How HRT Rewrites Your DNA

Not exactly basic biology, is it now?

I had the privilege of going to a pair of dear friends’ wedding last month. It was queer as hell, the setting dripping in fairy-tale magic and dark wood-paneled walls. The brides brewed themselves a cup of tea and enjoyed it while their attendants talked about love beneath the balcony where they held their service. Then, they fasted their hands using a cord festooned with ribbons that all the many guests had tied onto it in celebration of their love. Afterwards, there were cocktails and board games and souvenir d20’s.

In short, it was astonishingly gay. I loved every moment of it.

It was also a chance for me to meet a bunch of friends in person for the first time. I’d known them for years, sure—but online. It’s different in person.

One of the people I got to meet for the first time that day happened to be the best man for the ceremony, and I use that term in every possible sense of the meaning. A trans man I’d met before his transition, before he’d ever even considered the testosterone he’d been taking for most of the last year, he was absolutely resplendent in his very first three-piece suit, hair flawlessly styled and exuding an explosive joy and confidence that was completely unlike the hesitant, quiet person he’d been when I’d met him.

He was, to quote Neil Gaiman, every last inch The Man Jack. Enormous in spirit and presence, and thrilling in the skin and the hair and the voice that testosterone was giving him.

After a while, glasses were insistently rung, and the Maid of Honor and the Best Man rose for their respective speeches. Our Man Jack took center stage last, opened his mouth, and let his brand new voice boom through us.

It was incredible to see him in that moment. With every word, it seemed, he settled more fully into himself, grew to fill the room with the sort of charisma you usually only see in the very best used car salesmen—the ones where you leave the lot knowing he got the better end of the deal, but utterly unable to feel even remotely bad about it, because he so completely swept you away with his charisma as he declared that one of the brides, his dearest friend, had “literally made him the man he was today.” I mean, look at our boy here:

It was wonderful to watch him rejoice in all of the little physical facets of masculinity that had been the bane of my life, from his roughened skin to his roughened voice—and all this, at less than a year of testosterone. He was all but unrecognizable, next to what he’d looked like so recently. So many little physical changes, at every single level of his body, from nose to toes, all wrought by a single little chemical.

49 atoms. Just 49 atoms, and now he’s a completely different person.

There’s a kind of magic in the scale of that change in that timeframe. But, in this case, the magic is strictly emotional. The rest? It’s science, and we’re finally starting to learn exactly how it is that those 49 atoms caused such a radical change in his body in such a short time.

And the really cool part? It’s because testosterone modified his DNA at the molecular level, just like how estrogen modified mine.

Epigenetics and You

Here’s a brain-teaser for you: why do identical twins have different fingerprints?

Stop and really think about it for a moment. After all, those twins have exactly the same DNA, and we all learned in high school that DNA tells your body exactly how to grow and create all the cells and structures and processes that make us who we are. So, if DNA is this permanent blueprint, then their fingerprints should be identical… right? But identical twins’ fingerprints aren’t, and often aren’t even similar.

Take it a step further. When one identical twin is transgender, it’s pretty common for the other to not be—only about 30% of the time are both twins trans (side note: Jubilee, who’s featured in that article, is heckin’ cool. You should go check out her stuff), even though we know that somewhere between 30-50% of what makes us trans comes from our genetics. Which, cool, right? Except how can being trans be half genetic? How does that even make sense?

Just wait, it gets even weirder than that.

About half the time, when one identical twin donates a kidney to the other, their twin has to go on immunosuppressants, just like they would if the kidney had come from someone else. Even though these twins’ DNA is identical, the immune system in one twin sees the cells of the other twin’s kidney and knows that it came from another human being. How can that possibly be?

All this was a huge mystery in the medical community for decades—almost since the discovery of DNA—because it didn’t seem to make any sense at all, given what we know about the body, physical development, and how DNA was supposed to guide human development. But, as you’ve probably guessed from the “was” in that last sentence, we’ve got the answer now. And that answer? It’s going to upset everything you probably think you now about how DNA works.

Identical twins don’t quite have identical DNA. The structures are all the same, sure—but not all the genes in their DNA are doing the same things. Now, we used to think that this came down to a sort of random chance, like mutations in human development and other weird stuff like that. Turns out, though, that that didn’t quite work either.

Because the genes in our DNA can be activated and deactivated over the course of a person’s life by the things we do. It’s how some whole fish species reproduce at all. And it’s why identical twins can be radically different from one another, even though all their genetic blueprints are the same.

That’s epigenetics: the study of how nurture changes nature on a genetic level. (Well, it’s actually a lot more complicated than that. There’s a bunch of asterisks and exceptions to that statement, but that’s advanced biology. We’re just trying to get up to intermediate biology for now.)

