CW mental health, stress, academic work, brain determinism, dysphoria.

Late last night drank again coffee so as to be able to work another two hours. It was a bad idea regardless because unlike in the past, 7dl coffee at 22 prevented me now from falling asleep at 03. In the end, slept some, possible through low-dose atarax and phenibut. Cancelled some meetings, cut others short, emotional but kept under control during day – felt disapproval of collaborator for how slowly we have delivered on one project, felt helpless from not being able (or willing) to force my postdoc to work faster.

Finally ended up on train ride. There is so much to do in regards to real work, and it frustrates me that I will have so little time for it during the next few days of my course; I will have to somehow do data crunch and coding and emails during the night, plus a planned phone conference. This causes a sense of fear because I know I have to do this, have to make it work.

To add insult to injury, I came across a new Nature article that fucks me up further ( https://www.nature.com/articles/s41398-020-0742-9 ). It is not bad science, nor is the pursuit of this knowledged bad, nor are the methods so flawed. It moves Sry genes around and includes gonadectomies to test for sex differences between animals in a way that separates genetic (double X chromosome double expression dosage for genes escaping X-inactivation, actual Y gene expression in adults (Sry apparently expresses in adult mouse brain)) from organizational (sex hormone levels during development and puberty changing reactivities for later) from each other and from either anatomy (since you have XX mice with testes, XY mice with ovaries this way) or circulating hormone levels.

Long ago I blogged about major depressive disorder, how it corresponds to very different brain activation networks in men and women. Apparently, from these results, inducing MDD-like disease in mice from chronic stress similarly causes almost entirely different gene networks and interregion patterns to activate between XY male and XX female mice, in line with this. Phenotypes may be similar, but mechanisms (which are heavily immune linked, interestingly) seem robustly very different, and these differences trace to both the genetic sex effect and to the organizational influence.

While the same authors previously showed similar things (but without the whole transcriptome level data) on genes involved in GABA and anxiety, they also showed in that earlier study that circulating testosterone impacted these behaviours independently of either gonadal (organizational and mouse cultural, such as it is) and genetic status, this leaves me still with the heavily dysphoric observation that for a dyadic trans woman (not karyotypically intersex), none of the changes we undergo with HRT reduce this vast set of gene expression/mechanism differences that separate us from cis women (some of which represent development terminal differentiation, which a CAIS XY woman would not have, some of which represent dosage effect, which a CAIS XY woman would have). While there may well be even more differences emerging between non-gonadectomied cis men and women, this is still a major difference.

I saw before this being the case for liver, that inflammation and starvation systems differ majorly between cis men and women (by extension) due to chromosome direct effects in a way which I cannot currently eliminate through transition treatment. But liver is less important. Systems like depression and anxiety are core to who we are. Fearing their mechanistic difference (even under similar observed behaviour) between me and my cisters make me feel extremely and terribly dysphoric, worried that I cannot fully understand the experience of a depressed XX person as a result, that I am shut out, able only to understand the men. It evokes, through no fault of the study authors, perceptions of essential prisons. I feel such thoughts as lead-heavy, death-urgent dysphoria.

Probably it is not quite so terrible as it seems, because more systems may be more subtly involved. These groups of many correlated genes imply this is the effect of a few top regulator factors cascading, and the immune involvement implies a system at least in part separable from the pure mood phenotype (and does not reveal, in this manner, causality). But linked to the functional network views this still is very dire (though perhaps those network changes also reflect more a consequence than cause of the experiential phenotype).

But the way I respond is terribly dark. I feel again like I learned I died, like my loved ones died, disappeared. I sense waves of hate and disgust over my body – not just the deformed parts which makes people see and hear me as male, but right now I feel no pride or happiness over my brain or personality either. What if through my garbage Sry and lack of a second X, and the times of my life from conception spent misassembling my chromatin under testosterone poisoning, what if from that I am doomed to function (under stress, anxiety, depression but also their resilience and counterparts) in some manner which is unavoidably like male persons, leaving me unable to fully understand on an emotional level my sisters? It makes me feel fully and wholly dissociated from this rotting corpse body and from my thoughts and emotions, too, leaving me like a skull or shard inside something which holds neither thought or emotion. Dead. Never alive.

