A View From the Ivory Tower

An illuminating guest post by ML

Lately I’ve been highlighting some of the more glaring defects in the marquee studies that will inevitably cross the radar of anyone who digs into the social contours of ‘changing sex.’

These name-brand studies are attractive low-hanging fruit for the non-scientist because they don’t even aspire to measure the impact of medical sex reassignment on human organs or tissue. They are essentially customer-satisfaction questionnaires, and short-term ones at that. In the case of the Dutch Studies, it’s become clear in retrospect that the clinicians defined success almost entirely in aesthetic terms, with the job of puberty blockade being prevention of the development of physical cues that would betray the patient’s sex. If these scientists managed to grow an adult male who looked convincingly female, their triumph would be complete.

There is, it turns out, another category of research, some of it high quality, that’s far more instructive: you just need to know where to look, and how to interpret what you’re looking at.

Today’s guest post illustrates this point quite powerfully. The author is both an academic researcher and the father of a young adult son who began identifying as ‘trans’ in college — as a legal adult with easy access to ‘affirming’ hormones at the student health center. His father had both the motivation and the training to undertake a higher level interrogation of the available data. His rhetorical skill in communicating his findings to an adult peer —someone in a position, though perhaps not of an inclination, to act on them— is also impressive. This post, first published on the PITT Substack last week, explains how that’s going for him and, by extension, for all of us. —-JPA

Our son recently started graduate school. He began hormone therapy during his final year of undergraduate education. Because he began to identify as a lesbian, transgender woman at 20 and showed no sign of gender dysphoria before that, we never had a chance to reflect – or advise him – on his choices. Going through the published medical research on the effects of estrogen made me aware that psychologically, excess estradiol in the serum causes depression among males, and physiologically, there are potentially much more severe side effects, including some impacting the brain and the immunological system. More of that in a minute.

Fast forwarding to the present day, before our son left for graduate school at a University with one of the country's most renowned medical schools. I decided to write to their student health center and share the studies I had found and, more relevantly, the psychological history of our child. What follows is the text of the letter and, after deleting potentially identifying information, the response from a high-ranking official within the health center. They are, for the lack of a better phrase, quite revealing.

First, my letter (I have not disclosed the name of the university and have changed the name of our child here, with apologies to the real Jonathans of the world; furthermore, apologies for the triggering usage of pronouns – I did not want to be dismissed as the “usual, hateful, bigoted transphobe”; rather, I wanted to be considered as the deadly serious parent who would do anything in their power to prevent their child from coming to harm):

Dear Apex University Health Center,

Our child, Jonathan, who is joining the graduate program at Apex University this Fall, identified themself as transgender during their sophomore year in college (2021) and started estrogen therapy in early 2023. Since every one of these interventions is off-label, I have been looking up the peer-reviewed literature on the effect of estrogen and whether there are any risks that our child needs to be aware of as they continue on this path. My findings, which I summarize below (and link to the sources), have been alarming. Several endocrinologists – some who publish extensively – have told me they were unaware of the new literature. I have also been in touch with the Endocrine Society, and their response heightened my alarm.

While we respect our child's identification with their gender identity, we felt that they exhibited several psychological symptoms right before identifying as a lesbian, transgender woman (Jonathan was assigned male at birth and did not show any inclinations to identify as female before April 2021), and these co-occurring symptoms were not considered at all before he started on the prescribed medicines. Most tellingly, just before identifying as transgender, Jonathan's romantic advances were rebuffed by the woman of their affection. Subsequently, Jonathan also lost every friend they had, thereby remaining completely alone in their dorm room for the greater part of their last two years of undergraduate education. However, these psychological symptoms were never explored. Jonathan was recommended to start on estradiol and spironolactone immediately, which they did – and their physical and mental health symptoms have deteriorated since. Jonathan is also quite depressed, spending all their time without emerging from their room.

That is not surprising since, when it comes to the recent research on estrogen in natal males, excess estrogen in the serum in natal males has been associated with depression – studies among adult men and adolescent boys show that. Clinical studies (i.e., studies that recruit actual subjects and follow them clinically rather than rely on anonymous, online, non-probability surveys) that promote gender medicine fail to show any improvement in psychosocial outcomes among natal males. For example, the New England Journal of Medicine study from early 2023 concluded that hormone therapy is psychologically beneficial for transgender youth. However, in the main text, the study finds no improvement in depression, anxiety symptoms, or life satisfaction among natal male youth (the relevant paragraph is at the bottom of page 244 of the journal issue).