And HRT is one of the things that make those changes.

You’re Saying HRT Changes My DNA?

Yep. Well, not me, per se—I’m just explaining it. People smarter than I am are saying it. And they brought a whole bunch of evidence with them.

Before you can understand what’s going on here, you need to get up to speed on something called methylation. This is complex biochemistry, and if you haven’t taken advanced classes in biology or chemistry, you probably haven’t even heard of it before, so let me break it down.

When you add a chemical version of methane (which is one carbon atom and three hydrogen atoms) to another chemical, you methylate it, changing what the combined chemical does. This is a really, really common chemical reaction (I mean, carbon and hydrogen—name a more iconic combination, right?), and because it’s common and easy to make happen (and reasonably easy to undo with a handy-dandy enzyme), a lot of biological processes use it to transport nutrients, control information transfer, and a bunch of other things.

But we’re talking about DNA today, so let’s focus on that for now. If you remember from high school, your DNA is made up of four chemicals: Adenine, Guanine, Thymine, and Cytosine (well… kinda. The actual names for those four chemicals are adenosine triphosphate, guanosine triphosphate, thymidine triphosphate, and cytidine triphosphate, but each of those are quite the mouthful. The short versions of those chemical names—the ones we use—are actually just a component of the full chemicals, but people get lazy, which is why you’re used to hearing the short versions). The last one of those, cytosine, very conveniently works with an enzyme called DNA methyltransferase to turn into a chemical called 5-Methylcytosine. Cytosine, when it’s in a certain order with the other three chemicals, really seems to like being 5-methylcytosine, so at any given time, between 80-90% of all of your CpG sites, as they’re called, are methylated.

Phew, that’s a lot of big words. I promise: they’re not on the test. 😉

Here’s what matters: when a CpG site is methylated, the rest of your body will ignore the DNA sequence that follows it, until there’s a different signal. It’s like if a computer programmer turns part of computer code into a comment—the information is still all there, but your body just pretends it isn’t. As long as the CpG site is methylated, it’s like that part of your DNA doesn’t even exist.

How HRT Changes Your Genes

Some really cool new research that’s been coming out lately has been finding thousands of different CpG sites that either get methylated or unmethylated when you go on HRT—nearly 10,000 different sites in total so far, and we’re still looking for more! What that means in practice is that, while the core sequence of your DNA stays the same—like, the order that AGTC comes in doesn’t change—whether your body notices and does anything about those thousands of genes does.

The really cool part of all this is that these changes are reversible and, to a degree, appear negotiable based on hormone balance. Take estrogen for a while, but that makes you too physically feminine? Some testosterone will swap some CpG sites back and course correct. Need a mix of both? According to this research, seems very doable. Estrogen and testosterone tell your body where to methylate or unmethylate your DNA, so more masculine, feminine, or androgynous body features show up.

Put a different way: every “boy” has a genetically-coded cup size, and taking estrogen will let them know what it is. Or, alternately as my friend is discovering to his delight, every “girl” has a genetically-encoded deep voice waiting to be discovered, and all they need to do is take some testosterone to find out what it sounds like—and the longer they take it, the more they’re going to find out!

If a DNA Sequence Falls in a Forest and Nobody Hears It, Does it Make a Sound?

One of the things that transphobes loooove talking about is that “you can never change your DNA,” but like… that’s kind of beside the point, isn’t it? After all, if you just methylated every CpG site, that'd probably be really bad, because so much of your genetic code is just turned off. Same deal if you unmethylated everything. How bad? We don’t know either way, because we’ve never actually seen it happen—which, by itself, should tell you something important.

The blueprints really don’t matter, because what’s built from them never actually matches them all. It’s like an old Victorian house that’s been remodeled a dozen times over the years—knowing the original plan is nice and all, but it doesn’t actually matter anymore, because the coal chute’s been bricked up, the gas lines torn out and replaced with electric, the sitting and living room combined, and now there’s indoor plumbing. If you start tearing into a wall with a Sawzall based on those original plans, you’re gonna have a really, really bad time.

What’s there matters. What we originally planned on being there? Not so much.

Gene expression is the foundation for a huge amount of medical research, and there’s a really good chance that it’s how we’re going to cure cancer and heart disease.

Your transition really is about changing your whole body, from the DNA up—and anybody who claims that “basic biology” says otherwise just plain doesn’t understand how biology actually works.

---

Afterword: I am deeply indebted to my dear and brilliant friend, Jen Hess, Ph.D, Professor and Chair of Biology at Aquinas College, for helping me with my understanding of genetics in this article.