I had more coffee and two emergency phenibut, and I am glad I brought more on this journey in case I will risk being sleepless in next nights (fun fact: systems studied here ALSO are involved in phenibut action). I wanted to not use it so much, and hope to cease to need it, but this places me in such sad darkness. Of course it is not so bad as it seems. A Turner X0 woman or CAIS XY woman has many of these effects in place, yet is no less a woman for that. A CAH XX woman might have some of the other effects, and is also no less a woman (unless, like some elevated fraction of CAH people, he is a trans man).

Sanity requires I accept somehow that there are even important aspects of my neurobiology where my current husk of a body functions like men function, but that this does not diminish my womanhood. I am an atypical woman, like a combination of multiple intersex conditions as well as some unique ones. I am still female in all ways I am, for all that. I just feel dysphoric over my chemistry or transcription profile or epigenome in the exact same way as I do over my awful voice or big head or hands, or damnable genitals. Disgusting, but I change all I can.

Not for the first time I find myself wondering, can we build on this? Can we somehow activate these programs differently? Can we treat this in transition care? For liver I was hoping to rebuild the organ with the right karyotype and epigenetics, but of course eventually that might lead to immune incompatibility (or not? Perhaps cell differentiation cannot break the own/vs foreign influence?). But could we mimic the effect of an XX karyotype by somehow elevating expression of the genes in question? It would be hard, not least because this all might be tissue specific. If nothing else, then the fact these are interlinked gene networks would make it easier than it could be. But still risky, might lead to uncontrolled growth.

And of course there will also be direct hormone effects, relevant ones, and those I do fix. And some terrible cases where early exposure may mean I cannot benefit from my new estrogen balance the way I could have without early testosterone exposure. It is all terrible, and I see as yet no way to fix myself the way I would want. (And it seems XY genotype increases anxiety risks where circulating T reduces it, implying XX compensates a little through dosage compensation for lower T, and placing me as an XY woman in even higher risk of anxiety since I definitely want no more T. Be that as it may.)

Though I suppose as a mad science witch I should have goals. Defeating death is not enough, becoming biologically exactly the same as a cis girl is the other thing I need. But while the rest can be replaced, the brain is harder. Can’t clone a new XX brain and replace my present one with it, my individuality would not come along. Now even the thought of my mind and personality disgusts me, how much of it is dependent on these awful male-like system differences?

(Spirit. You should read this paper, it is good and will interest you. Understanding networks underlying major depressive disorder, which you almost certainly have, with anhedonic subtype, that is one application of network work and epigenomics that might address this major disease. It lies very well within your research interest and can be a further direction you go in, even. I suggest it because perhaps you can succeed within decades even if I don’t, in working out some way of medicating these networks to mitigate such effects on a clinically relevant scale. Then I could build on that research in turn to make something that lets me and other trans sisters function more like XX people. I envy you your body, for so many reasons, but I love you deeply and I am glad that you have it, even those parts which matter much less to you than to me. If I was AFAB XX, I would probably be even more like you.)

Never mind. I am myself. I am the woman that I am, and I will change everything about me that I can. Even if my resilience and perseverence might be affected by certain types of immune activation in my brain under stress that are characteristic of the male brain, that does not deny or make unimportant all the rest of me. And I will do studies that are the opposite of this, see what factors clearly do change under transition, and take some solace in them.

I feel such sorrow and pain and envy. For all those who don’t have to do this, defend this, seek this, just to be that which I need to be.

The medication is working, at least. I am more calmly coldly focusing. I will share this with my loved ones so you know how I feel. Then I will do some work on my own science instead. Make a small dent in the mountain, working towards safety. I will never give up my willpower or resilience. I will always strive towards my goals. I just wish the world did not make it so hard. I wish I had emerged in a different genotype and phenotype.