Estradiol impact on Autism Spectrum Disorder, Empathy, and Depersonalization

When I started investigating depersonalization I ran into this medium.com article:

Depersonalization in gender dysphoria: widespread and widely unrecognized

https://medium.com/@zinniajones/depersonalization-in-gender-dysphoria-widespread-and-widely-unrecognized-baaac395bcb0

Cool… I was in a dark place and my depersonalization I realized was sky high. Was it always this bad? I felt like my body was a stranger’s body and I was stuck inside of it. Do I have gender dysphoria? I didn’t feel like I did… I had no strong feelings about gender at all; but I could relate so strongly to about 70% of the first hand accounts in the article.

One citation about NMDA receptor function points to this article:

Why Are Transgender People Immune To Optical Illusions?

At the time of first reading about and studying this mask animation, my ASD (Autism Spectrum Disorder) brain did not “fall for” the mask illusion… it took a bit of staring at it for my brain to “flip” and be able to see the illusion… interesting, but not surprising. I could see it both ways, but initially did not glitch in my perception.

Does your brain seem to flip this mask illusion, or do you see the inverted mask rather than your brain glitching?

I’ve been dosing Estradiol for almost 5 months at the time of this writing, and now when I look at this mask I CANNOT see anything but the optical illusion!

Also, when I started dosing Estradiol and trying to figure out if I had gender dysphoria, I challenged myself by shaving my beard instead of trimming it like I normally would. So every couple of weeks I shaved it off entirely… and it really messed with me. It was like staring at the Sun – I looked at my face and was distressed by who I saw. Who the heck is that?

One thing I also noticed for many years was that when someone changed their hair style, I would have to spend a lot of time adjusting to even see them as the same person. I chalked all this up to my ASD and didn’t think much of it.

I shaved my face a couple of weeks ago and for the first time, I did not experience distress. I just saw my face as myself but shaved. What the heck?

Estradiol and the effects on NMDA function

NMDA (N-methyl-D-aspartate) receptor function and depersonalization have strong connections, and Estradiol has strong influence on NMDA receptor function in the brain:

1. Estradiol increases delayed, N-methyl-D-aspartate receptor-mediated excitation in the hippocampal CA1 region

We conclude that estradiol pretreatment enhances NMDA receptor function in the female hippocampus by increasing not the monosynaptic, but rather a late NMDA receptor-mediated response. Variations in the magnitude of this late response may well contribute to ovarian steroid-dependent modulation of hippocampal synaptic plasticity.

https://pubmed.ncbi.nlm.nih.gov/15489046/

2. Estradiol-Induced Enhancement of Object Memory Consolidation Involves NMDA Receptors and Protein Kinase A in the Dorsal Hippocampus of Female C57BL/6 Mice

The enhanced object memory and increased ERK phosphorylation observed with E2 alone was reduced by APV and Rp-cAMPS, suggesting that estrogenic enhancement of object memory involves NMDA receptors and PKA activation within the dorsal hippocampus.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673328/

3. Ovarian steroids and selective estrogen receptor modulators activity on rat brain NMDA and AMPA receptors

Ovarian steroid withdrawal by ovariectomy is without effect on NMDA and AMPA receptors in most brain regions, except in hippocampus, where it decreases NMDA receptor specific binding, compared to intact rat values. Estradiol treatment increases hippocampal NMDA receptor specific binding of ovariectomized rats while it decreases this binding in frontal cortex and striatum.

https://pubmed.ncbi.nlm.nih.gov/11744083/

Estradiol and connections with Empathy

I was always challenged when put in social situations, but I recall that I had strong empathy before puberty. Over time my empathy decreased throughout my 20s and 30s (age), to the point where I really couldn’t even relate to what people considered to be sad or happy at all. I could see happy faces or sad faces and felt very little… even animals I considered cute during my mid 20s and previously no longer seemed cute… I just felt nothing.

By my early 30s my Anhedonia was incredibly high. When my wife was pregnant I was setting goals like, “I have to live long enough to at least meet this baby when it is born.” My suicidal ideation was almost constant; easily over 50% of the time, and every day was a challenge just to survive. I kept myself busy with work and other projects to distract myself as much as possible.

