with schizophrenia and a substantial number with autism are on medication that causes weight gain. While there are is research on how to reduce this weight gain, if the weight gain causes more estradiol, there actually is some potential benefit.

Estrogen Plays Key Role in Male Brain Development

Male Brains Need Estrogen for Good Memory

"We found that testosterone alone can improve an aspect of memory known as spatial memory -- the kind of memory needed to drive, get dressed, use a knife and fork -- what you need to learn to navigate three-dimensional space," Asthana says. "But men with both testosterone and estrogen had better verbal memory."

Asthana thinks that new estrogen-like drugs that lack sex-hormone effects such as breast enlargement might be useful to preserve memory in aging men. He says he is planning to test this theory in human trials

An estrogen-like drug, raloxifene, was trialed unsuccessfully in women with Alzheimer’s, but not in men.

Estradiol is a research therapy for males with prostate cancer.

Estradiol in Autism

We saw in the science heavy earlier post that that children with autism do not have sufficient estrogen receptor beta expression to mediate the protective benefits of estrogen.

Estrogen receptor beta agonists, which are already known to improve brain plasticity and memory in animals, have been proposed to help reverse autism's behavioral deficits.

High testosterone, low aromatase and correspondingly low estradiol are features of autism and will compound the effect of reduced estrogen receptor beta expression.

Conclusion

There are far less issues with the use of estradiol in females with autism.  Given there have already been trials in Schizophrenia and Bipolar on females using estradiol, it is about time a psychiatrist made a trial in autism.

I think that via the effect on RORα, there will be numerous positive effects.  The risks and side effects will be exactly the same as in the previous Schizophrenia and Bipolar trials.

Having seen what, if any, positive effects the females with autism experience, it would be time to consider adult males.  Is there a behavioral benefit in small enough doses of estradiol that do not cause feminization?

It would also be useful to measure the level of estradiol in overweight males to get some benchmarks of what is “normal" today in males.

Later on, using bone-age and indeed estradiol levels it might be possible to identify a sub-group of autism who might be likely to benefit from this therapy.  There may even be familial markers, like problems associated with low bone density, which might predispose the person with autism to have low levels of estradiol.

The other issue is the lack of estrogen beta-type receptors in people with autism.