Thus, psychologically, there is ample evidence that excess estrogen is associated with depression among natal males. Physiologically, recent research shows that estrogen might have far more deleterious effects. A study showed that 12 months of estrogen treatment among transgender women leads to a decrease in serum BDNF levels. That is significant because a separate study shows that this decrease in serum BDNF level is associated with increased risks of developing MDD (or major depressive disorder).  Lower levels of brain BDNF levels have also been associated with neurodegenerative disorders and found in the brains of patients with Alzheimer's, Parkinson’s, MS, and Huntington’s disease.

A high-quality rodent study shows that estrogen therapy among adult male rats leads to changes in their brains that resemble the changes in the brains of trans women. (There have been several other studies (2 links) among trans women that have shown these changes, but the rodent study indicated the mechanism by which these changes occurred in the brain.) Specifically, estrogen seemingly reduced the water content in the astrocytes and thereby disturbed the delicate homeostasis in the brain by increasing the relative concentration of glutamate (the brain's most abundant excitatory neurotransmitter), leading to glutamate excitotoxicity. As the Cleveland Clinic informs us, an increase in glutamate in the brain is associated with higher risks of neurological disorders like Alzheimer's disease, ALS, and many other diseases like multiple sclerosis. The research also showed that estrogen decreased brain cortical thickness and volume (which other studies have linked to patients with schizophrenia and bipolar disorder and lower levels of general intelligence). Furthermore, it was found to reduce cortical white matter integrity (which is related to cognitive instability). There is also empirical evidence of the lowering of cognitive abilities among transgender women that was presented at the EPATH conference in April 2023 (in Killarney, Ireland) - the researchers noted this decline among long-term patients at Amsterdam's famed gender clinic.

Research in the last few years shows that estrogen therapy among trans women has been associated with higher risks of various autoimmune diseases, from multiple sclerosis (recall, too, the association of MS with an increase in glutamate) to rheumatoid arthritis and many others in between. It has been associated with increases in the risks of prostate cancer and breast cancer. It increases risks of cardiovascular diseases (2 links), often by as much as tenfold compared to their cisgender counterparts.

Empirically, we see a much higher incidence of many of these physical and neurological diseases in the transgender population. It is perhaps not a coincidence, therefore, that population cohort studies (2 links) show that trans women, on average, die decades earlier than either cisgender men or women.

When I approached the Endocrine Society with what I had found and pointed out that many of these findings came out after the publication of their guidelines in 2017, I received an email from their Director of Clinical Practice Guidelines that they are currently fast-tracking a revision of those guidelines. She also mentioned that their evidence evaluation criteria have changed since the guidelines were published and that they now use the GRADE criteria for evaluating evidence. This is encouraging, but I have no idea how long it will take for the new guidelines to appear.

I point all of this out because Jonathan has the chance to start afresh and be reevaluated at Apex University's healthcare system. We increasingly see them stumbling with their memory, something that we could not even think of a year earlier – Jonathan used to have a photographic memory ever since they were a child. Having heard so much about Apex's medical school, we have high hopes that Jonathan's evaluation at Apex University's medical system will be more thorough than it has been so far. Let me be clear: We have no doubt about their gender dysphoria or their intense discomfort in their traditional gender role – we worry about that all the time. It is just that we have observed that medicalization has not brought them any balm so far – in fact, just the opposite. While the absence of any upsides (and the possible significant downsides) in the literature – psychological or otherwise – heightens our alarm.

After all, it is not only a lone voice like ours, but even mainstream media like the Economist (their April 5 issue with the cover story “The evidence to support medicalized gender transitions in adolescents is worryingly weak” comes to mind) and storied institutions like the British Medical Association and the systematic reviews of the literature from national medical associations of very transgender-friendly countries like Sweden, Finland, Norway, the UK, and (most recently) Denmark that are raising the alarm on the lack of high-quality evidence of any benefits from hormone therapy. (And these reviews I mention above cover only the evidence of the psychological effects of the hormones – they do not even consider the long-term physiological consequences.)