Anhedonia is a diverse array of deficits in hedonic function, including reduced motivation or ability to experience pleasure.

https://en.wikipedia.org/wiki/Anhedonia

During the first month of taking Estradiol, I was getting massive amounts of dopamine; Estradiol Euphoria. I just sat around after a dose and “felt”. I also noticed colors were brighter – I could literally recognize and see colors better. My brain lit up and I was feeling things for the first time in years.

Over the months I noticed small things, like remembering something and laughing about it – feeling good about a memory. I would push my daughter on our backyard swing and laugh with her about silly things. I actually enjoyed spending time with her. My relationship with my wife was improving every day and we began to like each other again.

For many years people would do “nice” things for me, which I was only capable of interpreting as annoying. I had several realizations that what they were intending as nice, was actually nice… I actually “felt” their actions were a kindness for the first time.

4. Testosterone administration impairs cognitive empathy in women depending on second-to-fourth digit ratio

Here, we show that administration of testosterone in 16 young women led to a significant impairment in their cognitive empathy

https://pubmed.ncbi.nlm.nih.gov/21300863/

5. Empathy, estradiol and androgen levels in 9-year-old children

The Kruskal–Wallis test revealed the existence of interaction effects of estradiol-gender and testosterone-gender on empathy. Girls with low testosterone levels scored higher in Cognitive Empathy than girls with high testosterone levels.

https://www.sciencedirect.com/science/article/abs/pii/S0191886913000469

Gender Diversity and overlap with ASD (Autism Spectrum Disorder)

Although it has been commonly acknowledged that there are overlaps in ASD and gender diversity, increasingly data sets have confirmed these correlations.

6. Largest study to date confirms overlap between autism and gender diversity

Autistic people are more likely than neurotypical people to be gender diverse, several studies show, and gender-diverse people are more likely to have autism than are cisgender people2,3.

For all five datasets, autism diagnoses are more common among gender-diverse individuals than among their cisgender peers.

On average, gender-diverse people scored higher on measures of autism traits and lower on a measure of empathy than did their cisgender peers.

https://www.spectrumnews.org/news/largest-study-to-date-confirms-overlap-between-autism-and-gender-diversity/

Summary

I’ve had many functional improvements since I started dosing Estradiol and my capability to experience happiness has dramatically improved. I couldn’t find an anti-depressant that worked for my atypical depression/anhedonia, and it was a shot in the dark whether Estradiol would help.

At the time of this writing, I still do not experience what I would classify as gender dysphoria in the typical sense. After much reflection I realized I don’t experience gender pretty much at at. I classify best as Non-Binary Agender, and since I’m dosing Estradiol I could be classified as Transfeminine.

One thing that triggered investigation into whether I was Transgender was that I was taking Adderall and working out a lot; I was beginning to look like I belonged on a magazine cover due to how fit I was and how much muscle I was building. Instead of feeling good about this, I felt distressed. The feminizing effects of Estradiol do make me feel more “at home” with myself; but at the same time I don’t have any more interest in being 100% a woman than 100% a man – either binary is fairly distressing.

I also have no dysphoria or distress about having a penis. I suppose this simply indicates that I fall into a gender diverse category, ie Non-Binary.

A couple of months ago when I did labs to measure my hormone levels, my Estradiol was too high, so I dropped down again to an introductory level dosage and will be doing labs again in a few days. Going back down to about 1/3rd the previous dosage of Estradiol has definitely increased depression and dysphoria – though not as bad as during my first month on a roughly equivalent dosage. My interpretation of this result is that I am still benefiting to some extent from Estradiol Euphoria, but there are also some longer term functional improvements.

Even on the lower dosage I still have glimpses happiness and empathy that I was previously incapable of. I anticipate years of Estradiol therapy will continue to improve my quality of life and functional capacity.

If you can relate to many of the things I’ve written about here, you might consider Estradiol therapy. The primary long term consideration in my mind is reproductive consequences of hormone therapy. You may lose your ability to reproduce regardless of being AMAB or AFAB (Assigned Male/Female at Birth), so that should be carefully anticipated and weighed.

If you are struggling with Depersonalization, and are not interested in exploring Gender Diversity or Estradiol therapy; you might try taking a look at this article I found while researching citations:

7. Depersonalization: Its Causes and Potential Solutions

Magnesium is nature’s natural NMDA blocker and NMDA over-activation in the prefrontal cortex is one underlying cause of depersonalization. Load up until you get diarrhea and then back off.

https://selfhack.com/blog/depersonalization-its-causes-and-potential-solutions/