If all the evidence from the past few years is to be believed, there is now quite a body of evidence of genuine harm from administering estrogen to the natal male body (I have not researched the effects of excess testosterone on the natal female body, and so I cannot comment on that.)

As one of the world's leading lights in healthcare to nudge society toward better outcomes through research, Apex University will be well placed to lead the march for evidence-based care in gender-affirming care.

Thank you very much for reviewing the evidence that I have found and considering our child's health as they start their journey at Apex University. Please let me know if you have any questions. I look forward to hearing back from you.

With warmest regards,

XXX

A few days later, I got their response. I have highlighted the relevant portions of their email and annotated them within brackets [all formatting mine]. As I said, it’s quite revealing.

Dear XXX:

Thank you very much for sharing your concerns about your child with us.

…Apex U's Student Health Center (Apex SHC) is not directly affiliated with Apex Medical School and we do not provide care under the umbrella of the hospital. [Is the respondent making sure that the medical school is not implicated if something goes wrong with our son?] However, we do collaborate closely with our colleagues at the hospital and medical school, including in the management of our students receiving gender affirming care.

…

Gender affirming care is a unique process in medicine in that we are not aiming to treat and eliminate a disease process. [Ah, an admission that there is no real goal of treatment through this care. Finally! But read on…it gets better.] Instead, we are using the tools of medicine to help individuals achieve very personal and sometimes nebulous [nebulous? WTF? After all these years of "settled science," all we have is “nebulous?”] physical and emotional goals. Success is not based on a clinical metric but usually involves a better quality of life balanced with potential risks including morbidity and mortality. [So, finally, an explicit admission – success is not based on any clinical metric. That makes complete sense to us inconvenient parents. After all, how can there be? There never have been any metrics, ever. At. All. All we have are some "nebulous" ideas of "better quality of life" – as decided by the patient right now, with no consideration of what might happen in the future as a result of the free dispensation of off-label medication. And oh, by the way, that "better quality of life" includes morbidity factors and dying much faster.] We at the Apex SHC make every effort to ensure that our patients are well-informed [in other words, make sure that they have signed the informed consent forms!] about each decision that they make and have time to consider these impacts without pressure [The irony of the sentence – “have time to consider these impacts without pressure.” Wow! really?]

Should your child decide to engage with us in care, our commitment to them is to prioritize their safety [oh, the irony, once more!], the elements of their well-being that we can support [the rest – whether caring for them for the rest of their lives or paying for their illnesses and hospitalizations, with a big fuck you to your dwindling retirement funds – is up to you, you bigoted parents!], and to help them make a bright future for themselves.

Very best,

AAA

As I read and re-read the email, all I could think was – Wow! What an amazing letter! AAA has no qualms admitting that there are no clinical goals of treatment when it comes to gender-affirming care. This is really quite convenient if you think about it—if there are no aims, any outcome is fine! No wonder these physicians get all flustered when we inconvenient parents ask them about clinical goals and outcomes.

All that these caring physicians want to achieve are some nebulous (which the dictionary defines as unclear, vague, or indefinite) goals. Oh, and please remember – once again – that those are personal goals, so please don’t ask about evidence of well-being. (An inconvenient question, though – why should such personal goals be funded by others, whether it is the government or private insurance?)

And what if, as a result of those nebulous goals, the patients go through psychological, emotional, and physical distress for the rest of their lives, as detailed in the medical literature? Really, shame on you, you bigoted parents! Always such a nag! Always the party pooper. Why do you have to ask such inconvenient questions? Haven’t these caring physicians already made it clear that these are personal goals and that it really doesn’t matter that young children who are distressed might have no idea how to make a rational choice about the future? Who cares if they become hyper-fixated about something, as young children are wont to?

But then again, really, there is no pressure. No pressure at all. These kids are otherwise well-adjusted grown adults who know exactly who they are. Probably from the time they were toddlers. (What? You want evidence? This is getting really tiring. Give it a break, will you?) These are kids who are not immersed online, who do not gulp down narratives about “gender euphoria.” They are stable, rational human beings with a very clear idea of what the future holds.

All these well-meaning saints – these gender-affirming physicians – want is to give these kids a bright future: a future so bright that it will probably include that intense bright light these pitiable young men will see when they die decades earlier than their non-medicalized peers. Who are you parents to stand in their way?